GERIATRIC GASTROENTEROLOGY. [2 ed.] 9783030301910, 3030301915

Table of contents :
Foreword
Preface to Second Edition
Preface to the First Edition
Acknowledgments
Contents
About the Editors
Contributors
Part I: Perspectives and Trends
1 Geriatric Gastroenterology: A Geriatrician´s Perspective
Introduction
Terminology: Older Adult, Elderly, Senior, or Geriatric Person?
The Black Swan: An Interesting Theory
An Aging Society: The Era of Centenarians and Supercentenarians
Living Longer and Healthy: Biological and Chronological Aging
Aging Statistics: Life Expectancy, Morbidity, and Mortality
Aging Associations
How Does the Geriatric Individual Differ?
Gastrointestinal Disorders in Older Adults
Key Points
References
2 Geriatric Gastroenterology: A Gastroenterologist´s Perspective
Introduction
Key Points
References
3 Epidemiology of Gastrointestinal Diseases
Introduction
Geriatric Population in the United States
Benign Disorders of the Gastrointestinal Tract
Gastroesophageal Reflux Disease
Swallowing Disorders
Peptic Ulcer Disease
Gastrointestinal Bleeding
Abdominal Pain
Abdominal Wall Hernias
Diverticular Disease
Gallstones
Pancreatitis
Inflammatory Bowel Disease
Clostridium difficile
Liver Disease
Gastrointestinal Cancers
Colorectal Polyps and Cancer
Pancreatic Cysts and Pancreatic Cancer
Barrett´s Esophagus and Esophageal Cancer
Key Points
References
4 Centenarians: Life Style for a Long Healthy Life
Introduction
Centenarians Are the Fastest Growing Segment of the Population
Health Care Professionals Attitudes Towards Aging
Lifestyle Factors from the World´s Blue Zones
Behavioral and Social Patterns of Centenarians in Traditional Cultures
Role of the Elements and Nature in Eastern Complementary Medicine
Health Literacy as Connection and Understanding of the Natural World
Common Factors: Centenarians from around the World
Contagious Positive Attitude Regardless of Setbacks
No Fear of the Future, the Goals and Life Purpose of Centenarians
Healthy Mind and Body Exercises of Centenarians
Eating Habits of Centenarians
Traditional, Complementary, and Alternative Healing Practices of Centenarians
Service, Gratitude, and Inclusion Contribute to Natural Feelings of Worthiness
Patterns of Social Support and Extraversion Among Centenarians
Spiritual Beliefs of Traditional Elders
Implications for Health Care Professionals Interested in Working with the Aging Population
Conclusion
Key Points
References
Informative Websites Pertinent to Centenarians
5 Ethical Issues in Geriatric Gastroenterology
Introduction
A Theory of Ethics
Ethics Is Normative
Ethics and the Older Patient
General Principles of Medical Ethics
Background
Physician-Patient Relationships
Consent, Communication, and Decision-Making
Privacy, Confidentiality, and Medical Records
Genetics
End of Life
Challenges in Medical Ethics
Ethical Considerations in Geriatric Care
Capacity Versus Competence
Advance Care Planning (ACP)
Barriers to Care at the End of Life
Bias
Restraints and Abuse
Bereavement and Suicide
Ethics Education
Ethical Issues in Gastroenterology in the Older Adult
Background
Endoscopy and Colonoscopy
Screening for Malignancy
Diagnostic Endoscopy
Percutaneous Endoscopic Gastrostomy (PEG) and Nutrition
Solid Organ Transplant in the Older Adult
Practical Applications: Case Illustrations
Autonomy
Case 1: Declining a Colonoscopy
Case 2: Declining an Endoscopy
Beneficence and Nonmaleficence
Case 3: Request for Upper Endoscopy
Case 4: Request for Colonoscopy
Justice
Case 5: Requesting Genetic Screening
Case 6: Choosing Wisely
Case 7: Cancer in the Elderly
Disclosing Medical Errors
Case 8: Perforation During Colonoscopy
Case 9: Post-endoscopic Retrograde Cholangiopancreatography (ERCP) Pancreatitis
Key Points
References
Part II: Basic Science
6 Physiology of Aging
Introduction
Life Expectancy and Life Span
Maximum Life Span
Exceptional Longevity
Mortality: Causes
Aging Theories and Concepts
The Blue Zones
Aging and Vulnerability to Disease
Frailty
Clinical Relevance
Gait and Balance
Clinical Relevance
Skin, Hair, and Nails
Morphology and Physiology
Clinical Relevance
Anthropometrics, Body Composition, and Sarcopenia
Clinical Relevance
Vital Signs
Clinical Relevance
Vision and Hearing
Morphology and Physiology
Clinical Relevance
Gastrointestinal System
Oral Health
Appetite, Taste, and Smell
Clinical Relevance
Anorexia of Aging
Cardiovascular System
Morphology and Physiology
Vascular Aging
Clinical Relevance
Respiratory System
Morphology and Physiology
Clinical Relevance
Kidneys
Morphology and Physiology
Clinical Relevance
Endocrine System
Morphology and Physiology
Clinical Relevance
Nervous System
Morphology and Physiology
Clinical Relevance
Immune Function
Clinical Relevance
Sleep
Physiology
Clinical Relevance
Successful Aging
Key Points
References
7 Gastrointestinal Physiology and Aging
Introduction
Part I. System Based
Oral Health
Teeth
Clinical Application
The Tongue
Clinical Application
Saliva
Clinical Application
The Taste Sensation
The Luminal G.I Tract
The Esophagus
Clinical Application
The Stomach
Clinical Application
Gastric Motility
Gastrointestinal Fluid Secretions and Electrolyte Balance
Gastrointestinal Exocrine Secretions, Volume, and Characteristics
Acid-Base and Electrolyte Abnormalities Associated with Gastrointestinal Disorders (Gennari and Weise 2008)
Gastric and Small Bowel Motility
Clinical Application
Small Intestines (SI)
Clinical Application
Large Intestine
Clinical Application
Pancreas
Clinical Application
Hepatobiliary System
Clinical Application
Table: Physiology of BAs
Functions of BAs
Albumin Synthesis
Clinical Application
Physiology of Enterohepatic Circulation of Bile Acids
Coagulation Factors
Clinical Application
Physiology of Bilirubin
Neurogastroenterology (Gastrointestinal Motility and Functional G.I. Disorders)
Gut-Brain Interactions (Neurogastroenterology)
Functional Disorders In Adults
Clinical Application
The Enteric Nervous System (ENS)
Enteric Nervous System
Clinical Application
The Role of Gut Microbiota
Clinical Implications
Opioid Receptors in the GI Tract
Clinical Application
Gut Hormones and Neuropeptides
Key Points
References
8 Comprehensive Geriatric Assessment
Introduction
The Concept of Comprehensive Geriatric Assessment
CGA Is a Team Approach
Domains and Elements of Assessment
History and Evaluation
Periodic Medication Review and Reconciliation
Psychosocial Assessment
Functional Status
Improve Communication for Clinical Decisions
Advance Directives
End of Life Care
Prevention Is Effective
Counseling
Diet
Physical Activity
Tobacco and Alcohol Use
Screening for Unhealthy Drug Use
Prevention of Falls
Unintentional Injuries
Driving Skills
Immunizations
Aspirin
Hormone Replacement Therapy
Secondary Prevention
Screening for Cognitive Impairment
Depression
Vision
Hearing Impairment
Osteoporosis
Diabetes Mellitus
Dyslipidemia
Hypertension
Abdominal Aortic Aneurysm (AAA)
Electrocardiograms
Elder Abuse and Mistreatment
Lung Disease
Screening for Cancer
Breast Cancer
Colorectal Cancer
Cervical Cancer
Ovarian Cancer
Prostate Cancer
Lung Cancer
Skin Cancer
Other Disorders
Caregiver Support and Burden
Choosing Wisely
Key Points
References
Part III: Pharmacology
9 Pharmacology of Aging
Introduction
Pharmacokinetics
Absorption
Oral
Rectal
Transdermal
Ocular
Miscellaneous
Distribution
Water-Soluble Drugs
Fat-Soluble Drugs
Protein Binding
Metabolism
Phase 1 Metabolism
Phase 2 Metabolism
Non-liver Metabolism
Elimination
Renal Excretion
Renal Secretion
Non-renal Elimination
Pharmacodynamics
Central Nervous System
Cardiovascular System
Polypharmacy
Definitions
Causes
Prevention and Intervention
Deprescribing
Relevant GI Medications
Nausea and Vomiting Medications
Serotonin Receptor Antagonists
Dopamine Receptor Antagonists
Antimuscarinic Agents and Antihistamines
Medication Causes
Gastroesophageal Reflux Medications
Medication Causes
Proton Pump Inhibitors
Histamine-2 Receptor Antagonists
Antacids
Sucralfate
Peptic Ulcer Disease
Misoprostol
Inflammatory Bowel Disease
5-Aminosalicyic Acids (5-ASA)
Antibiotics
Corticosteroids
Immune Modulator Therapy
Biologic Agents
Chronic Constipation
Diverticular Disease
Dysphagia
Medication Causes
Key Points
References
10 Drug Effects on the Gastrointestinal System: A Physician Perspective
Introduction
Mouth
Local Effects
Systemic Effects
Esophagus
Local Effects (Pill Esophagitis)
Systemic Effects
Stomach
Systemic
Small Bowel
Local Effects
Systemic
Colon
Local
Systemic
Anus and Rectum
Pancreas
Medication Use and Related Concerns in Older Adults
Deprescribing, One Answer to Polypharmacy
The Beers Criteria: Need for Awareness
Key Points
References
11 Adverse Drug Effects Involving the Gastrointestinal System (Pharmacist Perspective)
Introduction
Definitions
ADE Burden in Older Adults
Surveillance and Causality Assessment for ADE
Drug-Induced Upper Gastrointestinal Ulceration
Pill Esophagitis
Bisphosphonates
NSAIDs
Anticoagulants and Antiplatelets
Prevention and Management
Drug-Induced Nausea, Vomiting, and Anorexia
Opioids
Chemotherapy
Digoxin
Prevention and Management
Drug-Induced Diarrhea
Antiretroviral Therapy (ART)
Antidiabetic Agents
Antibiotics
Prevention and Management
Drug-Induced Constipation
Opioids
Anticholinergic Agents
Antipsychotic Agents
Antidepressants
Cardiovascular Agents
Prevention and Management
Drug-Induced Xerostomia
Anticholinergic Agents
Antihypertensive and Diuretic Agents
Antidepressants
Antiseptic Mouth Washes
Prevention and Management
Drug-Induced Infections of the Gastrointestinal Tract
Inhaled Corticosteroids
Antibiotics
Acid Suppressive Therapy
Cancer Chemotherapy
Immunosuppressive Agents and Systemic Corticosteroids
Prevention and Management
Drug-Induced Acute Pancreatitis
HMG-CoA Reductase Inhibitors (Statins)
Antihypertensive and Diuretic Medications
Antiretroviral Therapy (ART)
Postmenopausal Hormone Replacement Therapy
Incretin Mimetic Agents
Prevention and Management
Drug-Induced Lower Gastrointestinal Tract Injury
Sodium Polystyrene Sulfonate
NSAIDs
Mycophenolate Mofetil
Proton Pump Inhibitors
Ipilimumab
Prevention and Management
Adverse Effects of Medications Administered Through Enteral Tubes
Occlusion of Feeding Tubes
Osmotic Diarrhea
Bezoar Formation
Prevention and Management
Key Points
References
12 GI Toxicities from Cancer Therapy
Chemotherapy
Oropharyngeal Mucositis
Diarrhea
Nausea and Vomiting
Constipation
Hepatotoxicity
Neutropenic Enterocolitis
Other GI Toxicities
Radiographic Findings
Targeted Therapies
Oral Mucositis
Other Oral Toxicities with Targeted Therapies
Diarrhea
Other Gastrointestinal Toxicities
Hepatotoxicity
Hepatitis B Reactivation Under Cancer Treatment
Pancreatic Toxicity
Biliary Toxicity
Immunotherapies
Key Points: Cancer Therapy and GI Adverse Effects in General
Key Points: Cancer Therapy and GI Adverse Effects in Older People
References
13 Drug-Nutrient Interactions
Introduction
Drug-Nutrient Interactions Are a Public Health Matter
Relevant Aging Changes that May be Contributory
Provider Approach to Drug-Nutrient Interactions in Practice
Types of Drug-Nutrient Interactions
Timing of Medications in Relation to Meals: How and When should a Drug be Taken?
Select Common Drug-Nutrient Interactions
Situations Pertinent to Older Adults
Herbs, Vegetables, Supplements, and Drug Interactions
Fruits, Juices, and Drug Interactions
Fruits or Fruit Juices?
Other Interactions
The Goal: Minimize the Occurrence of DNIs
Key Points
References
Part IV: Nutrition
14 Anorexia, Appetite, Hunger, and Satiety in Older Adults
Introduction
Anorexia of Aging (AOA)
Prevalence of AOA
External Risk Factors for AOA
Physiological Factors Influencing Appetite as a Result of Age-Related Sensory Changes
Taste and Appetite
Neurohumoral Factors for Appetite Control (Sasaki et al. 2016)
Appetite-Stimulating Gut Hormones
Appetite-Suppressing Gut Hormones
Hypothalamic Neuropeptides and Appetite Regulation
Fat-Derived Hormones
Non-homeostatic Control of Appetite (Borer 2010)
Assessment of Anorexia of Aging
Management Options for Anorexia of Aging
Conclusions
Key Points
References
15 Geriatric Nutritional Assessment and Treatment Frameworks
Geriatric Nutritional Assessment and Treatment Frameworks
Introduction
Epidemiology of Undernutrition in Older Persons
Adverse Effects of Undernutrition in Older Persons
Etiologic Factors of Undernutrition in Older Adults
Assessment of Nutritional Status in Older Persons
Management of Undernutrition in Older Adults
Overnutrition Among Older Persons
Nutrition, Physical Activity, and Cognitive Impairment
The Need for Education
Key Points
References
16 Tube Feeding: Techniques and Procedure
Introduction
Nasogastric Tube Feeding
Nasoduodenal/Nasojejunal Tube Feeding
Percutaneous Endoscopic Gastrostomy (PEG)
The Technique of Percutaneous Endoscopic Gastrostomy
Pull Technique
Push Technique
Introducer Method
Removal of PEGs
Percutaneous Endoscopic Gastrojejunostomy (PEG/J)
Complications of Enteral Nutrition
Key Points
References
17 Enteral Nutrition
Introduction
Diagnostic Criteria for Malnutrition
Pathophysiology of Malnutrition
Methods of Nutritional Support
Oral Nutritional Supplements
Enteral Nutrition
Enteral Formulations
Standard Polymeric Formula
Fiber Containing Formula
Predigested
Blenderized Formulas
Disease-Specific Formulas
Diabetes Mellitus (Type 2)
Hepatic Disease
Chronic Kidney Disease
Pulmonary Disease
Immune-Enhancing Formula
Outcomes in Older Adults
General
Dementia
Older Adults with Severe Neurological Dysphagia
Depression
Orthopedic Surgery
Pressure Ulcers
Adverse Effects Associated with Enteral Nutrition
Mechanical Complications
Nasoenteric Tube Syndrome
Gastrointestinal Intolerance
Diarrhea
Failure to Attain Nutritional Goal
Fluid, Electrolyte, and Glucose Abnormalities
Refeeding Syndrome (RFS)
Key Points
References
18 Percutaneous Endoscopic Gastrostomy in Dementia: Expectations, Outcomes, and Ethical Aspects
Introduction
Costs of Feeding and Attitudes
Appropriate Indications for PEG
Perceived Reasons for PEGs (or PEJs) and Expectations
Physician´s Perspectives Regarding PEG
Surrogate´s Perspectives on PEGs
Nurse´s Perspective on Artificial Nutrition or Hydration
Speech-Language Pathologist´s (SLP) Perspective on Artificial Nutrition or Hydration
Community Members´ Perspectives
PEG and Outcomes in Dementia
PEGs and Risk of Aspiration
PEGs and Nutritional Status
PEGs: Short-Term and Long-Term Mortality
Other Predictive Factors and Outcomes
Guidance Statements from Geriatric Medicine Societies
Ethical Aspects and PEG
An Ethics Committee´s Viewpoint
Tube-Related Consequences
Caregiver and Provider´s Discussions Regarding Outcomes
Decision-Making Process and Suggested Approach
Key Points
References
19 Perioperative Nutrition
Introduction
Integrate Nutrition as Part of Overall Care
Avoid Preoperative Fasting
Resume Nutrition Early
Early Nutrition Support
Enteral Nutrition
Parenteral Nutrition
Enteral, Parenteral, or Combined Nutrition
Hypocaloric or Trophic Feedings
Physical Activity and Nutritional Support
Minimize Stress Factors
Key Points
References
20 Nil Per OS (NPO) Prior to Endoscopy or Surgery
Introduction
Current Uses of NPO
Gastric Emptying
Complications of Prolonged NPO
Procedure Priority Recommendations
Key Points
References
21 Water, Potassium, Sodium, and Chloride in Nutrition
Background
Introduction to the Dietary Reference Intakes
Water in Nutrition
Potassium in Nutrition
Sodium and Chloride in Nutrition
Key Points
References
22 Intravenous Fluid Administration
Introduction
Age-Associated Alterations Relating to Fluid Balance
Water
Sodium
Maintenance Fluid Requirements for IV Infusion
General Recommendations for IV Fluid Selection
Fluid Management in Settings Relevant to the Old
Key Points
References
23 Water Soluble Vitamins: B1, B2, B3, and B6
Vitamin B1 (Thiamin)
Introduction
Absorption
Distribution
Metabolism
Excretion
Toxicity
Deficiency
Screening and Diagnosis for Thiamin Deficiency
Treatment of Thiamin Deficiency
Food Sources of Thiamin
Dietary Requirements and Recommended Dietary Intake of Thiamin
Geriatric and Gastrointestinal Considerations for Thiamin
Vitamin B2 (Riboflavin)
Introduction
Absorption
Distribution
Metabolism
Excretion
Toxicity
Deficiency
Screening and Diagnosis for Riboflavin Deficiency
Treatment of Riboflavin Deficiency
Food Sources of Riboflavin
Dietary Requirements and Recommended Dietary Intake of Riboflavin
Geriatric and Gastrointestinal Considerations for Riboflavin
Vitamin B3 (Niacin)
Introduction
Absorption
Distribution
Metabolism
Excretion
Toxicity
Deficiency
Screening and Diagnosis for Niacin Deficiency
Treatment of Niacin Deficiency
Food Sources of Niacin
Dietary Requirements and Recommended Dietary Intake of Niacin
Geriatric and Gastrointestinal Considerations for Niacin
Vitamin B6 (Pyridoxine)
Introduction
Absorption
Distribution
Metabolism
Excretion
Toxicity
Deficiency
Screening and Diagnosis for Vitamin B6 Deficiency
Treatment of Vitamin B6 Deficiency
Food Sources of Vitamin B6
Dietary Requirements and Recommended Dietary Intake of Vitamin B6
Geriatric and Gastrointestinal Considerations for Vitamin B6
Nutrient-Nutrient Interactions Across Vitamins B1, B2, B3, and B6
Key Points
References
24 B12 and Folic Acid
B12 (Cobalamin)
Introduction
Epidemiology
Vitamin B12 Absorption
Causes of B12 Deficiency
Requirements and Life Styles
Clinical Manifestations
Diagnosis
Homocysteine: Implications
Stages of B12 Deficiency
Treatment
Monitoring B12 Status
Does B12 Toxicity Exist?
Folic Acid
Introduction
Epidemiology
Absorption, Transport and Storage
Causes of Folic Acid Deficiency
Clinical Manifestations
Diagnosis of Folate Deficiency
Folate Requirements
Folate Deficiency Related Morbidity and Mortality
Alcohol and Folate
Treatment
Folic Acid Fortification and Masking B12 Deficiency: The Debate Continues
B12 and Folate Biochemical Interactions
Key Points
References
25 Fat-Soluble Vitamins: A, E, and K
Vitamin A
Introduction
Absorption
Distribution
Metabolism
Excretion
Toxicity
Deficiency
Screening and Diagnosis of Vitamin A Deficiency
Treatment of Vitamin A Deficiency
Food Sources of Vitamin A
Dietary Requirements and Recommended Dietary Intake of Vitamin A
Geriatric and Gastrointestinal Considerations for Vitamin A
Vitamin E
Introduction
Absorption
Distribution
Metabolism
Excretion
Toxicity
Deficiency
Screening and Diagnosis of Vitamin E Deficiency
Treatment of Vitamin E Deficiency
Food Sources of Vitamin E
Dietary Requirements and Recommended Dietary Intake of Vitamin E
Geriatric and Gastrointestinal Considerations for Vitamin E
Vitamin K
Introduction
Absorption
Distribution
Metabolism
Excretion
Toxicity
Deficiency
Screening and Diagnosis for Vitamin K Deficiency
Treatment of Vitamin K Deficiency
Food Sources of Vitamin K
Dietary Requirements and Recommended Dietary Intake of Vitamin K
Diet-Drug Interactions
Geriatric and Gastrointestinal Considerations for Vitamin K
Key Points
References
26 Vitamin D
Introduction
Prevalence of Deficiency
Is It a Hormone or Vitamin?
Osteoporosis Versus Osteomalacia
Risk Factors for Deficiency
The Institute of Medicine Report
The NIH Conference Points
United States Preventive Services Task Force (USPSTF) Recommendation
Vitamin D: Basic Physiology
Gastrointestinal Disorders and Vitamin D
Background
Gastrointestinal Cancer
Inflammatory Bowel Disease
Chronic Liver Disease
Bariatric Surgery
Malabsorption
Vitamin D Assays and Levels
Clinical Features of Deficiency
Vitamin D Deficiency and Outcomes
Mortality
Musculoskeletal Disorders, Including Falls
Fatigue, Weakness, and Frailty
Cognition, Depression, and Other Mental Disorders
Pain
Kidney Disease and Diabetes
Cardiovascular Disease
Cancer
COVID-19 Infection
Vitamin D Requirements
Vitamin D: Sources and Treatment of Deficiency
Sunlight
Diet
Supplements and Dosing
Key Points
References
27 Iron-Deficiency Anemia of Gastrointestinal Origin
Background, Definitions, and Prevalence of Anemia
Consequences of Anemia
Etiology of Anemia
Basics of Ferrokinetics
Distribution of Iron
Absorption of Iron
Role of Hepcidin and Ferroportin in Iron Homeostasis
Iron Deficiency
Insufficient Dietary Intake
Gastrointestinal Absorption Defect
Celiac Disease
Other Causes of Malabsorption
Gastrointestinal Blood Loss
Miscellaneous Causes
Evaluation of Iron Deficiency and Related Anemia
Diagnostic Markers of Iron Deficiency
Red Blood Cell (RBC) Indices
Serum Indices
Ferritin
Serum Iron, Transferrin Saturation, Transferrin Iron-Binding Capacity
Management
Oral Iron Therapy
Duration of Iron Therapy and Response
Parenteral Iron Therapy
Key Points
References
28 Copper and Zinc
Introduction
Copper
Copper Absorption, Transport, Storage
Features of Copper Deficiency
Copper Administration
Zinc
Zinc Kinetics
Requirements of Zinc
Zinc Deficiency
Zinc and the Gastrointestinal System
Zinc Status in the Body
Zinc Replacement
Zinc Toxicity
Key Points
References
29 Magnesium
Introduction
Magnesium Absorption, Transportation, and Storage
Physiology
Magnesium and Aging
Magnesium Deficiency
Features of Magnesium Deficiency
Sources of Magnesium
Hypermagnesemia
Magnesium-Drug Interactions
Magnesium-Hormone Interactions
Formulations: Oral, Transdermal, and Intravenous
Considerations in the Old
Key Points
References
30 Calcium and Phosphorus
Introduction
Calcium
Calcium Physiology
Blood Calcium and Age
Gastrointestinal Absorption
Hypocalcemia
Hypercalcemia
Calcium Requirements
Recommendations from Organizations
American Geriatrics Society Workgroup
United States Preventive Services Task Force (USPSTF)
National Osteoporosis Foundation and American Society for Preventive Cardiology
Calcium: At-Risk Settings
Diseases
Post-menopause
Bariatric Surgery
Calcium-Alkali Syndrome
Lactose Intolerance
Vegetarians
Medications
Caffeine and Alcohol
Calcium and Outcomes, Evidence Based
Source of Calcium: Diet Versus Supplements
Phosphorus
Physiology
Phosphorus Absorption and Excretion
Phosphorus Requirements
Dietary Phosphorus Intake and Health
Hypophosphatemia and Hyperphosphatemia
Hypophosphatemia
Hyperphosphatemia
Phosphorus Derangement in Critical Care Settings
Combined Calcium and Phosphorus Deficiency
Key Points
References
31 Dietary Fiber
Introduction
Components of Dietary Fiber
Insoluble Fiber (IF)
Soluble Fiber (SF)
Physiologic Responses
Alterations in Gastrointestinal Functions
The Glycemic Response and T2DM Control
The Decrease in Serum Cholesterol
Laxative Effect
Prevention of Colon Cancer
Obesity
Insulin Resistance
DF as Prebiotics
Side Effects of DF
Key Points
References
32 Healthy Diet for Older Adults: A Focus on Mediterranean Diet
Introduction
The Effect of Aging on Nutritional Status and Digestion
Body Composition
Digestion, Metabolism, and Appetite
Optimal Dietary Patterns for the Aging Adult
Mainstream Diets in the Older Population
Mediterranean Diet
Risk Reduction, Disease, and Mortality Outcomes
Pathophysiology
Age-Associated Gastrointestinal Disease and the Mediterranean Diet
Constipation
Diverticulosis
Gastrointestinal Cancer
Exercise
Key Points
References
33 Nutrition Therapy for Intestinal Disorders
Introduction
Celiac Disease and Gluten Intolerance Disorders
Overview
Nutrition Recommendations
Macronutrient and Micronutrient Needs
Constipation
Overview
Nutrition Recommendations
Inflammatory Bowel Disease (Crohn´s Disease and Ulcerative Colitis)
Overview
Nutrition Recommendations
Diet Therapy
Enteral Nutrition Therapy
Macronutrient and Micronutrient Needs
Nutrition-Specific Medication Side Effects
Nutrition-Specific Needs for Surgical Patients
Irritable Bowel Syndrome
Overview
Nutrition Recommendations
The Low FODMAP Diet Should Be Dietitian Delivered
Small Intestinal Bacterial Overgrowth
Overview
Testing Methods and Prevalence
Clinical Presentation and Nutritional Implications
Treatment: Diet and Medical
Key Points
References
34 Nutrition Therapy for Dysphagia, EoE, Gastroparesis, GERD, and Liver Disease
Introduction
Dysphagia
Nutrition Recommendations
Eosinophilic Esophagitis
Overview
Causative Foods and Nutritional Balance
Determining Nutritional Status
HRQOL and Adherence
Gastroesophageal Reflux Disease
Overview
Nutrition and Lifestyle Recommendations
Gastroparesis
Overview
Dietary Recommendations
Nutrition Support
Nonalcoholic Fatty Liver Disease
Overview
Nutrition and Lifestyle Recommendations
Macronutrient and Micronutrient Needs
Cirrhosis
Overview
Nutrition Recommendations
Micronutrient and Fluid Needs
Key Points
References
35 Obesity in Older Adults: Pathophysiology and Clinical Implications
Introduction
Epidemiology
Definition and Diagnosis
Body Mass Index
Abdominal Obesity
Defining Obesity in Older Adults
Etiology and Pathophysiology
Comorbidities Associated with Obesity
Nutritional Status in Obesity
Obesity Paradox
Approaches to Weight Loss
Behavioral Modifications
Medical Management
Surgical Interventions
Key Points
References
36 Malnutrition in Obesity
Introduction
Nutritional Deficiencies in Older Adults with Obesity (Before BS)
The Confounding Effects of Age and Obesity on Nutrition
Adverse Nutritional Consequences of Dieting
Malnutrition in the Obese Older Adult Before and After Bariatric Surgery
Protein Deficiency in Obese Adults Before and After BS
Micronutrient Deficiencies
Nutritional Deficiency Anemias After BS
Protein Deficiency States Are Often Associated with Deficiencies of Unrecognized Hematopoietic Factors
Iron Deficiency
Vitamin B12 and Folic acid Are Among the Many Contributors to Nutritional Deficiency Anemias
Deficiencies of Other Essential Vitamins and Minerals
B Vitamins
Vitamin D/Calcium Deficiency
Zinc Deficiency
Copper Deficiency in Obese Adults Before and After BS
Key Points
References
Part V: Endoscopy
37 Gastrointestinal Endoscopy: Considerations
Introduction
Gastrointestinal Tract in the Elderly
Oropharynx
Esophagus
Stomach
Small Bowel
Colon
Biliary Tract
Indications for Endoscopy
Patient Preparation
Management of Anticoagulants and Antiplatelet Agents
Emergency Gastrointestinal Endoscopy for Patients with Acute Gastrointestinal Bleeding on Oral Anticoagulants
Acute Gastrointedstinal Bleeding While on Antiplatelet Agents
Elective Endoscopy
Pacemakers and Internal Defibrillators
Sedation
Esophagogastroduodenoscopy (EGD)
Colonoscopy
Endoscopic Retrograde Cholangiopancreatography (ERCP)
Enteroscopy
Capsule Endoscopy (CE)
Key Points
References
38 Intravenous Sedation for Endoscopy
Introduction
Definition of Sedation
The Older Individual, Singularities, and Special Features
Sedating the Older Adult: Who Should Perform Sedation?
Sedating Older Patients: A Tailored Sedation Schedule
Sedation Plan and Patient Monitoring During Procedure
Special Situations in Older Adult Sedation
The Endoscopy Room, Drugs, and Emergency Equipment
Dosing Drugs for Endoscopic Sedation (Table 5)
Complications of Intravenous Sedation and Their Management
Recovery and Discharge from the Endoscopy Unit
Unsedated Endoscopy in the Elderly
Training Programs for Intravenous Sedation in Endoscopy
Key Points
References
39 Gastrointestinal Luminal Stenting
Introduction
Stent Types and Characteristics
Special Considerations Based on Anatomical Location
Esophageal Stents
Duodenal Stents
Lumen-Apposing Metal Stents
Colon Stents
Initiation of Nutrition After Stent Placement
Key Points
References
40 Role of ERCP in Older Adults
Introduction
Preprocedural Evaluation
Implanted Cardiac Pacemakers and Internal Defibrillators
Prophylactic Antibiotics
Sedation
Efficacy of ERCP in Older Adults
Adverse Events Related to ERCP in Older Adults
Post-ERCP Pancreatitis
Bleeding After ERCP
Cardiopulmonary Complications
Risk of Perforation
Infections and Mortality
Indications for ERCP in the Elderly
Choledocholithiasis
Clinical Presentation
Risk Stratification and Management
Management of Large and Difficult Choledocholithiasis
Role of Bile Duct Stents in the Management of Choledocholithiasis
Gallstone Pancreatitis
Acute Cholecystitis
Benign Biliary Strictures
Malignant Biliary Strictures
Pancreatic Cancer
Cholangiocarcinoma
Gallbladder Cancer
Ampullary Carcinoma
Role of ERCP in the Diagnosis and Management of Distal Biliary Obstruction
Dilated Pancreatic Duct
Summary
References
41 Wireless Capsule Endoscopy
Introduction
Role for Wireless Capsule Endoscopy
WCE in Specific Diseases
Small Bowel Bleeding: Overt and Occult
Drug-Induced Enteropathy
Small Bowel Tumors
Evaluation of Celiac Disease
Crohn´s Disease and WCE
Surveillance of Inherited Polyposis Syndromes
Chronic Abdominal Pain
Special Considerations of WCE in the Older Adult
Contraindications for WCE
Limitations of Capsule Endoscopy
Preparation
Other Capsule Endoscopic Procedures
Esophageal WCE
Colon Capsule
Elements of Capsule Report
Key Points
References
Part VI: Imaging
42 Gastrointestinal Radiology: A Case-Based Presentation
Introduction
Appropriate Use of Imaging Modalities
Contrast Versus Noncontrast CT Abdomen
Concern in Using IV Contrast
Magnetic Resonance Imaging (MRI)
Appropriate Use of Imaging
Key Points
References
43 Imaging in Clinical Geriatric Gastroenterology
Introduction
Key Points
44 Advanced Imaging of Geriatric Gastrointestinal Pathology
Introduction
Magnetic Resonance Cholangiopancreatography (MRCP)
CT Colonoscopy
Acute Gastrointestinal (GI) Bleeding
Radionuclide Imaging (Scintigraphy)
Catheter-Directed Angiography (CA)
CT Angiography (CTA)
Acute Mesenteric Ischemia and Chronic Mesenteric Insufficiency
Key Points
References
Part VII: Pathology
45 Laboratory Testing in Older Adults: Indications, Benefits, and Harms
Introduction
The Emergence of Laboratory Testing
Is Old Age a Reason to Perform Laboratory Tests?
Manifestations Must Determine the Need for Tests
Unwanted Testing May Carry Risks More than Benefits
Common or Routine Tests
Hemoglobin and Hematocrit
Ferritin, Transferrin Saturation, B12, and Folate
Renal Function
Liver Function
Serum Albumin
Serum Lipids
Specific or Individualized Tests
Fecal Occult Blood Testing (FOBT)
Screening for Celiac Disease
Screening for Diabetes
Acute Pancreatitis
Testing for Bleeding and Coagulation
Vitamin D Status
Testing for Clostridium difficile
Laboratory Testing in Rheumatology
Homocysteine
Selecting Tests Prior to a Procedure
Preoperative Hematological Assessment
Key Points
References
46 Gastrointestinal Pathology in the Older Adult
Introduction
Part VIII: Motility Disorders
47 Oropharyngeal Dysphagia
Introduction
Mechanism of Swallow: Oropharyngeal Phase
Pathophysiology of Oropharyngeal Dysphagia
Screening and Diagnosis
Instrumental Evaluation of Swallow
Clinical Management of Oropharyngeal Dysphagia
Key Points
References
48 Gastroparesis in Older Adults
Introduction
Epidemiology
Normal Gastric Motility
Effects of Aging on Gastric Motility
Etiologies
Clinical Presentation
Differential Diagnosis
Diagnostic Approach
Initial Evaluation
Evaluate for Etiologies and Complications
Exclude Mechanical Obstruction
Confirm Delayed GE
Treatment
Diet and Lifestyle Modifications
Pharmacological Therapy
Role of Botulinum Toxin
Role of Feeding/Venting Tubes
Gastric Electrical Stimulation
Role of Pyloroplasty
Chronic Constipation and Gastric Emptying
Key Points
References
49 Gastroesophageal Reflux Disease and Complications
Introduction
Epidemiology
Etiopathogenesis of GERD
Acid Production
Acid Clearance
Impaired Peristalsis
Salivary Hyposecretion or Dysfunction
Mucosal Defense
Increased Intra-Abdominal Pressure
Clinical Features
Complications
Esophageal Complications
Extraesophageal Complications
Diagnosis
Management
Lifestyle Management
Antacids
Histamine-2-Receptor Antagonists
Proton Pump Inhibitors
PPI-Clopidogrel Interaction
Potential Adverse Effects of Chronic PPI Use
PPI Use and Pneumonia
PPI Therapy and Enteric Infections
PPIs, Osteoporosis, and Fractures
PPI, AKI, and CKD
PPI and Gastric Cancer
Endoscopic Therapy
Antireflux Surgery
Key Points
References
Part IX: Signs and Symptoms
50 Abdominal Pain
Introduction
Assessment of Pain
Causes of Abdominal Pain
Dealing with Abdominal Pain
Key Points
References
51 Functional Abdominal Pain
Centrally Mediated Abdominal Pain Syndrome (CAPS)
Introduction
Renaming the Syndrome
Epidemiology
Pathophysiology
Psychology of Abdominal Pain
Evaluation of the Patient
Medical History
Physical Exam
Diagnostics
Differential Diagnoses
Treatment
General Principles of Treatment
Centrally Acting Neuromodulators
Psychotherapy
Other Interventions
Key Points
References
52 Gas, Belching, Bloating, and Flatulence: Pathogenesis, Evaluation, and Management
Introduction
Background
Gas in the Gastrointestinal Tract
Physiology of Intestinal Gas
Nitrogen
Carbon Dioxide
Hydrogen
Methane
Sources of Intestinal Gas
Clinical Gas Syndromes
Belching
Supragastric Belching
Bloating
Flatulence
SIBO
Pathogenesis of Gas and Bloating
Lactose Intolerance
Fructose Intolerance
Sorbitol Intolerance
High-Fiber Diet
Challenges Unique to the Older Adult
Treatment of Intestinal Gas
Conclusions
Key Points
References
53 Constipation
Introduction
Definitions
Relevant Age-Related Physiological Changes
Pathogenesis
Evaluation
History
Physical Examination
Diagnostic Tests
Management
Lifestyle Modification
Bowel Training and Education
The Role for Squatting
Exercise and Diet
Fiber
Pharmacotherapy of Constipation
Stool Softeners and Emollients
Bulk Laxatives
Saline Laxatives
Stimulant Laxatives
Osmotic Laxatives
Enemas
Serotonin Agonists
Intestinal Secretagogues
Peripherally Acting μ-Opioid Receptor Antagonists (PAMORAs)
Other Agents
Laxative Abuse or Misuse
Miscellaneous Modalities
Manual Fragmentation
Endoscopy Intervention
Surgical Therapy
Biofeedback Therapy
Indications for Referral
Approach to Constipation: AGA Medical Position Statement
Key Points
References
54 Chronic Diarrhea in the Older Adult
Introduction
Changes in Intestinal Structure and Function with Normal Aging
Differential Diagnosis of Diarrhea in the Elderly
Secretory Diarrhea
Osmotic Diarrhea
Inflammatory Diarrhea
Fatty Diarrhea
Other Situations Presenting as ``Diarrhea´´
Evaluation and Management of Chronic Diarrhea in Older Adults
Initial Evaluation
Further Evaluation
Therapy
Key Points
References
55 Upper Gastrointestinal Bleeding
Introduction
Risk Factors for Upper GI Bleeding
Presentation
Etiologies
Peptic Ulcer Disease and H. pylori
Initial Evaluation
Management
Management of Anticoagulation in Acute Upper GI Bleeding
Key Points
References
56 Lower Gastrointestinal Bleeding
Introduction
Definitions and Clinical Presentation
Aggravating Factors in Older Adults
Medical Comorbidities
Medications
Evaluation, Assessment, and Management
History
Physical Examination and Initial Laboratory Studies
Resuscitation
Assessment and Diagnostic Approach
Endoscopic Therapy
Special Considerations in Geriatric Patients
Bowel Preparation
Sedation Safety and Complications
Anticoagulation Management
Non-endoscopic Management
Angiography
Surgery
Balloon Tamponade
Causes of Lower Gastrointestinal Bleeding
Diverticulosis
Vascular Ectasias
Colitis
Ischemic Colitis
Infectious Colitis
Inflammatory Bowel Disease
Neoplasms
Anorectal Sources
Post-polypectomy Bleeding
Radiation Proctitis
Key Points
References
Part X: Hepatobiliary System and Pancreas
57 Aging Liver and Interpretation of Liver Tests
Introduction
Aging and Liver
Aging and Liver Function
Aging, Inflammation, and Liver
Liver Regeneration or Recovery
Routine Biochemical Tests of Liver
Evaluation of an Abnormal Liver Chemistry Test
Liver Tests and Disorders
Key Points
References
58 Viral Liver Diseases
Introduction
Hepatitis A
Clinical Features and Diagnosis
Treatment
Prevention
Hepatitis E
Hepatitis C
Mode of Transmission and Risk Factors
Clinical Features and Diagnosis
HCV Genotypes
Extrahepatic Manifestations
Treatment
Hepatitis B (HBV)
Clinical Features and Diagnosis
HBV Genotypes
Reactivation of HBV
Treatment of HBV
Hepatitis Delta (HDV)
Key Points
References
59 Tumors of the Liver
Introduction
Benign Liver Tumors Requiring No Further Investigation
Hepatic Hemangiomas
Focal Nodular Hyperplasia
Simple Hepatic Cyst
Polycystic Liver Disease (PCLD)
Benign Liver Tumors Requiring Further Investigation and Therapy
Hepatocellular Adenoma (HCA)
Nodular Regenerative Hyperplasia (NRH)
Malignant Liver Lesions Requiring Appropriate Investigation and Therapy
Hepatocellular Carcinoma (HCC)
Cholangiocarcinoma (CCA)
Liver Metastases
Key Points
References
60 Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH)
Introduction
Epidemiology and Prevalence of NAFLD and NASH
Diagnosis of NAFLD and NASH
Clinical Evaluation
Imaging Studies
Pathophysiology
Pathology
Management of NAFLD
Key Points
References
61 Drug-Induced Liver Injury in Older Adults
Introduction
Pathophysiology
Patterns of Liver Injury
Medications in Older Adults
Safety and Risks of Common Drugs
Antibiotics
Antineoplastics
Steroids
Nonsteroidal Anti-inflammatory Drugs
Alcohol and Drug Interactions
Cardiovascular Drugs
Statins
Other
Herbals and Dietary Supplements
Clinical Presentation and Diagnosis
Management
Next Steps: Future Goals
Key Points
References
62 Gallstones and Benign Gallbladder Disease
Introduction
Epidemiology
Age and Gender
Ethnicity
Obesity
Pathogenesis
Clinical Features of Gallstone Disease (Table 3)
Biliary Pain
Acute Calculous Cholecystitis and its Complications
Common Bile Duct (CBD) Stones
Ascending Cholangitis
Biliary Pancreatitis
Chronic Cholecystitis (See Fig. 2)
Porcelain Gallbladder
Pyogenic Liver Abscess
Diagnostic Studies for Biliary Disease (See Table 9)
US Abdomen (See Fig. 3)
Cholescintigraphy (HIDA) Scan (See Figs. 4 and 5)
Computerized Tomography Scan
Magnetic Resonance Cholangiopancreatogram
Endoscopic Retrograde Cholangiopancreatogram
Endoscopic Ultrasound
Management of Gallstones and Complications
Asymptomatic Gallstones
Management of Acute Calculous Cholecystitis (See Table 10)
Uncomplicated Acute Cholecystitis in a Good Surgical Candidate
Management of Complicated Gallbladder Disease in the Elderly
CBD Stones
Acute Cholangitis
DVT Prophylaxis
Acute Acalculous Cholecystitis
Functional Gallbladder Disorder
Biliary Strictures
Key Points
Key Points 2
References
63 Biliary Neoplasms
Introduction
Gallbladder Polyps
Gallbladder Cancer
Cholangiocarcinoma
Key Points
References
64 Acute Pancreatitis
Introduction
Epidemiology
Older Age Increases the Severity of AP and Mortality (Kara et al. 2018; Forsmark et al. 2016; Ahn et al. 2010)
Difficulties in Diagnosing AP in the Older Adult
AP Based on Etiological Factors
Gallstones
Alcoholic Pancreatitis
Post ERCP Pancreatitis (PEP)
Pancreatic Cancer
Drug-Induced AP (DIP)
Idiopathic AP
Physical Examination Findings
Initial Laboratory Studies
Severity Assessment
Imaging Studies
General Management of AP
Pain Management
Fluid Administration in Older Adults
Nutritional Care
Pharmacological Agents
Antibiotics
Emergent ERCP in AP
Surgery in Acute Pancreatitis
Complications and Their Management
Key Points
References
65 Chronic Pancreatitis
Introduction
Epidemiology
Effects of Aging on the Pancreas
Functional Changes
Pathological Changes
Morphological Changes
Risk Factors
Idiopathic Chronic Pancreatitis
Obstructive Pancreatitis
Alcoholic Chronic Pancreatitis
Tobacco
Recurrent Acute Pancreatitis
Other Causes
Clinical Presentation
Diagnosis
Tests of Function
Tests of Structure
Treatment
Abdominal Pain
Endoscopic Therapy
Surgery
Steatorrhea
Diabetes Mellitus
Nutritional Deficiencies
Key Points
References
66 Autoimmune Pancreatitis
Introduction
Lymphoplasmacytic Sclerosing Pancreatitis (LPSP)
Diagnosis
Histology
Imaging
Serology
Other Organ Involvement
Response to Therapy
Other Criteria for Diagnosis
Other Laboratory Findings
Treatment and Long-Term Outcomes
Idiopathic Duct-Centric Pancreatitis (IDCP)
Clinical Presentation
Laboratory Findings
Histopathology
Imaging and Endoscopy
Treatment
Complications of AIP
Key Points
References
Part XI: Luminal Disorders
67 Oral Health in Older Adults
Introduction
Background and Significance
Oral-to-Systemic Health and Disease
Periodontal Disease and Diabetes
Periodontal Disease and Cardiovascular Disease
Periodontal Disease and Neurodegenerative Disease
Prevention and The Aging Mouth
Access and Barriers to Care
Periodontal Inflammation and Gastrointestinal Disorders
Oral Manifestations of Gastrointestinal Disorders
Common Oral Mucosal Disorders in the Elderly
Medications Affecting Oral Health
Financial Implications of Oral Care for the Elderly
The Future of Oral Care and Teledentistry for Older Adults
Key Points
Book Chapter Quiz Questions: Oral Health in Older Adults
References
68 Gut Microbiota and Aging: A Broad Perspective
Introduction
Gut Microbiota Evolution
Aging and GM
Gut-Brain Axis
Gastrointestinal Disorders and GM
Gut Microbiota and Appetite
GM and Obesity
Sarcopenia
GM and Diabetes Mellitus
Gut Microbe and Atherogenesis
Colonic Disorders
Irritable Bowel Syndrome (IBS)
Inflammatory Bowel Diseases (IBD) (Fig. 4)
Colonic Neoplasms
Gastric Cancer
Liver Diseases (Betrapally et al. 2017)
NAFLD
Alcoholic Liver Diseases
Primary Sclerosing Cholangitis (PSC)
Therapeutic Benefits of Probiotic Therapy
Key Points
References
69 Peptic Ulcer Disease
Introduction
Clinical Presentation
Presentation as Dyspepsia
Presentation as an Ulcer Complication
Diagnosis of Peptic Ulcers
Dyspepsia Presentation
Gastric and Duodenal Ulcer Disease and H. pylori
Pathogenesis of Duodenal Ulcers
Pathogenesis of Gastric Ulcers
Endoscopic Evaluation of Gastroduodenal Ulcers
H. pylori Ulcers
H. pylori Therapy
NSAID Ulcers
Risk Assessment for NSAID Users
Other Drug-Induced Ulcers
Stress Ulcers
Stress Ulcer Treatment and Prevention
Ulcers in the Zollinger-Ellison Syndrome
Diagnosis of Zollinger-Ellison Syndrome
Acid Suppression Therapy in Zollinger-Ellison Syndrome
Idiopathic (Non-H. pylori, Non-NSAID) Ulcers
Ulcer Therapy
Ulcer Healing
Prevention of Ulcer Recurrence
Ulcer Complications
Obstruction
Saline Load Test
Penetration
Perforation
Ulcer Bleeding
Medical Management of Ulcer Bleeding
Endoscopic Management of Ulcer Bleeding
Prediction of Rebleeding After Endoscopic Hemostasis
Additional Risk Factors for Rebleeding
Why Do Patients Rebleed?
Oral or Intravenous PPI Therapy
Antisecretory Therapy and Endoscopic Hemostasis Combined
Key Points
References
70 Celiac Disease
Introduction
A Paradigm Shift in the Epidemiology of CD
Pathology and Pathogenesis
Genetics
Clinical Presentations (Figs. 1 and 2)
Anemia
Osteoporosis
Cancers
Malnutrition
Obesity
Exocrine Pancreatic Insufficiency (EPI)
Liver Diseases
Autoimmune Diseases
Dermatitis Herpetiformis
Neurology
Irritable Bowel Disease (IBS)
Miscellaneous Manifestations
Diagnosis
Management
Key Points
References
71 Small Intestinal Bacterial Overgrowth Syndrome
Introduction
The Normal Gut Flora
Prevalence of SIBO
Predisposing Factors and Associations: Evidence Based
Manifestations
Diagnosis
Management
Considerations in Older People
Key Points
References
72 Irritable Bowel Syndrome
Introduction
Pathophysiology of IBS in an Aging Gut
Challenges in the Diagnosis of IBS in the Older Individual
Depression
Microscopic Colitis
Diverticular Disease
Colon Cancer and Inflammatory Bowel Disease (IBD)
Celiac Disease
Idiopathic Bile Acid Diarrhea
Small Intestinal Bacterial Overgrowth (SIBO)
Other Disorders
Management
Conclusions
Key Points
References
73 Gastrointestinal Infections
Introduction
Part 1: The Immune Response
Innate Immunity
Adaptive Immunity
Part 2: Infectious Gastrointestinal Syndromes in the Older Population
Part 2, Section I: Biliary Sepsis
Acute Cholecystitis
Ascending Cholangitis
Part 2, Section II: Extrabiliary Intra-Abdominal Infection
Diverticulitis
Infectious Diarrhea
Enteric Fever: Typhoid and Paratyphoid Fever
Pancreatitis and Necrotizing Pancreatitis
Extrabiliary-Complicated Intra-Abdominal Infections
Peritonitis
Section I: Spontaneous Bacterial Peritonitis
Section II: Secondary and Tertiary Peritonitis
Section III: Peritoneal-Dialysis Catheter-Associated Peritonitis
Liver Abscess
Pyogenic Liver Abscess
Amebic Liver Abscess
Clostridioides (Previously Clostridium) Difficile
Part 3: Pre-procedure Prophylaxis and Post-procedure Infections
Part 4: Antibiotic Choice
Part 5: Antibiotic Resistance
ESKAPE Pathogens
Resistance in Enteric Pathogens
New and Emerging Antibiotics for Complicatied Intrabdominal Infection
Key Points
References
74 Challenges in the Management of Inflammatory Bowel Disease
Introduction
``A Different Biology´´
Immunosenescence
Altered Gastrointestinal Function and Microbiome
Pharmacokinetics and Drug Metabolism
IBD Drugs´ Pharmacokinetics in the Elderly
Comorbidity
Polypharmacy
Experience with Drugs for IBD
Aminosalicylate
Corticosteroids
Immunomodulators (IMDs)
Thiopurines and Lymphoproliferative/Non-melanotic Skin Cancer
Biologics
Anti-TNF
Anti-integrins
Surgery in Elderly IBD
Cancer
Colorectal Cancer (CRC) Screening in Older Adults with IBD
Treatment Goals in Older Adults with IBD
Symptom Improvement Trumps Mucosal Healing
Conclusions
Takeaway Notes
References
75 Non-IBD and Noninfectious Colitis
Introduction
Microscopic Colitis (MC)
Epidemiology
Pathophysiology
Clinical Manifestations
Diagnosis
Treatment
Drug-Induced Colitis
Clinical Presentation
Diagnosis
Treatment
Immune Checkpoint Inhibitor-Induced Colitis
Segmental Colitis Associated with Diverticulosis (SCAD)
Epidemiology
Pathophysiology
Clinical Presentation
Diagnosis
Treatment
Ischemic Colitis
Epidemiology
Pathophysiology
Clinical Presentation
Diagnosis
Treatment
Diversion Colitis
Epidemiology
Pathophysiology
Clinical Presentation
Diagnosis
Treatment
Radiation Colitis
Epidemiology
Pathophysiology
Clinical Presentation
Diagnosis
Treatment
Eosinophilic Colitis
Epidemiology
Pathophysiology
Clinical Presentation
Diagnosis
Treatment
Behçet´s Colitis
Epidemiology
Pathophysiology
Clinical Presentation
Diagnosis
Treatment
Key Points
References
76 Clostridium (Now Clostridioides) difficile-Associated Disease
Introduction
Epidemiology
Classification Based on Mode
Epidemics and Colonization
Epidemiology in Older Adults
Risk Factors (See Table 1)
Pathogenesis
Transmission
Antibiotic-Associated Diarrhea
Diagnosis and Evaluation
Clinical Presentation
Severity of Disease
Fulminant CDI
Diagnostic Tests (See Table 2)
Background
Two-Step Testing
NAAT (PCR)
Cycle Threshold and Fecal Markers
Treatment (Table 3)
Introduction
Initial Infection
Vancomycin
Fidaxomicin
Additional Measures
Treatment of Fulminant CDI
Recurrent C. difficile Infection (rCDI)
Pathogenesis of rCDI
Diagnosis of rCDI
Treatment of rCDI
Pulsed-Taper Vancomycin
Fecal Microbiota Transplantation for rCDI
Fecal Microbiota Transplantation for rCDI in Older Adults
Extended Duration Vancomycin for rCDI
Prevention of rCDI
Prevention of CDI
Infection Control
Bezlotoxumab
Probiotics
Community-Acquired CDI
Future Directions
Oral Spore-Containing Formulations
Antibiotics
Enzymes and Vaccines
Key Points
Reference
77 Diverticular Disease
Introduction
Terminologies
Epidemiology and Epidemiological Changes Globally
Pathology (Table 2)
Clinical Features (Tables 3 and 4)
Asymptomatic
Symptomatic Uncomplicated Diverticular Disease (SUDD)
Diverticulitis (Table 5)
Diverticular Bleeding
Diagnostic Studies (Prospective Multicenter Study (Umezawa et al. 2018))
Key Points
References
78 Acute Colonic Pseudo-Obstruction
Introduction
Pathophysiology
Clinical Manifestations and Diagnosis
Management
Key Points
References
79 Fecal Incontinence
Introduction
Epidemiology
The Physiology of Continence
Age-Related Changes
Etiology
History and Physical Examination
Incontinence Scoring System
Diagnostic Testing
Anorectal Physiology
Anorectal Manometry
Electromyography
Pudendal Nerve Terminal Motor Latency
Endoanal Ultrasound
Defecography
Medical Management
Dietary Modification
Pharmacologic Agents
Bowel Management Regimen
Pelvic Floor Exercises
Biofeedback Training
Miscellaneous Approaches
Anal Hygiene
Surgical Treatment
Sphincteroplasty
Artificial Bowel Sphincter
Sacral Nerve Stimulation
Percutaneous Tibial Nerve Stimulation
Radiofrequency Energy
Anal Canal Bulking Agents
Colostomy
Future Research
Key Points
References
80 Rectal Prolapse
Introduction
History
Definition
Etiology
Surgical Anatomy and Physiology
Presentation
Associated Conditions
Evaluation
History and Physical Examination
Imaging Studies
Nonoperative Treatment
Operative Treatment
Mucosal Prolapse Operative Options
Complete or Full Thickness Rectal Prolapse Operative Options
Perineal or Transanal Operative Options
Transabdominal Operative Options
Role of Minimally Invasive Surgery
Conventional Laparoscopic or Laparoscopic-Assisted Minimal Access Surgery
Robotic or Robotic-Assisted Minimal Access Surgery
Key Points
References
81 Anorectal Disorders
Introduction
Approach to Rectal Bleeding
Constipation and Fecal Impaction
Stool Incontinence
Treatment of FI
Medical Therapy
Anal Fissure
Pathophysiology
Diagnosis
Medical Treatment
Dietary and Behavioral Modification
Topical Nitroglycerin
Topical Calcium Channel Blockers
Botulinum Toxin A
Rectal Prolapse
Symptomatology
Diagnosis
Treatment
Pruritis Ani
Infectious Etiologies
Dietary Associations
Management
Hemorrhoids
Disease Severity and Management
External Hemorrhoids
Key Points for the Chapter
References
Part XII: Neoplasms
82 Esophageal Cancer
Introduction
Epidemiology
Risk Factors
Age/Gender
Gastroesophageal Reflux Disease
Barrett´s Esophagus
Smoking
Alcohol
Diet
Structural Esophageal Disease
Tylosis
Obesity
Occupational Risk
Clinical Presentation
Diagnosis
TNM Staging
Prognosis
Management
Early Stage Disease
Locally Advanced Disease
Metastatic Disease
Single-Agent Chemotherapy
Combination Chemotherapy
Targeted Therapies
Immunotherapy
How Do Older Adults Respond to Treatment?
Key Points
References
83 Gastric Cancer
Epidemiology
Background
Incidence
Geographical Variation and African Enigma
Mortality
Time Trends
Migration Studies
Change in Location and Histology
Etiology and Pathogenesis
Pathogenesis
Classification of Gastric Cancer
Anatomical Classification
Histological Classifications
Molecular Classifications
Symptoms and Diagnosis
Early Gastric Cancer
Importance of Early Diagnosis
Clinical Presentations
Diagnosis and Staging
Comorbidities
TNM Staging
Treatment
Surgical Treatment
Locoregional Cancer
Metastasic or Recurrent Gastric Cancer
Palliative Chemotherapy
Radiation Therapy
Follow-Up
Palliation of Advanced Cancer
Financial Toxicity and Cost Effectiveness
Conclusions
Key Points
References
List of National and Global Guidelines on Gastric Cancer
84 Gastric Tumors (Other than Adenocarcinoma)
Introduction
Histological Types and Their Clinical Associations
Hyperplastic Polyps (HPs)
Fundic Gland Polyps (FGPs)
Gastric Adenomas
Gastric Malignant Tumors
GIST
Introduction
Management Options
Gastric Neuroendocrine Tumors
Introduction
Management
Gastric Lymphoma
Introduction
Primary Gastric Lymphoma (PGL)
MALT Lymphoma
Primary Gastric Hodgkin´s Lymphoma
Squamous Cell Carcinoma of the Stomach
Key Points
References
85 Pancreatic Cancer
Introduction
Epidemiology
Risk Factors
Genetic/Hereditary Factors
Environmental and Dietary Factors
Host Factors
Other Factors
Pathology
Clinical Presentation
Symptoms
Signs
Staging
Management
Diagnosis
Tumor Markers
Imaging
Endoscopic Ultrasound (EUS)
Treatment
Surgery
Chemotherapy and Radiotherapy
Palliation
Prognosis
Screening
Key Points
References
86 Cystic Lesions of the Pancreas
Introduction
Epidemiology
Classification of Pancreatic Cystic Lesions
Benign Pancreatic Cystic Lesions
Neoplastic Pancreatic Cystic Lesions
Cancer Risk for Pancreatic Cystic Neoplasm
Surveillance Guidelines
Indications for Surgery and Its Complications
Quality of Life and Survival After Pancreatic Resection
Summary
Key Points
References
87 Pancreatic Neuroendocrine Tumors
Introduction
Clinical Features and Classification
WHO Clinico-pathologic Classification of Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)
Staging
Prognostic Factors in PNETs
Tumor Markers
Molecular Pathogenesis
Diagnosis and Imaging: Tumor Localization
Overview
Computed Tomography
Magnetic Resonance Imaging
Endoscopic Ultrasonography (EUS)
Somatostatin-Receptor Scintigraphy (Octreoscan)
Laser Confocal Endomicroscopy with Fluorescein-Labeled Somatostatin Analogs
Arterial Stimulation Venous Sampling
Intraoperative Localization Techniques
Management
Surgical Management of PNET
Sporadic PNET
PNET Associated with MEN1
Treatment of Hepatic Metastases
Surgical Management
Liver Transplantation
Hepatic Artery Embolization
Radiofrequency Ablation and Cryoablation
Role of Neoadjuvant Therapy
Newer Advances
VEGF Pathway Inhibitors
mTor Inhibitors
Peptide Receptor Radionucleotide Therapy (PRRT)
Key Points
References
88 Colorectal Cancer Screening
Introduction
Epidemiologic Considerations
CRC Screening (Mis)utilization
Screening Modalities
Benefits and Harms of Screening
Surveillance
Life Expectancy and Screening Outcomes
Tailoring Screening Decisions
Guidelines
Conclusion
References
89 Colorectal Cancer
Introduction
Epidemiology of CRC in Relevance to the Older Adults
Worldwide Epidemiology
Epidemiology of CRC in the USA
Morphology of Colon Polyps and CRC
Adenoma -Carcinoma Sequence (The Chromosomal Instability Pathway)
The Serrated Adenoma Pathway
The Microsatellite Instability (MSI) Pathway
Hereditary CRC
The Risk Factors
Modifiable Risk Factors
Clinical Features of CRC
Screening for CRC in the Older Adults (When to Do, What to Do, and When to Stop)
Stool Based Tests
Treatment Options of CRC in Older Adults
Preoperative Management of CRC in Older Adults
Radiation Therapy
Chemotherapy
Newer Approaches
Nutritional Support
Palliative Care
Key Points
References
90 Chemoradiotherapy for Gastrointestinal Malignancies
Introduction
Assessment Tools
Tumor-Agnostic Therapies
Colorectal Cancer
Gastric Cancer
Esophageal Cancer
Pancreatic Cancer
Biliary Tract Cancers
Conclusions
Key Points
References
Part XIII: Vascular Disorders
91 Intestinal Ischemia
Introduction
Classification of Ischemic Disorders of the Bowel
Intestinal Blood Supply
Ischemic Colitis (IC)
Pathogenesis
Diagnosis
Diagnostic Studies
Imaging Studies
Outcome and Management
Mesenteric Ischemia
Classification
Epidemiology
Clinical Features
Pathophysiology
Diagnosis
Serum Markers for Intestinal Ischemia
Management of AMI
Mesenteric Venous Thrombosis (MVT)
Nonocclusive Mesenteric Ischemia (NOMI)
Chronic Mesenteric Ischemia (CMI)
Key Points
References
92 Abdominal Aortic Aneurysm
Introduction
Risk Factors
Presentation
Screening and Surveillance
Management
Lifestyle Measures
Pharmacological Measures
Surgery
Additional Considerations
Key Points
References
Part XIV: Palliative Care
93 Palliative Gastroenterology
Introduction
Palliative Care and Hospice
Primary Versus Specialty Palliative Care
Referral Indications
Palliative Care Assessment
Prognostication
Symptom Management
Conclusion
Key Points
References
Part XV: Surgery
94 Bariatric Surgery in Older Adults
Introduction
Physiology of Morbid Obesity in Elderly
Patient Selection
Patient Preparation
Types of Bariatric Surgery
Intragastric Balloon
Sleeve Gastrectomy
Roux-En-Y Gastric Bypass
Mini Gastric Bypass or One-Anastomosis Gastric Bypass
Biliopancreatic Diversion +/- Duodenal Switch
Adjustable Gastric Banding
Single-Anastomosis Duodeno-Ileal Bypass (SADI-S)
Effects of Bariatric Surgery
Weight Loss Improvements
Metabolic and Gastrointestinal Improvements
Impact of Bariatric Surgery on Obstructive Sleep Apnea, GERD, and Joint Pain
Impact of Bariatric Surgery on Quality of Life and Psychological Health
Economic Impact of Bariatric Surgery
Complications Following Bariatric Surgery Procedures
Mortality
Leaks and Fistulas
Internal and Incisional Hernias
Strictures
Ulcers
Nutritional Deficiencies
Dumping
Other Complications
Outcomes Compared to Younger Patients
Key Points
References
95 Surgical Abdomen
Introduction
Anesthesia and Perioperative Considerations in the Older Adult
Abdominal Pain
Biliary Tract Disease
Appendicitis
Peptic Ulcer Disease
Diverticulitis
Intestinal Obstruction
Early Postoperative Obstruction
Volvulus
Cecal Volvulus
Acute Mesenteric Ischemia
Ruptured Abdominal Aortic Aneurysm
Hernia
Key Points
References
96 Colostomy and Ileostomy Care
Introduction
Ostomy Classification
Colostomies
Ileostomies
Lifestyle Considerations
Complications
Key Points
References
Part XVI: Systems Disorders
97 Gastrointestinal Manifestations of Non-GI Disorders
Introduction
Gastrointestinal Manifestations of Rheumatological Disorders
Overview
Systemic Sclerosis
Pathogenesis
Clinical Manifestations
Gastrointestinal Manifestations
Systemic Lupus Erythematosus
Pathophysiology
Clinical Manifestations
Diagnosis
GI Manifestations
Rheumatoid Arthritis
Etiology and Pathophysiology
Classic Manifestations and Diagnosis
GI Manifestations
Inflammatory Myositis
Etiology, Manifestations, and Diagnosis
Immunoglobulin G4-Related Disease
Gastrointestinal Manifestations from Cardiovascular Diseases
Cardiac Cachexia in Congestive Cardiac Failure (CCF)
Liver Manifestations in Cardiac Diseases
G.I. Is Bleeding in Cardiac Disorders
Heart Surgery and GI Manifestations:
Gastrointestinal Manifestations from Pulmonary Diseases
GI Manifestations of Patients in ICU (or Critically Ill)
GI Manifestations in Chronic Renal Failure
GI Manifestations of Common Neurologic Disorders
Dysphagia
Key Points
References
98 Gastrointestinal Manifestations of Endocrine Disease
Introduction
Hypothalamus and Pituitary
Multiple Endocrine Neoplasia Syndrome (MEN 1)
Thyroid Dysfunction
Hyperthyroidism
Management of GI Manifestations of Hyperthyroidism
Hypothyroidism
Parathyroid Dysfunction
Hyperparathyroidism
Hypoparathyroidism
Diabetes Mellitus
GI Manifestations of Diabetes Mellitus in Older Adults
Oral Cavity Diseases
Esophageal Dysfunction
Gastroparesis
Celiac Disease and Changes in Small Intestinal Microflora
Diabetic Diarrhea
Liver in Diabetes
Adrenal Disorders
Adrenal Insufficiency
Cushing´s Syndrome
Neuroendocrine Neoplasms (NENs) of the Gastrointestinal Tract
Carcinoid Syndrome
When to Suspect a Gastroenteropancreatic Neuroendocrine Neoplasm (GEP NEN)?
Key Points
References
99 Rheumatological Manifestations of GI Disorders
Introduction
Background
Relationship Between Mucosal and Systemic Immunity, Genetic Factors, Gut Microbiota, and Dietary Factors
Pathogenesis Underlying the Gut and Extra-Intestinal Manifestations (EIM) of Rheumatic Diseases
Rheumatological Manifestations of Gastrointestinal Diseases
Therapeutic Options for Rheumatological (Extra-Intestinal) Manifestations of Gastrointestinal Diseases
Key Points
References
100 Gastrointestinal Disorders in Long-Term Care
Introduction
Weight Loss
Common GI Symptoms Seen in LTC
Constipation
Diarrhea
Dysphagia
Nausea
Flatulence
Chest Pain
Abdominal Pain
Gastroenterological Conditions with Features Specific to LTC
Peptic Ulcer Disease
Hepatobiliary Disease
Colorectal Disease
Oral Health
End of Life Care
Artificial Nutrition and Hydration
Long-Term Care Patient Management and the Gastroenterologist
Key Points
References
101 Mucocutaneous Manifestations in Gastrointestinal Disease
Introduction
Oral Cavity
Kaposi´s Sarcoma
Mucocutaneous Candidiasis
Angular Cheilitis
Behçet Syndrome
Esophagus and Stomach
Plummer-Vinson Syndrome
Tylosis
Epidermolysis Bullosa
Systemic Sclerosis
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
Intestines
Peutz-Jeghers Syndrome
Blue Rubber Bleb Nevus Syndrome
Gardner Syndrome
Dermatitis Herpetiformis
Crohn´s Disease
Liver and Pancreas
Hemochromatosis
Porphyria Cutanea Tarda
Pancreatic Fat Necrosis
Glucagonoma
Lichen Planus
Acanthosis Nigricans
Visceral Neoplasms
Muir-Torre Syndrome
Cowden Disease
Cronkhite-Canada Syndrome
Other Manifestations: Parasitic Diseases
Strongyloidiasis
Leishmaniasis
Additional Considerations in Older Adults
Key Points
References
102 Atlas of Dermatological Manifestations in Gastrointestinal Disease
Introduction
Cutaneous Manifestations of Hereditary GI Cancers
Familial Colorectal Cancer Syndromes
Hamartomatous Syndromes
Paraneoplastic Syndromes Associated with GI Malignancies
Inflammatory Bowel Disease
Immune-Mediated Conditions
Vascular Disease
Genodermatoses
Nutritional Deficiencies
Cutaneous Side Effects of GI Medications
Key Points
References
103 HIV in Older Adults
Introduction
Epidemiology of HIV/AIDS in the Elderly
Gastrointestinal System and HIV
Anorexia and Weight Loss
Esophagus
Stomach
Small and Large Bowel
Biliary Tract
Liver
Malignancy in HIV
Conclusion
Key Points
References
104 Gastrointestinal Manifestations of COVID-19
Introduction
Pathogenesis
Immunosenescence and Inflammaging
Immune Response in COVID-19
Gastrointestinal Involvement in Covid-19
Gastrointestinal Symptoms
Anosmia and Dysgeusia
Nonspecific GI Symptoms
Pancreas and Gallbladder
Colon Involvement
Hepatic Manifestations
Abnormal Liver Function Tests
Liver Failure
Chronic Liver Disease and COVID-19
COVID-19 in Liver Transplant (LT) Recipients
Fecal-Oral Transmission
Key Points
References
105 Psychiatric Issues in Older Adults with Gastrointestinal Disorders
Introduction
Geriatric Psychiatry
The Dementias
Mood Disorders
Psychosis
Anxiety
Substance Abuse
Delirium
Insomnia
The Brain and the Gut
Functional Gastrointestinal Disorders
Upper GI System
Rumination Syndrome
Burning Mouth Syndrome
Xerostomia
Globus
Dysphagia
Esophageal Disorders
Gastroesophageal Reflux Disease (GERD)
Functional Heartburn
Gastroparesis
Peptic Ulcer Disease (PUD)
Liver Diseases
Minimal Hepatic Encephalopathy
Psychopharmacology in Geriatric Gastroenterology
Burning Mouth Syndrome (BMS)
Xerostomia
Dysphagia
Gastroesophageal Reflux Disease (GERD)
Non-erosive Reflux Disease (NERD)
Gastroparesis
Peptic Ulcer Disease (PUD)
Liver Diseases
Hepatitis
Inflammatory Bowel Disease (IBD)
Irritable Bowel Syndrome (IBS)
Cognitive Enhancers
Psychiatric Side Effects of Gastrointestinal Medications
Key Points
References
Index

Citation preview

C. S. Pitchumoni T. S. Dharmarajan Editors

Geriatric Gastroenterology Second Edition

Geriatric Gastroenterology

C. S. Pitchumoni • T. S. Dharmarajan Editors

Geriatric Gastroenterology Second Edition

With 662 Figures and 499 Tables

Editors C. S. Pitchumoni Department of Medicine Robert Wood Johnson School of Medicine Rutgers University New Brunswick, NJ, USA

T. S. Dharmarajan Department of Medicine Division of Geriatrics, Montefiore Medical Center Wakefield Campus Bronx, NY, USA

Department of Medicine New York Medical College Valhalla, NY, USA

Department of Medicine Albert Einstein College of Medicine Bronx, NY, USA

Division of Gastroenterology Hepatology and Clinical Nutrition Saint Peters University Hospital New Brunswick, NJ, USA

Department of Medicine New York Medical College Valhalla, NY, USA

ISBN 978-3-030-30191-0 ISBN 978-3-030-30192-7 (eBook) ISBN 978-3-030-30193-4 (print and electronic bundle) https://doi.org/10.1007/978-3-030-30192-7 1st edition: © Springer Science+Business Media, LLC 2012 2nd edition: © Springer Nature Switzerland AG 2021 All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Dedicated to my parents, My wife Prema And children Sheila, Shoba, and Suresh, and Grandchildren Shreya, Salena, Tara, Ajay, and Aneel For all their love and support CSP Dedicated to my mother, My wife Lekshmi, And Kumar, Kavita, Iyla, and Jaiya, With much love and gratitude! TSD

Foreword

I’ll never forget the first time I met Professor C.S. Pitchumoni. It was 1997 and I was a fourth-year medical student still contemplating how to focus my career. I wanted to become a surgeon, but wasn’t sure I could awaken before dawn for the rest of my working life. I liked psychiatry, but wasn’t sure I could pursue a non-procedural specialty. I had not thought of gastroenterology as a career at that point, not for a nanosecond. Professor Pitchumoni changed all of that. I attended one of Dr. Pitchumoni’s lectures on irritable bowel syndrome where I came to realize that gastroenterology is, in fact, a curious hybrid between surgery and psychiatry. Here was this ebullient, articulate, engaging master clinician who held me spellbound with patient stories. He described the “brain-gut axis,” explained that many people with IBS have concurrent psychosocial distress, yet also emphasized that some patients need a colonoscopy to rule out underlying organic disease. Gastroenterology, it seemed, required a deep and abiding knowledge about mind and body. I realized this was a field like no other, and I was being taught by a professor like no other. There was something magical about this man. Something about how he entranced his audience, how he brought a topic like IBS to life, how he exuded expertise in biopsychosocial medicine, and how people could laugh hysterically at his unique humor while maintaining a serious focus on the material. To this day, Dr. Pitchumoni is the most effective teacher I have ever witnessed. I am here, writing this foreword, because he inspired me to become a gastroenterologist. Early in his academic career, Dr. Pitchumoni focused his research on pancreatic disorders, but his clinical interests always spanned across the entire spectrum of gastroenterology. In over five decades of his academic career, he has authored over 200 peer-reviewed papers and over 100 chapters in textbooks, in addition to editing 7 books. If it weren’t for C.S. Pitchumoni, I probably would be doing an appendectomy right now or rounding at 5:00 AM in the SICU. Instead, I am writing about a truly special man who has now co-authored a truly special second edition of his masterwork, Geriatric Gastroenterology. Dr. Pitchumoni is joined by another master educator and co-author T.S. Dharmarajan, Professor of Medicine, Vice Chair of Medicine, and

vii

viii

Clinical Director of Geriatrics at Montefiore Medical Center (Wakefield Campus), Albert Einstein College of Medicine, Bronx, New York. Dr. Dharmarajan leads one of the largest hospital-based geriatric programs and geriatric medicine fellowships and has an extensive track record of exceptional scholarship in his burgeoning field. He has published over 200 papers, presented over 400 scientific abstracts, and has been a principal investigator for a wide range of impactful studies in geriatric medicine. Together with Dr. Pitchumoni, Dr. Dharmarajan has teamed up to publish a number of previous studies and textbooks, most notably the very successful first edition of the current text. Now, after their book became a best seller, this dynamic duo returns with their second edition to expand and further strengthen an extraordinary text. One glance at the table of contents reveals an expansive treatment of geriatric gastroenterology. The text is organized into 15 parts and detailed in over one hundred authoritative chapters written by key opinion leaders. The book begins with a thoughtful overview of perspectives and trends, including views from both the geriatrician and gastroenterologist about the importance of understanding how age affects the digestive system. Next comes a detailed review of the relevant basic science and physiology of aging, with special reference to the alimentary canal, together with key facts and figures regarding the epidemiology of GI diseases. A comprehensive part on pharmacology follows, including a discussion about the pharmacology of aging, GI toxicities of special interest to the geriatric population, and drug-nutrient interactions – an area often underappreciated in traditional GI educational programs. The part on nutrition is of special interest given the expanding evidence that what we eat truly matters to GI health. Chapters in this part cover geriatric nutritional assessment, tube feeding and enteral nutrition, and peri-operative nutrition in geriatric populations; this part also contains a series of chapters on individual vitamin and mineral deficiencies, often prevalent yet underdiagnosed in senior populations. The book continues with careful treatments about the role of endoscopy in older adults, GI radiology considerations in the geriatric population, common motility disorders, and clinical approaches to prevalent symptoms, including abdominal pain, gas and bloating, constipation, and diarrhea, among others. Later parts offer deep discussions about hepatobiliary and pancreatic issues among seniors; common luminal disorders like peptic ulcer disease, intestinal ischemia, diverticular disease, and intestinal infections; and an expansive part on neoplasms. Appropriate for this volume, the book also includes a thoughtful part about palliative care considerations for the gastroenterologist. This is a master work edited by two master clinicians who have dedicated their respective careers to educating the next generations (note the plural) of gastroenterologists and geriatricians. I count myself as one of the lucky students to have been inspired by these authors, who have supported and crafted many careers far beyond my own. I hope you enjoy reading this comprehensive and insightful book as much as I have enjoyed writing about

Foreword

Foreword

ix

it, and I thank the authors for giving me the opportunity of writing the foreword to their magisterial work. American Journal of Brennan Spiegel, MD, MSHS, FACG, AGAF Gastroenterology Co-Editor-in-Chief Professor of Medicine and Public Health Cedars-Sinai Medical Center Assistant Dean of Clinical and Translational Research David Geffen School of Medicine at UCLA Los Angeles, California September 2020

Preface to Second Edition

We are pleased to present Geriatric Gastroenterology, the second edition and a Major Reference Work, a Springer publication. Although initially reluctant to take on what appeared to be an intimidating, massive venture, the considerable success of the first edition of Geriatric Gastroenterology published in 2012 has made a difference in encouraging us on. The first edition was a best seller in the Springer category of books, with over 150,000 chapter downloads, providing us the stimulus to move forward with this work. The entire work has been completed in about 3 years. Importantly, the final year of work was done amidst the COVID-19 pandemic. The final product far exceeded the initial plans of the editors in terms of content and scope of work. Trends in global aging have focused attention on the manner in which we care for older adults, and we must be prepared to meet the demands of healthrelated disorders and societal concerns in our aging population. Most specialties, gastroenterology included, have increasingly promoted the blending of medical subspecialty training with expertise in the care of the older adult. The American Gastroenterology Association Future Trends Committee Report highlighted several years ago the areas for improvement in healthcare delivery, including the need to identify “best evidence-based care” for the older adult, to develop guidelines for care of specific gastrointestinal issues in geriatrics, to modify current practices to meet the complex needs of older individuals, and to adapt the healthcare workforce to meet the demands of specialized treatments in gastroenterology for older people. As editors, specialized in gastroenterology and geriatric medicine, we believe in the concept of editing and writing material for textbooks to address the physiology, pathology, evaluation, and management of digestive disorders in older people. Too often, most clinical complaints are attributed to “old age” by patients and providers alike. Physicians must be better trained to discern physiological and pathological processes and distinguish healthy aging from the disease. Providers of care must understand the impact of polypharmacy and adverse drug events, which often mimic gastrointestinal disorders, and increase healthcare burden and costs. They need to be aware that the average older adult presenting with digestive disorders will likely manifest multiple comorbid diseases, some obvious and some hardly recognizable. And physicians must be focused and sensitive to ethical aspects of care the old. Effort has been made to limit (but not exclude) the term “elderly” and briefly address the controversies associated with the use of terms such as “elderly, older, and xi

xii

geriatric” individuals. We have preferentially used the term “older adults” in conformity with the current trends. This book attempts to clarify several challenging and controversial aspects related to the diagnosis and care of the geriatric individual. The standard format adopted for the first edition has been retained. Most chapters begin with an introduction, followed by discussion, and conclude with key points. The concept of key points at the end of each chapter is retained as in the first edition. Numerous tables and figures present succinct accounts to emphasize content. Certain chapters are mostly pictorial and abundant on pictures focusing on endoscopy, radiography, dermatological disorders, and pathology relevant to gastroenterology. The book offers value to residents, fellows, nutritionists, and practicing physicians alike. The current work differs in many ways from the first edition. As a major reference work, it has 50% more chapters, for a total of 105 and a page content well in excess of 2000, over three times the content of the first version. The parts have been altered and many chapters substantially enlarged in information. The parts of nutrition and pharmacology, both most relevant in the care of older adults, have been substantially broadened to include several relevant and new topics. The topic of medical ethics has been given due importance and also obesity in older adults, including bariatric surgery. Imaging and dermatology chapters are studded with illustrations that are succinctly explained. There is a marked increase in tables and figures, with many illustrations in color. Each chapter is preceded by an abstract which briefly describes its content. We did not hesitate to add a chapter on COVID-19, the hottest topic in medicine today, under the current circumstances. The popular “key points” that present bulleted themes regarding the entire text at the end of each chapter have been improved upon, based on the feedback received from readers of the first edition, who remarked that “if one is too busy to read the book, the least that an individual can do is to review the key points at the end of each chapter.” Although a major reference work, it is by no means all inclusive, yet offers a comprehensive range of chapters in the field of geriatric gastroenterology. Credit is due to two pioneers who wrote books on the field: Gastrointestinal Disorders of the Elderly by Lawrence J. Brandt, MD, and Aging and the Gastrointestinal Tract by Peter R. Holt, MD. The two provided the initial motivation for our efforts. We salute the numerous giants in the field of geriatrics: William R. Hazzard, Christine K. Cassel, Joseph G. Ouslander, Mary E. Tinetti, Laurence Z. Rubenstein, John E. Morley, and others; and in the field of Gastroenterology: Howard M. Spiro, Henry L. Bockus, Sir Francis Avery Jones, Dame Sheila Sherlock, Marvin H. Sleisenger, John S. Fordtran, Edward J. Berk, Lawrence R. Schiller, and others. These scholars blazed the trail for us to follow. Special thanks are due to Dr. Brennan Spiegel who graciously agreed to write the foreword to the book. We are indebted to the numerous physicians and surgeons who contributed to the work and gave their precious time, which added tremendous value to the work. Their efforts during the COVID-19 pandemic have been remarkable, in that they responded favorably to our calls almost invariably.

Preface to Second Edition

Preface to Second Edition

xiii

Springer was supportive all along and instrumental in helping us formulate the concepts and implement the process to produce a major reference work. The staff was most helpful in the submission, e-proofing, and publication of each chapter throughout the editing process; their patience with the editors is highly appreciated. The Meteor system introduced by Springer was new to us and it took a while to comprehend its benefits. Both the editors had earlier written a series of articles on the theme of geriatric gastroenterology, and Springer was largely instrumental in bringing to fruition the concept of our initial textbook of geriatric gastroenterology in 2012. Springer followed by helping our dream of creating a major reference work for the current second edition come true to life. We appreciate the tremendous support from members of our families, as always, throughout, for which we remain eternally grateful. Our families were a source of encouragement and inspiration; their patience, understanding, and sacrifices during the period are commendable. As teachers and mentors, we acknowledge our students, residents, fellows, and professional colleagues in providing the stimulus to enrich our knowledge and clinical skills. But above all, we pay tribute to our older patients in community, hospital, and nursing home settings, from whom we have learnt so much and without whom we do not matter! In this work, we have emphasized the importance of function, quality of life, and ethical aspects (besides the disease) in caring for the old. It is important to care, even if one cannot cure. We quote Abraham Lincoln: “And in the end, it’s not the years in your life that count. It’s the life in your years,” and Jeanne Louise Calment (1875–1997), the oldest documented individual: “I had to wait 110 years to become famous; I wanted to enjoy it as long as possible.” C. S. Pitchumoni, MD T. S. Dharmarajan, MD

Preface to the First Edition

Over the past several decades, trends in global aging have focused attention on the manner in which we care for older adults. How can we be best prepared to meet the demands of medical illness in our aging population? Many of the medical societies have increasingly promoted the blending of medical sub-specialty training with expertise in the care of the older adult. In this regard, the American Gastroenterologic Association Future Trends Committee Report recently highlighted several areas for improvement in health care delivery, including the need to identify ‘best evidence-based care’ for the older adult; to develop guidelines for care of specific gastrointestinal issues in geriatrics; to modify current practices in order to meet the complex needs of older individuals; and to adapt the healthcare workforce to meet the demands of specialized treatments in gastroenterology for older people. Until there are sufficient trained personnel in both geriatrics and gastroenterology, providers must handle the daunting task with knowledge gained in other ways. As editors specialized in gastroenterology and geriatric medicine, we see the need for a textbook to address the physiology, pathology, evaluation and management of digestive disorders in the elderly. Too often, clinical complaints are attributed to ‘old age’ by patient and provider alike. Physicians must be better trained to discern physiological from pathological processes and normal aging from disease. Disorders such as constipation and diverticular disease are common in the old, but are they pathological, or the result of aging? As age is associated with immune dysfunction, the role of the gut in the elderly has become a subject of increasing importance. How should the age-related decline in homeostatic mechanisms, known as homeostenosis, alter medical care in the elderly? Added to the complex situation is the impact of polypharmacy and adverse drug events which often mimic gastrointestinal disorders, with increasing health care costs. How can we learn to be more focused and sensitive to these issues? This book attempts to clarity these challenging and controversial issues in the diagnosis and care of the geriatric individual. A standard format has been adopted for this text, whereby most chapters conclude with key summary points. Numerous tables and figures are included to emphasize content. There are abundant pictures focusing on endoscopy, radiography and pathology. Several relevant gastrointestinal topics unique to the older person are included. We anticipate the book will be a valuable resource for residents, fellows, and practicing physicians alike. A section providing Questions with multiple choice Answers and brief discussions xv

xvi

Preface to the First Edition

relating to the chapters is hosted in an electronic platform (Springer Extras); this may be an additional benefit particularly to residents and fellows in training. This work is by no means all-inclusive, but does offer solid grounding in geriatric gastroenterology. It is also not the first text on the subject: the first comprehensive book was written in 1984 by Lawrence J. Brandt MD, Emeritus Chairman of Gastroenterology at Albert Einstein College of Medicine, entitled “Gastrointestinal Disorders of the Elderly.” Tremendous credit is due to Peter R. Holt MD of Saint Luke’s Hospital of New York-Presbyterian Medical Center for pioneering the concept of ‘Aging and the Gastrointestinal Tract’. These two provided the initial motivation for our efforts. We salute as well many pioneers in the field of Geriatrics: William R. Hazzard, Christine K. Cassel, Joseph G. Ouslander, Mary E. Tinetti, Laurence Z. Rubenstein, John E. Morley, and others; and the field of Gastroenterology: Howard M. Spiro, Henry L. Bockus, Sir Francis Avery Jones, Dame Sheila Sherlock, Marvin H. Sleisenger, John S. Fordtran, Edward J. Berk, and others. All of these scholar-mentors in medicine paved the path for us to follow. Special thanks are due to Martin H. Floch MD of Yale University, who has graciously provided the Foreword for the book. We are grateful to the many contributors who responded to our call and gave generously of their time to provide chapters for the book. Springer has been supportive from the start of this venture and throughout the editing process. Both of us wrote a series of articles over the past 15 years on the theme of geriatric gastroenterology, and Springer has been instrumental in bringing to fruition our dream of a textbook of geriatric gastroenterology. Support and encouragement from our family was ever present, and for this we are eternally grateful. Our families were a source of strength and inspiration; their patience, understanding and sacrifices commendable. As teachers and mentors, we acknowledge our students, residents, fellows and professional colleagues for providing the opportunity to enrich our knowledge and clinical skills. And above all, we pay tribute to our older adult patients in community, hospital and nursing home settings, from whom we have learned so much. It is our hope that this textbook serves as a resource towards fulfillment of a goal so aptly stated by Abraham Lincoln: “And in the end, it’s not the years in your life that count. It’s the life in your years.” C. S. Pitchumoni, MD T. S. Dharmarajan, MD

Acknowledgments

The editors remain forever grateful and acknowledge All Authors for contributing the many valuable chapters to this work And Vasowati Shome, Consultant, Major Reference Works, Mohanapriya Caliamourthy, Project Manager, Alexa Steele, Editor, Major Reference Work, And all others at Springer Who helped make this work happen!

xvii

Contents

Volume 1 Part I 1

2

Perspectives and Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1

Geriatric Gastroenterology: A Geriatrician’s Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . T. S. Dharmarajan

3

Geriatric Gastroenterology: A Gastroenterologist’s Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. S. Pitchumoni

19

3

Epidemiology of Gastrointestinal Diseases . . . . . . . . . . . . . . . Jorge D. Machicado, Julia B. Greer, and Dhiraj Yadav

27

4

Centenarians: Life Style for a Long Healthy Life . . . . . . . . . Murali D. Nair and Elise Marie Collins

49

5

Ethical Issues in Geriatric Gastroenterology . . . . . . . . . . . . . Cynthia L. Vuittonet, T. Patrick Hill, T. S. Dharmarajan, and C. S. Pitchumoni

65

Part II

Basic Science

........................................

99

6

Physiology of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 T. S. Dharmarajan

7

Gastrointestinal Physiology and Aging C. S. Pitchumoni

. . . . . . . . . . . . . . . . . 155

8

Comprehensive Geriatric Assessment T. S. Dharmarajan

. . . . . . . . . . . . . . . . . . 201

Part III Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 9

Pharmacology of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 Lisa C. Hutchison xix

xx

Contents

10

Drug Effects on the Gastrointestinal System: A Physician Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 Vishal Jain, T. S. Dharmarajan, and C. S. Pitchumoni

11

Adverse Drug Effects Involving the Gastrointestinal System (Pharmacist Perspective) . . . . . . . . . . . . . . . . . . . . . . 297 Pavel Goriacko and Keith T. Veltri

12

GI Toxicities from Cancer Therapy . . . . . . . . . . . . . . . . . . . . 341 Amanda J. Podolski and Rasim Gucalp

13

Drug–Nutrient Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . 381 Srinivas Guptha Gunturu and T. S. Dharmarajan

Part IV

Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409

14

Anorexia, Appetite, Hunger, and Satiety in Older Adults . . . 411 C. S. Pitchumoni and Rahul Chaudhari

15

Geriatric Nutritional Assessment and Treatment Frameworks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439 Kumar Dharmarajan

16

Tube Feeding: Techniques and Procedure . . . . . . . . . . . . . . . 459 Amit Sohagia and Hilary Hertan

17

Enteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473 Maanit Kohli, Allen Andrade, and T. S. Dharmarajan

18

Percutaneous Endoscopic Gastrostomy in Dementia: Expectations, Outcomes, and Ethical Aspects . . . . . . . . . . . . 495 T. S. Dharmarajan, Krishna P. Aparanji, and C. S. Pitchumoni

19

Perioperative Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521 Nanakram Agarwal

20

Nil Per OS (NPO) Prior to Endoscopy or Surgery C. S. Pitchumoni and Cynthia L. Vuittonet

21

Water, Potassium, Sodium, and Chloride in Nutrition . . . . . 539 Kumar Dharmarajan

22

Intravenous Fluid Administration . . . . . . . . . . . . . . . . . . . . . 555 Eugene C. Corbett Jr and T. S. Dharmarajan

23

Water Soluble Vitamins: B1, B2, B3, and B6 . . . . . . . . . . . . . 569 Lauren Cornell and Kellie Arita

24

B12 and Folic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597 T. S. Dharmarajan and Srinivas Guptha Gunturu

25

Fat-Soluble Vitamins: A, E, and K . . . . . . . . . . . . . . . . . . . . . 631 Lauren Cornell, Kellie Arita, and Rebecca Goodrich

26

Vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653 T. S. Dharmarajan

. . . . . . . . 533

Contents

xxi

27

Iron-Deficiency Anemia of Gastrointestinal Origin . . . . . . . . 683 T. S. Dharmarajan, D. Lourdusamy, and C. S. Pitchumoni

28

Copper and Zinc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701 Srinivas Guptha Gunturu and T. S. Dharmarajan

29

Magnesium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 717 T. S. Dharmarajan and Srinivas Guptha Gunturu

30

Calcium and Phosphorus . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735 Lindsay Dowhan Hoag and T. S. Dharmarajan

31

Dietary Fiber . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 765 Shreya Narayanan and C. S. Pitchumoni

32

Healthy Diet for Older Adults: A Focus on Mediterranean Diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 781 Carolyn Newberry and Octavia Pickett-Blakely

33

Nutrition Therapy for Intestinal Disorders . . . . . . . . . . . . . . 795 Emily Haller, Kelly Issokson, Jessica Lebovits, and Kate Scarlata

34

Nutrition Therapy for Dysphagia, EoE, Gastroparesis, GERD, and Liver Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . 819 Emily Haller, Lorraine Bonkowski, Courtney Schuchmann, and Bethany Doerfler

35

Obesity in Older Adults: Pathophysiology and Clinical Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 837 Cynthia L. Vuittonet, Avishkar Sbharwal, and C. S. Pitchumoni

36

Malnutrition in Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 857 C. S. Pitchumoni

Volume 2 Part V

Endoscopy

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 877

37

Gastrointestinal Endoscopy: Considerations . . . . . . . . . . . . . 879 Klaus Mönkemüller and Lucia C. Fry

38

Intravenous Sedation for Endoscopy . . . . . . . . . . . . . . . . . . . 909 Eduardo Redondo-Cerezo

39

Gastrointestinal Luminal Stenting . . . . . . . . . . . . . . . . . . . . . 927 Chiranjeevi Gadiparthi and Andrew Korman

40

Role of ERCP in Older Adults . . . . . . . . . . . . . . . . . . . . . . . . 941 Sonmoon Mohapatra and Arkady Broder

41

Wireless Capsule Endoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . 961 Anwar Dudekula and C. S. Pitchumoni

xxii

Contents

Part VI

Imaging

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985 . . . 987

42

Gastrointestinal Radiology: A Case-Based Presentation Judith K. Amorosa and C. S. Pitchumoni

43

Imaging in Clinical Geriatric Gastroenterology . . . . . . . . . . 1017 David Hirschl, Melanie Moses, and Rona Orentlicher

44

Advanced Imaging of Geriatric Gastrointestinal Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1067 Fernanda Samara Mazzariol

Part VII

Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1077

45

Laboratory Testing in Older Adults: Indications, Benefits, and Harms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1079 T. S. Dharmarajan and C. S. Pitchumoni

46

Gastrointestinal Pathology in the Older Adult . . . . . . . . . . . 1099 Noam Harpaz, Mohammad Raoufi, and Hongfa Zhu

Part VIII

Motility Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1125

47

Oropharyngeal Dysphagia . . . . . . . . . . . . . . . . . . . . . . . . . . . 1127 Custon Nyabanga, Abraham Khan, and Rita M. Knotts

48

Gastroparesis in Older Adults . . . . . . . . . . . . . . . . . . . . . . . . 1145 Richard W. McCallum, Ashish Malhotra, Marco A. Bustamante Bernal, and Luis O. Chavez

49

Gastroesophageal Reflux Disease and Complications . . . . . . 1161 Adharsh Ravindran and Prasad G. Iyer

Part IX

Signs and Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1179

50

Abdominal Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1181 C. S. Pitchumoni and T. S. Dharmarajan

51

Functional Abdominal Pain . . . . . . . . . . . . . . . . . . . . . . . . . . 1191 Douglas A. Drossman and Jill K. Deutsch

52

Gas, Belching, Bloating, and Flatulence: Pathogenesis, Evaluation, and Management . . . . . . . . . . . . . . . . . . . . . . . . . 1203 C. S. Pitchumoni, Debra R. Goldstein, and Cynthia L. Vuittonet

53

Constipation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1229 T. S. Dharmarajan, David Widjaja, and C. S. Pitchumoni

54

Chronic Diarrhea in the Older Adult . . . . . . . . . . . . . . . . . . . 1265 Lawrence R. Schiller

Contents

xxiii

55

Upper Gastrointestinal Bleeding . . . . . . . . . . . . . . . . . . . . . . . 1289 Nicholas J. Costable and David A. Greenwald

56

Lower Gastrointestinal Bleeding . . . . . . . . . . . . . . . . . . . . . . 1305 Edward Sheen, Jennifer Pan, Andrew Ho, and George Triadafilopoulos

Part X

Hepatobiliary System and Pancreas . . . . . . . . . . . . . . . . . . . 1327

57

Aging Liver and Interpretation of Liver Tests . . . . . . . . . . . . 1329 Ritu Agarwal

58

Viral Liver Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1353 Satheesh Nair and Rajanshu Verma

59

Tumors of the Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1367 Mumtaz Niazi, Pratik A. Shukla, and Nikolaos Pyrsopoulos

60

Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH) . . . . . . . . . . . . . . . . . . . 1381 Steven Krawitz and Nikolaos Pyrsopoulos

61

Drug-Induced Liver Injury in Older Adults . . . . . . . . . . . . . 1391 Ethan D. Miller, Hamzah Abu-Sbeih, and Naga P. Chalasani

62

Gallstones and Benign Gallbladder Disease . . . . . . . . . . . . . . 1407 C. S. Pitchumoni and Nishal Ravindran

63

Biliary Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1437 C. S. Pitchumoni and Nishal Ravindran

64

Acute Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1449 C. S. Pitchumoni

65

Chronic Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1483 Sonmoon Mohapatra, Gaurav Aggarwal, and Suresh T. Chari

66

Autoimmune Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1499 Sajan Nagpal

Volume 3 Part XI

Luminal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1515

67

Oral Health in Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . 1517 Mary S. Haumschild, Barbara Hammaker, Ileana Pino, Katherine Woods, and Nicolle Dickey

68

Gut Microbiota and Aging: A Broad Perspective . . . . . . . . . 1543 C. S. Pitchumoni, Sidharth P. Mishra, and Hariom Yadav

69

Peptic Ulcer Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1565 David Y. Graham and Natalia Khalaf

xxiv

Contents

70

Celiac Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1597 C. S. Pitchumoni

71

Small Intestinal Bacterial Overgrowth Syndrome . . . . . . . . . 1617 T. S. Dharmarajan and C. S. Pitchumoni

72

Irritable Bowel Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1645 Eamonn M. M. Quigley and Vineet Gudsoorkar

73

Gastrointestinal Infections Marnie E. Rosenthal

74

Challenges in the Management of Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1675 Seymour Katz and Yingheng Liu

75

Non-IBD and Noninfectious Colitis . . . . . . . . . . . . . . . . . . . . 1691 Chung Sang Tse, Abbas Rupawala, Osman Yilmaz, and Samir A. Shah

76

Clostridium (Now Clostridioides) difficile-Associated Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1713 R. Ann Hays and Christina Surawicz

77

Diverticular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1733 C. S. Pitchumoni

78

Acute Colonic Pseudo-Obstruction . . . . . . . . . . . . . . . . . . . . . 1753 David Widjaja and T. S. Dharmarajan

79

Fecal Incontinence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1765 Sanjiv K. Patankar and Negar M. Salehomoum

80

Rectal Prolapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1781 Rodolfo Pigalarga and Sanjiv K. Patankar

81

Anorectal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1795 Frederick B. Peng and Waqar Qureshi

Part XII

. . . . . . . . . . . . . . . . . . . . . . . . . . . 1655

Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1811

82

Esophageal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1813 Jennifer Chuy and Noah Kornblum

83

Gastric Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1829 Mohandas K. Mallath

84

Gastric Tumors (Other than Adenocarcinoma) . . . . . . . . . . . 1881 C. S. Pitchumoni, Abhijeet Chaubal, and Gopal Desai

85

Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1903 Suresh T. Chari, Dhruv P. Singh, Gaurav Aggarwal, and Gloria Petersen

86

Cystic Lesions of the Pancreas . . . . . . . . . . . . . . . . . . . . . . . . 1917 Jaime de la Fuente and Shounak Majumder

Contents

xxv

87

Pancreatic Neuroendocrine Tumors . . . . . . . . . . . . . . . . . . . . 1933 Thiruvengadam Muniraj and Harry R. Aslanian

88

Colorectal Cancer Screening . . . . . . . . . . . . . . . . . . . . . . . . . . 1953 Charles J. Kahi and Douglas K. Rex

89

Colorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1963 C. S. Pitchumoni

90

Chemoradiotherapy for Gastrointestinal Malignancies . . . . 1991 Jonathan B. Wallach and Michael J. Nissenblatt

Part XIII

Vascular Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2005

91

Intestinal Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2007 C. S. Pitchumoni

92

Abdominal Aortic Aneurysm . . . . . . . . . . . . . . . . . . . . . . . . . 2029 T. S. Dharmarajan and Nilesh N. Balar

Part XIV 93

Palliative Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2045

Palliative Gastroenterology . . . . . . . . . . . . . . . . . . . . . . . . . . . 2047 Geoffrey P. Dunn

Part XV

Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2059

94

Bariatric Surgery in Older Adults . . . . . . . . . . . . . . . . . . . . . 2061 Salvatore Giordano, Carlo M. Oranges, Mario Cherubino, and Pietro G. di Summa

95

Surgical Abdomen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2079 Carlos A. Pelaez and Nanakram Agarwal

96

Colostomy and Ileostomy Care . . . . . . . . . . . . . . . . . . . . . . . . 2103 Juan J. Omana and Nanakram Agarwal

Part XVI Systems Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2115 97

Gastrointestinal Manifestations of Non-GI Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2117 Sangeetha Pabolu, Anwar Dudekula, and C. S. Pitchumoni

98

Gastrointestinal Manifestations of Endocrine Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2167 Naushira Pandya and Elizabeth Hames

99

Rheumatological Manifestations of GI Disorders . . . . . . . . . 2183 Mandakolathur R. Murali

100

Gastrointestinal Disorders in Long-Term Care . . . . . . . . . . . 2201 Roy J. Goldberg and Mahesh Jhurani

xxvi

Contents

101

Mucocutaneous Manifestations in Gastrointestinal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2219 Robert A. Norman, Trupal Patel, and Tam H. Nguyen

102

Atlas of Dermatological Manifestations in Gastrointestinal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2249 Holly Kanavy, Steven R. Cohen, and Alana Deutsch

103

HIV in Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2277 C. S. Pitchumoni and Mitesh A. Desai

104

Gastrointestinal Manifestations of COVID-19 . . . . . . . . . . . . 2299 Joseph J. Alukal and Paul J. Thuluvath

105

Psychiatric Issues in Older Adults with Gastrointestinal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2313 Rafael Gonzalez Alonso, Maria Fernanda Gomez, and Mary Alice O’Dowd

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2333

About the Editors

C. S. Pitchumoni MD, MPH, MACP, MACG, FRCPC, FRCPE, AGAF Clinical Professor of Medicine, Robert Wood Johnson School of Medicine Rutgers University, New Brunswick, NJ, USA Adjunct Professor, New York Medical College, Valhalla, New York, USA Emeritus Chief of the Division of Gastroenterology, Hepatology and Clinical Nutrition Saint Peters University Hospital, New Brunswick, NJ, USA Professor C.S. Pitchumoni is an acclaimed author, a dedicated teacher, a well-published researcher, and an editor of several popular books and prestigious journals in the field of clinical gastroenterology. For his many academic contributions spanning more than five decades at New York Medical College, Robert Wood Johnson School of Medicine, and Drexel University, Dr. Pitchumoni has the rare distinction of being recognized as a master of two leading professional organizations, the American College of Physicians as well as the American College of Gastroenterology. Medical students and residents in internal medicine and fellows in gastroenterology look up to Dr. Pitchumoni, or “Pitch,” as they affectionately call him, fondly remember his guidance during the period of training and beyond for many decades. His mentors in gastroenterology at Yale and New York Medical College, Dr. Howard Spiro, Dr. Martin H Floch, and Dr. Gerzy B Glass, inculcated in him the value of hard work and readiness to share knowledge. Following his role models, he has no desire to retire from teaching and writing. True to his learning, Dr. Pitchumoni xxvii

xxviii

About the Editors

shares his knowledge and experience and continues to teach and help many students worldwide despite the COVID-19 pandemic restrictions. Dr. Pitchumoni’s publication of over 250 articles in major peer-reviewed journals and more than 100 chapters in the reputable textbooks are in addition to 7 edited books. A long period of six decades in academic medicine, Dr. Pitchumoni considers, is a boon to satisfy his desire to learn and teach. The return is his vast knowledge of internal medicine and gastroenterology. Dr. Pitchumoni has received various awards and recognitions. The one award that he takes pride in is the recognition by students of Drexel University with the covetable Blockley-Osler award for excellence in teaching clinical medicine at bed side in the tradition of Sir William Osler. The Royal Colleges of Physicians of Ottawa, Canada, and the Royal College of Physicians of Edinburgh have honored Dr. Pichumoni as a fellow of the respective colleges. Dr. Pitchumoni is board certified in internal medicine, gastroenterology, and clinical nutrition. The MPH qualification from New York Medical College substantially expands his broad knowledge in clinical medicine, clinical epidemiology, and research methods. With his professional experience at senior levels in teaching and administration for over 50 years, he is currently the emeritus chief of gastroenterology, hepatology, and clinical nutrition at Saint Peters University Hospital, Robert Wood Johnson School of Medicine; emeritus chairman of medicine at Our Lady of Mercy Medical Center of New York Medical College; adjunct Professor of medicine at New York Medical College; and clinical Professor of medicine at Rutgers University. The initial publications that brought him to the academic forefront were focused on pancreatology; his pioneering work in the field is well quoted in the literature. However, his passion was to be a general gastroenterologist, he expanded his interests to cover nutrition and geriatrics. The desire to emphasize the older adults’ unique needs encouraged Dr. Pitchumoni to work closely with Professor Dharmarajan, a longtime professional colleague with a similar background and professional

About the Editors

xxix

achievements. Both the editors, one with tremendous experience in the science of geriatrics and the other an experienced clinical gastroenterologist, perceived the need for a comprehensive book in geriatric gastroenterology. The success of the first edition of Geriatric Gastroenterology by Springer, which was released in 2012, prompted the authors to expand the book with many more chapters in the second edition. The editors expect the same enthusiastic reception for the second edition.

T. S. Dharmarajan MD, MACP, AGSF, FRCPE Vice Chairman, Department of Medicine Clinical Director, Division of Geriatrics Program Director, Geriatric Medicine Fellowship Program Montefiore Medical Center, Wakefield Campus, Bronx, NY, USA Professor of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA Adjunct Professor of Medicine, New York Medical College, Valhalla, NY, USA T. S. Dharmarajan, MD, is vice chairman, Department of Medicine; clinical director, Division of Geriatrics; and program director of the geriatric medicine fellowship program at Montefiore Medical Center (Wakefield Campus) Bronx, a University Hospital of Albert Einstein College of Medicine (AECOM), Bronx, New York. He is a Professor of medicine, AECOM, and adjunct Professor of medicine at New York Medical College. He was formerly Professor of medicine and Associate Dean of New York Medical College, Valhalla, New York, and chairman of the Department of Medicine at Our Lady of Mercy Medical Center, until its transition to Montefiore Medical Center. Dr. Dharmarajan is certified by the American Boards in Internal Medicine, Nephrology and Geriatric Medicine. He is a fellow of the American Geriatrics Society (AGSF), Master of the American College of Physicians (MACP), and fellow of Royal College of Physicians, Edinburgh (FRCPE).

xxx

About the Editors

Dr. Dharmarajan was instrumental in developing a reputable inpatient geriatric medicine program at Our Lady of Mercy Medical Center in the Bronx (currently Montefiore Medical Center), with clinical, academic, and research components, including a fully accredited fellowship program (for 10 fellows) in geriatrics. Dr. Dharmarajan co-edited the textbook Clinical Geriatrics (CRC Press/Parthenon Publishing) released in 2003. His second textbook, Geriatric Gastroenterology (Springer), co-edited with CS Pitchumoni, was released in July 2012. Dr. Dharmarajan authored several chapters in the two books. The latter was a best seller in the Springer category of textbooks. Based on its success, he co-edited Geriatric Gastroenterology, a Major Reference Work (Springer), a far more comprehensive work. His publications in peerreviewed journals and textbooks number around 200. He has over 500 scientific presentations (abstracts) in county, state, national, and international conferences. He has been a principal investigator for several research projects, including national multicenter studies for the AMDA Foundation. He won the Howard Gutterman Award for best research project in the National Annual AMDA (2006) meeting; several of his abstracts were winners in county, state, or national society meetings. At Montefiore, he received the first prize for best clinical science paper published in 2016 and the second prize in 2019. He received a Lifetime Achievement Award at New York City in April 2019 and in the same year received Recognition for Leadership and Community Services from Montefiore at the tenth anniversary celebrations. Dr. Dharmarajan is a regular speaker at local, national, and international conferences. Some of his many recognitions in medicine include: Teacher of the Year; Peer to Peer recognition by the Bronx County Society; Dedication as Teacher and Mentor to young Physicians in the Bronx (from American Assn. of Physicians of Indian origin); and Unparalleled Leadership in the Medical Community for medicine and research (from the Bronx County Society). In 2013, he was featured on the cover of AgingWell magazine, as one of five noteworthy geriatricians.

About the Editors

xxxi

Dr. Dharmarajan was the president of the Montefiore Physician Council, Wakefield Campus, for 5 years until 2015; he was a member of the board of trustees at Our Lady of Mercy Medical Center. For much of his professional career, Dr. Dharmarajan has been fortunate to be associated with a renowned colleague and master teacher, Professor CS Pitchumoni. During the period that spanned decades, the two initially published a series of articles in the field of geriatric gastroenterology, which caught Springer’s attention, and became the foundation for the first edition of Geriatric Gastroenterology. The huge success of the first edition laid the platform for the more comprehensive second edition of Geriatric Gastroenterology, the current Major Reference Work.

Contributors

Hamzah Abu-Sbeih Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Ritu Agarwal Division of Liver Diseases, The Mount Sinai Hospital, Icahn School of Medicine, New York, NY, USA Nanakram Agarwal New York Medical College, Valhalla, NY, USA Montefiore Medical Center, Bronx, NY, USA Gaurav Aggarwal GA Bellevue Medical Center, Bellevue, WA, USA Division of Epidemiology, Mayo Clinic, Rochester, MN, USA Joseph J. Alukal Mercy Medical Center, Institute of Digestive Health and Liver Diseases, Baltimore, MD, USA Judith K. Amorosa Robert Wood Johnson School of Medicine, Rutgers University, New Brunswick, NJ, USA Faculty Development and Academic Affairs, Department of Radiology, RUTGERS Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA University Radiology Group, East Brunswick, NJ, USA Allen Andrade Brookdale Department of Geriatrics and Palliative Care, Icahn School of Medicine at Mount Sinai, New York, NY, USA Krishna P. Aparanji Department of Critical Care Medicine, Springfield Clinic, Springfield, IL, USA Southern Illinois University School of Medicine, Springfield, IL, USA Kellie Arita Lauren Cornell Nutrition, Inc., Los Angeles, CA, USA Harry R. Aslanian Yale University School of Medicine, New Haven, CT, USA Nilesh N. Balar New York Medical College, Valhalla, NY, USA Department of Surgery, St. Michael’s Medical Center, Newark, NJ, USA xxxiii

xxxiv

Lorraine Bonkowski Adult Liver Transplant/Hepatology Clinic, Michigan Medicine, Ann Arbor, MI, USA Arkady Broder Division of Gastroenterology and Hepatology, Saint Peter’s University Hospital – Rutgers Robert Wood Johnson School of Medicine, New Brunswick, NJ, USA Marco A. Bustamante Bernal Department of Internal Medicine, Texas Tech University Health Science Center, El Paso, TX, USA Department of Internal Medicine, Division of Gastroenterology, Texas Tech University Health Science Center, El Paso, TX, USA Naga P. Chalasani Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA Suresh T. Chari Department of Gastroenterology, Hepatology and Nutrition, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Abhijeet Chaubal Department of Anatomic Pathology, Saint Peters University Hospital, New Brunswick, NJ, USA Rahul Chaudhari University of Pennsylvania Health System, Philadelphia, PA, USA Luis O. Chavez Department of Internal Medicine, Texas Tech University Health Science Center, El Paso, TX, USA Mario Cherubino Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy Jennifer Chuy Department of Medical Oncology, Montefiore Medical Center, Bronx, NY, USA Steven R. Cohen Department of Medicine, Division of Dermatology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA Elise Marie Collins Chakra Tonics Inc., San Francisco, CA, USA Eugene C. Corbett Jr Division of General Medicine, Geriatrics and Palliative Care, University of Virginia Health Science Center, Charlottesville, VA, USA Lauren Cornell Lauren Cornell Nutrition, Inc., Los Angeles, CA, USA Nicholas J. Costable Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA Jaime de la Fuente Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Sciences, Rochester, MN, USA Gopal Desai Department of Radiation Oncology, Saint Peters University Hospital, New Brunswick, NJ, USA

Contributors

Contributors

xxxv

Mitesh A. Desai Centers for Disease Control and Prevention, Atlanta, GA, USA Alana Deutsch Department of Medicine, Division of Dermatology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA Jill K. Deutsch Section of Digestive Diseases – Department of Internal Medicine, Yale University School of Medicine – Yale New Haven Hospital, New Haven, CT, USA Kumar Dharmarajan Clover Health, Jersey City, NJ, USA Yale School of Medicine, New Haven, CT, USA T. S. Dharmarajan Department of Medicine, Division of Geriatrics, Montefiore Medical Center, Wakefield Campus, Bronx, NY, USA Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA Department of Medicine, New York Medical College, Valhalla, NY, USA Nicolle Dickey Boise State University, Boise, ID, USA Pietro G. di Summa Department of Surgery, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland Bethany Doerfler Northwestern Medicine, Division of Gastroenterology and Hepatology, Digestive Health Center, Chicago, IL, USA Lindsay Dowhan Hoag Cleveland Clinic, Center for Gut Rehabilitation and Transplantation, Cleveland, OH, USA Douglas A. Drossman Division of Gastroenterology and Hepatology, University of North Carolina, Center for Education and Practice of Biopsychosocial Care and Drossman Gastroenterology PLLC, Chapel Hill, NC, USA Anwar Dudekula Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Peter’s University Hospital/Rutgers-RWJ Medical School, New Brunswick, NJ, USA Geoffrey P. Dunn Depaertment of Surgery, UPMC Hamot, Erie, PA, USA Lucia C. Fry Department of Gastroenterology, Helios Frankenwaldklinik, Kronach, Germany Department of Geriatrics, Helios Frankenwaldklinik, Kronach, Germany Chiranjeevi Gadiparthi Division of Gastroenterology and Hepatology, Saint Peter’s University Hospital, New Brunswick, NJ, USA Salvatore Giordano Department of Surgery, Vaasa Central Hospital, and University of Turku, Turku, Finland

Geoffrey P. Dunn has retired.

xxxvi

Roy J. Goldberg Division of Geriatrics, Albert Einstein College of Medicine, Bronx, NY, USA Kings Harbor Multicare Center, Bronx, NY, USA Debra R. Goldstein Department of Gastroenterology, Saint Peters University Hospital, New Brunswick, NJ, USA Rutgers University School of Medicine, New Brunswick, NJ, USA Maria Fernanda Gomez Department of Psychiatry and Behavioral Sciences, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA Rafael Gonzalez Alonso Department of Psychiatry and Behavioral Sciences, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA Rebecca Goodrich DaVita Kidney Care, Santa Monica, CA, USA Pavel Goriacko Center for Pharmacotherapy Research and Quality, Department of Pharmacy, Montefiore Medical Center, Bronx, NY, USA David Y. Graham Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, and Baylor College of Medicine, Houston, TX, USA David A. Greenwald Department of Internal Medicine, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Julia B. Greer Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Rasim Gucalp Department of Medical Oncology, Montefiore Medical Center, Bronx, NY, USA Vineet Gudsoorkar Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Houston, TX, USA Srinivas Guptha Gunturu Advanced Endoscopy, Gastroenterology, Phoebe-Putney Memorial Health System, Albany, GA, USA Emily Haller Division of Gastroenterology and Hepatology, Michigan Medicine, Ann Arbor, MI, USA Elizabeth Hames Kiran Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, USA Barbara Hammaker Department of Dental Hygiene, Broward College, Davie, FL, USA Noam Harpaz Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Contributors

Contributors

xxxvii

Mary S. Haumschild St. Petersburg College, St. Petersburg, Florida, USA Bachelors Health Services Administration, State College of Florida, Bradenton, FL, USA R. Ann Hays Division of Gastroenterology, University of Virginia, Charlottesville, VA, USA Hilary Hertan Montefiore Medical Center-Wakefield Campus, The Bronx, NY, USA T. Patrick Hill Edward J. Bloustein School of Planning and Public Policy, Rutgers University, New Brunswick, NJ, USA David Hirschl Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA Andrew Ho Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA Division of Gastroenterology and Hepatology, Santa Clara Valley Medical Center, San Jose, CA, USA Lisa C. Hutchison College of Pharmacy and College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA Kelly Issokson Cedars-Sinai, Digestive Diseases Center, Los Angeles, CA, USA Prasad G. Iyer Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA Vishal Jain Coastal Gastroenterology Associates, Brick, NJ, USA Mahesh Jhurani Kings Harbor Multicare Center, Bronx, NY, USA Charles J. Kahi Roudebush VA Medical Center, Indiana University School of Medicine, Indianapolis, IN, USA Holly Kanavy Department of Medicine, Division of Dermatology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA Seymour Katz Department of Medicine Gastroenterology Division, New York University School of Medicine, New York, NY, USA Natalia Khalaf Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, and Baylor College of Medicine, Houston, TX, USA Abraham Khan Division of Gastroenterology. Department of Medicine, NYU Langone Health, NYU School of Medicine, New York, NY, USA Rita M. Knotts Division of Gastroenterology. Department of Medicine, NYU Langone Health, NYU School of Medicine, New York, NY, USA

xxxviii

Maanit Kohli Division of Hospital Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA Andrew Korman Division of Gastroenterology and Hepatology, Saint Peter’s University Hospital, New Brunswick, NJ, USA Noah Kornblum Department of Medical Oncology, Montefiore Medical Center, Bronx, NY, USA Steven Krawitz VA New Jersey Health Care System, East Orange VA Medical Center, East Orange, NJ, USA Jessica Lebovits Irving Medical Center, Columbia University, New York, NY, USA Yingheng Liu Department of Medicine, Division of Gastroenterology and Hepatology, Mount Sinai Beth Israel, New York, NY, USA D. Lourdusamy Geriatrics, Montefiore Medical Center, Bronx, NY, USA Jorge D. Machicado Division of Gastroenterology and Hepatology, Mayo Clinic Health System, Eau Claire, WI, USA Shounak Majumder Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Sciences, Rochester, MN, USA Ashish Malhotra Department of Gastroenterology and Hepatology, Seton Hall University of Health and Medical Sciences, Paterson, NJ, USA Mohandas K. Mallath Department of Digestive Diseases, Tata Medical Center, Kolkata, India Fernanda Samara Mazzariol Radiology, New York Presbyterian Hospital/ Weill Cornell Medicine, New York, NY, USA Richard W. McCallum Department of Internal Medicine, Texas Tech University Health Science Center, El Paso, TX, USA Department of Internal Medicine, Division of Gastroenterology, Texas Tech University Health Science Center, El Paso, TX, USA Ethan D. Miller Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Sidharth P. Mishra Department of Internal Medicine- Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA Sonmoon Mohapatra Division of Gastroenterology and Hepatology, Saint Peter’s University Hospital – Rutgers Robert Wood Johnson School of Medicine, New Brunswick, NJ, USA Klaus Mönkemüller Department of Gastroenterology, Helios Frankenwaldklinik, Kronach, Germany Otto-von-Guericke University, Magdeburg, Germany University of Belgrade, Belgrade, Serbia

Contributors

Contributors

xxxix

Melanie Moses Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA Thiruvengadam Muniraj Yale University School of Medicine, New Haven, CT, USA Mandakolathur R. Murali Division of Rheumatology, Allergy and Clinical Immunology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Sajan Nagpal University of Chicago, Chicago, IL, USA Murali D. Nair Suzanne Dworak-Peck School of Social work, University of Southern California, Los Angeles, CA, USA Satheesh Nair Medical Director of Liver Transplantation, Endowed Chair of Excellence in Transplant Medicine, University of Tennessee Health Science Center, Memphis, TN, USA Shreya Narayanan Morsani College of Medicine, University of South Florida, Tampa, FL, USA Carolyn Newberry Innovative Center for Health and Nutrition in Gastroenterology, Weill Cornell Medical Center, New York, NY, USA Tam H. Nguyen Larkin Community Hospital, Miami, FL, USA Mumtaz Niazi Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers University, New Jersey Medical School, Newark, NJ, USA Michael J. Nissenblatt Regional Cancer Care Associates, East Brunswick, NJ, USA Robert A. Norman Center for Geriatric Dermatology, Integrative Dermatology and Neuro-Dermatology, Nova Southeastern University, Tampa, FL, USA Custon Nyabanga Department of Medicine, NYU Langone Health, NYU School of Medicine, New York, NY, USA Mary Alice O’Dowd Department of Psychiatry and Behavioral Sciences, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA Juan J. Omana Adventhealth, Kissimmee, FL, USA Carlo M. Oranges Department of Surgery, Geneva University Hospital, Geneva, Switzerland Rona Orentlicher Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA Sangeetha Pabolu Saint Peters University Hospital, New Brunswick, NJ, USA

xl

Jennifer Pan Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Medical Center, Palo Alto, CA, USA Naushira Pandya Kiran Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, USA Sanjiv K. Patankar Colon and Rectal Surgery, Colon and Rectal Surgeons of Central New Jersey, East Brunswick, NJ, USA Trupal Patel American University of Antigua COM MSIV University of Florida, B.S. Biology, Gainesville, FL, USA Carlos A. Pelaez Iowa Methodist Medical Center, Des Moines, IA, USA Carver College of Medicine, University of Iowa, Iowa City, IA, USA Frederick B. Peng Department of Medicine, Baylor College of Medicine, Houston, TX, USA Gloria Petersen Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA Octavia Pickett-Blakely GI Nutrition, Obesity and Celiac Disease Program, University of Pennsylvania Perelman School of Medicine, Perelman Center for Advanced Medicine, Philadelphia, PA, USA Rodolfo Pigalarga GastroHealth, Miami, FL, USA Ileana Pino School of Health Sciences, Miami Dade College Medical Campus, Miami, FL, USA C. S. Pitchumoni Department of Medicine, Robert Wood Johnson School of Medicine, Rutgers University, New Brunswick, NJ, USA Department of Medicine, New York Medical College, Valhalla, NY, USA Division of Gastroenterology, Hepatology and Clinical Nutrition, Saint Peters University Hospital, New Brunswick, NJ, USA Amanda J. Podolski Department of Medical Oncology, Montefiore Medical Center, Bronx, NY, USA Nikolaos Pyrsopoulos Department of Medicine, Division of Gastroenterology and Hepatology, Physiology, Pharmacology and Neuroscience, Medical Director Liver Transplantation, Rutgers – New Jersey Medical School, University Hospital, Newark, NJ, USA Eamonn M. M. Quigley Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Houston, TX, USA Waqar Qureshi Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA

Contributors

Contributors

xli

Mohammad Raoufi Department of Pathology and Laboratory Medicine, Henry Ford Health System, Detroit, MI, USA Adharsh Ravindran Department of Internal Medicine, University at Buffalo, Buffalo, NY, USA Nishal Ravindran Robert Wood Johnson School of Medicine, Rutgers University, New Brunswick, NJ, USA Saint Peters University Hospital, New Brunswick, NJ, USA Eduardo Redondo-Cerezo Endoscopy Unit. Gastroenterology Department, ‘Virgen de las Nieves’ University Hospital, Granada, Spain Douglas K. Rex Indiana University School of Medicine, Indianapolis, IN, USA Marnie E. Rosenthal Department of Medicine, St. Peter’s University Hospital and Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA Abbas Rupawala Alpert Medical School of Brown University, Providence, RI, USA Negar M. Salehomoum Department of Surgery, John Muir Medical Center, Walnut Creek, CA, USA Avishkar Sbharwal Hackensack University Medical Center, Hackensack, NJ, USA Kate Scarlata For a Digestive Peace of Mind, LLC., Medway, MA, USA Lawrence R. Schiller Baylor University Medical Center, Dallas, TX, USA Texas A&M College of Medicine, Dallas Campus, Dallas, TX, USA Courtney Schuchmann Section of Gastroenterology, Hepatology and Nutrition, University of Chicago Medicine, Chicago, IL, USA Samir A. Shah Alpert Medical School of Brown University, Providence, RI, USA Gastroenterology Associates Inc, The Miriam Hospital, Providence, RI, USA Edward Sheen Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA Pratik A. Shukla Department of Radiology, Division of Interventional Radiology, Rutgers University, New Jersey Medical School, Newark, NJ, USA Dhruv P. Singh Department of Gastroenterology, Mayo Clinic, Rochester, MN, USA Amit Sohagia Twin River Gastroenterology Center, Easton, PA, USA Christina Surawicz Division of Gastroenterology, University of Washington, Seattle, WA, USA

xlii

Paul J. Thuluvath Mercy Medical Center, Institute of Digestive Health and Liver Diseases, Baltimore, MD, USA Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA George Triadafilopoulos Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA Chung Sang Tse Alpert Medical School of Brown University, Providence, RI, USA Keith T. Veltri Touro College of Pharmacy, New York, NY, USA Montefiore Medical Center, Bronx, NY, USA Rajanshu Verma Division of Transplant Hepatology, University of Tennessee Health Science Center, Memphis, TN, USA Cynthia L. Vuittonet Director of Addiction Medicine, Jewish Renaissance Medical Center, Perth Amboy, NJ, USA Jonathan B. Wallach Department of Radiation Oncology, Saint Peter’s University Hospital, New Brunswick, NJ, USA David Widjaja Bogor Senior Hospital, Bogor, Indonesia Katherine Woods St. Petersburg College, Pinellas Park, FL, USA Dhiraj Yadav Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Hariom Yadav Department of Internal Medicine- Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA Osman Yilmaz Alpert Medical School of Brown University, Providence, RI, USA Hongfa Zhu Hackensack Pathology Associates, Hackensack University Medical Center, Hackensack, NJ, USA

Contributors

Part I Perspectives and Trends

1

Geriatric Gastroenterology: A Geriatrician’s Perspective T. S. Dharmarajan

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4

Terminology: Older Adult, Elderly, Senior, or Geriatric Person? . . . . . . . . . . . . . . . . . .

5

The Black Swan: An Interesting Theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5

An Aging Society: The Era of Centenarians and Supercentenarians . . . . . . . . . . . . . . .

5

Living Longer and Healthy: Biological and Chronological Aging . . . . . . . . . . . . . . . . . .

7

Aging Statistics: Life Expectancy, Morbidity, and Mortality . . . . . . . . . . . . . . . . . . . . . . . .

7

Aging Associations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 How Does the Geriatric Individual Differ? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Gastrointestinal Disorders in Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Abstract

Aging trends in the United States and worldwide suggest an increasingly aging population, characterized by a longer life expectancy.

T. S. Dharmarajan (*) Department of Medicine, Division of Geriatrics, Montefiore Medical Center, Wakefield Campus, Bronx, NY, USA Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA Department of Medicine, New York Medical College, Valhalla, NY, USA e-mail: [email protected]

Many live on to be nonagenarians, and some reach the stage of centenarians, with a few luckiest living to be supercentenarians. Older people are working longer, fulfilling societal demands. But alongside, they also manifest a significant decline in their functional status and cognitive function, along with a whole range of complex comorbid disorders. Frailty and care dependency are common in the old. Biological age poorly matches chronological age and deserves far more consideration. The ultimate goals while caring for older adults are to restore functional status where possible, understand risks and benefits of invasive and noninvasive management, adhere to the patient’s expressed

© Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_1

3

4

T. S. Dharmarajan

wishes and advance directives, and keep quality of life foremost in mind. The chapter provides data on life expectancy and other demographics, comorbid disorders and functional limitations in aging people, lifestyles, and causes of mortality. Bearing in mind this background, specialists, including gastroenterologists, must adopt an approach that differs significantly from that used for younger individuals. Considerations must include life expectancy, comorbid and functional status, decision-making capacity, patient’s current wishes or prior expressed directives as part of advance care planning, and ethical aspects; some or all of them may factor in decisionmaking for a diagnostic procedure and medical and surgical management. Keywords

Centenarians · Supercentenarians · Functional status · Physiological age · Chronological age · Gastrointestinal (GI) illness in older adults · Gastrointestinal disorders in older adults · Communication between primary physician and specialist · Communication between geriatrician and gastroenterologist · Geriatric gastroenterology and the future · Physiology versus pathology · Chronological versus physiological age · Aging statistics · Causes of mortality in older people · Life expectancy · Comorbidity in older people · Older adults · Elderly · Elder individuals · Older person · Senior · Elder · Demographics · Lifestyles · Dietary trends · Chronic health conditions in older people · Functional limitations · Features of older people · Characteristics of older individuals · Unique features of older people

Introduction Society is witnessing a remarkable increase in life expectancy resulting in an aging population in the United States and worldwide. The welcome change is largely a result of better health care with resultant delay in functional decline, in conjunction with a decrease in lethal disorders such as heart disease, cancer, and stroke (Evert

et al. 2003). Accordingly, providers now require a reasonable background knowledge in essential geriatric medicine to cope with the health problems of older patients. Gastrointestinal disorders are common in the geriatric age group, with the typical older adult manifesting additional other chronic disorders. Yet, the specialty of geriatric medicine, devoted to care of older people, is itself a young one and still evolving (Forciea 2014). The world is rapidly changing. According to the World Health Organization (WHO), between 2015 and 2050, the world’s population of 60+-year-old adults will double from 12% to 22%; around the year 2020, older people will outnumber children below 5 years. The pace of population aging is much faster than in earlier years. Health and social systems are ill prepared to meet the challenges. Although genes may play a role, the WHO believes that physical and social environments and personal characteristics, including socioeconomic status, play roles accounting for change (World Health Organization 2018a). Table 1 provides a selection of countries across the world and their demographics relevant to the 65 years and older people (Federal Interagency Forum on Aging-Related Statistics 2016). Despite the slow but obviously definite aging population trends and the available data on associated morbidity and mortality, countries have been ill prepared to meet the challenges socially and medically. Geriatricians are skilled in comprehensive assessment including the recognition of atypical presentations, complex morbidity, functional Table 1 Older people worldwide (Centenarian 2020) Number of people worldwide 65 years and older: a selection of countries (2015) 65 years and 65 years and over Country over (%) Japan 33,750 26.6 Germany 17,346 21.5 Italy 13,110 21.2 Greece 2204 20.5 Sweden 1959 20.0 United 47,830 14.9 States China 136,890 10.0

1

Geriatric Gastroenterology: A Geriatrician’s Perspective

assessment, medication management, communication, and ability to lead interdisciplinary teams; however, they are in significant shortage. The ramifications are many and solutions are few for most nations; proposals for enhanced training in geriatrics at medical school level and improvement in curriculum are lagging behind, although the skills are badly needed (Lester et al. 2019).

Terminology: Older Adult, Elderly, Senior, or Geriatric Person? There has been much debate on usage of the appropriate terminology to define older people. An article on “terms to reference aging” states that the English language “seems to lack appropriate positive terminology to reference aging” and further adds that “elderly” connotes frailty. Apparently in Canada, the word senior indicates one who is 65 years or older; even the term “older adult” was not deemed ideal. The terminology to fragment aging suggests categories: younger old for 65– 74 years, old for 75–84 years, and oldest old for 85 years and over (Taylor 2011). The terms “senile, demented, and aged” were used in the past and have been termed unfortunate; the term “elderly” if used for both a robust person and a frail individual does not aptly describe either; it is also considered ageist, a form of prejudice (Avers et al. 2011). The same authors suggest in their paper that the United Nations committee rejected the term “elderly” for the term “older persons” and that older adults dislike the term “elderly” when applied to them. The suggestion was to use the term older adult or older person (Avers et al. 2011). It appears that older people who use a significant share of health services have signaled their wishes to be addressed respectfully; a European survey suggested a preference for “older” or “senior” and found the terms “elderly” and “aged” especially unacceptable; apparently, the Human Rights Commission of the United Nations echoed these sentiments (Falconer and O’Neill 2007). A recent publication in AARP suggests it is time to stop using the term “senior citizen” (Burke 2019). Ultimately, when dealing with older adults, as stated by an author, “language matters.” The American Geriatrics Society and

5

other organizations explored the matter and as to how this can change, essentially, “reframing aging.” The article states that certain terms may “not go well with the public and may do more harm than good” (Warshaw and Lundebjerg 2017). In this work on geriatric gastroenterology, the author’s preferences to describe older people have varied substantially; the editors have attempted to use the term “older adults or people” as much as applicable and minimized the use of other terms. However, as may be expected, the terminology is not standard for range of chapters in the work.

The Black Swan: An Interesting Theory The term “Black Swan” is an old English belief that such a swan could not have existed. Eventually as black swans became recognized and were known to exist, the term was used to suggest that even the “impossible can happen,” as described eloquently in a book which uses the term for rare, hard-topredict events (Taleb 2007). The Black Swan theory was extrapolated to humans, in that it was hard to predict that people could live on the age of 100 or even 110 years. But it now appears feasible that people can commonly live to be centenarians and less commonly to be supercentenarians. In accordance with the Black Swan theory, we know that rare and poorly anticipated events can occur and have happened with aging. But along with the successful aging to the stage of centenarians and supercentenarians, society may not have anticipated the emergence of socioeconomic, medical (including gastrointestinal), and surgical disorders in these individuals (Vacante et al. 2012).

An Aging Society: The Era of Centenarians and Supercentenarians A centenarian is one who has lived to 100 years, while supercentenarians have reached the age of 100 years. One in 1000 centenarians lives to 110; ever rarer is for a person to live to 115 years, with about 100 people recorded to reach the milestone. The United Nations believes there are about 573 centenarians worldwide, with Japan having a

6

large number of them (Centenarian 2020). Upon reaching the milestones, the individual may typically receive a well-deserved congratulatory note from the queen, king, president, or head of the nation. Countries with the highest number of centenarians per 100,000 people include Japan, Portugal, South Africa, Italy, Barbados, Spain, Thailand, and France, with Japan leading with 48 centenarians per 100,000 people. The United States and United Kingdom have 22 per 100,000 persons, while countries with the fewest centenarians are South Korea, India, Ireland, Mexico, Peru, Czech Republic, and China, among others (Centenarian 2020). While Japan has the highest number of centenarians per 100,000 people, the United States is the country with the highest number of centenarians. In other words, the United States has the most centenarians overall, but fewer per capita than many countries. By 2050, it is estimated that the world’s centenarian population may top 3.5 million. By 2100, the number of centenarians should reach 25 million; the global number increases more rapidly over time; and ultimately the sex ratio appears to likely decrease from 3.7 to 1 femaleto-male centenarian ratio in 2015 to 1.9 females to 1 male ratio in 2100 (Jean-Marie and Cubaynes 2017). Table 2 provides the number of centenarians per 100,000 people along with the total number for select countries across the globe. The oldest old are among the fastest-growing people, largely possible due to several lifestyle

Table 2 Centenarians across the world (Centenarian 2020) Centenarians by country, per 100,000 persons and total Country Centenarians (per Total (in the (estimate year) 100,000 persons) country) China (2011) 3.6 48,921 Japan (2017) 48 67,824 Portugal 38.9 4066 (2015) Spain (2016) 37.5 17,423 United 21.5 13,170 Kingdom (2018) United States 22 72,000 (2015) World (2015) 6.2 451,000

T. S. Dharmarajan

factors, foremost being healthy diets and physical activity, along with the optimal maintenance of cognitive health into late age (Hausman et al. 2011). There appears an association between good nutritional status and better physical and mental status, which promote both longevity and quality of life (Hausman et al. 2011). Japan has been a front-runner of super-aged societies. The percentage of people over 65 years reached 25% in 2013 and will far exceed this number in 2025. To accommodate the medical demands of an aging society, Japan has made remarkable achievements in their health-care system from a cure-seeking medical care approach to a “cure- and support-seeking medical care” focus, with quality of life being maximized for the individual; alongside, an attempt has been made to change from a “hospital-centered medical care” to “community-oriented medical care” system. There is also a call to establish centers of geriatrics and gerontology in each regional block and alter the curriculum in medical schools with regard to geriatrics (Arai et al. 2015). A study of 32 supercentenarians, who are 110 years or older, demonstrated that supercentenarians markedly delay and even escape clinical expression of vascular disease at the end of their lives and are able to function independently with little assistance (Schoenhofen et al. 2006). For one to live up to 110, it appears essential that functional status should be largely preserved and disability delayed till the individual reaches 100 years. In summary, many make it to 100 years, but the jump from 100 to 110 is far more difficult and achieved by very few. The oldest person to meet the Guinness standards was Jeanne Calment, a French woman who died at the age of 122 years in 1997. The current oldest person is currently 117 years old; she is a Japanese woman. This age group would have provided challenges in care to perplexed health-care providers, as most of them would have hardly the opportunity to care for such individuals, although this may change in the future. The author of this chapter had the opportunity to offer care to several centenarians and a near supercentenarian who underwent successful emergency surgery; the patient’s daughter was in the 80s, and the wgranddaughter was close to 60 years (Dharmarajan and Sohagia 2007).

1

Geriatric Gastroenterology: A Geriatrician’s Perspective

Living Longer and Healthy: Biological and Chronological Aging Successful aging is associated with little to no functional decline and comorbid illness. Good health is associated with better quality of life, leave alone longevity. Physiological or biological aging must be distinguished from chronological aging. Chronological age is the actual age of an individual from the time of birth to a specific date and is measured in terms of years, months, and days; it does not change irrespective of lifestyle factors. It is the primary way to define one’s age. On the other hand, biological aging is the end result of several factors that cause damage to the cells or tissues of the body; this aspect of aging goes beyond the time accumulated from the day one is born. Biological age, also known as physiological age, is a sum result of genes, lifestyle, nutrition, disease, and environmental and numerous known and unknown factors. A person with a chronological age of 80 years may have a biological age of 70 (appears younger than 80) or 90 (appears older than 80) (Hamczyk et al. 2020). Aging is hence a somewhat modifiable risk factor for most chronic diseases; various aging interventions and preventive measures have the ability to target aging and lifespan (Gonzalez-Freire et al. 2020). Physical activity involving specific exercises in conjunction with dietary interventions through supplementation of certain nutrients has been credited with shaping the immune system during aging (Weyh et al. 2020). Calorie restriction is a potent modulator of longevity in multiple species, and increasing evidence suggests that calorie restriction without malnutrition lowers risk factors promoting type 2 diabetes, cardiovascular disease, and cancer; accordingly, several dietary approaches are utilized to promote healthy aging (Dorling et al. 2020). And consistent with the thought, the editors of this work have included an entire section on nutrition with several chapters on a range of nutritional approaches in older people. Health-care providers including geriatricians and gastroenterologists caring for older persons will need to make several judgments: whether a patient is in good health and will live long enough

7

to benefit from an intervention and whether the life expectancy is only a few months and a qualifier for hospice or if death is imminent (Coll 2010). Life expectancy is influenced by age, disease, and disability; predicting life expectancy may be often difficult and imprecise. Older adults should be judged by their physiological or biological age rather than the chronological age. Many geriatric patients may benefit from treatments as much as the young, whereas others may require alternative treatment approaches. People in their 90s or older (referred to as the oldest old) may at times be healthier and more robust than some who are 20 years younger (Perls 1995). In summary, the use of biological age, with a determination of functional status, cognition, and social support, enables providers to make more appropriate decisions. The concept of “successful aging” has been used for persons with an excellent genetic background and who lived an exemplary lifestyle (Rowe and Kahn 1987).

Aging Statistics: Life Expectancy, Morbidity, and Mortality How long is one expected to live? Life expectancy refers to the average number of years an individual is expected to live; it is an estimate provided at birth or at any given time of life (age-specific). The number in years varies with race, sex, and country. Interestingly, as a general rule, women have a longer life expectancy than men in most countries. In 2017, the life expectancy at birth in the United States for males was 76.1 years while for females 81.1 years, and the average at birth was 78.6 years. Life expectancy was higher by 3 years for male and female Hispanic populations compared to non-Hispanic white and black populations (Kochanek et al. 2019; Murphy et al. 2018). Also interestingly, life expectancy has kept increasing for the larger part of the past 60 years, although the rate of increase has slowed and actually decreased a little after 2014 (Woolf and Schoomaker 2019). The data on key indicators for older adults in this chapter are provided from the Federal Interagency Forum on Aging-Related Statistics (2016). In the United States, the older population

8

over 65 years grew from 3 million in 1900 to 46 million in 2014; however, the oldest old (those over age 85 years) grew from 100,000 in 1900 to 6 million in 2014. Figure 1 demonstrates past, current, and projected trends over the next few decades. In 2015, older men were more likely to be married than older women; the pattern continued to the oldest old age group, with more men married than not. In effect, older men (compared to women) better benefit from a spousal partner for support (Fig. 2). Poverty decline in older people has been now apparent, a welcome trend. More aged individuals remained in the labor force, after ages 65 and 70 years, including both men and women. Life expectancy varies with race and sex. At birth, the life expectancy for whites is 3.4 years higher than for blacks; at age 65 years, whites are expected to live 1.1 years longer than blacks, but at age 85 years, life expectancy for blacks is higher than for whites, at 6.9 versus 6.5 years. In general, life expectancy for women is longer by about 2.5 years at age 65 and 1.1 years at age

T. S. Dharmarajan

85 years. Life expectancy is influenced by race and sex and can be estimated at any age (Fig. 3). Based on WHO statistics, the top ten global causes of death in 2016 are depicted in Fig. 4. The most common were ischemic heart disease and stroke; dementias were the fifth most common cause. However, in lower-income countries, the most common causes of death were lower respiratory infections and diarrheal diseases, followed by ischemic heart disease (WHO 2018a). The leading cause of death in the United States based on 2017 data suggest that heart disease and cancer are the most common causes of death, followed surprisingly by accidents (unintentional injuries) which were more common than strokes. Table 3 provides the top 15 causes of death in the United States. The trends show the declining death rates for heart disease and stroke due to significant preventive efforts. Of note, gastrointestinal disorders represented by chronic liver disease and cirrhosis are the eleventh most common cause of death; however, importantly, most older people with GI illness are likely to manifest

Fig. 1 People aged over 65 years and over 85 years, with projections (Federal Interagency Forum on Aging-Related Statistics 2016)

1

Geriatric Gastroenterology: A Geriatrician’s Perspective

9

Fig. 2 Marital status of older man and women in the United States (Federal Interagency Forum on Aging-Related Statistics 2016)

Fig. 3 Life expectancy in the United States in older people, by race and gender (Federal Interagency Forum on AgingRelated Statistics 2016)

comorbid disorders included in the top causes of death. Stroke, Alzheimer’s disease, diabetes mellitus, and influenza/pneumonia are common causes of death (Kochanek et al. 2019) (Fig. 5).

Complex comorbidity increases with age. Chronic health conditions reported in people over age 65 years are listed in Fig. 6; heart disease, hypertension, diabetes, cancer, and arthritis are the

10

T. S. Dharmarajan

Top 10 global causes of deaths, 2016 Deaths (millions) 0

2

4

6

8

10

Ischaemic heart disease Stroke Chronic obstructive pulmonary disease Lower respiratory infections Alzheimer disease and other dementias Trachea, bronchus, lung cancers Diabetes mellitus Road injury Diarrhoeal disease

Cause Group Communicable, matemal, neonatal and nutritional conditions Noncommunicable diseases Injuries

Tuberculosis Source: Global Health Estimates 2016: Deaths by Cause, Age, Sex, by Country and by Region, 2000-2016. Geneva, World Health Organization; 2018

Fig. 4 The top causes of death worldwide (WHO 2018b)

Table 3 The leading causes of death in the United States (Kochanek et al. 2019) Heart disease Malignant neoplasms Accidents (unintentional injury) Chronic lower respiratory diseases Cerebrovascular accidents Alzheimer’s disease Diabetes mellitus Influenza and pneumonia Intentional self-harm (suicide) Chronic liver disease and cirrhosis Septicemia Hypertension and renal disease Parkinson’s disease Pneumonitis due to solids and liquids

most common disorders. Of note, the prevalence of edentulism, referring to having no natural teeth, is twice as high in the age group 85 and older, as compared to the age group 65–74 years. Dementia is a disorder of relevance to most health-care providers. Patients need to have capacity, essentially, an understanding of care provided and be able to participate in decision-making. Unfortunately, cognitive status is not routinely screened for in practice. The

prevalence of dementia increases with age; over a quarter of community individuals over age 85 are likely to have dementia (Fig. 7). Many are depressed, another factor associated with nonadherence. Additional reasons for disability and poor participation in care may relate to the presence of functional limitations which clearly increase with age. Functional limitations involve one or more of vision, hearing, mobility, communication, cognition, and mood (agitation, depression) and highlight the importance of screening for these, as well as the support systems required (Fig. 8) (Federal Interagency Forum on Aging-Related Statistics 2016). Cancer is the second highest cause of death in older people, and therefore, screening for breast and colorectal cancer offers value and makes sense. The percentage of both men and women who underwent colorectal cancer screening is higher in age group 65–75 years, a welcome trend, versus the age group 50–64 years (Federal Interagency Forum on AgingRelated Statistics 2016) (Fig. 9). Among health-risk behavior indicators, diet quality and physical activity bear a relationship to the weight and body mass index of individuals and to several disorders such as diabetes mellitus, hypertension, and hyperlipidemia. Eating patterns and dietary adequacy based on

1

Geriatric Gastroenterology: A Geriatrician’s Perspective

11

Fig. 5 Trends in the top causes of death in older people in the United States (Federal Interagency Forum on AgingRelated Statistics 2016)

Fig. 6 Chronic health disorders in older men and women in the United States (Federal Interagency Forum on AgingRelated Statistics 2016)

12

T. S. Dharmarajan

Fig. 7 Dementia estimates in older US adults in the community (Federal Interagency Forum on Aging-Related Statistics 2016)

12 components, 9 of which are adequacy components and three are moderation components, are provided in Fig. 10. The consequence of poor physical activity and excessive dietary intake is obesity, a disorder which has increased in the past two decades in the United States, even in older people; the pattern has been observed in people over age 65 years and also in those over age 75 years, in both men and women (Federal Interagency Forum on AgingRelated Statistics 2016).

Aging Associations Most older people, even those without complaints, following evaluation, are likely to manifest impairments and/or complex multi-morbid disorders. Illness may not be apparent as complaints, when the patient is initially seen by a gastroenterologist. Functional limitations increase with age; atypical presentations are common;

polypharmacy is rampant; and adverse drug events result, presenting as geriatric syndromes such as syncope, falls, cognitive worsening, delirium, depression, constipation, and diarrhea. The presence or lack of capacity matters in decisionmaking prior to gastrointestinal procedures or surgery; and if capacity is lacking, one needs to determine if it is temporary or permanent. In the absence of capacity, the presence of a wellexecuted advance directive is most helpful, although, based on current trends, advance care planning is seldom executed in a timely manner. The approach to an older person with impaired function and complex comorbidity is best addressed by the use of a multidisciplinary team rather as compared to a single provider (Takahashi and Odera 2020). Such a team includes the primary physician who is ideally knowledgeable in the care of older people, specialists (individualized to the patient) such as gastroenterologist, cardiologist, nephrologist, psychiatrist or others,

1

Geriatric Gastroenterology: A Geriatrician’s Perspective

13

Fig. 8 Common causes of disability in older men and women (Federal Interagency Forum on Aging-Related Statistics 2016)

nurse, psychosocial worker, pharmacist, nutritionist, physiatrist, occupational therapist, pastoral care, and others deemed necessary. The team can be tailored to the needs of the patient.

How Does the Geriatric Individual Differ? Is the older adult with GI illness similar to any other individual? “Yes and No”; the topic is well addressed by a geriatrician-gastroenterologist in an American Gastroenterological Association Perspective and in depth in the Association Future Trends Committee Report (Hall et al. 2005). Several gastrointestinal disorders such as constipation and cancer are common in the geriatric age group; but additionally, the older adult is likely to manifest several comorbid conditions including but not limited to cardiac and renal disease, alterations in weight, malnutrition, impaired cognition, hearing

and visual impairment, and a proneness to falls, delirium, and incontinence. With polypharmacy and inappropriate prescribing a concern in this age group, adverse drug events (ADEs) are common; they may manifest as GI illness, such as constipation, diarrhea, GI bleeding, peptic ulcer disease, and pill esophagitis, a partial list. Further, ADEs are a common reason for hospitalization and health-care costs. The problem is best addressed by appropriate deprescribing of medications, a process to discontinue or reduce dosages of unnecessary medications in a programmed manner; the aim is to decrease cost, improve quality of life, and lower adverse drug events (Dharmarajan et al. 2020). The older adult may not comprehend or adhere to recommendations for a procedure or related management, because of underlying dementia; patients are labeled as nonadherent, when in fact the patient needs simplified instructions along with supervision in the presence of impaired cognition. Dysphagia and aspiration are

14

T. S. Dharmarajan

Fig. 9 Screening for colorectal and breast cancer by age (Federal Interagency Forum on Aging-Related Statistics 2016)

common basis for morbidity and mortality; predispositions to dysphagia and aspiration include neurological disorders such as Parkinson’s disease or dementia of any cause, rather than mechanical upper esophageal obstruction. The risk for aspiration is not minimized by a feeding gastrostomy tube feeding either. Older adults with dysphagia also have difficulty with intake of oral medications and are prone to pill esophagitis. With such a partial list of scenarios, a multidisciplinary approach helps in addressing the many problems, coupled with meaningful caregiver oversight.

Gastrointestinal Disorders in Older Adults As one ages, several organs tend to decline. Typical organ dysfunction involves the brain, heart, and kidneys. Gastrointestinal (GI) tract changes in older adults are no exception. While some GI disorders are typical in older people (e.g., diverticular disease), they are by no means restricted

to the geriatric population. As with the rest of the body, changes in the GI tract may be physiological or pathological. Changes occur anywhere from the oral cavity to the large bowel and also involve extraintestinal abdominal organs such as the liver, spleen, pancreas, and vasculature (Dumic et al. 2019). Drug metabolism involves gastrointestinal absorption and hepatic metabolism and protein binding; several medications are excreted by the GI system. In fact, adverse drug effects often involve the GI system. Cancers of the GI system including the liver and pancreas are common in older people. The prevalence of GI symptoms and signs is higher with age but may be superimposed by the effects of comorbidities and environmental exposure, including alcohol, tobacco, and medications (Durazzo et al. 2007). Sometimes with multiple coexisting illnesses, the presentations may not be consistent with typical presentations of the disease (Durazzo et al. 2007). Primary providers are often the initial physicians to recognize or suspect a GI disorder in

1

Geriatric Gastroenterology: A Geriatrician’s Perspective

15

Fig. 10 Health eating adequacy patterns in older adults in the United States (Federal Interagency Forum on AgingRelated Statistics 2016)

older people and seek a gastroenterology consultation to help confirm and advocate management. In an estimate of the burden of gastrointestinal disease in the United States, abdominal pain was the most common GI symptom, while gastroesophageal reflux was the most common GI diagnosis; hospitalizations for acute pancreatitis and Clostridium difficile infection are high; and colorectal cancer accounted for over half of GI cancers and was the leading cause of GI-related deaths (Peery et al. 2012). Similar to several medical societies, the American Geriatrics Society and the American Medical Directors Association have provided Choosing Wisely recommendations, in collaboration with the American Board of Internal Medicine Foundation. An example pertinent to geriatric gastroenterology is “don’t recommend the use of percutaneous feeding tubes in those with

advanced dementia, instead offer oral assisted feeding” (AGS Health in Aging Foundation 2013–2014). Healthy People 2020 is a health agenda for the United States to promote societal vision where individuals will lead long healthy lives, free of preventable disease, disability, and premature death. A range of risk factors including diet, alcohol, and tobacco in addition to disease have been identified; if addressed appropriately, perhaps the country may move forward to a better state of health (Koh and Parekh 2018). The primary provider, geriatrician, and specialists, including the gastroenterologist, are all involved in such an agenda; they need to complement each other in dealing with the US or any nation’s burden of disease. Table 4 provides selected “pearls” pertinent to older adults, applicable in practice to primary providers of care as well as specialists.

16 Table 4 A selection of pearls in geriatric medicine Biological age may not correlate with chronologic age Atypical presentations of illness need to be recognized Evaluation often delineates silent unrecognized disease Complex multi-morbidity is the rule and increase with age, assess cognition, and functional impairment area result Polypharmacy is rampant; deprescribing is the answer Adverse drug events present as geriatric syndromes The serum creatinine poorly reflects renal function in the old; as a rule, measure estimated glomerular filtration rate Fever and leukocytosis may not be present with infection Fecal impaction can present as urinary retention or diarrhea Offer and institute advance care planning in time Geriatric medicine works best with a multidisciplinary team

Key Points • Population trends suggest that health-care providers need to deal with an increasingly aging population with multiple chronic illnesses. • There are more centenarians living today, although there is wide range in numbers based on countries across the globe. • Life expectancy has been on the increase for both men and women but appears to be plateauing; it is consistently higher in women across the globe. • Impaired cognition is common in older people and may be associated with impaired decisionmaking capacity and poor adherence to care. • Functional limitations with disability from comorbid illness are common and increase with age, many unsuspected until full evaluation. • Presentations in older individuals are often atypical or even asymptomatic. • The common causes of death in developed countries are heart disease and cancer, while in lower-income countries, it is respiratory infection or diarrheal illness. • Gastrointestinal illness is common in geriatric patients; importantly, most older adults with GI illness also manifest several additional chronic disorders. • Polypharmacy is highly prevalent in older adults and must be addressed.

T. S. Dharmarajan

• Adverse drug events are a consequence of polypharmacy; they present as new-onset syndromes, some being GI manifestations. • Polypharmacy is addressed by medication reconciliation and appropriate deprescribing in a systematic manner. • Biological age must be prioritized over chronological age in decision-making, with attention paid to remaining life years, quality of life, and functional status. • Adequate communication between the primary care physician and gastroenterologist is essential to ensure patient satisfaction and participation in decision-making and the ultimate goal of better outcomes. • Providers need to address the full chain of decision-making, including screening, evaluation, management, and follow-up. • Providers will benefit from background knowledge in basic geriatric medicine to cope with older patients. • Health-care decisions must factor the following: the patient’s current or prior expressed wishes; risk versus benefits of care offered including any procedures involved; resultant quality of life; and remaining life expectancy.

References AGS Health in Aging Foundation. Choosing wisely: 10 things physicians and patients should question. 2013–2014. HealthinAging.org. https://www.healthinaging.org/sites/ default/files/pdf/Choosing.Wisely.Ten_Things.pdf Arai H, Ouchi Y, Toba K, et al. Japan as the front-runner of super-aged societies: perspectives and medical care in Japan. Geriatr Gerontol Int. 2015;15(6):673–87. Avers D, Brown M, Chi KK, et al. Editor’s message. Use of the term “elderly”. J Geriatr Phys Ther. 2011;34 (4):153–4. Burke C. It is time to stop using the term “senior citizen”. AARP. 2019. https://www.aarp.org. 10 July 2019. Centenarian. Wikipedia. 2020. https://en.wikipedia.org/ wiki/Centenarian. Accessed 3 Nov 2020. Coll PP. Determination of life expectancy: implications for the practice of medicine. Ann Long Term Care. 2010;18(4):21–4. Dharmarajan TS, Sohagia A. Urgent surgery in a near super centenarian nursing home resident: possible with favorable outcome! J Am Med Dir Assoc. 2007;8:543–4.

1

Geriatric Gastroenterology: A Geriatrician’s Perspective

Dharmarajan TS, Choi H, Hossain N, et al. Deprescribing as a clinical improvement focus. J Am Med Dir Assoc. 2020;21:355–60. Dorling JL, Martin CK, Redman LM. Calorie restriction for enhanced longevity: the role of novel dietary strategies in the present obesogenic environment. Ageing Res Rev. 2020:101038. https://doi.org/10.1016/j. arr.2020.101038. Dumic I, Nordin T, Jecmenica M, et al. Gastrointestinal tract disorders in older age. Can J Gastroenterol Hepatol. 2019;2019:6757524. https://doi.org/10.1155/ 2019/6757524. Durazzo M, Campion D, Fagoonee S, Pellicano R. Gastrointestinal tract disorders in the elderly. Minerva Med. 2007;108(6):575–91. Evert J, Lawler E, Bogan H, et al. Morbidity profiles of centenarians: survivors, delayers, and escapers. J Gerontol A Biol Sci Med Sci. 2003;58A:M232–7. Falconer M, O’Neill D. Out with “the old”, elderly and aged. BMJ. 2007;334:316. Federal Interagency Forum on Aging-Related Statistics. Older Americans 2016: key indicators of Well-being. Washington, DC: US Government Printing Office; 2016. Forciea MA. Geriatric medicine: history of a young specialty. Virtual Mentor. 2014;16(5):385–9. Gonzalez-Freire M, Diaz-Ruiz A, Hauser D, et al. The road ahead for health and lifespan interventions. Ageing Res Rev. 2020;59:101037. https://doi.org/10.1016/j.arr. 2020.101037. Hall KE, Proctor DD, Fisher L, et al. American Gastroenterological Association future trends committee report: effect of aging of the population on gastroenterology practice. Educ Res Gastroenterol. 2005;129:1305–38. Hamczyk MR, Nevado RM, Barettino A, et al. Biological versus chronological aging: JACC Focus Seminar. J Am Coll Cardiol. 2020;75(8):919–30. Hausman DB, Fischer JG, Johnson MA. Nutrition in centenarians. Maturitas. 2011;68(3):203–9. Jean-Marie R, Cubaynes S. Worldwide demography of centenarians. Mech Aging Dev. 2017;165:59–67. Kochanek KD, Murphy SL, Xu JQ, Arias E. Deaths: final data for 2017. Natl Vital Stat Rep. 2019;68(9):1–75. Koh HK, Parekh AK. Towards a United States of health: implications of understanding the US burden of disease. JAMA. 2018;319:1438–40.

17 Lester PE, Dharmarajan TS, Weinstein E. The looming geriatrician shortage: ramifications and solutions. J Aging Health. 2019:898264319879325. https://doi. org/10.1177/0898264319879325. Murphy SL, Xu JQ, Kochanek KD, Arias E. Mortality in the United States, 2017, NCHS data brief no. 328. Hyattsville: National Center for Health Statistics; 2018. Peery AF, Dellon ES, Lund J, et al. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology. 2012;143(5):1179–87. Perls TT. The oldest old. Sci Am. 1995;14(3):6–11. Rowe JW, Kahn RI. Human aging: usual and successful. Science. 1987;237:143–9. Schoenhofen EA, Wyszynski DF, Andersen S, et al. Characteristics of 32 super centenarians. J Am Geriatr Soc. 2006;54(8):1237–40. Takahashi R, Odera K. Multidisciplinary approach to aging. Yakugaku Zasshi. 2020;140(3):379–82. Taleb NN. The Black Swan: the impact of the highly improbable. New York: Random House; 2007. Taylor A. Older adult, older person, senior, elderly or elder: a few thoughts on the language we use to reference aging. 2011. https://www.bcli.org/older-adult-olderperson. Accessed 3 Oct 2020. Vacante M, D’Agata V, Motta M, et al. Centenarians and super centenarians: a Black Swan. Emerging social, medical and surgical problems. BMC Surg. 2012;12 (Suppl 1):S36. Warshaw G, Lundebjerg NE. When it comes to older adults: language matters. Ann Long Term Care Aging. 2017;25(4):6–7. Weyh C, Kruger K, Strasser B. Physical activity and diet shape the immune system during aging. Nutrients. 2020;12(3):pii: E622. https://doi.org/10.3390/nu120 30622. Woolf SH, Schoomaker H. Life expectancy and mortality rates in the United States, 1959–2017. JAMA. 2019;322:1996–2016. World Health Organization. Ageing and health. 2018a. https://www.who.int/news-room/fact-sheets/detail/age ing-and-health World Health Organization. The top 10 causes of death. Global health estimates 2016: deaths by cause, age, sex, by country and by region, 2000–2016. Geneva: WHO; 2018b.

2

Geriatric Gastroenterology: A Gastroenterologist’s Perspective C. S. Pitchumoni

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Abstract

According to all reports, aging population is likely to become one of the most significant social transformations of the twenty-first century. The elderly population’s rapid increase has shifted the heavy burden of infectious diseases of the past century to chronic noncommunicable diseases including cancers. As age advances, many physiological functions of the gastrointestinal system such as immunity, gastrointestinal motility, various digestive functions, enzyme, and hormone secretion are affected. The functional decline is associated

C. S. Pitchumoni (*) Department of Medicine, Robert Wood Johnson School of Medicine, Rutgers University, New Brunswick, NJ, USA Department of Medicine, New York Medical College, Valhalla, NY, USA Division of Gastroenterology, Hepatology and Clinical Nutrition, Saint Peters University Hospital, New Brunswick, NJ, USA e-mail: [email protected]

with an increasing predisposition to neoplastic diseases and malnutrition. Few diseases are specific and limited to advanced age, but many are more prevalent in the older age group and may require special care.

Keywords

US Census Bureau report · Demographic change · Pancreatic cancer · Colorectal cancer · Obesity · Diabetes mellitus · Nonalcoholic fatty liver disease (NAFLD) · Cerebrovascular disease · Parkinson’s disease Alzheimer’s disease · Oropharyngeal (transfer) dysphagia · Malnutrition · Frailty · Aspiration pneumonia · NSAIDs

Introduction Demographic change in the last few decades, showing a shift toward an older age distribution, is an admirable achievement of modern medicine.

© Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_2

19

20

C. S. Pitchumoni

Substantial scientific advances in preventative and curative medicine, improved sanitation and water supply, and enhanced food production are a few of the notable reasons (Gavrilov and Heuveline 2003; Eberstadt 1997). The concurrent decline in both fertility and mortality and consequent increase in the percentage of the older adults (a term preferentially used in the book instead of the “elderly”) is a prominent global trend. In the United States, the population age 65 and over numbered 49.2 million in 2016, representing 15.2% of the population, about 1 in every 7 Americans. The number of older Americans increased by 12.1 million or 33% since 2006, compared to an increase of 5% for the under-65 population. In the United States, there were 17,000 nursing homes and 1.5 million residents in 2004 (Eberstadt 1997). According to a 2018 U.S. Census Bureau Report, in 2035 there will be 78.0 million people 65 years and older outnumbering the 76.4 million under the age of 18. No wonder the need for long-term care facilities is steadily increasing. According to a report from the Organisation for Economic

Co-operation and Development (OECD), between 2000 and 2009, the number of beds in nursing homes grew in most countries, reaching an average of 44 per 1,000 inhabitants over 65. This is expected to continue to grow (3). Nineteen of the 20 world’s “oldest countries” are in Europe. In Europe, 17.1% of the population was over 65 years-old in 2008, and this is expected to rise to 23.5% in 2030 (Jones et al. 2009; Konstantinos Giannakouris 2010): even many of the so-called Third World countries – such as India, China, and Latin America – are demonstrating the same trend (see Figs. 1 and 2). This “graying” of the population has brought with it many economic, ethical, and social challenges, including alarming financial issues in trying to meet healthcare needs. Aging of the population is an index of improvement in living conditions. But it is a mixed blessing with challenges that will no doubt continue. The Second World Assembly on Ageing, Madrid, April 8–12, 2002, recognized that the demographic shift had resulted in substantial changes in the epidemiology of diseases and also in their associated morbidity and mortality. Among

Fig. 1 Number of persons aged 65 and over: 19002060 (numbers in millions). (Note: Increments in years are uneven. Lighter bars indicate projections. Source: U.S. Census Bureau, Population Estimates and Projections. Sources: U.S. Census Bureau, Population Division, Annual Estimates of the Resident Population for Selected Age Groups by Sex for the United States, States, Counties, and Puerto Rico Commonwealth and Municipios: April 1, 2010 to July 1, 2016, Release Date: June 2017; Intercensal Estimates of the Resident Population by Sex and Age for the United States: April 1, 2000 to July 1, 2010.

Release Date: September 2011; Intercensal Estimates of the White Alone Not Hispanic Resident Population by Sex and Age for the United States: April 1, 2000 to July 1, 2010. Release Date: September 2011; 2014 National Population Projections: Summary Tables, Table 3. Projections of the Population by Sex and Selected Age Groups for the United States: 2015–2060, released December 10, 2014; and NP2014_D1: Projected Population by Single Year of Age, Sex, Race, and Hispanic Origin for the United States: 2014–2060. Release date: December 2014)

2

Geriatric Gastroenterology: A Gastroenterologist’s Perspective

21

Fig. 2 Number and distribution of persons aged 60 or over by region, in 2017 and 2050. (Data source: United Nations (2017). World Population Prospects: the 2017 Revision)

the many systemic disorders, the gastrointestinal tract warrants special attention, and we highlight a few of the problems of particular interest. Aging, often not associated with major symptoms, affects the entire gastrointestinal tract. All elderly adults need not suffer from diseases of the gastrointestinal tract. However, older age is associated with progressive damage to the structure and function of the entire gastrointestinal tract. The injury affects the enteric nervous system, gastrointestinal motility, small intestinal permeability related to the gastrointestinal tract mucosal defense system, and the gut-associated lymphoid tissue (GALT), which play important roles in the digestion and absorption of nutrients and protection against ingested pathogens (Soenen et al. 2016). The relative slowing of gastric emptying with aging has implications for appetite regulation. “Anorexia of aging” may be partly attributable to gastroparesis. The second most important shift in the population along with the “graying” is the alarming increase in obesity that complements the deleterious effects of aging (Dong et al. 2018). Overweight and obesity are not just cosmetic issues but etiologically related to increased risk of 13 types of cancer. As the body mass index increases by 5 kg/m2, the cancer mortality increases by 10% (Basen-Engquist and Chang 2011). These cancers account for about 40% of all cancers diagnosed in the United States. Esophageal, gastric, gallbladder, liver, colon, and the pancreatic are a few of the obesity-related

gastrointestinal cancers. Nonalcoholic fatty liver disease (NAFLD), a component of metabolic obesity, is replacing chronic viral hepatitis as a leading cause of cirrhosis; in the future, it may be the most common cause of hepatoma. Older age itself is the non-modifiable cause of increased occurrence of cancers; obesity is a modifiable risk that needs to be addressed as early as possible. Understanding of the pathogenesis of weight gain and the need for appropriate lifestyle modifications are priorities. Bariatric surgical techniques are increasingly being available; less and less invasive bariatric procedures are available. Currently, older age itself is not considered a contraindication for a bariatric surgical procedure (Giordano and Victorzon 2015; Lynch and Belgaumkar 2012). Controversy persists concerning the effectiveness and safety of bariatric/metabolic surgery in elderly patients. It is an ethical question whether bariatric surgery should be considered in the obese elderly. Many gastrointestinal problems are unique to the older adult. There is a high prevalence of cerebrovascular disease, Parkinson’s disease, and Alzheimer’s disease among the elderly causes oropharyngeal (transfer) resulting in malnutrition, frailty, and aspiration pneumonia. Esophageal dysphagia (transit) causing food impaction, frequent choking, and the need to visit the emergency room of a hospital are the result of pill esophagitis, stricture, achalasia and Schatzki ring in addition to esophageal cancer.

22

The incidence of gastrointestinal bleeding in older adults has increased as a result of the use of anticoagulants and NSAIDs in most. The number of patients who are being treated with anticoagulant or antiplatelet therapy to either treat or prevent cardiovascular XE “Cardiovascular disease” and cerebrovascular diseases is increasing (Lynch and Belgaumkar 2012; Gutermann et al. 2015). Placement of pacemakers or artificial valve replacements and comorbid conditions such as stroke, atrial fibrillation, deep vein thrombosis, and pulmonary embolism need an anticoagulant therapy. The rate of gastrointestinal bleeding varies from 5% to 15% for patients on oral anticoagulant therapy for atrial fibrillation, and this risk is higher in older patients. American College of Gastroenterology guidelines for managing patients with a bleeding ulcer provide advice about how to handle anticoagulant or antiplatelet therapies (Laine and Jensen 2012). The use of aspirin as prophylaxis for myocardial infarction is associated with increased risk of major gastrointestinal bleeding (Huang et al. 2011). A meta-analysis found an approximately twofold higher risk of gastrointestinal bleeding among individuals regularly using aspirin compared to placebo (McQuaid and Laine 2006). In addition to the use of an acid-reducing agent, the adverse effects of aspirin therapy can be minimized by using the lowest effective dose among both short-term and long-term users. More than 80% of the deaths from bleeding PUD in the United States occur in those 65 and older. The incidence of upper gastrointestinal bleeding is more often secondary to the use of a nonsteroidal anti-inflammatory drug (NSAID) than peptic ulcer caused by Helicobacter pylori. NSAID-induced PUD is often painless, occurs more often in women, and may be associated with severe underlying anemia and massive upper gastric intestinal bleeding (Griffin et al. 1991). The proton pump inhibitors (PPI) are extremely useful in the treatment of acid-related disorders, and in reducing bleeding, their overuse has been related to the increased incidence of Clostridium difficile colitis, bacterial pneumonia, vitamin B12, iron and calcium malabsorption, diarrheal disorders, osteoporosis with fractures, and acute interstitial nephritis. The incidence of these complications is perhaps overrated (Khara and Pitchumoni 2009). Current

C. S. Pitchumoni

guidelines for the first time recommend a definite endpoint for therapy. Interventional endoscopy has achieved tremendous progress in controlling upper gastrointestinal bleeding from variceal and non-variceal causes. Endoscopic techniques such as endoscopic injection sclerotherapy (EIS), endoscopic variceal ligation (EVL), cyanoacrylate obliteration, argon plasma coagulation (APC), and the application of hemoclip are some examples. Constipation may be chronic, recalcitrant, and debilitating. The dollars spent on laxatives exceed $400 million annually. Fecal impaction and incontinence, which bring patients repeatedly to the emergency rooms, lead to hospitalizations, nosocomial infections, and both invasive and expensive diagnostic procedures (Rey et al. 2014). It is the result of chronic or severe constipation and is frequent in the elderly population. The typical associated symptoms are abdominal pain and distention, nausea, vomiting, and anorexia simulating an intestinal obstruction. Many medications reduce intestinal motility. The list includes opiate analgesics, anticholinergic agents, calcium channel blockers, antacids, and iron preparations frequently needed in the patient. The colon carcinoma is one of the most frequent lethal disorders in the United States and other affluent nations. Over 90% of the cases of colon cancers are seen in patients older than 50 years of age. Diverticular disease increases in prevalence with age (Jacobs 2007). In many western countries, more than half of the population may have diverticular disease, often silent, which is the single most common cause for hospitalization in patients aged 75 and over. Inflammatory bowel disorders (IBD), Crohn’s, and ulcerative colitis have a dual peak of onset. This late-onset peak creates the diagnostic and therapeutic dilemma, as ischemic bowel disorders, lymphocytic or collagenous colitis, druginduced colitis, and infectious colitis are all part of the differential diagnosis. The increased incidence of Clostridium-associated colitis with the newly detected virulent form (Quebec Strain) has posted an epidemiological problem in the institutionalized as well as free-living elderly. Hospital admissions with the principal diagnosis of cholecystitis increase sharply with age.

2

Geriatric Gastroenterology: A Gastroenterologist’s Perspective

Although generally more common in women, after age 75, the gender difference disappears. Older adults may present atypically and with complications, such as acute cholecystitis, cholangitis, gallbladder perforation, gangrene, emphysematous cholecystitis, and gallstone pancreatitis. Benign and malignant diseases of the pancreas pose a severe threat to the elderly, with older age in itself a prognostic marker for serious outcome. Chronic alcoholic pancreatitis is rare in the geriatric patient, but idiopathic chronic pancreatitis of late onset (“senile pancreatitis”) is a cause of pancreatic insufficiency. The new entity of autoimmune pancreatitis treatable with steroids is mistaken for pancreatic malignancy. The incidence of pancreatic cancer dramatically increases with age. Liver transplantation once considered an option solely for the young is being offered to the older adult. Transplant recipients over the age of 60 have the same postoperative mortality rate and life expectancy as those younger. Older recipients of liver transplants enjoy a quality of life similar to the younger recipients (Singhal et al. 2010). The explosion of knowledge in the last two decades is in the field of gut microbiota that has identified the bundle of tens of trillions of organisms in the intestines as a new organ – carrying out specific functions which are crucial to maintaining optimal health. Like any other organ, the gut microbiome has its physiology and pathology. Many metabolic, neurologic, and gastrointestinal disorders are being identified as due to dysbiosis (World Health Organization, Aging, and Lifecourse. http://www.who.int/aging/en/WHO, Health statistics and health information systems. Global burden of disease. The gut-brain access known previously as contributed by neuropeptides is also profoundly influenced by the interaction between gut microbiota and nutrients in the gut. http://www.who.int/healthinfo/global_bur den_disease/metrics_daly/en/index.html). Economists caution against overspending. According to Brookings Institute, for multiple reasons, physicians tend to “overmedicalize” aging in America by focusing too much on repairing people and not enough on preventive actions or maintenance care (Butler 2015). Equally concerned are physicians. Overmedication hurts the wallet but

23

also causes many iatrogenic complications related to drugs. Care of the elderly encompasses knowledge of geriatrics and should go beyond guidelines created for the younger adults mostly. Until too long ago, the older adults were considered not good candidates for organ transplantation, dialysis, or advanced surgical procedures based on presumed poor results and excessive cost of care (Keehan et al. 2008). Older age alone is not a valid reason to deny appropriate care. The technology has also changed, and less invasive endoscopic or laparoscopic procedures replace many open surgical procedures. For ethical, moral, and legal reasons, the elderly should be treated like everyone else. Age has become irrelevant in treatment decisions (Callahan and Prager 2008). Aword of caution is needed. The basic principles of good clinical medicine needs to be reemphasized; the care of the older adult requires time and patience. The choice of technology needs to be guided by clinical judgment. Today’s medical care appears to be dependent on multiple imaging studies before a clinical diagnosis. The number of CT examinations performed in the United States has increased geometrically over the decades, rising from 3 million annually in 1980 to close to 80 million currently (Brenner and Hricak 2010). Advances in endoscopic therapeutic interventions along with endoscopic ultrasound have made it feasible to offer management options in many life-threatening situations in the older adult. For example, therapeutic endoscopy plays a major role in the management of biliary disorders including cholangitis. What was once considered to be contraindicated because of older age has become the choice of therapy currently. Use of technology without critical thinking is dangerous. Incidentalomas or the incidental imaging findings in an asymptomatic patient or a symptomatic patient undergoing imaging for an unrelated reason are fast becoming a modern medical crisis (O’Sullivan et al. 2018). Cystic lesions of the pancreas are a good example. The title of an article “VOMIT” (victims of contemporary imaging technology) is an appropriate acronym for our times very well applicable to the care of the older adult with a gastrointestinal problem (Hayward 2003).

24

Key Points 1. In the United States, the population age 65 and over numbered 49.2 million in 2016, representing 15.2% of the population, about 1 in every 7 Americans. 2. Older age is noted to be associated with progressive damage to the structure and function of the entire gastrointestinal tract. 3. There is an increased incidence of many gastrointestinal cancers, in particular cancers of the colon, pancreas, and liver. 4. There is a second peak of inflammatory bowel diseases. 5. Many older adults are given suboptimal treatment solely based on age which is inappropriate. 6. The incidence of gastrointestinal bleeding in older adults has increased as a result of the use of anticoagulants and NSAIDs. 7. Advances in endoscopic therapeutic interventions along with endoscopic ultrasound have made it feasible to offer management options in many life threatening situations in the older adult.

References Basen-Engquist K, Chang M. Obesity and cancer risk: recent review and evidence. Curr Oncol Rep. 2011;13(1):71–6. https://doi.org/10.1007/s11912-010-0139-7. Brenner DJ, Hricak H. Radiation exposure from medical imaging. JAMA. 2010;304(2):208. https://doi.org/ 10.1001/jama.2010.973. Stuart M. Butler. Time to end the incentives to overmedicalize. Brookings. https://www.brookings.edu/opinions/time-toend-the-incentives-to-overmedicalize/. Published 2015. Callahan D, Prager K. Medical care for the elderly: should limits be set? Virtual Mentor. 2008;10(6):404–10. https://doi.org/10.1001/virtualmentor.2008.10.6.oped10806. Dong H-J, Larsson B, Levin L-Å, Bernfort L, Gerdle B. Is excess weight a burden for older adults who suffer chronic pain? BMC Geriatr. 2018;18(1):270. https:// doi.org/10.1186/s12877-018-0963-4. Eberstadt N. World population implosion? Public Interest. 1997;129:3–22.. https://www.popline.org/node/270944. Accessed 29 Dec 2018 Gavrilov LA, Heuveline P. Aging of population. In: The encyclopedia of population. New York: Macmillan Reference USA; 2003. p. 32–7.

C. S. Pitchumoni Giordano S, Victorzon M. Bariatric surgery in elderly patients: a systematic review. Clin Interv Aging. 2015;10:1627–35. https://doi.org/10.2147/CIA.S70313. Griffin MR, Piper JM, Daugherty JR, Snowden M, Ray WA. Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons. Ann Intern Med 1991;114(4):257–263. http:// www.ncbi.nlm.nih.gov/pubmed/1987872. Accessed 29 Dec 2018. Gutermann IK, Niggemeier V, Zimmerli LU, Holzer BM, Battegay E, Scharl M. Gastrointestinal bleeding and anticoagulant or antiplatelet drugs. Medicine (Baltimore). 2015;94(1):e377. https://doi.org/10.1097/ MD.0000000000000377. Hayward R. VOMIT (victims of modern imaging technology) an acronym for our times. BMJ. 2003;326(7401):1273. https://doi.org/10.1136/bmj.326.7401.1273. Huang ES, Strate LL, Ho WW, Lee SS, Chan AT. Longterm use of aspirin and the risk of gastrointestinal bleeding. Am J Med. 2011;124(5):426–33. https://doi. org/10.1016/j.amjmed.2010.12.022. Jacobs DO. Clinical practice. Diverticulitis N Engl J Med. 2007;357(20):2057–66. https://doi.org/10.1056/NEJM cp073228. Jones AL, Dwyer LL, Bercovitz AR, Strahan GW. The National nursing home survey: 2004 overview. Vital Health Stat. 2009;13(167):1–155.. http://www.ncbi. nlm.nih.gov/pubmed/19655659. Accessed 29 Dec 2018 Keehan S, Sisko A, Truffer C, et al. Health spending projections through 2017: the baby-boom generation is coming to Medicare. Health Aff. 2008;27(2):w145–55. https://doi.org/10.1377/hlthaff.27.2.w145. Khara HS, Pitchumoni CS. Proton pump inhibitors: a better prescription is needed. J Clin Gastroenterol. 2009; 43(6):597–8. https://doi.org/10.1097/MCG.0b013e31 8194c452. Konstantinos Giannakouris. Regional population projections EUROPOP2008: Most EU regions face older population profile in 2030; 2010. Laine L, Jensen DM. Management of patients with ulcer bleeding. Am J Gastroenterol. 2012;107(3):345–60. https://doi.org/10.1038/ajg.2011.480. Lynch J, Belgaumkar A. Bariatric surgery is effective and safe in patients over 55: a systematic review and metaanalysis. Obes Surg. 2012;22(9):1507–16. https://doi. org/10.1007/s11695-012-0693-1. McQuaid KR, Laine L. Systematic review and metaanalysis of adverse events of low-dose aspirin and Clopidogrel in randomized controlled trials. Am J Med. 2006;119(8):624–38. https://doi.org/10.1016/j. amjmed.2005.10.039. O’Sullivan JW, Muntinga T, Grigg S, Ioannidis JPA. Prevalence and outcomes of incidental imaging findings: umbrella review. BMJ. 2018;361:k2387. https://doi. org/10.1136/bmj.k2387. Rey E, Barcelo M, Jiménez Cebrián MJ, Alvarez-SanchezA, Diaz-Rubio M, Rocha AL. A nation-wide study of prevalence and risk factors for fecal impaction in

2

Geriatric Gastroenterology: A Gastroenterologist’s Perspective

nursing homes. PLoS One. 2014;9(8):e105281. Bayer A, ed. https://doi.org/10.1371/journal. pone.0105281. Singhal A, Sezginsoy B, Ghuloom AE, Hutchinson I V, Cho YW, Jabbour N. Orthotopic liver transplant using allografts from geriatric population in the United States: is there any age limit? Exp Clin Transplant

25

2010;8(3):196–201. http://www.ncbi.nlm.nih.gov/ pubmed/20716036. Accessed 29 Dec 2018. Soenen S, Rayner C, Jones K, Horowitz M. Current opinion in clinical nutrition and metabolic care. Rapid Science Publishers; 2016. https://digital.library.adelaide.edu. au/dspace/handle/2440/99433. Accessed 29 Dec 2018.

3

Epidemiology of Gastrointestinal Diseases Jorge D. Machicado, Julia B. Greer, and Dhiraj Yadav

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Geriatric Population in the United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Benign Disorders of the Gastrointestinal Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gastroesophageal Reflux Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Swallowing Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Peptic Ulcer Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gastrointestinal Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abdominal Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abdominal Wall Hernias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diverticular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gallstones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clostridium difficile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Liver Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28 29 31 31 32 32 33 33 33 34 34 35 35

Gastrointestinal Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Colorectal Polyps and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pancreatic Cysts and Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Barrett’s Esophagus and Esophageal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

36 39 40 40

Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

Abstract J. D. Machicado Division of Gastroenterology and Hepatology, Mayo Clinic Health System, Eau Claire, WI, USA e-mail: [email protected] J. B. Greer · D. Yadav (*) Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA e-mail: [email protected]; [email protected]

The numbers of older adults are on the rise due to declining fertility and mortality rates. In 2019, the global number of people aged 65 years or over was ~730 million, which represents 9% of the world’s population, and will double by 2050, reaching ~1.5 billion people or 16% of the population. This chapter presents an overview of the epidemiology of a select group of benign and

© Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_7

27

28

J. D. Machicado et al.

malignant gastrointestinal disorders in the geriatric population. Gastrointestinal bleeding, peptic ulcer disease, abdominal hernias, diverticular disease, gallstones, acute pancreatitis, inflammatory bowel disease, Clostridium difficile infection, and liver diseases are among some of the some benign conditions discussed that cause high morbidity and mortality in geriatric individuals. Other common gastrointestinal disorders in older adults such as gastroesophageal reflux disease and swallowing disorders represent a significant burden in the ambulatory setting, but with low associated mortality. Cancer in the colorectum, pancreas, esophagus, liver, and stomach are the five most common gastrointestinal neoplasms in the old age group. Pancreatic and esophageal cancers are highly lethal. Colonic polyps, pancreatic cysts, and Barrett’s esophagus are premalignant lesions frequently detected in old individuals that offer an opportunity to reduce the incidence and mortality of some malignancies. Keywords

Older adults · Geriatric patients · Epidemiology of benign and malignant gastrointestinal disorders · Prevalence of GI disorders · Incidence of GI disorders · Natural history · Population · Mortality · Gastrointestinal disease · Gastroesophageal reflux disease · Clostridium difficile · Gastrointestinal bleeding · Diverticulitis · Inflammatory bowel disease · Pancreatitis · Abdominal hernia · Esophageal cancer · Barrett’s esophagus · Colon cancer · Colon polyps · Pancreatic cancer · Pancreatic cysts

Introduction The world’s population is growing older, due to declining fertility and mortality rates. In 2019, the number of people in the world aged 65 years or over was ~730 million people, 9% of the world’s population. This is projected to more than double by 2050, reaching ~1.5 billion people or 16% of the population (United Nations 2019). Similarly, the number of people aged more than 80 years is projected to triple from 143 million to 426 million

by 2050. The age composition of every country is highly variable – most developed countries in Europe and North America have more aging populations, while developing countries with high fertility rates in Africa, Asia, and Latin America have relatively younger populations. This chapter will present an overview of the epidemiology of benign and malignant gastrointestinal conditions in the geriatric population (65 years). While the chapter focuses on disorders in the United States, the information may be applicable to most developed nations.

Geriatric Population in the United States Table 1 displays the recent trends and future projections of the older adults in the United States. One in six people (16%) in the United States is over age 65, and this is projected to grow to one in four people by 2050 (United Nations 2019). Life expectancy at birth is currently ~79 years, which is 10 years more than in 1950 (~69 years), and is projected to be 10 years longer by 2100 (~89 years) (United Nations 2019; Arias and Xu 2019). This older population is predominantly composed of women, which doubles the number of men by age 85 and quadruples its number in centenarians. Improvements in life expectancy have dramatically increased the burden of chronic diseases and disability, which now account for half of the US health burden (Murray et al. 2013). The economic impact of greater longevity is reflected by the more than double medical expenditures in older people compared to the national average (De Nardi et al. 2016). This creates higher demands in US hospitals for diagnosis, prevention, and treatment for a variety of benign and malignant conditions highly prevalent in these patients and creates a need for subspecialists with interests in geriatric medicine.

Benign Disorders of the Gastrointestinal Tract Up to 55% of the US population over 65 years of age experience at least one gastrointestinal (GI) symptom weekly (Almario et al. 2018). The

3

Epidemiology of Gastrointestinal Diseases

29

Table 1 Estimates and projections of the elderly population in the United States (1950–2100) Year 1950 2000 2010 2020 2030 2050 2100

Total population (millions) 158.8 281.7 309.0 331.0 349.6 379.4 433.9

Population aged 65+ (millions) 13.0 34.7 40.1 55.1 70.8 84.8 120.6

Percent of population aged 65+ (%) 8.2 12.3 13 16.6 20.3 22.4 27.8

Life expectancy at birth (years) 68.7 76.5 78.2 78.8 79.8 83.1 88.6

Data derived and adapted from United Nations (2019)

most common symptoms reported include heartburn, abdominal pain, bloating, changes in bowel habits, nausea, dysphagia, and bowel incontinence. Explanations for these clinical manifestations include physiologic aging changes, extra-intestinal chronic diseases, adverse pharmacologic events, primary GI tract diseases, or a combination of these factors. The burden of chronic diseases in the older people is better estimated with prevalence rates and disability-adjusted life years (DALYs) – healthy life lost due to a medical condition or disability. In the United States, two thirds of older adults have at least two chronic conditions, with the most prevalent being hypertension (59%), musculoskeletal disorders (34%), diabetes mellitus (28%), and ischemic heart disease (28%) (Chronic Condition Data Warehouse (CCW) 2019). Some of the leading causes of DALYS in the United States include ischemic heart disease, chronic obstructive pulmonary disease (COPD), diabetes mellitus, Alzheimer’s disease, depression, musculoskeletal disorders, and stroke (Murray et al. 2013). Many of these prevalent chronic conditions in the elderly population also impact the GI tract, causing dysfunction or pathology (Erwin 1988). A nonexhaustive list of chronic conditions with their corresponding prevalence and possible GI manifestations is presented in Table 2. The burden of primary benign GI disorders in the USA has been estimated through age-specific national rates of ambulatory care visits, hospital admissions, and primary causes of death (Table 3) (Everhart 2008; Peery et al. 2015, 2019). For every benign disease, these indicators are higher in older individuals compared to the general

population. Some specific diseases, such as gastroesophageal reflux disease (GERD), chronic constipation, irritable bowel syndrome (IBS), and hemorrhoids, are leading causes almost exclusively of ambulatory visits. Most other GI conditions cause a high burden of both outpatient and inpatients visits, including peptic ulcer disease, gallstones, pancreatitis, hernias, diverticular disease, and liver diseases. Among these common GI diagnoses, liver disease carries the highest mortality among individuals of any age (Everhart 2008; Peery et al. 2015, 2019). The epidemiology of a selected group of common benign GI disorders in the geriatric population will be described in the following text.

Gastroesophageal Reflux Disease Previous population-based studies of GERD, defined as heartburn and/or regurgitation on at least 1 day a week, have reported that the pooled prevalence is 13%, increasing over time, and is highest in South Asia, Southeast Europe, and North America (El-Serag et al. 2014; Eusebi et al. 2018). Although inconsistent, most population studies have demonstrated that increasing age is modestly associated with higher prevalence and new incident cases of GERD (Eusebi et al. 2018; Mohammed et al. 2003; Hallan et al. 2015; Petrick et al. 2016). In the USA, the prevalence of GERD in the general population is ~20% and may be as high as ~40% in older people (El-Serag et al. 2014; Richter and Rubenstein 2018; Locke 3rd et al. 1997). Potential explanations for the increasing prevalence of GERD with age include weakened and impaired esophageal motility, decreased

30

J. D. Machicado et al.

Table 2 Common medical conditions in the elderly population associated with gastrointestinal dysfunction or pathology

Medical condition Osteoarthritis, physical inactivity Ischemic heart disease Diabetes

Prevalence of medical condition in elderly (age  65 years) 34% 28%

Gastrointestinal effect of the medical condition Constipation, fecal impaction

Chronic kidney disease Hypothyroidism

25%

Depression Congestive heart failure Chronic obstructive pulmonary disease Dementia Stroke

16% 14%

Mesenteric ischemia, abdominal aortic aneurysm/dissection, gastrointestinal bleeding Gastroesophageal reflux disease, gastroparesis, diabetic diarrhea, small intestinal bacterial overgrowth Delayed gastric emptying, anorexia, nausea, vomiting, gastrointestinal bleeding Constipation, ileus, small intestinal bacterial overgrowth, decreased taste sensation, fatty liver, possible pernicious anemia and celiac disease Constipation, anorexia, weight loss Congestive hepatopathy, ischemic hepatitis, malabsortion

12%

Gastroesophageal reflux disease, weight gain or loss

11% 4%

Malnutrition, fecal incontinence, constipation, aspiration Dysphagia, aspiration, gastrointestinal bleeding

28%

16%

Data derived and adapted from Chronic Condition Data Warehouse (CCW) (2019) Table 3 Rates of ambulatory care visits, hospital discharges, and death due to common gastrointestinal disorders in the elderly US population Disorder Abdominal wall hernia Diverticular disease Liver disease Gallstones Peptic ulcer disease Pancreatitis Appendicitis Crohn’s disease Ulcerative colitis Gastroesophageal reflux disease Chronic constipation Irritable bowel syndrome Hemorrhoids

Ambulatory care rates 2686 2607 986 883 812 279 – – – 4433 2423 1290 1065

Hospital discharges rates 189 477 129 341 285 197 59 18 23 – – – –

Mortality rates 2.5 8.3 37.5 2.5 8 2.5 0.8 1 0.7 – – – –

All rates are per 100,000 persons. Data presented are adapted from 2008 publication (Everhart 2008); no updated estimates stratified by age since then are available

salivary and bicarbonate secretion, reduced lower esophageal sphincter pressure, hiatal hernia due to diaphragmatic weakness, use of medications (e.g., anticholinergics, antidepressants, nitrates), and comorbidities (e.g., diabetes, Parkinson’s disease). Other risk factors that alter the individual risk to GERD include male sex, white race, abdominal obesity, tobacco use, and genetic

factors (Eusebi et al. 2018). Increasing age is also associated with greater risk of severe GERD symptoms, erosive esophagitis, and esophageal strictures (Richter and Rubenstein 2018; Johnson and Fennerty 2004; Diaz-Rubio et al. 2004). This may be explained by sensory changes in esophageal perception and increased acid contact time in older people (Fass et al. 2000).

3

Epidemiology of Gastrointestinal Diseases

Acid suppression with either proton-pump inhibitors (PPIs) or H2-receptor antagonists (H2RAs) remains the mainstay therapy for GERD and other peptic related diseases. The use of PPI therapy has doubled in the general population over the last decade. In a study from Iceland, over a third of users of PPIs in the population over age 80 years remained on PPIs after a year on these drugs (Halfdanarson et al. 2018). This has raised concern towards the potential over-use of PPIs from inappropriate indications, excessive dose, and prolonged duration. In older people, PPIs can interact with other prescribed medications and alter their drug concentration (e.g., decrease HIV drugs; increase warfarin, digoxin, diazepam) (Kanno and Moayyedi 2019). Initially, it was thought that PPIs could inhibit the action of antiplatelet drug clopidogrel and increase cardiovascular events; however, this assertion has not been confirmed in most subsequent observational studies and randomized controlled trials (Laine and Hennekens 2010; Bhatt et al. 2010). Moreover, several harms have been linked to the longterm use of PPI therapy – enteric infections (e.g., Clostridium difficile) (Leonard et al. 2007; Dial et al. 2005), micronutrient deficiencies (e.g., vitamin B12, calcium, magnesium) (Liao et al. 2019), fractures (Hussain et al. 2018), renal dysfunction (Lazarus et al. 2016), dementia (Li et al. 2019), and pneumonia (Herzig et al. 2009). Despite a plausible explanation for each of these health consequences, current epidemiologic evidence is biased and not supportive of causality, including retrospective studies, use of pharmacy claim databases, inconsistent results, weak associations (odds ratios 75 mg independently increases the risk of PUD by 2–4 fold, compared to nonusers (Garcia Rodriguez and Hernandez-Diaz 2004). The combination of aspirin with NSAIDs, antithrombotic agents, alcohol, or H. pylori in the old leads to more gastric injury and complications when compared with aspirin therapy alone (Huang et al. 2002; Fukushi et al. 2018). The prevalence of H. pylori in this age group ranges from 40% to 60% in asymptomatic individuals and is >70% in those with gastroduodenal disease (Pilotto and Salles 2002). In addition to PUD, H. pylori infection can also cause chronic atrophic gastritis, vitamin B12 deficiency, iron deficiency anemia, intestinal metaplasia, and gastric cancer (Pilotto and Franceschi 2014). Triple therapy for H. pylori eradication is safe and effective, even in older adults (Kobayashi et al. 2019).

J. D. Machicado et al.

improvements in access to and quality of endoscopic therapy, adoption of best practice clinical guidelines, and better risk stratification tools (Laine et al. 2012; Oakland 2019). Older adults age 65–75 have higher incidence of upper (197/100,000) and lower GIB (128/100,000) compared to younger adults, and GIB is greater in patients over 75 years (425/100,000 for upper GIB, and 380/100,000 for lower GIB) (Laine et al. 2012). This is partially explained by the higher risk in the geriatric age group of specific causes of upper (PUD, angiodysplasias, esophageal ulcers, Dieulafoy’s lesion) and lower GIB (diverticular disease, angiodysplasias, hemorrhoids, rectal ulcer). Prescription of antiplatelets or anticoagulation in roughly 40–60% of the elderly population also accounts for the increased risk of GIB (Williams et al. 2015). Aspirin use in older patients is associated with higher long-term risk of major GIB by three-fold and disabling or fatal upper GIB by ten-fold, as compared to younger patients (Li et al. 2017). Clopidogrel, warfarin, direct-oral anticoagulants, and heparin derivatives also increase the risk of GIB. Compared to the use of a single agent, the risk for bleeding-related admissions increases with dual and triple combination therapy, specifically, 2.6% with aspirin, 4.6% with clopidogrel, 4.3% with warfarin, 5.1% with aspirin + warfarin, 12.3% with clopidogrel + warfarin, and 12% for triple therapy (Sorensen et al. 2009). The risk of GI bleeding with combination therapy further increases with advancing age; patients over 75 years receiving combination therapy have the highest risk (17% per year) (Abraham et al. 2020). Nonvariceal GIB ceases spontaneously in most patients; however, systolic blood pressure 4 mm in diameter, small amounts of inspissated secretions in the dilated ducts in addition to a mild degree of periductal fibrosis are observed in autopsy studies of the pancreas of older adults (Matsuda 2019; Matsuda et al. 2019). Intraductal stones are reported in octogenarians’ pancreas (Ammann and Sulser 1976; Nagai and Ohtsubo 1984). The abnormalities in endoscopic ultrasound (EUS) mimic those in chronic pancreatitis imaging or histopathology of early chronic pancreatitis. These changes observed have led to a term of “senile pancreatitis,” a mostly asymptomatic entity. It is uncertain whether these changes do have any relationship to either pancreatic cancer or age-related glucose intolerance. The overall insulin secretion by the aged pancreas in response to a glucose load remains normal (Adelman 1989). Five percent of people older than 70 years and 10% older than 80 years have pancreatic exocrine insufficiency (PEI) as assessed by a fecal elastase-1 below 200μg in stool, and 5% have severe PEI with fecal elastase-1 below 100μg in stool (Löhr et al. 2018). The laboratory abnormality has very little clinical relevance; even in advanced age groups clinical malabsorption caused by exocrine insufficiency is uncommon. Only less than 10–20% of functioning pancreas is required for normal digestion; aging per se. in the absence of alcoholism, cigarette smoking, and duodenal by-pass surgery is unlikely to result in extensive acinar cell atrophy. Further, many older adults would have modified their diet, consuming less fat; also, the structural changes seen in imaging studies do not appropriately reflect a true loss of acinar cells.

176

Clinical Application Pancreatic enzyme replacement therapy (PERT) in the asymptomatic older adult is not indicated. PERT however may prevent serious nutritional complications when such patients have symptomatic EPI. Clinical symptoms associated with EPI include steatorrhea (large-volume, foulsmelling stools), diarrhea, weight loss, flatulence, and abdominal pain. The subtle symptoms may be caused by low serum levels of fat-soluble vitamins, micronutrients, and lipoproteins. Since there is no readily available reliable test to evaluate exocrine insufficiency and micronutrient deficiency symptoms, a therapeutic trial is appropriate. Considering the benign nature of enzyme therapy in selected cases and in those who had gastric or pancreaticobiliary surgery, there is a good indication. Additional details on pancreatic disorders in the older adult are presented in ▶ Chap. 85, “Pancreatic Cancer,” by Chari and associates.

Hepatobiliary System The liver, the largest solid organ in the body, has a volume of about 1862 cm3, with an average weight of 1400–1600 g in men and 1200– 1400 g in women. The liver’s two lobes are divided into eight segments, with each part having its arterial supply and venous and biliary drainage. The dual blood supply to the liver comes from the hepatic artery and the portal vein. The common hepatic artery originates from the celiac axis and divides into left and right hepatic arteries, supplying the two lobes. The portal vein, the second source of blood supply, is formed by the superior mesenteric and splenic veins’ confluence. An excellent recent review by Trefts et al. forms the basis of the following discussion (Trefts et al. 2017). The hepatocytes account for 80% of the liver cell population. Additionally, there are biliary epithelial cells, stellate cells, smooth muscle cells, vascular endothelial cells, various immune cells, and sinusoidal and endothelial cells. Each one of these cell types possesses a unique function but collectively regulates liver function at multiple levels.

C. S. Pitchumoni

The liver is the most complex in function. The liver mediates numerous physiological processes, including protein synthesis, macronutrient metabolism, cholesterol and lipid homeostasis, endocrine control of growth signaling pathways, drug detoxification, and more. The critical functions are participation in macronutrient metabolism, blood volume regulation, immune system support, glycogen storage, blood sugar regulation, endocrine control of growth signaling pathways, lipid and cholesterol homeostasis, and the breakdown of xenobiotic compounds, including many drugs. The hepatic response to overnutrition and insulin resistance is associated with metabolic syndrome, type II diabetes, nonalcoholic fatty liver disease, and cardiovascular disease. The liver handles protein and amino acids and disposal of nitrogenous waste from protein degradation in urea metabolism (Trefts et al. 2017). The peptide hormone hepcidin from the liver reduces the iron absorption from the duodenum and iron recycling macrophages by blocking iron export (Pagani et al. 2019). In discussing the liver’s age-related changes, one has to look at anatomical changes, disturbances in physiology, and regenerative capacity after an injury (Huda et al. 2019). Most of the age-related alterations in the structure and function are nonpathologic, with drug metabolism an exception. There are a few age-related morphological and physiological changes. The reduction of hepatic blood flow (mainly consecutive to fibrosis) without intrahepatic shunting is notable (Zoli et al. 1999; Anantharaju et al. 2002). An age-dependent decrease in hepatic blood flow of about 35% in persons over 65 years compared to those below 40 years has been noted (Zoli et al. 1999). Results from animal models indicate that the different hepatic functions are not affected in the same way by aging (Jourdan et al. 2004). However, aging predisposes to a few hepatic functional and structural impairment and metabolic risks (Sheedfar et al. 2013). Whether the age-related changes are clinically significant or not will be subjects of careful studies with the increase in the number of older adults, even centenarians. In this regard, an observation based on epidemiological and laboratory data suggests that there might exist

7

Gastrointestinal Physiology and Aging

an age window in which the livers of the very elderly become resistant to the development of injury. A decline in total body size, total body water, lean body mass, kidney mass and function, liver mass, liver blood flow and function, serum albumin, and increase in body fat stores are all responsible for altered drug metabolism in aging. A decrease in liver mass with aging is a probable cause for the decline in hepatic drug metabolism. Phase I metabolism of medications is dependent on hepatic blood flow and consequentially more affected than phase 2 metabolism. The incidence of adverse drug reactions in older adults is two to three times that of younger people, a feature likely related to the above factors, especially for low extraction drugs like phenytoin, alcohol, and theophylline (Anantharaju et al. 2002). The decrease in clearance of high extraction drugs such as hydralazine, nitrates, lidocaine, verapamil, propranolol, and morphine correlate with the decline in hepatic blood flow. The liver’s excellent regenerating capacity is well established; as little as 25% of a liver can regenerate into a whole liver. However, a decline in hepatic regeneration following hepatectomy or any other liver injury occurs in older age groups (Regev and Schiff 2001). A topic of importance discussed in the recent literature is increased inflammatory changes in older age, known as “inflamm-aging,” that have a detrimental effect on the regenerative response (Franceschi et al. 2000). As a result of inflammaging, there is an unbalanced stimulation/ response of the immune system. There is an increase in levels of inflammatory markers such as cytokines, chemokine, reactive oxygen species (ROS), as well as decreased levels of antioxidant enzymes such as superoxide dismutase (SOD) and phase 1 detoxifying enzymes (inflamm-aging theory). The changes increase susceptibility to agerelated diseases/disabilities. Considerable new information is available on the role of the liver in metabolic disorders. Many liver diseases have multisystem involvement, the pathogenesis of which is just being explored. Besides their well-established roles in dietary lipid absorption and cholesterol homeostasis, it has been recognized that Bile acids (BAs) are

177

also signaling molecules, with systemic endocrine functions (Houten et al. 2006). Overall there is not much age-related damage to the structure or decrease in functions as exemplified by the fact that livers from donors ranging in age from 50 to 70 can be transplanted with nearly the same success rate as those procured from younger donors (Adam et al. 1993; Regev and Schiff 2001; Paterno et al. 2016). A molecular level observation explains lipid accumulation in the liver. One of these is the new G protein-coupled receptors (GPCRs), cell surface receptors, which mediate the function of a vast number of extracellular ligands, neurotransmitters, and hormones. Understanding how GPCRs work at the molecular level has important therapeutic implications, particularly in older adults, as 30–40% of the drugs currently in clinical use mediate therapeutic effects by acting on GPCRs (Kimura et al. 2020). Understanding the metabolic role of GPCRs in hepatocytes is expected to help develop novel drugs useful in older adults for the treatment of various metabolic diseases, including type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). In this review, we describe the functions of multiple GPCRs expressed in hepatocytes and their role in metabolic processes. Liver volume decreases with age, with a decline in size but not in the number of hepatocytes. Minor alterations in serum alanine aminotransferase (ALT) are noted. In women, levels continue to increase with age, whereas in men, levels increase to around 50 years (Elinav et al. 2005). In the frail old, ALT levels demonstrate a bell-shaped curve with lower levels in the old-old (McLachlan and Pont 2012). Although the liver function is little altered, there is a general decline in the animals’ P450 enzyme system. Of note, a more significant reduction occurs in the activity of rapid metabolism. The fact that age minimally alters liver physiology is supported by the fact that livers from donors over age 80 are transplanted satisfactorily. The biliary duct is marginally dilated with age due to increased connective tissue; the upper limit for normal is 8.5 mm (Perret et al. 2000).

178

Clinical Application 1. Drug-induced liver disease Studies indicate increased frequency and severity of the disorder in older adults compared with younger individuals. The overall incidence of druginduced hepatitis is 20 per one million person-years. As age advances, the incidence increases to a maximum of 50 per one million person-years in persons aged 70–79 years (Almdal and Sørensen 1991). 2. High risk for fulminant hepatitis. A meaningful age-related change is decreased regenerative capacity explaining the poor recovery after severe viral or toxic injury. Acute hepatitis A, rare in patients older than age 65, is associated with a higher incidence of acute liver failure and a higher mortality rate compared with younger patients. 3. Hepatocellular carcinoma. The incidence of hepatocellular carcinoma, the most common cause of cancer-related mortality worldwide, increases progressively as age advances and peaks in incidence around ages 70–75 (ElSerag 2012). The complicated relationship between old age, NASH, and HCC observed in epidemiological studies is not fully understood. Every day the liver produces about 500–600 mL of bile isosmotic with plasma, which contains water, electrolytes, BAs, bilirubin, cholesterol, and phospholipids(lecithin), a few other organic compounds, and proteins that regulate gastrointestinal function and drugs or their metabolites. The degradation product of senescent RBCs and hemoglobin is bilirubin. BAs are conjugated with taurine or glycine residues to give anions called bile salts (BS). The two primary BS synthesized by the liver cells from cholesterol are cholic (CA) and chenodeoxy cholic acid (CDCA), conjugated with taurine and glycine by the enzymes BASCoA synthase (BASCS) and BAS-amino acid transferase (BAST) through a series of enzymatic reactions that convert hydrophobic cholesterol into more water-soluble amphipathic compounds (Fuchs 2003; Russell 2003; Claudel et al. 2005;

C. S. Pitchumoni

Staels and Fonseca 2009). There are two major bile acid synthetic pathways: the classic (or neutral, 7alpha dehydroxylase) pathway in the liver and the alternate (or acidic) pathway in peripheral tissues and the liver (Grant and DeMorrow 2020). It is standard information that BAs are biologic detergents with functions in regulating cholesterol metabolism, elimination of toxins (drug metabolites), keeping cholesterol in solution in bile (prevention of lithogenesis), and fat absorption by micelle formation in the small intestine. The BAs are reabsorbed in the ileum back to the liver as part of enterohepatic circulation; a small amount is lost in the stool. Bile acid homeostasis is essential for protecting the liver and other tissues and cells from cholesterol and bile acid toxicity. BAs are the major organic compounds found in bile. Bile salts (BS) and conjugated BAs (BAs) are terms used interchangeably. BAs have various functions in human physiology. The two synthesized BAs are cholic and chenodeoxy cholic acid, which is conjugated to the amino group of taurine or glycine to form four groups of BAs. The conjugated BAs are subsequently stored in the gallbladder until the duodenal hormone cholecystokinin stimulates contraction and emptying into the duodenum, the small intestine, and colon. The liver synthesizes approximately 0.5 g of BAs per day. Primary BAs are steroids produced specifically in peroxisomes. The total bile acid pool is 3 g, of which 95% is reabsorbed from the terminal ileum. The enterohepatic cycle recurs 4–12 times per day. A small amount, approximately 0.2 g/day to 0.6 g/day, is lost in the stool, replaced by new bile acid synthesis in hepatocytes (Barkun et al. 2013). The traditional functions of BAs mentioned in standard textbooks discussed are (a) keeping the cholesterol in solution in canalicular and gallbladder bile preventing stone formation, (b) digestion and absorption of fat by forming mixed micelle (except probably medium-chain triglycerides MCT which do not require micelle formation), (c) cholesterol metabolism, (d) a cofactor for pancreatic lipase, (e) hepatic excretion of lipid-soluble xenobiotics and drugs. Other functions include neutralization of gastric acid and the carriage of some immune factors. A major advance in

7

Gastrointestinal Physiology and Aging

the science of BAs is the discovery in 1999 that BAs have many endocrine properties with multiple systemic roles. Our long-held concept of bile salts’ functions is only the tip of the iceberg (Wang et al. 1999). BAs act as hormones themselves and as inducers of FGF15/19, and regulate diverse facets of hepatic metabolism ranging from their synthesis to protein and carbohydrate homeostasis (Houten et al. 2006; Zhou and Hylemon 2014; Kliewer and Mangelsdorf 2015). BAs are potent “digestive surfactants” that promote lipids’ absorption (including fat-soluble vitamins) by forming micelles of digested triglycerides. The BAs participate in the absorption of products of lipolysis by the pancreatic lipase on dietary triglycerides. The minimum amount of BAs needed for adequate micelle formation is called the “critical micellar concentration,” which may be decreased in chronic liver diseases, loss of BAs above and beyond the liver’s capacity to compensate, and bacterial overgrowth syndromes (SIBO). A small amount of BS influenced by the intestinal bacteria are deconjugated and are absorbed passively and actively back to the liver to be conjugated. The major reabsorption is in the distal ileum, where nearly 90% of the BAs are reabsorbed into the portal system to the liver, completing the enterohepatic circulation. A small amount escapes into the colon. (Fig. 1 Enterohepatic circulation of Bile Salts (bile acaids)). The colonic bacteria deconjugate and dehydroxylate the BAs to form, respectively, lithocholic acid and deoxycholic acid (DCA). The BA level in the liver and serum is carefully regulated by hepatic biosynthesis and transport and enterohepatic circulation. Cholestasis (accumulation of toxic BAs) is a result of dysregulation in the process (OʼLeary and Pratt 2007; Chiang and Ferrell 2018). The liver’s capacity to balance the loss may be overcome in severe ileal disease and after ileectomy, usually of more than 100 cms in length. The essential points in the physiology of BAs are summarized in the table. The hormonal properties indicate that BAs may be attractive therapeutic targets for treating metabolic disorders, such as NAFLD, and even many

179

neurological conditions (Grant and DeMorrow 2020). That BAs’ signaling plays a significant role in BAs secretion and glucose, lipid, and energy metabolism has led to the therapeutic possibilities of activation of farnesoid X receptor (FXR) and the G protein-coupled membrane receptor 5 (TGR5) in reducing hepatic bile salt, improved insulin sensitivity, and glucose regulation increased energy expenditure, and anti-inflammatory effects. BAs further play a crucial role in the intestines in regulating the gut microbiota, a major central point of many metabolic disorders. BAs metabolism by high-fat diets, alcohol, and drugs causes dysbiosis and many other metabolic diseases (Chiang and Ferrell 2018). Novel approaches to treat cholestatic diseases, primary biliary cholangitis (PBC), nonalcoholic fatty liver disease, and diabetes through BAs modification is quite promising (Donkers et al. 2019). Chronic diarrhea, secondary to malabsorption of BAs, remains underdiagnosed in geriatric medicine. BAs-induced diarrhea may be associated with no structural abnormality. In clinical practice, there is a tendency to dismiss a gastrointestinal disease if endoscopic, histopathologic, and radiologic imaging procedures are normal and as a symptomatic treatment prescribe a constipating agent. After appropriate diagnostic studies to exclude serious conditions, a therapeutic test is justifiable using bile acid sequestrants such as cholestyramine, colestipol, and colesevelam (Walters 2020). BAs malabsorption (BAsM)-induced diarrhea may mimic IBS, result predominantly from the interruption of the enterohepatic circulation. BAs are secretagogues in the colon (Walters and Pattni 2010). Camilleri classifies BAs-induced diarrhea as four types (Camilleri 2015). Type 1 (secondary to ileal dysfunction), type 2 (idiopathic), type 3 (secondary to gastrointestinal disorders not associated with ileal dysfunction), and type 4 because of excessive BAs synthesis. The estimated prevalence of BAsMs is 33% in diarrhea-predominant irritable bowel syndrome (type 2) and is a frequent finding postcholecystectomy or postvagotomy (type 3). Type 4 important in older adults is (oral hypoglycemic drug, metformin) associated with increased hepatic BAs synthesis (Barkun et al.

180

2013; Miles et al. 2014). The estimated prevalence of idiopathic BASM in chronic diarrhea ranges from 37.5% to 59.6%; there is a good study assessing the prevalence in older adults but is likely ignored in favor of other widespread diseases. Approximately one-third of patients with a diagnosis of IBS-D have underlying BASM as demonstrated by a positive SeHCAT (75 Selenium-homocholic acid taurine) test (retention 3000 nosocomial cases of CDAD diagnosed between August 2004 and March 2005; studies of this epidemic documented the presence of the hypervirulent toxinotype III Nap 1 BI strain, and risk factors for CDAD in this epidemic included older age and use of quinolones (Muto et al. 2005). Patients receiving chemotherapy, including cytosine arabinoside, cytarabine, cisplatin, vincristine, adriamycin, 5-fluorouracil, thioguanine, and mercaptopurine are at risk of developing necrotizing enterocolitis or neutropenic colitis (Petruzzelli et al. 1990). The common feature in all cases is profound druginduced leucopenia and neutropenia (90%)

Moderate (30–90%)

Low (10–30%)

Parenteral agents Anthracycline/cyclophosphamide for breast cancer Carmustine Cisplatin Cyclophosphamide 1500 mg/m2 Dacarbazine Mechlorethamine Streptozocin Alemtuzumab Azacytidine Bendamustine Carboplatin Clofarabine Cyclophosphamide 1000 mg/m2 Daunorubicin Doxorubicin Epirubicin Idarubicin Ifosfamide Irinotecan, liposomal irinotecan Oxaliplatin Romidepsin Temozolomide Thiotepa Trabectedin Aflibercept Belinostat Blinatumomab Bortezomib Brentuximab Cabazitaxel Carfilzomib Catumaxumab Cetuximab Cytarabine 1000 mg/m2 Docetaxel Eribulin Etoposide Fluorouracil Gemcitabine Ipilimumab Ixabepilone Methotrexate Mitomycin Mitoxantrone Paclitaxel and nab-paclitaxel Panitumumab Pegylated liposomal doxorubicin Pemetrexed Pertuzumab Temsirolimus Topotecan

Oral agents Altretamine (hexamethylmelamine) Procarbazine

Bosutinib Ceritinib Crizotinib Cyclophosphamide Imatinib Temozolomide Vinorelbine

Afatinib Axitinib Capecitabine Dabrafenib Dasatinib Etoposide Everolimus Fludarabine Ibrutinib Idelalisib Lapatinib Lenalidomide Nilotinib Olararib Pazopanib Ponatinib Regorafenib Sunitinib Tegafur uracil Thalidomide Vandetanib Vorinostat

(continued)

308

P. Goriacko and K. T. Veltri

Table 5 (continued) Level and frequency

Minimal (10 years (Oskarsson et al. 2014). Women who receive systemic hormone replacement therapy need to have their serum triglycerides monitored at least annually.

Incretin Mimetic Agents In 2013, the US Food and Drug Administration (FDA) has issued a warning about possible increased risk of pancreatitis associated with incretin mimetic medications used for the treatment of type 2 diabetes mellitus (The U.S. Food and Drug Administration 2013). Incretin mimetic drugs classes include GLP-1 agonists (e.g., exenatide, liraglutide) and DPP-4 inhibitors (e.g., sitagliptin, saxagliptin, alogliptin, linagliptin). The warning was based on early reports of pancreatitis with these agents. However, methodological issues with early reports make the association questionable, particularly because diabetes itself predisposes patients to acute pancreatitis (Tenner 2014). Systematic reviews of randomized trials failed to demonstrate this increased risk, while an extensive review of evidence by the FDA and the European Medicines Agency did not find data consistent with this association between incretin mimetics and pancreatitis (Egan et al. 2014; Monami et al. 2014). Given a lack of conclusive evidence, clinicians should provide more weight to other more established drug classes when evaluating an etiology in a patient with AP. Nevertheless, the

324

prescribing information for incretin mimetic agents recommends monitoring patients for signs and symptoms of acute pancreatitis.

Prevention and Management There are no evidence-based strategies for preventing drug-induced acute pancreatitis given the rare incidence of drug-induced basis for the disease. As with all medications in older adults, dosages should be adjusted for age-related renal and hepatic dysfunction to prevent toxic effects including acute pancreatitis. Sulfa-containing agents (such as sulfamethoxazole and loop diuretics) should be avoided in patients with documented sulfa allergy, as it may predispose patients to hypersensitivity-mediated acute pancreatitis. The treatment of drug-induced pancreatitis is no different than that of idiopathic acute pancreatitis. The suspected causal agents should be withdrawn to prevent recurrence of AP. However, since a causal relationship cannot be definitely established with many reported medications, clinicians will often need to weigh the risks and benefits of discontinuing suspected drugs. Finally, even when the suspected agent is discontinued, idiopathic acute pancreatitis can recur. Hence, clinicians should monitor patients for signs and symptoms of recurrence.

Drug-Induced Lower Gastrointestinal Tract Injury Many medications can induce injury to the lower gastrointestinal tract (Table 14). The types of injuries range from ulceration, strictures, microscopic colitis, and diaphragmatic disease of the colon to ischemic injury and colonic necrosis. Injury should be suspected in patients who present with diarrhea, abdominal pain, distension, gastrointestinal bleeding, nausea, vomiting, anemia, and weight loss (Curtin et al. 2014; Grattan et al. 2018; Harel et al. 2013). While diarrhea is the most common symptom upon presentation, many agents can induce inflammation and structural changes that may not resolve upon discontinuation as is the

P. Goriacko and K. T. Veltri Table 14 List of medications associated with various types of lower gastrointestinal tract injury (Bonderup et al. 2014; Geboes et al. 2006; Goldstein and Cryer 2015; Gupta et al. 2015; Marginean 2016; Palmer et al. 2008) Type of injury Ischemic colitis

Microscopic colitis

Ulcerations and strictures

Pseudomembranous colitis Eosinophilic/allergic colitis

IBD-like pattern

Colonic perforations Gastrointestinal necrosis

Associated medications Cocaine, estrogen, progesterone, ergot derivatives, vasopressin, alpha-blockers, beta-blockers, diuretics, digoxin, penicillin, neuroleptics, NSAIDs, flutamide SSRI, aspirin, ACEi, betablockers, PPIs, NSAIDs, H2RA, ticlopidine, carbamazepine, levodopabenserazide, ferrous sulfate, simvastatin, vinbumine, statins, SSRI, idelalisib Ergot derivatives, SPS, pancreatic enzyme supplements, Methotrexate, NSAIDs, acetaminophen (suppository form) Antibiotics, chemotherapy, corticosteroids Isotretinoin, penicillamine, clofazimine, acyclovir, sulfasalazine, carbamazepine, aspirin, chlorpropamide, methyldopa, ticlopidine Mycophenolate mofetil, NSAIDs, aminoglutethimide, clofazimine, SPS, corticosteroids, ipilimumab and tremelimumab SPS, clozapine

case with simple medication-induced diarrhea. Some patients may require pharmacotherapy or even surgical intervention to relieve the symptoms (Grattan et al. 2018; Wang et al. 2016). Older adults are at a high risk population for lower GI tract injury. Many older adults with chronic kidney disease require chronic management of hyperkalemia with cation-exchange resins, which puts them at a high risk of adverse effects. Additionally, CKD predisposes patients to ischemic injury of the GI tract via through angiotensin II-mediated vasoconstriction. Age greater than 60 and CKD have also been identified as risk factors for NSAID-mediated injury (Goldstein and Cryer 2015). Finally, the older adult population carries a higher risk of microscopic colitis due

11

Adverse Drug Effects Involving the Gastrointestinal System (Pharmacist Perspective)

to increased polypharmacy utilization (Masclee et al. 2015).

Sodium Polystyrene Sulfonate Sodium Polystyrene Sulfonate (SPS, commonly referred to by its brand name Kayexelate) is a cation-exchange resin used to treat hyperkalemia by eliminating potassium through the gastrointestinal tract. The prescribing information contains an FDA warning regarding the increased likelihood of cause gastrointestinal adverse events. The risks include intestinal necrosis, bleeding, ischemic colitis, and perforation (Faucon et al. 2018; Kao et al. 2015; Ribeiro et al. 2018; Takeuchi et al. 2013). In an analysis of a large dataset of advanced age adults, SPS use has been associated with a significant increase in hospitalizations for adverse GI events (Noel et al. 2019). While many initial case reports attributed the adverse effects to the sorbitol component of SPS, colonic necrosis has also been documented after administration of sorbitol-free formulations (Castillo-Cejas et al. 2013; Harel et al. 2013). SPS induces gastrointestinal injury through deposits of drug crystals in the intestinal wall, compounded by direct damage to the colon induced by sorbitol. Most patients will present with SPS crystals in the affected segments of the colon on histopathologic examination. Patients at risk for ischemia, particularly those who are postoperative, hypovolemic, or have CKD, are especially predisposed to SPS-related adverse effects (Harel et al. 2013; Ribeiro et al. 2018). Post-transplant patients are also at a higher risk due to immunosuppression which may impair normal GI protective function (Harel et al. 2013).

NSAIDs While gastric and duodenal ulcers are the most common gastrointestinal adverse effects of NSAIDs, their use has also been associated with damage to the small bowel and the colon (Lanas et al. 2005). NSAIDs inhibit COX-1 and COX-2 which leads to reduction of mucosal prostaglandins, causing superficial erosions and ulcers,

325

strictures, and increased apoptosis (Goldstein and Cryer 2015). Most NSAID-induced lower GI injury occurs in the ileocecal region and ascending colon, which can manifest as bleeding, strictures, ulceration, exacerbations of IBD, and diaphragmatic disease (Marginean 2016). A review of studies on NSAID-induced diaphragm-like strictures reports that around 60% of cases occurred in small intestine compared to about 30% of cases in the large bowel (Wang et al. 2016). In the colon, the lesions are usually limited to the right colon, although cases describe the entire colon involvement (Akashi et al. 2015). NSAIDs also predispose patients to the risk of microscopic colitis (Marginean 2016; Masclee et al. 2015; Verhaegh et al. 2016). The risk appears to be greatest when co-administered with PPIs, suggesting that increased intestinal permeability due to NSAID use may increase bacterial translocation in the intestine when normal microflora are disturbed by gastric acid inhibition (Verhaegh et al. 2016).

Mycophenolate Mofetil Mycophenolate mofetil is a commonly used medication for immunosuppression post-transplantation. A study in post-transplant recipients on MMF found that 9% of patients undergoing colonoscopy met the diagnostic criteria for MMF colitis, with most cases appearing in the proximal colon (de Andrade et al. 2014). Symptoms usually occur within first 6 months of use, although cases of late onset have been reported (Curtin et al. 2014). The GI adverse effects of mycophenolate therapy likely result from inhibition of enteral cell proliferation through its inhibition of de novo pathway of purine synthesis (Calmet et al. 2015). The damage of the GI tract may also occur through the formation of acyl glucuronide metabolite as well as alteration of microbial flora in the GI tract. It often presents similar to graft-versushost-disease on clinical and histological findings or ischemic colitis (Johal et al. 2014; Star et al. 2013). Discontinuation of MMF is usually sufficient to see complete resolution of symptoms (de Andrade et al. 2014; Johal et al. 2014; Moroncini et al. 2018). An enteric coated version

326

(mycophenolate sodium, marketed under the brand name Myfortic) has been developed with hopes of a more favorable GI safety profile compared to non-EC version. Although clinical trials did not demonstrate significant differences in GI adverse effects with EC formulation, some openlabel trials reported improved tolerability in patients switching from MMF to EC-MMF (Budde et al. 2010).

Proton Pump Inhibitors Proton pump inhibitors can induce microscopic colitis, a condition associated with persistent, watery, nonbloody diarrhea (Bonderup et al. 2014; Masclee et al. 2015; Verhaegh et al. 2016). The increased risk is likely due to PPI-induced alterations of bowel microflora, in addition to transmucosal leak that may lead to mucosal defects (Law et al. 2017). All PPI agents have been implicated in this increased risk of microscopic colitis, although lansoprazole carries the highest risk, potentially due to additional direct toxic effects on colonocytes (Bonderup et al. 2014; Law et al. 2017).

P. Goriacko and K. T. Veltri

the offending agent and consider possibilities of discontinuation or a switch to a different agent in the therapeutic class. Most cases of colonic injury are associated with chronic use, which means that clinicians should limit the use of these agents to the shortest evidence-based duration of therapy. In patients who develop microscopic colitis, symptoms can often be controlled with antimotility agents and corticosteroids. In patients requiring SPS for the management of chronic hyperkalemia, newer agents such as patiromer and sodium zirconium cyclosilicate have appeared on the market. These agents currently do not have any reports of lower GI injury, although more safety data are needed to detect these rare events (Meaney et al. 2017). If patients require the use of SPS, sorbitol-free formulations should be utilized whenever possible. Additionally, these agents should be avoided in postoperative patients or patients with acute or chronic constipation. In patients with mycophenolate mofetilinduced colitis, discontinuation of the agent most often results in the resolution of symptoms. If discontinuation is not possible, a trial of the enteric coated formulation is a reasonable approach to prevent further symptom development.

Ipilimumab

Adverse Effects of Medications Anticytotoxic T-lymphocyte-associated antigen 4 Administered Through Enteral Tubes (anti-CTLA) agents, which include ipilimumab and tremelimumab, have been implicated in the development of perforating colitis (Gupta et al. 2015). CTLA-4 is involved in maintaining immunity the colon mucosa, so its blockade has been directly correlated with the development of colitis. Patients often present with diarrhea, abdominal pain, nausea, vomiting, and fever. Severe disease can lead to bowel perforation (Gupta et al. 2015; Smith et al. 2007).

Prevention and Management In patients who develop symptoms consistent with lower gastrointestinal injury, medications should always be suspected as the etiology. Clinicians should carefully evaluate the indication for

Enteral tubes are often employed in delivering nutrition to elderly patients who are unable to swallow and have advanced dementia. The concepts of tube feeding are discussed in another chapter in this work. These tubes are also used for administering enteral forms of medications. The benefits of utilizing enteral medications include avoidance of potential intravenous line placement and infections associated with parenteral lines. However, improper medication administration techniques in this setting can lead to gastrointestinal adverse events, ranging from clogged tubes to diarrhea and bezoar formation. A study reported 5.8 medication administration errors occurring for every 1000 admissions in a major tertiary care teaching hospital (Winterstein et al. 2004). The frequency of errors is even higher

11

Adverse Drug Effects Involving the Gastrointestinal System (Pharmacist Perspective)

in patients with enteral feeding tubes (Sohrevardi et al. 2017). Clinician familiarity with adverse events associated with improper medication administration through enteral tubes and knowledge of techniques to avoid these errors can significantly improve the care process. Tube feeding is common in older adults, especially in those with cognitive impairment. In the United States, one study reports that 5.8% of nursing facility residents receive nutrition via enteral tubes. The prevalence is as high as 18–34% in patients with cognitive impairment (Dorner et al. 2011). Similar high rates are reported worldwide, in countries ranging from Israel to Malaysia (Bentur et al. 2015; Nordin et al. 2015). Despite high prevalence of use of feeding tubes, most studies report poor clinician familiarity with proper medication administration techniques in hospitals, SNFs, and outpatient pharmacies (de Amuriza Chicharro et al. 2012; Boullata 2009; Emami et al. 2012; Joos et al. 2015; Seifert and Johnston 2005). This fact, coupled with high prevalence of polypharmacy, puts older adults at an especially high risk of feeding tube-related medication adverse events.

Occlusion of Feeding Tubes Improper medication administration technique is one of the most common reasons for occluded feeding tubes (Bankhead et al. 2009). In one survey of LTC facilities across the United States, nurses who practiced three or more improper administration techniques had a significantly higher rate of tube occlusions (Seifert and Johnston 2005). Inappropriate medication crushing practices were associated with feeding tube occlusion rates of up to 10%.Occluded tubes can lead to poor outcomes, including unmet nutritional needs and missing scheduled medications. A common reason for tube occlusions is the incompatibility of medications with enteral nutrition formula, leading to formation of precipitate. Syrup dosage forms are especially prone to cause tube occlusions when mixed with enteral nutrition due to their acidic nature (Klang et al. 2013; Williams 2008). For example, liquid formulations of

327

morphine at a concentration of 2 mg/ml can alter the pH of certain feeding formulas, leading to precipitation and subsequent tube occlusion (Institute for Safe Medication Practices (ISMP) 2010). Additionally, the risk of tube occlusions is increased by crushing and mixing multiple medications together and crushing inappropriate dosage forms (e.g., enteric coated and sustained release), which results in coating material accumulating in the tube and causing occlusion. Finally, failure to adequately flush the tube prior to and after administering each medication can increase the risk for drug-drug and drug-formula interactions that contributes to the risk of feeding tube occlusions.

Osmotic Diarrhea Liquid forms of medications are designed for patients who have difficulty swallowing solid dosage forms, with a large proportion of the products intended for use in pediatric patients. As a result, many taste-masking substances are added to improve palatability of these dosage forms. These substances, such as sorbitol, often significantly increase the osmolarity of the medication dosage form well beyond the normal osmolar range of the gastrointestinal tract (Klang et al. 2013). While small volumes of highly osmolar substances are usually diluted in the stomach, administration of a large volume (suitable for adult doses) can result in undiluted product entering the small intestine (Williams 2008). In addition, certain feeding tubes may deliver medications directly to duodenum or jejunum, which are particularly sensitive to highly osmolar formulations. The high osmolar load in the small intestine often results in GI intolerance, commonly manifesting as osmotic diarrhea. A study found that 61% of diarrhea cases in tube-fed patients were directly attributed to medication effects rather than the feeding formula (Edes et al. 1990). Unfortunately, nearly all commercially available liquid dosage forms of commonly used medications significantly exceed the osmolar range of the GI tract, thus requiring dilution prior to administration via feeding tubes (Klang et al. 2013).

328

Bezoar Formation Patients receiving enteral nutrition through feeding tubes can sometimes form bezoars, which are an accumulation of indigestible foreign material in the gastrointestinal tract. In many of the bezoar formation cases reported in literature, enteral nutrition was co-administered with medications such as sucralfate or aluminum hydroxide antacids (Anderson et al. 1989; Krupp et al. 1995; Marcus et al. 2010; Schulthess et al. 1986). As such, administering aluminum-containing antacids or sucralfate to patients receiving caseincontaining tube feeding formulas should be minimized to avoid the risk of bezoar formation. Sodium polystyrene sulfate (Kayexelate) and calcium polystyrene sulfate have also been reported to induce bezoars when administered via an enteral feeding tube, although the risk is also present with oral administrations (Croitoru et al. 2015; Lai et al. 2013).

Prevention and Management Clinicians should be familiar with medication dosage forms that cannot be crushed. Most institutions compile “Do Not Crush” lists which contain formulary medications that cannot be crushed. These references should be consulted prior to initiating enteral therapy for patients with feedings tubes. An institution-agnostic list is also maintained online by the Institute for Safe Medication Practices (ISMP). Proper medication administration technique is crucial for preventing adverse events (Bankhead et al. 2009). Medications should never be mixed with enteral formula. Tablets should be crushed and dissolved in water, while gelatin capsules should be opened and the contents emptied and dissolved in water. The feeding tubes need to be flushed with 15–30 mL of sterile water before and after the administration of each medication. Commercially available liquid dosage forms should be diluted prior to administration to prevent GI intolerance, ideally to 250 mg/m2), cyclophosphamide (>1,500 mg/m2), doxorubicin (>60 mg/m2), epirubicin (>90 mg/m2), ifosfamide (>2 g/m2 per dose), mechlorethamine, and streptozocin

A. J. Podolski and R. Gucalp

(Grunberg et al. 2005). In order to prevent acute and delayed emesis with these agents, it is recommended that patients be pretreated with an NK1 receptor antagonist (e.g., aprepitant or fosaprepitant), a 5-HT3 receptor antagonist (e.g., ondansetron, palonosetron, or granisetron), and dexamethasone (Grabenbauer and Holger 2016). Olanzapine may also be added. Dexamethasone and olanzapine can be continued on days 2–4 post chemotherapy to further prevent vomiting. The agents/regimens that pose a moderate risk of emesis (>30%–90% frequency of emesis) include arsenic trioxide, azacitidine, bendamustine, busulfan, carboplatin (AUC 14 per week or > 4 drinks per occasion) involves on average 2–3% women and 9–10% men aged over 65 years (Moore et al. 2011). Excessive alcohol intake leads to malabsorption of several nutrients; for example, alcohol decreases folate binding at the enterocyte (Hamid and Kaur 2007) and possibly interferes with the enterohepatic circulation, causing folate deficiency (Hamid et al. 2009). Alcohol also increases renal excretion of folate and has an overall negative impact with regard to the nutrient. The magnitude of red wine and its effects on the CYP3A substrates vary with the amount and type of wine consumed; red wine components, trans-resveratrol and gallic

392

acid, inhibit CYP3A in noncompetitive reversible manner, although enteric inhibition is not clear. Beer has several phenolic acids and flavonoids, used for flavor and preservation; among the several types of beers, some are capable of inducing the inhibition of CYP3A4-mediated metabolism substantially (Choi and Ko 2017). In a study, 20% of older adults manifested drug–alcohol interactions; the most involved included men between in the age group 65– 74 years, followed by ages 75–85 years, nonHispanic white population, more educated, and wealthier individuals; they were at risk for drug–alcohol interactions if they consumed alcohol regularly. Antidepressants and analgesics (aspirin, acetaminophen, narcotics) were the most common medications with interactions; others were anxiolytics, sedative hypnotics, psychotropics and antidiabetic medications. Such individuals should be counseled and warrant education regarding the interactions. There were also differences in gender and age-related variations in the type of drugs ingested by those who drank excessively. Many emergency room visits and hospitalizations appear related to alcohol–drug interactions (Qato et al. 2015). Of interest DNIs may affect cognitive health. In a prospective cohort study, the Baltimore Longitudinal Study of Aging, cognitive outcomes were studied; alcohol and caffeine intake and nutrient adequacy were estimated. Caffeine intake was associated with better baseline global cognition performance, better baseline verbal memory, and slower rate of decline in attention domain (women); alcohol consumption was associated with slower improvement on letter fluency and global cognition over time, but in women 70 years, associated with better baseline attention and working memory. In summary, diet and cognition factors indicate associations with sex and age, although more studies are indicated in large samples (Beydoun et al. 2014). Alcohol and nutrient

S. G. Gunturu and T. S. Dharmarajan

status are also discussed in the chapter on B12 and folic acid. • Caffeine: Caffeine is the ingredient derived from the plant Coffea arabica, originating in Ethiopia. Caffeine may be the mostly commonly used psychoactive substance in regular use (Cappelletti et al. 2018). Caffeine is a white crystalline xanthine alkaloid that tastes bitter. Average daily caffeine intake in the USA ranges from 186 to 226 mg/d (Fulgoni et al. 2015) while other sources place the amount at approximately 300 mg/day per individual, three times the global average. (Gilbert 1984) Caffeine amount varies widely from 71–220 mg per 150 mL of coffee, 32– 42 mg per 150 mL of tea, and 32–70 mg per 330 mL of cola. (Nehlig 1999; Gilbert 1984). Energy drinks contain 70–100 mg caffeine per serving. It is detected in significant amounts in coffee-flavored, tea-flavored, and chocolate-flavored products and many energy drinks. Caffeine is typically used to stay awake and alert; as a popular beverage, it may be second only to water, with 1.6 billion cups consumed daily worldwide (Cappelletti et al. 2015). Caffeine is a methylxanthine compound that stimulates the central nervous system function though locomotor activity enhancement and anxiogenic properties, while its cardiac effects are positive inotropic and chronotropic effects. The mechanisms of action are complex and may include adenosine antagonism, intracellular calcium shifts, and inhibition of phosphodiesterase (Cappelletti et al. 2015). Caffeine is almost 100% bioavailable, easily and quickly absorbed with 99% of the oral dose absorbed within 45 min of ingestion (Blanchard and Sawers 1983). To evaluate the adverse events resulting from caffeine-containing products reported to the US Food and Drug Administration (FDA), retrospective data was collected from 2014 through 2018, on more than 23,000 reports to the FDA. Energy (weight loss) and pre-workout products saw an increase in the odds of

13

Drug–Nutrient Interactions

adverse events experienced, being death rather than less severe outcomes, when compared to non-caffeinated products, calling for healthcare providers to use this information to better educate patients regarding caffeine intake (Jagim et al. 2020). An accompanying editorial sums up the story of caffeine and its serious adverse effects eloquently (Lieberman 2020). Caffeine, a stimulant, is not a drug of abuse and is safe in low or moderate doses as seen in beverages. It acts through inhibition of adenosine receptors and affects several organs including central nervous system and cardiovascular function; however, it appears that serious adverse events are likely only when large doses of caffeine are ingested (Lieberman 2020). Caffeine is also available as powder or tablets; it is an ingredient of coffee, tea, and energizing drugs, besides medications. Plasma levels of caffeine at 15 mg/L or more can be associated with seizures, arrhythmias, and death, while 3–6 mgs are safe. Toxic levels are seen in athletes and those with psychiatry disorders. Caffeine intoxication (or “caffeinism”) manifests as agitation, restlessness, insomnia, tremors, gastrointestinal complaints, and death, typically from ventricular fibrillation, usually at levels of 80 mg/L (Cappelletti et al. 2018). Caffeine is metabolized by cytochrome P450 system and competitively interacts with substrates. Caffeine intake on a chronic basis over 300 mg per day increases bone loss by inhibiting osteoblast formation and decreasing vitamin D receptor expression, an observation made in lean postmenopausal women. (Rapuri et al. 2007; Korpelainen et al. 2003) The caffeine-induced urinary calcium loss from coffee is not sustained over 24 h and can be somewhat countered by consuming a glass of milk for each serving of coffee ingested. (Hallström et al. 2006) Caffeine potentiates antimigraine medications(Eadie 2001) and decreases efficacy of antiseizure medications (Jankiewicz et al. 2007) and understandably, sedatives

393

(Cysneiros et al. 2007). Although tea also contains caffeine, its other components such as flavanoids may favorably influence BMD to protect against osteoporosis; the effect of habitual tea drinking on bone density is small as shown in studies and does not significantly alter fracture risk in postmenopausal women. (Hegarty et al. 2000; Chen 2003; Devine et al. 2007) Table 6 provides caffeine-related interactions. • Green Tea: Green tea (GT) is consumed either as a tradition in several cultures or for the purported health benefits. GT may alter the kinetics and dynamics of several medications, such as certain statins, warfarin, nadolol, sildenafil, and tacrolimus, leading to either reduced drug efficacy or drug toxicity. The mechanisms are complex and involve influx transporters or the CYP3A system. Interindividual variability further compounds the difficulty in accurately predicting the interactions; further studies are warranted (Werba et al. 2018). • Nicotine: Smoking decreases the levels of caffeine, theophylline, propranolol, heparin, and warfarin (Nathisuwan et al. 2011); smoking is a known inducer of the cytochrome 450 system and enhances more rapid clearance of some medications. Smoking slows insulin absorption after subcutaneous administration (Zevin and Benowitz 1999), increases peak levels and total absorption of inhaled insulin (Kroon 2007). It also decreases efficacy of inhaled steroids, (Kroon 2007) sedatives, and opioid analgesics. (Zevin and Benowitz 1999). • Vitamin D: Phenytoin, carbamazepine, levetiracetam, isoniazid, and rifampin increase metabolism of vitamin D through the cytochrome 450 system and decreases the vitamin levels in the blood. Patients on chronic intake of these drugs should be monitored for hypovitaminosis D and managed accordingly. Valproic acid interferes with hydroxylation of vitamin D in liver thereby decreases the effective form of vitamin D level. Calcium channel blockers, cimetidine, statins decrease endogenous production of vitamin D. Fibrates,

394 Table 6 Caffeine and drug interactions (Cooper et al. 2004; Houston 2010a; Brosen 1998; Gunturu and Dharmarajan 2012)

S. G. Gunturu and T. S. Dharmarajan Drug/Nutrient/Disease Minor Aspirin Dipyridamole Melatonin Cimetidine Nicotine Diazepam Grapefruit juice Moderate Adenosine Theophylline Atazanavir Ciprofloxacin Lithium Fluvoxamine Methotrexate (MTX) High blood pressure (Houston 2010a) Gastroesophageal reflux disease Major: Tizanidine Peptic ulcer

mineral oil, cholestyramine, colestipol, orlistat decrease absorption of vitamin D. Gabapentin interferes with vitamin D physiology at all levels such as absorption, production, and function; adequate vitamin D status reduces side effects of gabapentin. Oral steroids decrease the absorption of vitamin D; the action is used to therapeutic benefit in sarcoidosis where steroids help manage hypercalcemia through blocking intestinal absorption. Vitamin D amplifies digoxin effects and toxicity through an increase in calcium absorption from the gut. • Vitamin B12: Vitamin B12 is commonly prescribed and consumed by older adults. Although gastric acidity and intrinsic factor are required for vitamin B12 absorption, the literature has conflicting results in demonstrating the influence of a decline in acidity through proton pump inhibitors (PPI) and H2 blockers on B12 absorption and levels. (Dharmarajan et al. 2008; Dharmarajan and Norkus 2008; Ito and Jensen 2010). The study

Effect of caffeine Increased aspirin levels Decreased effect of dipyridamole Increased serum concentrations Caffeine effects may be increased Decreased caffeine activity Decreased serum levels Increases the effect of caffeine Decreased efficacy of adenosine Increased serum concentrations Increased serum concentrations Caffeine effects may be increased Increased renal lithium excretion Increased caffeine concentrations Decreased efficacy of MTX [>180 mg caffeine/ day] Increase in systemic vascular resistance Caffeine relaxes LES and worsens GERD Increased levels of tizanidine Caffeine stimulates gastric acid secretion

suggested that H2 receptor blockers had no effect on vitamin B12 status but long-term PPI use for years caused a decline in levels. (Dharmarajan et al. 2008) The difference between H2 blockers and PPIs on B12 status may relate to the more potent and prolonged acid suppression achieved by PPIs. (Dharmarajan et al. 2008). The findings were subsequently confirmed by a large-scale study from the USA where B12 deficiency was found to be more prevalent in current and prior users of gastric acid inhibitors for over 2 years (Lam et al. 2013). However, absorption of crystalline B12 supplements is not affected by inhibition of gastric acid. (Stover 2010) Long-term metformin therapy is now well accepted to affect vitamin B12 status by decreasing uptake of B12 at the calcium-dependent ileal cell membrane receptors (Liu 2006). This can be overcome with calcium supplementation (Liu 2006). Cholestyramine and colchicine can also decrease vitamin B12 absorption.

13

Drug–Nutrient Interactions

• Bisphosphonates: Oral bioavailability of most bisphosphonates is very low at 1–5%, being the reason to administer the drug only with water, on an empty stomach and about 30 min prior to intake of any food. (Ezra et al. 2000; Mitchell et al. 2000; Gertz et al. 1995) Food decreases the rate of absorption but not the extent of the absorption. (Umland and Boyce 2001). Milk, coffee, and orange juice decrease oral bioavailability(Gertz et al. 1995). Acid suppressants such as H2 receptor blockers increase bioavailability of bisphosphonates (Gertz et al. 1995). • Anti-hepatitis C medications St. John’s wort induces P glycoprotein and thereby significantly decreases plasma concentrations of sofosbuvir, Mavyret (glecaprevir and pibrentasvir), Zepatier (elbasvir and grazoprevir), VOSEVI (sofosbuvir, velpatasvir, and voxilaprevir), EPCLUSA® (sofosbuvir and velpatasvir) and may reduce their therapeutic effect. (https://www.accessdata.fda.gov/ drugsatfda_docs/label/2015/204671s002lbl.pdf accessed on 8/21/20) (https://www.accessdata.fda. gov/drugsatfda_docs/label/2017/209394s000lbl. pdf accessed on 8/21/20) (https://www. accessdata.fda.gov/drugsatfda_docs/label/2016/ 208261Orig1s000lbl.pdf accessed on 8/21/20) • Direct acting oral anticoagulants (DAOA) Dabigatran, rivaroxaban, apixaban can be given with or without food. Currently there is inadequate information on herb–drug interactions involving DAOAs (Nutescu et al. 2011; Di Minno et al. 2017).

Situations Pertinent to Older Adults Tube feeding: Many older adults in long-term care are dependent on enteral tube feeding and receive medications through the same tube, typically a

395

gastrostomy. Medications need to be administered with at least 30 mL of free water, and the tube must be flushed with free water before and after medication administration to minimize interactions and enhance bioavailability. Immediate release formulations or tablets are pulverized and mixed with free water before administration; they should never be mixed in the bag containing tube feeding formulations (TFF) (Williams 2008). Liquid formulations are preferred for jejunostomy tubes as they are small bored tubes, to minimize occlusion (Williams 2008). Enteric coated and extended release formulations will lose bioavailability characteristics if crushed and therefore must not be administered via enteral tubes (Beckwith et al. 2004). PPIs are best provided with acidic fruit juices via gastrostomy, but offered with milk or sodium bicarbonate slurry via jeunostomy (Brown and Dickerson 2000). Warfarin binds to enteral tubes irreversibly at variable rates, with decline in bioavailability; therefore concentrated warfarin is administered rapidly with free water flushes before and after the administration (Klang et al. 2010). Compatibility of liquid formulations of psychotropic medications is detailed in Table 6. Older adults on tube feeding may be on psychotropic medications for behavioral manifestations; drug–nutrient interactions pertinent to enteral feeding recommendations, are listed in Table 7. Some everyday interactions involving medications and food ingredients are common, yet seldom considered or addressed are the loss of electrolytes especially sodium, potassium, and magnesium along with water, with the chronic use of diuretics; lithium, a mood-stabilizing agent, also affects the sodium channel and sodium proton exchanger resulting in high lithium levels, a result of loss of sodium and water in the urine; correction involves withdrawal of the drug and

Table 7 Psychotropic liquid formulations and interactions (Muramatsu et al. 2010; Gunturu and Dharmarajan 2012) Medication Risperidone Fluphenazine Thioridazine Doxepin

Compatible with Water, coffee, orange juice, low fat milk Tomato juice, milk Acidic juices Ensure, TwoCal HN, milk, juices

Incompatible with Cola or tea Caffeine, tannins, apple juice Water, milk, caffeine, tea Carbonated beverages

396

replacement of water with electrolytes. Potassium levels are raised by commonly used medications such as ACE inhibitors, angiotensin receptor blockers or spironolactone, a potassium sparing diuretic; in this case potassium content of the diet may need to be addressed. Licorice, a sweetener used in the form of candy, contains glycyrrhizin, a sweet compound from the licorice root, an ingredient sweeter than cane sugar (sucrose). The active form, glycyrrhetic acid (more potent than glycyrrhizin), inhibits 11-βhydroxysteroid dehydrogenase enzyme with a resultant mineralocorticoid effect. Snacks containing licorice include candy sticks, toffee bars, cakes, drinks, beer, tea, gum, and laxatives. Licorice acts as an aldosterone-like agent and causes sodium retention, hypertension (when used chronically), and hypokalemia, through loss of potassium in the urine. Unlike in primary aldosteronism where there is no edema, licorice intake causes fluid retention (manifesting as edema or heart failure), arrhythmias, and a blunting of diuretic therapy. It is black licorice that needs to be restricted in terms of excessive consumption; red licorice is largely candy and lacks the harmful ingredient present in black licorice (Omar et al. 2012). A recent report illustrates the concern. A patient was in apparent good health until a hospitalization after cardiac arrest following ventricular fibrillation; the potassium levels at the hospital ranged from 2.0 to 3.1 mEq/L (with a solitary value of 3.5 soon after arrival, all others lower). He was eating poorly, primarily several packs of candy daily; weeks prior to presentation; he had switched from eating fruit-flavored soft candy to licorice-flavored soft candy (which contains glycyrrhizic acid). The patient died 32 h after presentation (Edelman et al. 2020). Of note, only black licorice is associated with such adverse effects. Parenteral nutrition and interactions: Although this feeding route is today an uncommon mode of nutrition in geriatric patients, it is worthwhile reviewing the compatibility of various medications with parenteral nutritional formulations. Intravenous lipid formulations derived from phytosterols (safflower and soybean oil) contain vitamin K, a factor that lowers the INR of patients on warfarin (Brown and Dickerson 2000). Drug

S. G. Gunturu and T. S. Dharmarajan

compatibility and interactions with regard to parenteral nutrition are listed in Tables 8 and 9.

Herbs, Vegetables, Supplements, and Drug Interactions Herbs are of plant origin, inclusive of any part from root to flowers or seeds. Herbal medications are used by 20–49% of the US population for a variety of reasons. Herbal medicines are regarded to be safe by many and considered an answer to good health or the solution to many chronic illnesses with poor response to traditional medications or allopathic medicine. Herbs are taken for a variety of reasons, along with prescribed drugs, leading to interactions, which have now risen to prominence since the findings pertinent to grapefruit juice interactions. The NHANES data on nearly 38,000 noninstitutionalized US adults (1999–2012) revealed that 52% of US adults were using supplements (Kantor et al. 2016). In the USA, herbs are regarded as dietary supplements; they are easily available over the counter, but unlike drugs are not tightly regulated by the FDA with regard to accuracy of ingredients and safety (Gardiner et al. 2007; Sorenson 2002). In fact, there appears to be batch to batch and even bottle to bottle variations (within a pack) in the consistency or composition of supplement products. The most commonly used herbals, based on sales in the USA are echinacea, garlic, ginkgo biloba, saw palmetto, ginseng, grape seed extract, green tea, St. John’s wort, bilberry, and aloe; systematic reviews suggest few are likely to be effective (Bent 2004). Herbs contain potent bioactive substances that may benefit from more stringent regulation, as with prescribed drugs (Bent 2004). Several of the herb–drug interactions are a result of the impact on pharmacokinetics. A few examples of clinically significant drug–herbal interactions are: ginkgo biloba, increasing risk of bleeding through interactions with warfarin, aspirin, or NSAIDs; ginseng increasing risk of hypoglycemia by interacting with oral antidiabetic medications; St. John’s

13

Drug–Nutrient Interactions

397

Table 8 Drug-enteral nutrition interaction and aRecommendations (Wohlt et al. 2009) 1. Acyclovir, valacyclovir (Grade 2C): No medication administration changes required. 2. Aminophylline (Grade 1A): High protein and carbohydrate diets decrease absorption. 3. Amiodarone (Grade 2C): No medication administration changes required. Drug is administered with meals, as food increases the rate and amount of absorption. 4. Amoxycillin-clavulanic acid (Grade 2C): No medication administration changes required; fasting decreases the absorption rate. 5. Azithromycin (Grade 2C): For tablet form, no administration changes required. 6. Carbamazepine (Grade 2B): Suspension must be diluted with equal amounts of water; when provided with tube feeding formulations, bioavailability is significantly reduced. 7. Cimetidine and ranitidine (Grade 2B): No administration changes required. 8. Ciprofloxacin (Grade 2B) and levofloxacin (Grade 2C): are not administered via feeding tubes; food is provided an hour before or 2 h after ciprofloxacin. 9. Clindamycin (Grade 2C): No medication administration changes required. 10. Cyclosporine (Grade 2C): No medication administration changes required 11. Diazepam (Grade 2B): Solution form not to be given via enteral feeding tubes; tablets preferred. 12. Diltiazem (Grade 2C): No medication administration changes are needed. 13. Fluconazole (Grade 1A): No medication administration changes required. 14. Hydralazine (Grade 2B): No medication administration changes required. 15. Lansoprazole, pantoprazole, and omeprazole (Grade 2B): Separate from food intake by an hour before and after medication. For tube feeds lansoprazole in granules can be given either with acidic juices (apple or orange) or alkaline solutions (sodium bicarbonate) depending on the diameter of the enteral tube (for small tubes prefer alkaline, for large, prefer acidic juices). 16. Levothyroxine (Grade 2B): Separate food from drug by an hour before or after administration. 17. Linezolid (Grade 1A): No medication administration requirements. 18. Lorazepam (Grade 2C): No medication administration requirements. 19. Metoprolol (Grade 2C): No medication administration requirements. 20. Metronidazole (Grade 2C): No medication administration requirements. 21. Penicillin V (Grade 2B): Must be separated from food intake by an hour before and 2 h. 22. Phenytoin (Grade 2B): Must be separated from food intake by an hour before and 2 h. 23. Tacrolimus (Grade 1B): No medication administration requirements. 24. Theophylline (Grade 2B): Separate food from drug by an hour before and after administration. 25. Valproic acid (Grade 2C): No medication administration requirements. 26. Warfarin (Grade 2B): Separate food from medication by an hour before and after administration. Caution with use of ginger, garlic, ginkgo, and soy protein containing formulations. a

Recommendations may be: Grade 1A: Strong recommendations with high quality of evidence Grade 1B: Strong recommendations with moderate quality of evidence Grade 1C: Strong recommendations with low quality of evidence Grade 2A: Weak recommendations with high quality of evidence Grade 2B: Weak recommendations with moderate quality of evidence Grade 2C: Weak recommendations with low quality of evidence

Table 9 Drug incompatibility with parenteral nutrition (Mirtallo 2004) Aminoacids and carbohydrates in solution: Penicillins, cefazolin, metoclopramide, midazolam, phenytoin, sodium and potassium phosphate, sodium bicarbonate, cyclosporine, furosemide, cisplatin, cytarabine, methotrexate, doxorubicin, fluorouracil, amphotericin B, acyclovir, ganciclovir, and immune globulins. Aminoacids, carbohydrates, and fat emulsions: Ondansetron, erythromycin, haloperidol, lorazepam, midazolam, phenytoin, hydromorphone, morphine (high concentrations), cyclosporine, dopamine, doxorubicin, fluorouracil, acyclovir, gancyclovir, heparin, and immune globulins.

398

Wort, decreasing efficiency of digoxin, calcium channel blockers, warfarin, statins, and cyclosporine (Mouly et al. 2017). St. John’s Wort is a potent inducer of CYP450 enzymes and P-glycoprotein; it decreases the levels of cyclosporine, simvastatin, midazolam, nifedipine, theophylline, warfarin, amitriptyline, HIV protease inhibitors, and non-nucleoside reverse transcriptase inhibitors, phenytoin, phenobarbitone, warfarin, digoxin, and tacrolimus; it potentiates sumatriptan and selective serotonin re-uptake inhibitors (Hammerness et al. 2003; Henderson et al. 2002; Mason 2010). The hyperforin content of St. John’s wort determines the interaction of the herb with the CYP3A4 or p-glycoprotein substrates (ChrubasikHausmann et al. 2019). Another complex, but relevant fact is that the reactions can vary with different herbs and a single drug; the illustration is particularly relevant with a drug such as warfarin. The consequence may be either bleeding or loss of drug efficacy and thrombosis. Based on the evidence, alcohol and fish oil have a high probability of potentiating warfarin effect, while enteral feeding would inhibit the effect; on the other hand, cranberry juice has a low probability of potentiating the effect; while ginkgo has little to no expected effect (Mouly et al. 2017). The reactions may be difficult to comprehend for providers. Table 10 lists documented, inconclusive, and anticipated interactions of herbal medicines with food and involvement of the cytochrome isoenzymes in humans (Nowack 2008). Table 11 offers additional information on herbals, dietary supplements, and drug interactions.

S. G. Gunturu and T. S. Dharmarajan

Fruits, Juices, and Drug Interactions Fruit juice is derived from squeezing or crushing fresh fruit (Chen et al. 2018). Grapefruit juice (GPJ) and grapefruit are popular. With the USA being the largest supplier and consumer of grapefruit, many enjoy the beverage. Of all the fruits and fruit juices, GPJ has attracted significant attention largely due to the potential for drug interactions. GPJ is a lowcalorie beverage with about 40 Kcal in 100 ml of juice; it provides B and C vitamins, as also potassium and magnesium, with a glass providing a significant portion of the daily requirements of the nutrients (Ivanova et al. 2018). The active ingredient in grapefruit is furanocoumarin, which is not found in sweet orange juice (and therefore there are no interactions), although furanocoumarins are present in bitter (Seville) orange, lime, and pomelo with consequent interactions. About 200 ml of GPJ suffices for pharmacokinetic alterations, while larger amounts amplify the interaction. The CYP3A4 isoform of CYP450 is located in the liver and enterocytes and accounts for much drug metabolism. The inhibition of CYPA4 in the small intestine is irreversible and prolonged, hence it does not make much difference by separating the ingestion of juice and medications by even hours. If the reaction is profound, it may be better to avoid GPJ consumption. All forms of juice and the whole fruit can inhibit intestinal CYP3A4 activity; for the activity to occur, the drug must be in oral form (not intravenous) and undergo metabolism through CYP3A4. There may be a difference between white and pink GPJ, with the white juice acting faster with regard to acetaminophen interactions (Say et al. 2017).

Table 10 Level of evidence for interactions of select foods and herbs with CYP system (Nowack 2008; Poor et al. 2017; Tapaninen et al. 2010; Chretien et al. 2020) Well documented Food: grape fruit juice, pomelo juice, bitter oranges, red wine, white wine. Medicinal herbs: St. John’s Wort, herbal teas, goldenseal. Inconclusive evidence Food: Coffee, garlic, pepper, cranberry juice, tangerine. Medicinal herbs: Ginkgo, ginseng, milk-thistle, saw-palmetto, echinacea, black cohosh, valerian. Anticipated risk of interactions (in vitro evidence) Food: Soy protein, pomegranate juice, fish oil. Medicinal herbs: Kava, feverfew, cat’s claw, frankincense, dong quai, phellodendron, evening primerose.

13

Drug–Nutrient Interactions

399

Table 11 Commonly used herbs, dietary supplements, and drug interactions (Ernst 2002; Sanchez-Muniz et al. 2009; Ovesen et al. 1988; Deferme et al. 2002; Al-Ghazawi et al. 2010; Houston 2010b; Wittkowsky 2008; Ansell et al. 2009; Pae et al. 2007; Lourenco 2001; Sorenson 2002; Chen et al. 2018; Mouly et al. 2017) Herb Ginkgo (Bush et al. 2007; Mouly et al. 2017) Kava (Ernst 2002) Glucosamine (Bush et al. 2007) CoenzymeQ10 (Bush et al. 2007) Olive oil (Sanchez-Muniz et al. 2009) Echinacea (Bush et al. 2007) Garlic (Bush et al. 2007) Saw palmetto, flaxseed oil (Bush et al. 2007) Brussels sprouts and cruciferous vegetables (Ovesen et al. 1988) Pomelo juice (Al-Ghazawi et al. 2010; Chen et al. 2018) Green tea, black tea, seaweed (wakame), carotenoids (Houston 2010b) Cranberry juice (Wittkowsky 2008; Ansell et al. 2009; Chen et al. 2018) Fish oils and vitamin E (Lourenco 2001) Tomatoes, egg plants, potatoes (Sorenson 2002) Licorice (Bush et al. 2007) Soybeans, broccoli, cauliflower (Sorenson 2002) Guar gum (Sorenson 2002) Black pepper, piperine (Han 2011) Ginseng (Mouly et al. 2017) St. John’s wort (Mouly et al. 2017)

Aloe, Ma-huang (Mouly et al. 2017) Slavia (Mouly et al. 2017)

Effect Increase in serum concentrations of acetaminophen, diazepam, tramadol, simvastatin, amitriptyline, aspirin, losartan and decreased therapeutic efficacy of sodium valproate Increase effects of anxiolytics and alcohol Decreases analgesic effect of acetaminophen Potentiates hypoglycemic effect of glyburide Enhances effects of thiazides, fosinopril, metformin, and glipizide. Increases hypolipidemic action of statins Increases the drug level of simvastatin, lansoprazole, and losartan Increase effects of simvastatin, warfarin, ibuprofen, and antihypertensive medications Increase bleeding complications of aspirin and warfarin Increases the metabolic clearance of warfarin Decreases bioavailability of sildenafil by 40% and increases bioavailability of cyclosporine Potentiate antihypertensive medications Uncertain effect on warfarin and diclofenac; increased bioavailability of triple therapy and improve eradication rate of H.pylori Increase the effects of anticoagulation Delay recovery from anesthesia by inhibiting cholinesterases Decreases the effects of antihypertensives Predisposes for hypothyroidism and goiter Decreases absorption of metformin Short term: increases bioavailability of phenytoin, propranolol, theophylline, nevirapine, rifampin, and coenzyme Q10. Increased risk of hypoglycemia with oral hypoglycemics Decreased efficacy of digoxin, ivabradine, nifedipine, talinolol, verapamil, indinavir, nevirapine, cyclosporine, tacrolimus, OCPs, anticoagulants, BZDs, amitriptyline, buspirone, methadone, sertraline, phenytoin, simvastatin, atorvastatin, imatinib, irinotecan, omeprazole, cimetidine Laxative effect causes increased risk of cardiac arrhythmias, increased risk of HTN with MAO inhibitors Increased bleeding risk with Vitamin K antagonists

The increase in drug activity can be modest or marked. Although adults of all ages enjoy GPJ and grapefruit, older adults are on multiple medications, hence the greater potential for more adverse effects. Further, GPJ and orange juice may also manifest the reverse effect (decreased absorption of drugs) through a different mechanism via a transporting polypeptide, causing the

opposite effect. (Chretien et al. 2020) There is variability in magnitude of interactions among different individuals; studies are being attempted to forecast the interactions, although this appears a complex process. The ultimate options for provider and patient may well be: if grapefruit is consumed, monitor for adverse drug effects; versus the recommendation to avoid grapefruit (and

400

Seville orange and pomelo); or use an alternate non-reacting drug (Bailey 2017). Importantly, interactions between GPJ and medications depend on the individual drug and not the drug class (Say et al. 2017). GPJ inhibits intestinal cytochrome P450 isoenzymes, 11B-hydroxysteroid dehydrogenase, OATP-A transporter protein, and P-glycoprotein efflux transporter protein (Boobis et al. 2009) thereby increasing bioavailability of nicardipine, nimodipine, felodipine (Sica 2006), cyclosporine (Chan 2001; Chen et al. 2018), diazepam, midazolam, erythromycin, lovastatin, simvastatin, sildenafil, buspirone, tacrolimus (Dharmarajan and Pitchumoni 2002), atorvastatin, and sertraline (Genser 2008). GPJ inhibits OATP-A and B transporters decreasing bioavailability of fexofenadine and aliskiren (Tapaninen et al. 2010). Interestingly, GPJ does not affect levels of fluvastatin, pravastatin, and rosuvastatin, as they are not metabolized by CYP 3A4 intestinal enzyme. The inhibition appears to have minimal effect on hepatic enzymes. By inhibiting the metabolism of drugs, there is an increase in plasma drug concentration and area under the concentration time curve (AUC). GPJ increases the systemic bioavailability and cardiac repolarization of terfenadine in poor metabolizers of the drug, and does not reduce the oral bioavailability of desloratadine (Boobis et al. 2009). Naringenin, a flavanoid component of citrus juices such as grapefruit and orange, interacts with amiodarone, quinidine, and dofetilide increasing risk for arrhythmias (Lin et al. 2008). Decades ago, whole grapefruit was perceived not to have similar interactions (Brown and Dickerson 2000), but the current view is that both grapefruit and GPJ are associated with drug interactions. Rather than forbidding patients from consuming grapefruit juice, they may be told to consume juice in reasonable amounts maintaining regularity in habits for both the juice and medications; there may be exceptions to this advice and individualizing GPJ consumption and medication prescriptions is best (Dharmarajan and Pitchumoni 2002). When there is the potential for interaction, an alternate drug may deserve consideration. With regard to medical advice on avoiding GPJ while

S. G. Gunturu and T. S. Dharmarajan

taking statins, the validity was tested using a daily glass of GPJ and its impact on blood levels with simvastatin, lovastatin, and atorvastatin. When GPJ and statin were taken at the same time the drug levels went up higher as compared to 12 h apart; accordingly the impact on lowering the LDL was higher when drug and GPJ were taken together and correspondingly the impact on coronary artery disease (Lee et al. 2016). The authors believe GPJ consumption should not be regarded as a contraindication while on statins, and the focus on risk of rhabdomyolysis as a result of GPJ consumptions with statins ignores the far greater benefit on LDL cholesterol from statins. Further, GPJ does not interact with all statins as a class effect; fluvastatin and rosuvastatin are metabolized by CYP2C9, with no interaction (Lee et al. 2016; Choi and Ko 2017). Apple, grapefruit, and orange juice are considered potent inhibitors of organic anion transporting polypeptides such as OATPB1 and OATPA2. Apple juice has flavonoids, which are responsible for the effect (Chen 2018). Atenolol, celiprolol, and fexofenadine are considered the most sensitive substrates of these transporters and almost 85% of the drug absorption can be inhibited by these juices (Yan 2017). Orange juice can also decrease bioavailability of montelukast, alendronate, and fluoroquinolones. On the other hand, orange juice significantly increases the absorption of iron, through its vitamin C content, a property that can be utilized in the management of iron deficiency anemia (Chen 2018). Pomelo juice can increase concentrations of cyclosporine and decrease bioavailability of sildenafil. Lime juice is stated to interact with anti-epileptic drugs (Chen et al. 2018). Cranberry juice can increase the bioavailability of triple therapy medications for H. pylori thereby increasing the eradication rate (Shmuely et al. 2007). Cranberry juice appears not to alter the pharmacokinetics of warfarin. Blueberry juice can improve efficacy of etanercept. Wheatgrass juice can reduce side effects of fluorouracil, adriamycin, and cytoxan (Chen et al. 2018). Grapefruit, Seville orange (bitter orange), pomelo, and lime juice have furanocoumarins, which strongly and irreversibly inhibit intestinal CYP3A4. New CYP3A4 synthesis takes at least

13

Drug–Nutrient Interactions

24 h and complete reversal of these interactions at this intestinal enzyme level takes at least 72 h. Thus, ingestion of drug and these juices may need to be separated by at least 3 days for the effect to fully wear off. Clopidogrel bioavailability is decreased by these juices (Mouly et al. 2017). Sweet oranges are crossbreeds of pomelo and mandarins; clementines are crossbreeds of sweet orange and mandarins; grapefruits are hybrids of pomelo and sweet orange. Clementine juice has similar drug–nutrient interactions as grapefruit juice; both increase tacrolimus levels by inhibition of CYP3A4 (Poor et al. 2017). While all citrus juices induce drug transporters and drug metabolizing enzymes, GPJ has more profound effects; a paper comments on 156-fold and 34-fold induction of CYP450 by grapefruit juice and clementine juice, respectively. Pomegranate juice appears not to have a clinically relevant inhibitory potential on CVP4503A4 activity, as seen in a study where the mean levels of simvastatin were increased by grapefruit juice but not by pomegranate juice (Park et al. 2016). Table 12 provides interactions between drugs and juices. Tangerine can increase bioavailability of nifedipine and digoxin by stimulating CYP3A4 activity and inhibiting P glycoprotein. Mango can increase bioavailability of midazolam, diclofenac, verapamil by inhibiting cytochrome P450 enzyme system and P glycoprotein. Bananas are enjoyed by most people; they appear to decrease the potency of perhaps the most commonly used

401

analgesic, acetaminophen; the interaction results from the oxidation of acetaminophen by polyphenol oxidase activity in banana pulp, as noted in in vitro studies (Uesawa and Tsuji 2018). In summary, clementine juice, Seville orange, pomelo, and GPJ (and to a smaller extent mandarin juice) can induce drug metabolizing enzymes with potential for significant interactions (Theile et al. 2017). Table 13 lists the salient properties of GPJ.

Fruits or Fruit Juices? Which is the form that interacts more with medications? Some of the earlier literature stated that GPJ is associated with DNI, while the whole fruit is not. Currently it is believed that both unprocessed grapefruit and commercial GFJ are associated with drug interactions, calling for caution regarding therapeutic concerns with both the juice and the whole fruit. In the case of other fruits, the evidence appears less clear (Chen 2018). Many fruit drinks do not contain any fruit extract but only a fruit flavor.

Other Interactions Milk can decrease bioavailability of ciprofloxacin and tetracycline by complex formation with multivitamin cations present in the milk. Cow’s milk can decrease mercaptopurine bioavailability by

Table 12 Drug nutrient interactions and pharmacodynamics involving grapefruit juice, seville orange, and pomelo juices (Mouly et al. 2017) Antihypertensives – calcium channel blockers: weakness, hypotension, pedal edema Tyrosine kinase inhibitors such as erlotinib, nilotinib, crizotinib, vemurafenib, and anti-infective drugs such as erythromycin, primaquine, halofantrine, maraviroc, rilpivirine, and quinine: torsade de pointes and bone marrow suppression Sedatives such as midazolam and triazolam: increased bioavailability, increased sedation Immunosuppressants such as cyclosporine, everolimus, sirolimus and tacrolimus: nephrotoxicity and bone marrow suppression Cardiovascular medications such as amiodarone, apixaban, eplerenone, quinidine, rivaroxaban, ticagrelor, ivabradine: gastrointestinal bleeding, torsades de pointes and cardiac arrhythmias and hyperkalemia Increased bioavailability of oxycodone, fentanyl, alfentanil, pimozide and quetiapine: increased sedation and torsade de pointes Increased bioavailability of buspirone, dextromethorphan, ketamine, lurasidone: hallucinations, dizziness, increased sedation Increased bioavailability of domperidone (not available in USA): torsades de pointes Increased bioavailability of simvastatin and atorvastatin: may cause rhabdomyolysis

402

S. G. Gunturu and T. S. Dharmarajan

Table 13 Grapefruit juice interactions: salient facts (Bailey 2017; Choi 2017) Grapefruit juice is a common, popular beverage consumed by many adults (primarily over age 45 years) on multiple drugs The juice is a low-calorie beverage, which increases its popularity All forms of grapefruit and the juice are capable of drug interactions The juice causes inhibition of 50% CYP3A4 in the small intestines within 4 h of ingestion and to a much lesser extent in the liver The active constituent in GPJ is furanocoumarins The inhibitory action lasts well for over 24 h For a DNI, the drug must be taken orally, have low oral bioavailability and must be metabolized by CYP3A4 The separation of juice ingestion and medication intake by a few hours makes no difference There are benefits; e.g., increased bioavailability of statins and calcium channel blockers with better therapeutic benefit for cardiovascular health Some medications may also be rendered less bioavailable by GPJ The risk of rhabdomyolysis from GPJ interactions with statins is small in contrast to the marked benefits for health from enhanced statin efficacy Consumption of small amounts of GPJ is acceptable in those taking statins The most commonly used drugs that interact with GPJ include statins, calcium channel blockers, angiotensin receptor blockers, some beta blockers and anti-arrhythmic drugs, and vinblastine

Table 14 Antihistamines and food interactions (Pasko et al. 2017) Apple and orange juice decrease absorption of fexofenadine Food increases absorption of ebastine, loratadine, rupatadine (not available in USA), and decreases absorption of fexofenadine; no effect on absorption of cetirizine, desloratadine, levocetirizine Grapefruit juice increases absorption of rupatadine, but has no effect on absorption of cetirizine, desloratadine and decreases absorption of fexofenadine Alcohol has no significant interactions noted with low doses of bilastine, loratadine, desloratadine, ebastine, low doses of fexofenadine, mizolastine, low doses of rupatadine

stimulating xanthine oxidase. Piperine, an active ingredient of black pepper, may alter the bioavailability of drugs via these mechanisms: inhibiting CYP450 family of enzymes, to increase bioavailability of phenytoin, propranolol, cyclosporine A, and digoxin. (Han 2011). Flaxseed can increase tamoxifen effectiveness by estrogen receptor and growth factors signaling pathways (Amadi and Mgbahurike 2018). Turmeric can have anticoagulant effects, hypoglycemic effect, antiestrogenic effect, inhibition of cytochrome P450 system and drug transporters such as P-glycoprotein. Soy can bind to estrogen receptors and can have diuretic effect, hypoglycemic effect, inhibition of cytochrome P450, and biotransformation by gastrointestinal flora. Tyramine in fermented soy products can have interactions with MAO inhibitors; it can cause hypotension when given with isoniazid (Mouly et al. 2017). Silymarin and milk thistle

can have glucose lowering effect, inhibition of cytochrome P 450 system, and UGT (uro-glucuronide transferase) (Koziolek et al. 2019). Antihistamines and their interactions with foods and alcohol are presented in Table 14.

The Goal: Minimize the Occurrence of DNIs Minimizing the occurrence of DNIs should be a goal for healthcare providers who care for older adults in any setting. Factors that limit understanding and limit provider efforts include time constraints, shorter hospital stays, inadequate understanding of the vast drug formularies and interactions, and inadequate efforts directed at medication reconciliation and diet history. Nutritionists, nurses, pharmacists, and physicians must

13

Drug–Nutrient Interactions

utilize multidisciplinary efforts and a coordinated approach to benefit patients and prevent adverse outcomes. Standard drug administration schedules, education of healthcare providers and involved staff, proper labeling, computerized drug interactions screening, and warning software along with patient counseling may be helpful in minimizing the occurrence of DNIs (Gauthier and Malone 1998).

Key Points • Drug–nutrient interactions are common in the geriatric population, due to the impact of agerelated physiological changes, presence of multimorbidity and polypharmacy. • DNIs involve pharmacokinetic and pharmacodynamic properties of medications, resulting in amplification or nullification of the drug or nutrient effect. • Foods may also delay or accelerate medication effects. • Examples of commonly used drugs involved in DNIs include warfarin, phenytoin, bisphosphonates, PPIs, antimicrobials, statins, antihypertensive agents, cyclosporine, and cardiac medications. • History should include all medications that the patient consumes, including herbs and supplements. • When assessing for DNIs, the history must elicit fruit juice, milk, and caffeine ingestion, amounts consumed and timing in relation to medication intake. • Long-term medication adverse effects cause nutrient depletion, typically vitamins and minerals. • Ginseng, gingko, Echinacea, St. John’s wort and saw palmetto, and other herbs may contribute to life-threatening drug interactions. • Garlic and ginger are food products and in usual amounts do not cause any fatal drug interaction. • Providers need awareness of drug interactions involving common dietary items such as grapefruit and other juices, green leafy vegetables, dairy products, and caffeine in view of their everyday use.

403

• The timing of medication intake in relation to meals and the vehicle used to ingest the drug matter. • As a general rule, to minimize DNIs and for reasonable absorption, medications are best administered with water as the vehicle. • Water taken with medications should be adequate to ensure easy passage through the esophagus. • Prevention of DNIs includes a periodic, meticulous medication history in every older adult, along with an enquiry about herbal and nutritional supplement intake. • Providers of care have a responsibility to offer instructions regarding medication intake in relation to meals, vehicle used to ingest the drug, and the timing of administration.

References Abad MJ, Bedoya LM, Bermejo P. An update on drug interactions with the herbal medicine Ginkgo biloba. Curr Drug Metab. 2010;11:171–81. Akamine D, Filho MK, Peres CM. Drug nutrient interactions in elderly people. Curr Opin Clin Nutr Metab Care. 2007;10:304–10. Alemdaroglu NC, Dietz U, Wolffram S, Spahn-Langguth H, Langguth P. Influence of green and black tea on folic acid pharmacokinetics in healthy volunteers: potential risk of diminished folic acid bioavailability. Biopharm Drug Dispos. 2008;29:335–48. Al-Ghazawi MA, Tutunji MS, Aburuz SM. The effects of pummelo juice on pharmacokinetics of sildenafil in healthy adult male Jordanian volunteers. Eur J Clin Pharmacol. 2010;66:159–63. Amadi CN, Mgbahurike AA. Selected food/herb-drug interactions: mechanisms and clinical relevance. Am J Ther. 2018;25:e423–33. Ansell J, McDonough M, Zhao Y, Harmatz JS, Greenblatt DJ. The absence of an interaction between warfarin and cranberry juice: a randomized, double-blind trial. J Clin Pharmacol. 2009;49:824–30. Armbrecht HJ, Boltz MA, Kumar VB. Intestinal plasma membrane calcium pump protein and its induction by 1,25 (OH)2D3 decrease with age. Am J Physiol Gastrointest Liver Physiol. 1999;277:G41–7. Bailey DG. Predicting clinical relevance of grapefruit-drug interactions: a complicated process. J Clin Pharm Ther. 2017;42:125–7. Beckwith MC, Feddema SS, Barton RG, Graves C. A guide to drug therapy in patients with enteral feeding tubes: dosage form selection and administration methods. Hosp Pharm. 2004;39:225–37.

404 Bent S. Commonly used herbal medicines in the United States: a review. Am J Med. 2004;116:478–85. Beydoun MA, Gamaldo AA, Beydoun HA, Tanaka T, Tucker KL, Talegawkar SA, Ferrucci L, Zonderman AB. Caffeine and alcohol intakes and overall nutrient adequacy are associated with longitudinal cognitive performance among U.S. adults. J Nutr. 2014;144:890–901. Blanchard J, Sawers SJ. The absolute bioavailability of caffeine in man. Eur J Clin Pharmacol. 1983;24:93–8. Boobis A, Watelet J-B, Whomsley R, Et AL. Drug interactions. Drug Metab Rev. 2009;41:486–527. Bressler R. Herb-drug interactions. Interactions between saw palmetto and prescription medications. Geriatrics. 2005;60(32):34. Brosen K. Differences in interactions of SSRIs. Int Clin Psychopharmacol. 1998;13(Suppl 5):S45–7. Brown RO, Dickerson RN. Drug nutrient interactions. Am J Manag Care. 2000;5:345–55. Bush TM, Rayburn KS, Houoway SW, Sanchez-Yamamoto DS, Allen BL, Lam T, So BK, Tran DH, Greyber ER, Kantor S, Roth LW. Adverse interactions between herbal and dietary substances and prescription medications a clinical survey. Altern Ther Health Med. 2007;13:30–5. Cappelletti S, Piacentino D, Sani G, Aromatario M. Caffeine: cognitive and physical performance enhancer or psychoactive drug? Curr Neuropharmacol. 2015; 13:71–88. Cappelletti S, Piacentino D, Fineschi V, Frati P, Cipolloni L, Aromatario M. Caffeine-related deaths: manner of deaths and categories at risk. Nutrients. 2018;10 Chan LN. Drug-nutrient interactions in transplant recipients. J Parenter Enter Nutr. 2001;25:132–41. Chan LN. Drug nutrient interactions in clinical nutrition. Curr Opin Clin Nutr Metab Care. 2002;5:327–32. Chan LN. Drug-nutrient interactions. J Parenter Enter Nutr. 2013;37:450–9. Chen Z. Habitual tea consumption and risk of osteoporosis: a prospective study in the Women’s Health Initiative observational cohort. Am J Epidemiol. 2003; 158:772–81. Chen M, Zhou SY, Fabriaga E, Zhang PH, Zhou Q. Fooddrug interactions precipitated by fruit juices other than grapefruit juice: an update review. J Food Drug Anal. 2018;26:S61–71. Choi JH, Ko CM. Food and drug interactions. J Lifestyle Med. 2017;7:1–9. Chretien ML, Bailey DG, Asher L, Parfitt J, Driman D, Gregor J, Dresser GK. Severity of coeliac disease and clinical management study when using a CYP3A4 metabolised medication: a phase I pharmacokinetic study. BMJ Open. 2020;10:e034086. Chrubasik-Hausmann S, Vlachojannis J, McLachlan AJ. Understanding drug interactions with St. John’s wort (Hypericum perforatum L.): impact of hyperforin content. J Pharm Pharmacol. 2019;71:129–38. Chua YT, Ang XL, Zhong XM, Khoo KS. Interaction between warfarin and Chinese herbal medicines. Singap Med J. 2015;56:11–8.

S. G. Gunturu and T. S. Dharmarajan Chung J, Kesisoglou F. Physiologically based Oral absorption modelling to study gut-level drug interactions. J Pharm Sci. 2018;107:18–23. Cooper M, Safran M, Eberhardt M. Caffeine consumption among adults on benzodiazepine therapy: United States 1988–1994. Psychol Rep. 2004;95:183–91. Custodio J, Wu C, Benet L. Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption☆. Adv Drug Deliv Rev. 2008;60:717–33. Cysneiros RM, Farkas D, Harmatz JS, Von Moltke LL, Greenblatt DJ. Pharmacokinetic and Pharmacodynamic interactions between Zolpidem and caffeine. Clin Pharmacol Ther. 2007;82:54–62. Dawson-Hughes B, Harris SS, Lichtenstein AH, Dolnikowski G, Palermo NJ, Rasmussen H. Dietary fat increases vitamin D-3 absorption. J Acad Nutr Diet. 2015;115:225–30. De Lemos ML, Hamata L, Jennings S, Leduc T. Interaction between mercaptopurine and milk. J Oncol Pharm Pract. 2007;13:237–40. Deferme S, Mols R, Van Driessche W, Augustijns P. Apricot extract inhibits the P-gp-mediated efflux of talinolol. J Pharm Sci. 2002;91:2539–48. Deng J, Zhu X, Chen Z, Fan CH, Kwan HS, Wong CH, Shek KY, Zuo Z, Lam TN. A review of food-drug interactions on Oral drug absorption. Drugs. 2017; 77:1833–55. Devine A, Hodgson JM, Dick IM, Prince RL. Tea drinking is associated with benefits on bone density in older women. Am J Clin Nutr. 2007;86:1243–7. Dharmarajan TS, Davuluri S. Prescribing medications for older adults: dealing with obesity, misuse, polypharmacy and adverse drug events! Bentham Books; 2015. Dharmarajan L, Dharmarajan TS. Prescribing warfarin appropriately to meet patient safety goals. Am Health Drug Benefits. 2008;1:26–32. Dharmarajan TS, Norkus EP. Does long-term PPI use result in vitamin B12 deficiency in elderly individuals? Nat Clin Pract Gastroenterol Hepatol. 2008;5:604–5. Dharmarajan TS, Pitchumoni CS. Drug-nutrient interactions in older adults. Pract Gastroenterol. 2002; 26:37–55. Dharmarajan TS, Yoo J. Estimated glomerular filtration rate and muscle mass in older patients: diagnostic accuracy of creatinine-based equations and implications in practice. J Am Med Dir Assoc. 2020;21:566–7. Dharmarajan TS, Pitchumoni CS, Kokkat AJ. The aging gut. Pract Gastroenterol. 2001;25:15–27. Dharmarajan TS, Kanagala MR, Murakonda P, Lebelt AS, Norkus EP. Do acid-lowering agents affect vitamin B12 status in older adults? J Am Med Dir Assoc. 2008; 9:162–7. Dharmarajan TS, Choi H, Hossain N, Munasinghe U, Lakhi F, Lourdusamy D, Onuoha S, Murakonda P, Skokowska-Lebelt A, Kanagala M, Russell RO. Deprescribing as a clinical improvement focus. J Am Med Dir Assoc. 2020;21:355–60.

13

Drug–Nutrient Interactions

Di Minno A, Frigerio B, Spadarella G, Ravani A, Sansaro D, Amato M, Kitzmiller JP, Pepi M, Tremoli E, Baldassarre D. Old and new oral anticoagulants: food, herbal medicines and drug interactions. Blood Rev. 2017;31:193–203. Eadie MJ. Clinically significant drug interactions with agents specific for migraine attacks. CNS Drugs. 2001;15:105–18. Edelman ER, Butala NM, Avery LL, Lundquist AL, Dighe AS. Case 30-2020: a 54-year-old man with sudden cardiac arrest. N Engl J Med. 2020;383:1263–75. Ernst E. The risk-benefit profile of commonly used herbal therapies: Ginkgo, St. John’s Wort, ginseng, Echinacea, saw palmetto, and kava. Ann Intern Med. 2002; 136:42–53. Ezra A, Hoffman A, Breuer E, Et AL. A peptide prodrug approach for improving bisphosphonate oral absorption. J Med Chem. 2000;43:3641–52. Fernandez R, Phillips SF. Components of fiber bind iron in vitro. Am J Clin Nutr. 1982;35:100–6. Floren CH, Nilsson A. Binding of bile salts to fibreenriched wheat fibre. Scand J Gastroenterol Suppl. 1987;129:192–9. Fulgoni VL 3rd, Keast DR, Lieberman HR. Trends in intake and sources of caffeine in the diets of US adults: 2001-2010. Am J Clin Nutr. 2015;101:1081–7. Gardiner P, Graham R, Legedza ATR, Et AL. Factors associated with herbal therapy use by adults in the USA. Altern Ther Health Med. 2007;13 Gauthier I, Malone M. Drug-food interactions in hospitalised patients – methods of prevention. Drug Saf. 1998;18:383–93. Ge B, Zhang Z, Zuo Z. Updates on the clinical evidenced herb-warfarin interactions. Evid Based Complement Alternat Med. 2014;2014:957362. Genser D. Food and drug interaction: consequences for the nutrition/health status. Ann Nutr Metab. 2008;52:29–32. Gerber W, Steyn JD, Kotzé AF, Hamman JH. Beneficial pharmacokinetic drug interactions: a tool to improve the bioavailability of poorly permeable drugs. Pharmaceutics. 2018;10 Gertz BJ, Holland SD, Kline WF. Studies of the oral bioavailability of alendronate. Clin Pharmacol Ther. 1995;58:288–98. Gidwaney NG, Bajpai M, Chokhavatia SS. Gastrointestinal Dysmotility in the elderly. J Clin Gastroenterol. 2016;50:819–27. Gilbert RM. Caffeine consumption. Prog Clin Biol Res. 1984;158:185–213. Grannell L. When should I take my medicines? Aust Prescr. 2019;42:86–9. Gregory C. Drug and enteral feed interactions. J Hum Nutr Diet. 2006;19:237–9. Gunturu SG, Dharmarajan TS. Drug nutrient interactions. In: Pitchumoni CS, Dharmarajan TS, editors. Geriatric gastroenterology. 1st ed. New York: Springer; 2012. p. 89–98. Halli-Tierney AD, Scarbrough C, Carroll D. Polypharmacy: evaluating risks and Deprescribing. Am Fam Physician. 2019;100:32–8.

405 Hallström H, Wolk A, Glynn A, Michaëlsson K. Coffee, tea and caffeine consumption in relation to osteoporotic fracture risk in a cohort of Swedish women. Osteoporos Int. 2006;17:1055–64. Hamann GL, Campbell JD, George CM. Warfarincranberry juice interaction. Ann Pharmacother. 2011;45:e17. Hamid A, Kaur J. Long-term alcohol ingestion alters the folate-binding kinetics in intestinal brush border membrane in experimental alcoholism. Alcohol. 2007;41:441–6. Hamid A, Wani NA, Kaur J. New perspectives on folate transport in relation to alcoholism-induced folate malabsorption – association with epigenome stability and cancer development. FEBS J. 2009;276:2175–91. Hammerness P, Basch E, Ulbricht C, Barrette E-P, Foppa I, Basch S, Bent S, Boon H, Ernst E. St. John’s wort a systematic review of adverse effects and drug interactions for the consultation psychiatrist. Psychosomatics. 2003;44:271–82. Han H-K. The effects of black pepper on the intestinal absorption and hepatic metabolism of drugs. Expert Opin Drug Metab Toxicol. 2011;7:1–9. Hata M, Hayasaka M, Sezai A, Et AL. Proton pump inhibitors may increase the risk of delayed bleeding complications after open heart surgery if used concomitantly with warfarin. Thorac Cardiovasc Surg. 2008; 56:274–7. Heaney RP, Weaver CM. Effect of psyllium on absorption of co-ingested calcium. J Am Geriatr Soc. 1995;43:261–3. Hegarty VM, May HM, Khaw K. Tea drinking and bone mineral density in older women. Am J Clin Nutr. 2000;71:1003–7. Henderson L, Yue QY, Bergquist C, Gerden B, Arlett P. St. John’s wort (Hypericum perforatum) drug interactions and clinical outcomes. Br J Clin Pharmacol. 2002;54:349–56. Henley E. Sorbitol-based elixirs, diarrhea and enteral tube feeding. Am Fam Physician. 1997;55(2084):2086. Henry EB, Carswell A, Wirz A, Fyffe V, McColl KE. Proton pump inhibitors reduce the bioavailability of dietary vitamin C. Aliment Pharmacol Ther. 2005; 22:539–45. Hermida RC, Ayala DE, Mojón A, Fernández JR. Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. Chronobiol Int. 2010;27:1629–51. Houston MC. Nutrition and nutraceutical supplements in the treatment of hypertension. Expert Rev Cardiovasc Ther. 2010a;8:821–33. Houston MC. The role of cellular micronutrient analysis, nutraceuticals, vitamins, antioxidants and minerals in the prevention and treatment of hypertension and cardiovascular disease. Ther Adv Cardiovasc Dis. 2010b;4:165–83. Ito T, Jensen RT. Association of Long-Term Proton Pump Inhibitor Therapy with bone fractures and effects on

406 absorption of calcium, vitamin B12, Iron, and magnesium. Curr Gastroenterol Rep. 2010;12:448–57. Ivanova NN, Khomich LM, Perova IB, Eller KI. [Grapefruit juice nutritional profile]. Vopr Pitan, 2018; 87:85–94. Jagim AR, Harty PS, Fischer KM, Kerksick CM, Erickson JL. Adverse events reported to the United States food and drug administration related to caffeine-containing products. Mayo Clin Proc. 2020; 95:1594–603. Jankiewicz K, Chroscinska-Krawczyk M, Blaszczyk B, Czuczwar SJ. Caffeine and antiepileptic drugs: experimental and clinical data. Przeglad Lekarski. 2007;64:965–7. Johnstone J, Nerenberg K, Loeb M. Meta-analysis: proton pump inhibitor use and the risk of communityacquired pneumonia. Aliment Pharmacol Ther. 2010; 31:1165–77. Kafle A, Mohapatra SS, Sarma J, Reddy I. Food-drug interaction: a review. Oxford: Oxford University Press; 2018. Kantor ED, Rehm CD, Du M, White E, Giovannucci EL. Trends in dietary supplement use among US adults from 1999-2012. JAMA. 2016;316:1464–74. Khosravan R, Grabowski B, Wu J-T, Joseph-Ridge N, Vernillet L. Effect of food or antacid on pharmacokinetics and pharmacodynamics of febuxostat in healthy subjects. Br J Clin Pharmacol. 2008;65: 355–63. Kim T-E, Kim B-H, Kim J-R, Lim KS, Hong JH, Kim K-P, Kim H-S, Shin S-G, Jang I-J, Yu K-S. Effect of food on the pharmacokinetics of the oral phosphodiesterase 5 inhibitor udenafil for the treatment of erectile dysfunction. Br J Clin Pharmacol. 2009;68:43–6. Klang M, Graham D, Mclymont V. Warfarin bioavailability with feeding tubes and enteral formula. J Parenter Enter Nutr. 2010;34:300–4. Korpelainen R, Korpelainen J, Heikkinen J, Nen K, Kein, Nen-Kiukaanniemi S. Lifestyle factors are associated with osteoporosis in lean women but not in normal and overweight women: a population-based cohort study of 1222 women. Osteoporos Int. 2003; 14:34–43. Koziolek M, Alcaro S, Augustijns P, Basit AW, Grimm M, Hens B, Hoad CL, Jedamzik P, Madla CM, Maliepaard M, Marciani L, Maruca A, Parrott N, Pavek P, Porter CJH, Reppas C, Van Riet-Nales D, Rubbens J, Statelova M, Trevaskis NL, Valentova K, Vertzoni M, Cepo DV, Corsetti M. The mechanisms of pharmacokinetic food-drug interactions – a perspective from the UNGAP group. Eur J Pharm Sci. 2019;134:31–59. Kroon LA. Drug interactions with smoking. Am J Health Syst Pharm. 2007;64:1917–21. Kuo T, McQueen A, Chen TC, Wang JC. Regulation of glucose homeostasis by glucocorticoids. Adv Exp Med Biol. 2015;872:99–126. Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013;310:2435–42.

S. G. Gunturu and T. S. Dharmarajan Lee RD, Vakily M, Mulford D, Wu J, Atkinson SN. Clinical trial: the effect and timing of food on the pharmacokinetics and pharmacodynamics of dexlansoprazole MR, a novel dual delayed release formulation of a proton pump inhibitor – evidence for dosing flexibility. Aliment Pharmacol Ther. 2009;29:824–33. Lee JW, Morris JK, Wald NJ. Grapefruit juice and statins. Am J Med. 2016;129:26–9. Lieberman HR. Why are certain caffeine-containing products associated with serious adverse effects? Mayo Clin Proc. 2020;95:1562–4. Lin C, Ke X, Ranade V, Somberg J. The additive effects of the active component of grapefruit juice (naringenin) and antiarrhythmic drugs on HERG inhibition. Cardiology. 2008;110:145–52. Liu KW. Metformin-related vitamin B12 deficiency. Age Ageing. 2006;35:200–1. Lourenco R. Enteral feeding: drug/nutrient interaction. Clin Nutr. 2001;20:187–93. Mallet L, Spinewine A, Huang A. The challenge of managing drug interactions in elderly people. Lancet. 2007;370:185–91. Mason P. Important drug–nutrient interactions. Proc Nutr Soc. 2010;69:551–7. McCabe BJ. Prevention of food-drug interactions with special emphasis on older adults. Curr Opin Clin Nutr Metab Care. 2004;7:21–6. Mclean AJ. Aging biology and geriatric clinical pharmacology. Pharmacol Rev. 2004;56:163–84. Mirtallo JM. Complications associated with drug and nutrient interactions. J Infus Nurs. 2004;27:19–24. Mitchell DY, Eusebio RA, Sacco-Gibson NA. Dose-proportional pharmacokinetics of risedronate on singledose oral administration to healthy volunteers. J Clin Pharmacol. 2000;40:258–65. Mohn ES, Kern HJ, Saltzman E, Mitmesser SH, McKay DL. Evidence of drug-nutrient interactions with chronic use of commonly prescribed medications: an update. Pharmaceutics. 2018;10 Moore AA, Blow FC, Hoffing M, Welgreen S, Davis JW, Lin JC, Ramirez KD, Liao DH, Tang L, Gould R, Gill M, Chen O, Barry KL. Primary care-based intervention to reduce at-risk drinking in older adults: a randomized controlled trial. Addiction. 2011;106:111–20. Mouly S, Lloret-Linares C, Sellier PO, Sene D, Bergmann JF. Is the clinical relevance of drug-food and drug-herb interactions limited to grapefruit juice and Saint-John’s Wort? Pharmacol Res. 2017;118: 82–92. Mulligan GB, Licata A. Taking vitamin D with the largest meal improves absorption and results in higher serum levels of 25-hydroxyvitamin D. J Bone Miner Res. 2010;25:928–30. Muramatsu RS, Litzinger MHJ, Fisher E, Takeshita J. Alternative formulations, delivery methods, and administration options for psychotropic medications in elderly patients with behavioral and psychological symptoms of dementia. Am J Geriatr Pharmacother. 2010;8:98–114.

13

Drug–Nutrient Interactions

Nathisuwan S, Dilokthornsakul P, Chaiyakunapruk N, Et AL. Assessing evidence of interaction between smoking and warfarin: a systematic review and metaanalysis. Chest. 2011;139:1130–9. Nehlig A. Are we dependent upon coffee and caffeine a review on human and animal data. Neuroscience and Biobheavioral reviews. Neurosci Biobehav Rev. 1999;23:563–76. Norwood DA, Parke CK, Rappa LR. A comprehensive review of potential warfarin-fruit interactions. J Pharm Pract. 2015;28:561–71. Nowack R. Cytochrome P450 enzyme, and transport protein mediated herb–drug interactions in renal transplant patients: grapefruit juice, St. John’s Wort – and beyond! (Review article). Nephrology. 2008;13:337–47. Nutescu E, Chuatrisorn I, Hellenbart E. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. J Thromb Thrombolysis. 2011; 31:326–43. O’shea JP, Holm R, O’driscoll CM, Griffin BT. Food for thought: formulating away the food effect – a PEARRL review. J Pharm Pharmacol. 2019;71:510–35. Ogawa R, Echizen H. Drug-drug interaction profiles of proton pump inhibitors. Clin Pharmacokinet. 2010; 49:509–33. Omar HR, Komarova I, El-Ghonemi M, Fathy A, Rashad R, Abdelmalak HD, Yerramadha MR, Ali Y, Helal E, Camporesi EM. Licorice abuse: time to send a warning message. Ther Adv Endocrinol Metab. 2012;3:125–38. Ovesen L, Lyduch S, Idorn ML. The effect of a diet rich in Brussels sprouts on warfarin pharmacokinetics. Eur J Clin Pharmacol. 1988;33:521–3. Pae C, Lim H, Han C, Neena A, Lee C, Patkar A. Selegiline transdermal system: current awareness and promise. Prog Neuro-Psychopharmacol Biol Psychiatry. 2007; 31:1153–63. Park SJ, Yeo CW, Shim EJ, Kim H, Liu KH, Shin JG, Shon JH. Pomegranate juice does not affect the disposition of simvastatin in healthy subjects. Eur J Drug Metab Pharmacokinet. 2016;41:339–44. Parsad S, Ratain MJ. Food effect studies for oncology drug products. Clin Pharmacol Ther. 2017;101:606–12. Pasko P, Rodacki T, Domagala-Rodacka R, Owczarek D. A short review of drug-food interactions of medicines treating overactive bladder syndrome. Int J Clin Pharm. 2016;38:1350–6. Pasko P, Rodacki T, Domagala-Rodacka R, Palimonka K, Marcinkowska M, Owczarek D. Second generation H1 – antihistamines interaction with food and alcohol-A systematic review. Biomed Pharmacother. 2017; 93:27–39. Pelton R, Lavalle JB, Hawkins EB, Krinsky DL. Druginduced nutrient depletion handbook: 1999–2000. Hudson: Lexi-Comp; 1999. p. 1999. Péter S, Navis G, De Borst MH, Von Schacky C, Van Orten-Luiten ACB, Zhernakova A, Witkamp RF, Janse A, Weber P, Bakker SJL, Eggersdorfer M. Public health relevance of drug-nutrition interactions. Eur J Nutr. 2017;56:23–36.

407 Poor M, Boda G, Needs PW, Kroon PA, Lemli B, Bencsik T. Interaction of quercetin and its metabolites with warfarin: displacement of warfarin from serum albumin and inhibition of CYP2C9 enzyme. Biomed Pharmacother. 2017;88:574–81. Qato DM, Manzoor BS, Lee TA. Drug-alcohol interactions in older U.S. adults. J Am Geriatr Soc. 2015;63:2324–31. Rapuri P, Gallagher J, Nawaz Z. Caffeine decreases vitamin D receptor protein expression and 1,25(OH)2D3 stimulated alkaline phosphatase activity in human osteoblast cells. J Steroid Biochem Mol Biol. 2007;103:368–71. Reumerman M, Tichelaar J, Piersma B, Richir MC, Van Agtmael MA. Urgent need to modernize pharmacovigilance education in healthcare curricula: review of the literature. Eur J Clin Pharmacol. 2018;74:1235–48. Sanchez-Muniz FJ, Bastida S, Gutierrez-Garcia O, Carbajal A. Olive oil-diet improves the simvastatin effects with respect to sunflower oil-diet in men with increased cardiovascular risk: a preliminary study. Nutr Hosp. 2009;24:333–9. Savarino V, Dulbecco P, De Bortoli N, Ottonello A, Savarino E. The appropriate use of proton pump inhibitors (PPIs): need for a reappraisal. Eur J Intern Med. 2017;37:19–24. Say A, Ayar A, Çakir D. Interaction between grapefruit juice and drugs. Acta Phys Pol A. 2017;132:1030–1. Scarpignato C, Gatta L, Zullo A, Blandizzi C. Effective and safe proton pump inhibitor therapy in acid-related diseases – a position paper addressing benefits and potential harms of acid suppression. BMC Med. 2016;14:179. Schmidt LE, Dalhoff K. Food-drug interactions. Drugs. 2002;62:1481–502. Shmuely H, Yahav J, Samra Z, Chodick G, Koren R, Niv Y, Ofek I. Effect of cranberry juice on eradication of Helicobacter pylori in patients treated with antibiotics and a proton pump inhibitor. Mol Nutr Food Res. 2007;51:746–51. Sica D. Interaction of grapefruit juice and Calcium Channel blockers. Am J Hypertens. 2006; 19:768–73. Simon Z. The effect of milk components, especially of casein, on the bioavailability of ciprofloxacin tablets cannot be evaluated by dissolution testing. J Pharm Biomed Anal. 2010;53:819; author reply 819–20 Sorenson JM. Herb-drug, food-drug, nutrient-drug and drug-drug interactions: mechanisms involved and their medical implications. J Altern Complement Med. 2002;8:293–308. Stover PJ. Vitamin B12 and older adults. Curr Opin Clin Nutr Metab Care. 2010;13:24–7. Tapaninen T, Neuvonen PJ, Niemi M. Grapefruit juice greatly reduces the plasma concentrations of the Oatp2B1 and CYP3A4 substrate aliskiren. Clin Pharmacol Ther. 2010;88:339–42. Taylor L, Gidal B, Blakey G, Tayo B, Morrison G. A phase I, randomized, double-blind, placebo-controlled, single

408 ascending dose, multiple dose, and food effect trial of the safety, tolerability and pharmacokinetics of highly purified Cannabidiol in healthy subjects. CNS Drugs. 2018;32:1053–67. Theile D, Hohmann N, Kiemel D, Gattuso G, Barreca D, Mikus G, Haefeli WE, Schwenger V, Weiss J. Clementine juice has the potential for drug interactions – in vitro comparison with grapefruit and mandarin juice. Eur J Pharm Sci. 2017;97:247–56. Toyoshima M, Inada M, Kameyama M. Effects of aging on intracellular transport of vitamin B12 (B12) in rat enterocytes. J Nutr Sci Vitaminol (Tokyo). 1983; 29:1–10. Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol. 2003;38:843–53. Uesawa Y, Tsuji N. Bananas decrease acetaminophen potency in in vitro assays. PLoS One. 2018;13: e0205612. Umland EM, Boyce EG. Risedronate a new oral bisphosphonate. Clin Ther. 2001;24:835–6. Utermohlen V. “Nutrient–Drug Interactions” [Online]; 2003. Available: http://www.encyclopedia.com/doc/ 1G2-3403400440.html. Accessed 23 Jan 11. Valentini L, Ramminger S, Haas V, Postrach E, Werich M, Fischer A, Koller M, Swidsinski A, Bereswill S, Lochs H, Schulzke JD. Small intestinal permeability in older adults. Physiol Rep. 2014;2:e00281. Varum FJ, Hatton GB, Basit AW. Food, physiology and drug delivery. Int J Pharm. 2013;457:446–60. Wadhwa R, Huynh AP. The joint commission (TJC). StatPearls. Treasure Island: StatPearls Publishing; 2020. Copyright © 2020, StatPearls Publishing LLC WARD LS. The difficult patient: drug interactions and the influence of concomitant diseases on the treatment of

S. G. Gunturu and T. S. Dharmarajan hypothyroidism. Arq Bras Endocrinol Metabol. 2010;54:435–42. Werba JP, Misaka S, Giroli MG, Shimomura K, Amato M, Simonelli N, Vigo L, Tremoli E. Update of green tea interactions with cardiovascular drugs and putative mechanisms. J Food Drug Anal. 2018;26:S72–s77. Willemsen AE, Lubberman FJ, Tol J, Gerritsen WR, Van Herpen CM, Van Erp NP. Effect of food and acid-reducing agents on the absorption of oral targeted therapies in solid tumors. Drug Discov Today. 2016;21:962–76. Williams NT. Medication administration through enteral feeding tubes. Am J Health Syst Pharm. 2008; 65:2347–57. Wittkowsky AK. Dietary supplements, herbs and oral anticoagulants: the nature of the evidence. J Thromb Thrombolysis. 2008;25:72–7. Wohlt PD, Zheng L, Gunderson S, Et AL. Recommendations for the use of medications with continuous enteral nutrition. Am J Health Syst Pharm. 2009; 66:1458–67. Yadlapati R, Kahrilas PJ. When is proton pump inhibitor use appropriate? BMC Med. 2017;15:36. Yan JH. Food effect on Oral bioavailability: old and new questions. Clin Pharmacol Drug Dev. 2017;6:323–30. Zarowitz BJ. Pharmacologic consideration of commonly used gastrointestinal drugs in the elderly. Gastroenterol Clin N Am. 2009;38:547–62. Zevin S, Benowitz NL. Drug interactions with tobacco smoking. An update. Clin Pharmacokinet. 1999; 36:425–38. Zia A, Kamaruzzaman SB, Tan MP. Polypharmacy and falls in older people: balancing evidence-based medicine against falls risk. Postgrad Med. 2015; 127:330–7.

Part IV Nutrition

Anorexia, Appetite, Hunger, and Satiety in Older Adults

14

C. S. Pitchumoni and Rahul Chaudhari

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412 Anorexia of Aging (AOA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413 Prevalence of AOA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415 External Risk Factors for AOA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416 Physiological Factors Influencing Appetite as a Result of Age-Related Sensory Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419 Taste and Appetite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419 Neurohumoral Factors for Appetite Control (Sasaki et al. 2016) . . . . . . . . . . . . . . . . . . 421 Appetite-Stimulating Gut Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423 Appetite-Suppressing Gut Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423 Hypothalamic Neuropeptides and Appetite Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426 Fat-Derived Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428 Non-homeostatic Control of Appetite (Borer 2010) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429

C. S. Pitchumoni Department of Medicine, Robert Wood Johnson School of Medicine, Rutgers University, New Brunswick, NJ, USA Department of Medicine, New York Medical College, Valhalla, NY, USA Division of Gastroenterology, Hepatology and Clinical Nutrition, Saint Peters University Hospital, New Brunswick, NJ, USA R. Chaudhari (*) University of Pennsylvania Health System, Philadelphia, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_14

411

412

C. S. Pitchumoni and R. Chaudhari Assessment of Anorexia of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429 Management Options for Anorexia of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433 Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434

Abstract

The ingestion of food has at least three functions: to (a) satisfy hunger and promote survival (physiologic hunger), (b) offer pleasure to satisfy an emotional attachment to food (hedonic hunger), and (c) perform a social obligation with family and friends (social dining or social hunger). The demographic shift globally, in which we see a rapid increase in the number of older adults, comes with a responsibility for the society to keep older adults healthy while satisfying the three functions of a meal mentioned above. Although preventable in most cases, malnutrition in older adults is a growing problem even in affluent nations. Even short durations of poor eating in older adults can lead to protein energy-wasting, frailty, and multiple nutritional deficiency disorders. Undernutrition and malnutrition of older adults are often missed by clinicians who are currently more concerned about obesity, a major epidemic receiving much attention. Although neglected, malnutrition in older adults is a real problem with varying severity and prevalence. Weight loss in the older adult has a greater impact on the overall health, immunity status and quality of life, compared to the younger adults. The consequences of malnutrition in older adults are frailty, falls, immunodeficiency, and worsening of other comorbidities decreasing the life span. The combination of hunger, taste, appetite, and satiety is inter-related and regulated by the hypothalamus with stimuli arising from the brain as well as from an elaborate enteric hormonal system. Anorexia of aging (AOA) plays a major role in the pathogenesis of nutritional deficiency states. Multiple mechanisms individually or

more often collectively influence the incidence and severity of AOA. In this chapter, the authors have brought to light the hidden problem of malnutrition in the older adult as a result of AOA, discussed the pathophysiological basis of regulation of taste, appetite, and satiety, and address the clinical implications of AOA with potential preventive measures. Keywords

Anorexia · Satiation · Hunger · Physiologic appetite · Food liking · Food wanting · Hedonic appetite · Anorexia of aging · Nutrient sensing · Sensory-specific satiety · Energy balance · Energy density · Sarcopenia · Ghrelin · Leptin · Gut hormones · Cholecystokinin · Peptide YY · Hypothalamus · Oxyntomodulin · Neurotransmitters · Malnutrition · Rome IV criteria · Dysphagia · Ageusia · Anosmia · Cachexia · Protein-energy malnutrition (PEM) · Gut microbiota · Short-chain fatty acids (SCFA) · Geriatric assessment · Gastric accommodation · Interstitial cells of Cajal · Gastroparesis · Elder abuse · “Mealfellowship”

Introduction Aging, the process of becoming older, is often divided into chronological and biological aging. Chronological age is very accurate and is measured in years, while the biological age is estimated by a person’s physical and mental functions. Chronological age cannot be altered and is independent of our life habits. Conversely, biological age varies depending on our lifestyle and other factors. Biological age (also known as

14

Anorexia, Appetite, Hunger, and Satiety in Older Adults

physiological age) along with genetics is influenced by other factors that include diet and nutrition, exercise, stress, comorbid conditions, and exposure to environmental and other toxins mostly medications, to cite a few. Biological aging is in part under our control since food, exercise, cigarette smoking, alcohol abuse, and several factors influencing biological aging can be modified at will. Nutrition, a major determinant of aging, depends on a good appetite or the lack of it (anorexia). Hunger, appetite, and satiety, in addition to the availability of nutritious food items, determine the amount of food consumed. In addition to adequate total calorie intake, an important consideration in maintaining good health is the intake of protein. Loss of weight is not just a manifestation of the loss of fat but also indicates loss of muscle mass or sarcopenia, a major determinant of frailty (O’Keeffe et al. 2019). The process of aging is associated with physiological, psychological, and socioeconomic changes that affect food choice and quantity consumed. In addition to the physiological need for eating to satisfy hunger, one eats for the pleasant sensory experience of taste (and smell) and often as a social ritual at least three times a day as breakfast, lunch, and dinner (Depoortere 2014). A 2015 study found that 9.8 million (14.7%) US older adults faced the threat of malnutrition and are at high risk for developing nutrition-related chronic disorders (Eggersdorfer et al. 2018). Malnutrition in older adults is a major risk factor for the development of infectious and chronic diseases and suboptimal cognitive function, hospitalization, another major cause of anorexia and malnutrition (Avelino-Silva and Jaluul 2017). In Greek, orexis means appetite. Anorexia is from the Greek “An-” meaning without and “Orexis-” appetite. Historically, the concept of lack of appetite in older adults was perhaps first described by a Roman philosopher Marcus Cicero in 44 BC. John Morley (Morley and Silver 1988) in 1988, first described “anorexia of aging” (AOA) or the decline in appetite in the older adult as a special entity. AOA is a complex geriatric syndrome recognized as a partially modifiable risk factor for frailty and associated consequences (Martone

413

et al. 2013; Wysokiński et al. 2015). Causes of AOA are many and can be psychological (and environmental) and physiological, but both are not mutually exclusive. Indeed one influences the other (Pilgrim et al. 2015a). Appetite is the desire to accomplish a bodily need for energy and can be divided into three components: hunger, satiation, and satiety (Pilgrim et al. 2015a; Visvanathan and Chapman 2009). Hunger is not the same as appetite; it is a stimulus from the brain to eat. Although one might consider the stomach as the source of the desire to eat, it is the hypothalamus as the commander. In this chapter, we discuss the socioeconomic factors involved with eating and the physiological factors in regulating appetite, hunger, satiety, and maintenance of nutrition in older adults. Satiety is a sense of fullness after eating, in other words, an inhibitory effect of eating. Satiety gradually disappears to make way for hunger. The primary motivation to eat is hunger or a physiological need or what is called “physiologic hunger.” Hunger prompts the act of consumption of a meal, but several extrinsic factors also influence the appetite, the choice of foods and the amount consumed. Hedonic hunger in contrast to physiologic hunger is “the drive to eat to obtain pleasure in the absence of an energy deficit” (Lowe and Butryn 2007). In the younger age group, in affluent nations, in particular, hedonic hunger is frequent. Healthy older adults also retain hedonic hunger despite restrictions imposed by age-related chronic diseases (such as diabetes, hypertension, congestive cardiac failure), physician’s orders (salt- or sugar-restricted diet), or by socioeconomic issues (Pilgrim et al. 2015a). The various terminologies are defined in Table 1.

Anorexia of Aging (AOA) A complicated neuroendocrine basis exists for all three components hunger, satiation, and satiety (Mattes et al. 2005; Pilgrim et al. 2015b). A good appetite is required for adequate balanced food intake. Nutrition, in turn, is positively correlated with a good quality of life in older adult (Acar Tek and Karaçil-Ermumcu 2018).

414 Table 1 Terminologies used in the chapter ANOREXIA OF AGING is an age-related reduction in food intake from physiologic inappetence APPETITE is the desire to eat Hunger may be physiologic as when there is an acute state of caloric need. A pleasure basis to eat food in the absence of a need for calories is hedonic hunger NUTRIENT SENSING is a physiological sense for survival, a requirement for the maintenance of life. The small bowel mucosa senses and responds to nutrient levels in the body SARCOPENIA is the decline of skeletal muscle tissue with age SATIATION leads to the termination of eating as a result of feeling of satisfaction (terminates feeding) SATIETY is the feeling of fullness after a meal and the suppression of hunger SITOPHOBIA is from the Greek root words “sito” meaning food and “phobia” which means fear “fear of eating”

The question “Is a decrease in appetite a natural component of aging?” is often debated. Many older people do experience a decrease in appetite. Between 15% and 30% of older people are estimated to have AOA. AOA is a complex geriatric syndrome, which refers to a reduction in food intake from physiologic inappetence experienced by older people attributed largely to the aging process (Cox et al. 2019; Dent et al. 2019; Sanford 2017). Many comorbid conditions, socioeconomic factors, and medications influence appetite, hunger, satiety, and the physical and psychological health and life span (Dent et al. 2019; Landi et al. 2017; Sanford 2017; Roy et al. 2016). AOA need not be a normal component of aging. As a result of AOA, a decrease in energy intake exceeds the decreased energy expenditure in older adults. A decline in total calorie intake by 30% – a decline of 1321 calories per day for men and 629 calories per day for women between the ages of 20 and 80 due to aging – has been reported (Sjögren et al. 1994; Morley 2001; Giezenaar et al. 2015; Hara et al. 2019; Visvanathan 2015). Although the requirement of calories may be low, there is a need for adequate nutrients. The food intake in older adults is poor in both macronutrients and micronutrients (Hara et al. 2019). In older adults with

C. S. Pitchumoni and R. Chaudhari

AOA, the diet is often inadequate in proteins, fats, fibers, and micronutrients, but interestingly not carbohydrates. The composition indicates a worse quality of diet (Donini et al. 2013; Hara et al. 2019; van der Meij et al. 2017; Schröder et al. 2004; Sharkey et al. 2002). AOA is a well-recognized independent predictor of morbidity and mortality in different clinical settings (Landi et al. 2016). AOA is associated with other components of geriatric syndromes. Protein-energy malnutrition (PEM) is a consequence of AOA. The inappetence results in reduced and poor-quality nutrient intake contributing to undernutrition and weight loss resulting in disabilities, loss of independence, and poor quality of life. Several studies cross-sectional and longitudinal have demonstrated that energy intake is reduced as age advances: the mean calorie reduction between ages 40 and 70 years through food intake was 25% (Di Francesco et al. 2007; Briefel et al. 1995). A recent definition of anorexia, according to the Rome IV criteria, states that “anorexia” is a functional GI disorder (FGID) prevalent in all age groups affecting the quality of life markedly. FGID includes a spectrum of eating disorders (Drossman 2016). The individual may avoid specific foods or restrict the intake of some foods because of lack of interest, sensory characteristics of food, and the worst consequences. The consequences are significant weight loss, frailty, nutritional deficiency, bone fractures, dependence on enteral feeding, and nutritional supplements. All of this may be associated with physical and psychological dysfunction. AOA should not be considered a normal and inevitable consequence of aging but should be rather viewed as a disorder highly responsive to lifestyle modifications and, in some cases, pharmacotherapy. Anorexia is also a symptom of various gastrointestinal and non-gastrointestinal conditions and should not be considered a disease (Martone et al. 2013). AOA defined as a decrease in appetite and food intake in older adults is a major contributing factor to undernutrition and adverse health outcomes. AOA is independently associated with frailty (Tsutsumimoto et al. 2017) and sarcopenia

14

Anorexia, Appetite, Hunger, and Satiety in Older Adults

(reduced skeletal muscle mass and decreased muscle strength) (İlhan et al. 2019) which, in turn, causes disability. Many authors postulate the concept of a “frailty cycle,” where a decrease in dietary intake along with a decrease in physical exercise leads to a decline in muscle mass, rendering the older adults prone to develop secondary complications (e.g., sarcopenia, frailty, comorbidities, or disability) (Fried et al. 2001; Atalayer and Astbury 2013). Cachexia, one of the consequences of AOA, is defined as a multifactorial syndrome leading to a progressive loss of body weight and muscle mass that impairs physical function and patients’ wellbeing. Cachexia increases morbidity and mortality (von Haehling and Anker 2014; Ali and Garcia 2014; Evans 2005; Morley 2017). Besides, agerelated progressive loss of muscle mass, sarcopenia, is linked to metabolic alteration and further diminishes physical activity with aging. Chronic inflammatory disorders, such as advanced heart failure, diabetes mellitus, and rheumatoid arthritis, or severe inflammation including cancer can accelerate the development of cachexia and, finally, muscle atrophy that worsens the prognosis of the patients.

415

Prevalence of AOA The exact overall prevalence of AOA being highly variable is not certain but ranges from 10% to 30%. AOA is also higher in women than men affecting over 30% women and over 25% of men (Martone et al. 2013; Donini et al. 2011). Lack of awareness among clinicians, an overlap of secondary causes of anorexia in the older adult, and little consensus in making the diagnosis are the reasons for the poor recognition of the problem (Table 2). The variability in the prevalence of AOA in different countries becomes obvious from the following reports. A recent study in Brazil noted the overall prevalence of AOA to be 27.7% (67% were females) (Hara et al. 2019). Another study from Mexico (Vázquez-Valdez et al. 2010) showed the overall prevalence of AOA to be at 30.1% in the elderly Mexican community. In an Italian prevalence study by Donini et al. (2011), the prevalence of AOA was higher in elderly nursing home residents (31%) and hospitalized patients (31.5%). In the USA, overall AOA prevalence in older people in long-term care facilities, nursing homes,

Table 2 Prevalence of AOA in different studies Author Cornali et al. (2005)

Country Italy

VázquezValdez et al. (2010) Donini et al. (2011)

Mexico

Roy et al. (2015) van der Meij et al. (2017)

Canada

Prevalence 15.8% in older adults discharged from hospital – 18% men and 82% women 30.1%

USA

31% (in elderly nursing home residents) and 31.5% in hospitalized patients Less than 10% (5.6% in men and 10.8% in women) 21.8% in a community setting

Tsutsumimoto et al. (2018)

Japan

10.7%

Hara et al. (2019)

Brazil

27.7% (67% were females)

Italy

Comments Patients discharged from a Geriatric Evaluation and Rehabilitation Unit A cross-sectional study of 1247 persons aged 60 and older in older community-dwelling Mexicans living in the metropolitan area of Mexico City Patients aged over 65 from geriatric acute and rehabilitation wards in Italy recruited from April 2006 to June 2007 1793 free-living seniors (females, 52.4%) aged 67– 84 years old in good general health at recruitment A cross-sectional analysis of data from a longitudinal prospective study performed in the USA involving 2597 community-dwelling adults aged 70–79 An observational, longitudinal, cohort design in a community setting, including older adults (75.9  4.3 years) A cross-sectional study with 130 individuals aged 60 years or older, undergoing outpatient care in the city of Campinas, São Paulo

416

hospitals, and the community was 21.8% (van der Meij et al. 2017; Cornali et al. 2005). In summary, the prevalence of AOA is variable depending on various studies and ranges from 10 to 30% in different studies, with women having a higher prevalence than men. If the clinicians remain “nutrition-blind,” AOA goes unnoticed, until AOA precipitates as weight loss and sarcopenia associated with frailty (Martone et al. 2013; Clegg et al. 2013). Better awareness among the clinicians and prompt and appropriate steps for prevention are invaluable in offering the much-desired independence and good quality of life to our aging population (Visvanathan 2015).

External Risk Factors for AOA AOA is not always a component of aging; rather, several risk factors can be identified and potentially altered (Landi et al. 2016). The common risk factors include changes in body composition such as reduced muscle mass and increase in visceral fat, functional impairment, social and environmental conditions, acute and chronic diseases, and their treatments. Secondary anorexia and malnutrition are caused by a combination of functional, psychological, and economic factors. The risk factors associated with AOA can be roughly divided into the following categories: 1. Physical factors: Aging is associated with cognitive and physical slowdown, but the onset of the slowdown is not predictable. Functional impairment in the basic and instrumental activities of daily living (ADL and IADL) contributes to low food intake and loss of appetite. Physical impairment, fatigue, and weakness associated with aging may cause mobility limitations that, in turn, could be responsible for anorexia through multiple mechanisms. Problems in eating by oneself (loneliness), difficulty in getting foods, and lack of coping skills are relevant risk factors for anorexia of aging. Functional deficiencies and sensory impairments – hearing and vision – interfere with the ability of

C. S. Pitchumoni and R. Chaudhari

older persons to shop for, prepare, and consume food. Additional physical factors, such as poor dentition, poor-fitting dentures, and inflammatory condition of the oral cavity, may limit the type and quantity of food consumed. Chewing and swallowing problems in the elderly can lead to poor nutritional status by modifications in the type and quality of nutrient intake with lower intake of specific nutrients, including fiber, vitamins, calcium, and proteins, and with a higher intake of fats and cholesterol (Landi et al. 2013a; Mir et al. 2013). 2. Medical factors: Specific medical conditions in older persons, including gastrointestinal diseases, malabsorption syndromes, acute and chronic infections, and hypermetabolism (e.g., hyperthyroidism), often cause anorexia and micronutrient deficiencies, in the face of increased energy requirements. Older adults frequently suffer from diseases that modify the appetite and cause malabsorption or increase metabolism. For example, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), and Parkinson’s disease are frequently associated with both anorexia and increased energy expenditure. (a) Depression: Depression is one of the most common age-related psychological conditions. Older adults seemed to suffer more severe appetite and weight loss than younger persons among those diagnosed with depression. Depressed older individuals, specifically nursing home residents, have numerous symptoms and signs, including weakness, abdominal pain, nausea, and diarrhea, that can contribute to anorexia and weight loss (Wysokiński et al. 2015). Finally, depression is also associated with an increased CSF concentration of corticotropin-releasing factor which is a strong anorectic. Other psychiatric disorders such as anxiety also play a role in AOA. In the USA and Europe, an estimated number of 100 million people are suffering from anxiety-related diseases (Verma et al. 2016). (b) Cognitive impairment: Loss of appetite and reduced food intake are frequently

14

Anorexia, Appetite, Hunger, and Satiety in Older Adults

observed in older adults with cognitive impairment. Approximately 50% of institutionalized elderly with any type of dementia have protein-energy malnutrition (Morley 1997, 2013). (c) Medications: Older persons typically take many prescription medications as well as over-the-counter medications, several of which can cause taste disorders, malabsorption, and loss of appetite and ultimately reduced food intake (Onder et al. 2014). The risk of drug-induced anorexia is further increased by polypharmacy due to the enhanced odds of drug-drug interactions and gastrointestinal problems. Nausea, vomiting, and loss of appetite are common side effects of commonly used drugs like metformin, digoxin, and iron tablets. The medications excreted in saliva can affect the sense of smell by several mechanisms like a drug-receptor interaction, disturbance of action potential propagation in cell membranes of afferent and efferent neurons, and alteration of the neurotransmitter function. Xerostomia can also impact the sense of taste (Syed et al. 2016; Tuccori et al. 2011). A study

417

reported that solely taste alteration was reported in 75% of cases of ADRs and both taste and smell impairment were noted in 13% of ADRs. Macrolides, antimycotics, fluoroquinolones, protein kinase inhibitors, angiotensin-converting enzyme inhibitors, HMG-CoA reductase inhibitors (statins), and proton pump inhibitors were the leading agents. Antiretroviral medications have been associated with dysgeusia in HIV patients. Chemotherapeutic drugs especially 5-fluorouracil and its oral analogs have also been associated with dysgeusias. Resolution of symptoms varied, with improvement reported within days to a few months after discontinuation of the offending medicine. (Tuccori et al. 2011) Frequently used drugs causing dysgeusia and/or anorexia are tabulated (Tables 3 and 4). (d) Social isolation. Although eating is meant to replace fuel, it is an enjoyable social and cultural experience in the right surroundings irrespective of age. Often in westernized societies, the older adult is lonely at the dining table whether the individual lives at home or in a nursing home where

Table 3 List of common medications causing dysgeusia (Wick 2015) Name of the drug causing dysgeusia H1-antihistamine Cardiovascular medicines Antidiabetic medicines ACE inhibitors causing metallic taste and partial loss of taste (resolves with continued use) Antibiotics Cancer chemotherapy

Psychiatric medications Rheumatoid arthritis Insomnia medications Vitamins and minerals Anticholinergics Anesthesia

Examples Azelastine, emedastine Amiloride, flecainide Metformin (3%) – metallic taste in the mouth Captopril (2–7%), lisinopril, fosinopril, enalapril, trandolapril, quinapril, and ramipril Clarithromycin, tetracycline, metronidazole, trimethoprimsulfamethoxazole, azithromycin, ethionamide Cisplatin, carboplatin, paclitaxel, vincristine, methotrexate, dacarbazine, cyclophosphamide, mechlorethamine, doxorubicin Lithium (because it inhibits norepinephrine), antidepressant Allopurinol, gold salts, penicillamine, phenylbutazone Eszopiclone, zopiclone Calcitriol (dysgeusia is an early sign of vitamin D-induced hypercalcemia), oral iron supplements Oxybutynin, tolterodine (by causing dry mouth that is perceived as metallic taste), antihistamines Mainly local anesthesia (usually transient for 1–2 weeks but can last months)

418

C. S. Pitchumoni and R. Chaudhari

Table 4 Drugs causing anorexia (Douglass and Heckman 2010; Bromley 2000) Class Antibiotics Neurologic medicines Cardiac medications

Endocrine medications Antineoplastic drugs Anti-inflammatory medicines Psychotropics

Other

Medicines Ampicillin, tetracycline, trimethoprim, macrolide, quinolones, sulfamethoxazole, metronidazole, clarithromycin, griseofulvin Migraine medicines, CNS stimulants, antiparkinsonian drugs (levodopa), muscle relaxants (baclofen, dantrolene), anticonvulsants (carbamazepine, phenytoin) Anti-arrhythmic, diuretics, statins (fluvastatin, pravastatin, lovastatin), most antihypertensive (acetazolamide, amiloride, betaxolol, captopril, diltiazem, enalapril, hydrochlorothiazide, nifedipine, nitroglycerin, propranolol) and diuretics (hydrochlothiazide and spironolactone) Thyroid medicines (mainly methimazole, propylthiouracil by causing metallic taste) Cisplatin, doxorubicin, methotrexate, vincristine Auranofin, colchicine, dexamethasone, gold, hydrocortisone, penicillamine Most tricyclic antidepressants (amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline), some antipsychotics (clozapine, trifluoperazine), anxiolytics, mood stabilizers (lithium), hypnotics Antihistamines (chlorpheniramine, loratadine, pseudoephedrine), antineoplastic, bronchodilators, anti-inflammatories, smoking cessation aids, antifungals, antivirals

dining is usually in an unfamiliar circumstances, in contrast to many Afro-Asian societies where the older adults often live in extended families with their children and other relatives. The pleasure of social dining or “meal-fellowship” is a pleasant experience. The lack of enjoyment in eating alone, as a result of the loss of a partner or other family members, eliminates the pleasure of social dining, often misinterpreted as a lack of appetite. (e) Lack of food choices. External factors (sensory-specific satiety) depend on the food choice, the wholesomeness of food, eating environment, and meal-fellowship (eating alone versus eating with a spouse, relatives, and/or friends). Further, the choice of food in older adults is also influenced by cost, income, availability, and physical determinants such as access, education, and knowledge about food and nutrition. Comorbid conditions and their dietary restrictions also influence eating. There are social determinants such as ethnicity, culture, and religious restrictions in choosing a food item from the menu in a nursing home or hospital situation. Kosher food, vegetarian menu, pork-free, beeffree, or vegan food is not easily available

in some situations due to a lack of appreciation of cultural values. Failure by longterm care facilities to pay attention to the resident’s food preferences and stimulate a favorable environment to eat is an important factor related to the loss of appetite and reduced food intake among nursing home residents. In fact, among institutionalized older individuals, anorexia and subsequent unintentional weight loss may be the consequences of monotony and repetitiousness of daily foods. Older persons, due to lack of knowledge about the adverse effects of dietary restriction, are prone to consume a semi-starvation regimen. Proper education on age-related nutritional needs promotes adequate nutrition intake and an adequate variety of food choices. (f) Elder abuse. Although elder abuse is a sensitive topic for discussion with patient or close family members, it is common and results in a lack of motivation to eat. Abuse takes place in many forms. National Institute on Aging (NCOA) categorizes elder abuse as physical abuse, emotional abuse, psychological abuse, neglect, and abandonment. (Richmond et al. 2020; Lorraine 2019) According to NCOA, approximately 10% of adults over the age of 60 have

14

Anorexia, Appetite, Hunger, and Satiety in Older Adults

experienced some elder abuse, resulting in an estimated five million cases of abuse each year. (g) Economic factors. Socioeconomic inequality is one of the major factors contributing to the AOA. Inadequate financial means in older individuals make problems in buying foods of personal choice affecting the nutrient intake in terms of variety and macro- and micronutrient composition (De Castro 1993). (h) Miscellaneous factors. Difficulties with cooking and eating, loneliness, and poverty contribute to limitations in choosing the preferred food items. Inadequate financial means in older individuals make it difficult to obtain good-quality foods, thereby affecting the nutrient intake in terms of variety and macroand micronutrient composition (De Castro 1993).

Physiological Factors Influencing Appetite as a Result of Age-Related Sensory Changes Taste disorders (ageusia, dysgeusia). The human taste system functions as a gatekeeper of the digestive system to make sure that a person consumes essential nutrients for survival and functioning. Further, it aims at rejecting potentially harmful or toxic foods (Low et al. 2014; Simon et al. 2006). The taste sensation is influenced by the vision and smell of foods even before the physiological factors of actual tasting by the tongue begins. The sensory system (gustatory system) responsible for the perception of taste and flavor is comprised of taste cells in the mouth, several cranial nerves, and the gustatory cortex. The “tastants” sugars, salts, and others dissolve in saliva, bind to receptors in taste buds, and activate a chain of events leading to the perception of different tastes. Vision and appetite. Apicius, a collection of Roman cookery recipes, thought to have been compiled in the first century is right in coining

419

the phrase “We eat first with our eyes.” Sight, smell, and even thought of a good meal that can stimulate gastric secretions are components of the cephalic phase of gastric acid secretion (conditioned reflex), a topic of great interest to physiologists and physicians since its description by Pavlov 100 years ago (Yin et al. 2017). Even the images of desirable foods exacerbate the desire for food (“visual hunger”). A buffet dinner is more appealing than a single favorite item on a plate. The texture of a food item is an added factor in complementing taste, oral sensory perception, and appetite (Kindleysides et al. 2017). The flavor of food complements the sensation of taste. Smell disorders (anosmia, dysosmia) and appetite. Taste and smell, although they are separate senses with their receptor organs, are interconnected. Anosmia is more frequent than ageusia. There is a consistent decline in olfactory sensation (smell) with aging due to a decline in olfactory receptor activity; in fact smell declines with age, unlike taste. When smell is lost, there is a decline in appetite. Three cranial nerves maintain taste sensation, but only one cranial nerve influences the smell. Disorders of the nose are frequent in older adults. Dental and other oral disorders are additional causes. Many neuropsychiatric disorders, including Alzheimer’s dementia and Parkinson’s disease, are associated with dysosmia and dysgeusia. The list of conditions causing taste and smell disorders is very long, but our intention here is to bring to light the clinical importance of smell and taste in influencing appetite. A variety of neuropsychiatric disorders including Alzheimer’s dementia and Parkinson’s disease are associated with dysosmia and dysgeusia.

Taste and Appetite The human taste system includes five taste qualities: sweet, salty, bitter, sour, and umami (see Fig. 1: tongue). The first four sensations are well-known, but umami requires an explanation. Umami, less known, is a word in Japanese translated as “pleasant savory taste.” A strong umami flavor is present in broths, gravies, soups,

420

Fig. 1 Approximate distribution of major taste buds

shellfish, fish and fish sauces, tomatoes, mushrooms, hydrolyzed vegetable protein, meat extract, yeast extract, cheeses, and soy sauce, foods that contain high levels of L-glutamate. The taste buds are not specific to each one of the five basic tastes; overlap exists in their function. Ayurveda, the ancient system of Indian medicine, recognizes six tastes in our diet: sweet, sour, salty, pungent (spicy), bitter, and astringent. There are no specific receptors on the tongue for pungent and astringent. The astringent flavor in plant compounds is attributed to tannins (beans and lentils), some fruits (cranberries, pomegranates, pears, dried fruit), and vegetables (unripened bananas, unripe persimmons, broccoli, cauliflower, artichoke, asparagus, and others). The pungent (pungent is from the Latin word pungere meaning “to prick, sting”) taste, the hottest of all tastes, is found in chili peppers, black pepper, and ginger. The science of human taste is perhaps imperfect. The gastrointestinal tract contains a variety of sensitive nutrient sensors that trigger various neurotransmitters; sense of taste is an important one that regulates ingestive decisions and (Depoortere 2014). A salty taste suggests the presence of either sodium or minerals; excessive sour taste signals spoiled food; umami

C. S. Pitchumoni and R. Chaudhari

indicates the presence of proteins; a bitter taste often indicates the presence of poisons, and sweet taste indicates the presence of carbohydrates or energy in the food (Simon et al. 2006; Newman et al. 2013). The various smells of food are limitless since there are many flavoring agents. The flavor is an important sensory factor responsible for the preference of foods. The cranial nerves VII (facial), IX (glossopharyngeal), and X (the vagus) transmit the sensation of taste to the brain. The impulses reach the nucleus of the solitary tract (NTS). The vagus nerve transmits impulses from the epiglottis. Many older adults, due to lack of knowledge on the adverse effects of dietary restriction, are prone to consume a semi-starvation regimen. The trigeminal nerve is involved in appreciating sensations of temperature, texture, and spiciness, important in the qualitative enjoyment of a meal. Table 4 lists the medications frequently related to dysgeusia. Dysgeusia may manifest as an abnormal and unpalatable taste. Older age is associated with taste disorders for various reasons. There is a reduction in the density of fungiform papillae, and loss of taste is a side effect of many medications. The National Health and Nutrition Examination Survey (NHANES) 2011–2012 reported the prevalence of taste disorders to be 5% of the 142 US respondents and smell disorder in 10% (Syed et al. 2016). The prevalence of taste disorders is 13.9%, much higher than in the community-dwelling older adults. A metallic taste often occurs in patients with chronic kidney failure and malignancies. Nutritional deficiencies in particular that of zinc and iron may cause ageusia or dysgeusia. Often ignored in the care of the older adult is the defective zinc absorption that is significantly more common than in the young. Hence zinc deficiency is common in the old, especially those aged over 75 (Meunier et al. 2005). Many medications cause a distaste or anorexia (see Table 3). Although the temperature of a food item does not affect the taste, there is a preference for either hot or cold food. The choice depends on the

14

Anorexia, Appetite, Hunger, and Satiety in Older Adults

season, the type of food item, and previous experience. A hot cup of coffee and a cold glass of beer are examples. Hot foods are considered appetizing because heat usually volatilizes the ingredients (e.g., a cup of hot coffee), making it easier for the human palate to discern such aromas and tastes. Sight, smell, and thought can stimulate gastric secretions, which are components of the cephalic phase of gastric acid secretion. The conditional stimulus could be visual or auditory or olfactory or in various combinations (Yin et al. 2017). Satiety and satiation. (Lim and Poppitt 2019) Satiety is the feeling of fullness that persists after eating, potentially suppressing further energy intake until hunger returns, and satiation is the process that leads to the termination of eating, which may be accompanied by a feeling of satisfaction (Benelam 2009). Satiation refers to the termination of the desire to eat after a meal, the point at which one feels that he or she had enough to eat and does not desire any more (Benelam 2009). Several factors influence both satiation and satiety. The gastrointestinal-derived satiety peptides include CCK, GLP-1, and peptide YY. An increase in GI peptide concentrations occurs concurrently with suppression of appetite following a meal. The response to peptide hormones inhibiting appetite and inducing satiety is variable (Lim and Poppitt 2019; Konturek et al. 2004). The satiety cascade is altered with aging. Postprandial satiety is regulated by a sensory system that communicates between the gut and appetite-regulating centers in the brain (Perry and Wang 2012; Amin and Mercer 2016). Despite recognition of various peptides and recognition that the levels of circulating hormones CCK, GLP-1, and PYY as well as a parallel increase in satiation and satiety, it is not well established that these “satiety peptides” in turn elicit a physiological effect on aspects of eating behavior (Lim and Poppitt 2019). Age-related loss of cells within the myenteric plexus of the esophagus along with reduced

421

conduction velocity within the visceral neurons is related to reduced sensory perception with advancing age. This, in turn, reduces the sensory perception causing decreased food intake by inhibiting the positive stimuli for feeding (Visvanathan and Chapman 2009). Furthermore, the increase in nitric oxide (NO) associated with aging also has a role in AOA by impaired gastric accommodation response from altered fundic nitric oxide. Thus, early satiation results from the relaxation of the proximal stomach causing rapid antral filling and earlier antral stretch (Morley 2001; Chapman 2007). The major advances in the field of appetite regulation are in the area of gut and neural hormones. The growing interest in the area of neurohumoral agents in food intake has clarified many areas in the regulation of appetite, gastrointestinal motility, digestion, absorption, and satiety and promises a therapeutic opportunity in stimulating or suppressing hunger and appetite (Fig. 2).

Neurohumoral Factors for Appetite Control (Sasaki et al. 2016) The GI tract has been recognized as the largest endocrine organ in the body with the major role being the regulation of appetite and nutrition. Many major developments in the last few decades are in the field of neurohumoral agents in appetite control. Many hypothalamic and enteric hormones and neurotransmitters are functionally interconnected through complex networking. A fat-derived hormone leptin also plays a role in the complex system (Perry and Wang 2012). The direct input of nutrients and hormones to the arcuate nucleus (ARC) of the hypothalamus is the basis of humoral control. Anorexigenic pro-opiomelanocortin (POMC) neurons and orexigenic agouti-related peptide (AgRP) neurons constitute the two major types of neurons within the ARC. The reader is referred to many excellent articles (Gropp et al. 2005; Balthasar et al. 2005; Perry and Wang

Fig. 2 Neurohormonal factors affecting appetite

422 C. S. Pitchumoni and R. Chaudhari

14

Anorexia, Appetite, Hunger, and Satiety in Older Adults

2012). There are two types of hormones orexigenic (appetite-stimulating) and anorexigenic (appetite-suppressing) based on function. There are two types of neurons in the arcuate nucleus (ARC) within the hypothalamus, critical for the regulation of appetite and satiety. The orexigenic (neuropeptide Y (NPY) and agoutirelated peptide (AgRP)-expressing AgRP/NPY neurons) and the anorexigenic (pro-opiomelanocortin (POMC)-expressing POMC neurons) are tabulated (Table 5) and discussed in detail below (Gropp et al. 2005; Balthasar et al. 2005).

Appetite-Stimulating Gut Hormones The GI tract and central nervous system both local and enteric are involved in two-way extrinsic communication by parasympathetic and sympathetic nerves. The two systems comprise of efferent fibers such as cholinergic and noradrenergic, respectively (Konturek et al. 2004). The brain-gut signaling system functions through hormones, neuropeptides, cytokines, neurotransmitters, and inflammatory mediators. Ghrelin: Ghrelin, a 28-amino acid peptide hormone, secreted by P/D1 oxyntic cells mainly in the fundus of the stomach, is important in short-term food intake as it stimulates appetite (Camilleri 2015). Ghrelin (“appetite-stimulating”) is the only major appetite-stimulating gut hormone. Ghrelin passes through the blood-brain barrier and enhances appetite in the arcuate nucleus of the hypothalamus, which expresses a high level of GHSR1a (growth hormone secretagogue receptor type 1a). Peripherally, GHSR1a is synthesized in gastric vagal afferent neurons and transported to the stomach (Date et al. 2006). The concentration of ghrelin negatively correlates with advancing age (Serra-Prat et al. 2009). Whether there is a definite decrease in ghrelin levels in all older adults or the decrease is the major cause of AOA is not clear. Ghrelin has various physiologic effects in addition to stimulating appetite and increasing food intake. Ghrelin attenuates the sympathetic nervous system activity, exerts anti-inflammatory effect, increases cardiac output, and controls fat utilization (adipogenesis).

423

Appetite-Suppressing Gut Hormones (i) Cholecystokinin (CCK): CCK, present in the hypothalamus, cortex, and midbrain, is secreted by two separate cell types: endocrine cells of the proximal small intestine and various neurons in the gastrointestinal tract and central nervous system. Hence, CCK could be considered and could function as either a hormone or a neuropeptide (Liddle 1997). CCK is a major mediator of satiation; in addition to stimulate the gallbladder to contract and relax the sphincter of Oddi, its major physiological function is to provide negative feedback to the stomach (by fundic relaxation and antral inhibition slowing and delaying gastric emptying). Cholecystokinin (CCK) exerts its physiological actions through the activation of two structurally related class A G protein-coupled receptors (GPCRs) identified as type 1 CCK receptor (CCK1R) and type 2 CCK receptor (CCK2R) (also known as CCKAR and CCKBR, respectively, related to their prominent presence in “alimentary tract” and the “brain”) (Desai and Miller 2014). The precise mechanism of CCK-induced satiety remains unknown; it has been shown to alter the gene expression within the vagal neurons (Simpson et al. 2012). With aging, there is increased signaling of CCK contributing to the suppression of appetite and eventually weight loss. A significantly higher plasma level of CCK has been found in older adults with idiopathic anorexia compared to healthy young adults (Martinez et al. 1993; Perry and Wang 2012; Khalil et al. 1985). Fasting and fat-stimulated plasma levels of CCK increase with aging, and the sensitivity of the gallbladder muscle stimulation by CCK is diminished with aging; however, the kinetics of gallbladder emptying is little different in the aged due to the increased release of CCK with aging. Because of its appetite-suppressing property, CCK is considered a potential target for the treatment of AOA.

424

C. S. Pitchumoni and R. Chaudhari

Table 5 Hormones and neuropeptides in appetite regulation The predominant Gut hormone site of synthesis Function Relationship to aging Gut and other neurohumoral agents in appetite control: part A – gut hormones Ghrelin P/D1 cells in the 1. Stimulates appetite Weak negative relation with advancing fundus of the 2. Increases gastric motility and age stomach induces fat and NPY production 3. Decreases insulin secretion 4. Inhibition of insulin secretion 5. Regulation of gluconeogenesis and glycogenolysis 6. Decreases thermogenesis 7. Prevents muscle atrophy 8. Regulates bone formation 9. Stimulates GH secretion from the pituitary 10. Attenuates sympathetic nervous system activity 11. Anti-inflammatory effect 12. Increases cardiac output 13. Controls adipogenesis CCK I cells in 1. Binds to vagal sensory Increased signaling with aging duodenal mucosa terminals delivering to NTS a contributes to AOA and eventually sense of fullness weight loss 2. Relaxes the proximal stomach to increase its reservoir capacity 3. Inhibits gastric emptying and acid secretion 4. Induces gallbladder contraction and exocrine pancreatic secretion 5. Influences PYY release GIP (glucoseEnteroendocrine Stimulates insulin release with Unclear role in AOA dependent K cells eating insulinotropic polypeptide) Glucagon Pancreatic alpha1. Increases satiety Reduces meal size by increasing cells 2. Maintains blood glucose by glucose oxidation for energy activating gluconeogenesis and (experimental animal research so far in glycogenolysis appetite control) 3. Affects energy expenditure 4. Reduces meal size by retarding GE of liquids and inhibiting GI motility PYY Ileocolonic L 1. Stimulates Y2 receptors in Unclear whether PYY truly cells hypothalamic ARC nucleus contributes to the development of circuitry to regulate food intake AOA 2. Activates ileal brake and other feedback control of regional motor function 3. Delays gastric emptying for liquids 4. Inhibits gastric acid, pancreatic exocrine, and bile acid secretion Insulin β-Cells of the Acts as a satiety signal that Fasting and postprandial insulin islets in the decreases food intake by acting concentrations increase with aging pancreas on the ARC of the lateral hypothalamus (continued)

14

Anorexia, Appetite, Hunger, and Satiety in Older Adults

425

Table 5 (continued) Gut hormone Pancreatic polypeptide (PP)

The predominant site of synthesis PP cells (also known as F cells) in the pancreatic islets

Function Relationship to aging 1. Inhibits pancreatic secretions Plasma PP levels increase with aging and gallbladder motility 2. Delays gastric emptying and plays a major role in energy homeostasis Amylin β-Cells of the 1. Suppresses glucagon release Role in AOA to be investigated islets in pancreas 2. Stimulates brain satiety centers to limit caloric intake 3. Delays gastric emptying of solids Gut and other neurohumoral agents in appetite control: part B – hormones from adipose tissue Leptin Adipose tissue 1. Appetite suppression 1. Increased levels with aging from 2. Delays gastric emptying and increased adiposity inhibits jejunal motility (Depoortere 2014) Decline in the testosterone levels (in men) Adiponectin Fat tissue 1. Glucose regulation and fatty Unclear role in AOA acid oxidation Levels positively correlated with aging 2. Stimulates AMPK in the and negatively with BMI hypothalamus and increases food intake Resistin White adipose 1. Reduces energy intake by Unclear role in AOA tissue affecting NPY neurons 2. Suppresses insulin-stimulated glucose uptake in the fat

PVN paraventricular nuclei, LHA lateral hypothalamic area, PFA perifornical area, ARC arcuate nucleus, NTS nucleus tractus solitarius

(ii) Pancreatic polypeptide (PP): It is an amidated 36-amino acid peptide hormone. PP synthesized in the PP cells of the endocrine pancreas preferentially activates Y4 receptors regulating gastrointestinal processes and appetite (Holzer et al. 2012; Lin et al. 2009; Shi et al. 2013). PP has a range of regulatory functions including the inhibition of pancreatic secretions and gallbladder motility, delaying gastric emptying and playing a major role in energy homeostasis. It remains unknown whether the effects of PP on appetite are exerted directly through the brainstem or hypothalamus (via circulation) or through vagal afferents or through a combination of both (Simpson et al. 2012). (iii) Glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP): GIP, initially called enterogastrone, is an incretin hormone secreted from enteroendocrine K cells in response to glucose and fat ingestion. The major role of GIP

is to enhance the release of insulin and to inhibit gastric motility and acid secretion. It has minimal or no activity on appetite control but can potentiate the satietary activity of GLP-1. Aging is associated with increased secretion and levels of GIP, K cell number in the small intestine, and the mRNA expression levels of GIP in K cells (Ikeguchi et al. 2018; Korosi et al. 2001). (iv) Glucagon-like peptide 1 (GLP-1): GLP-1 is secreted by the intestinal L cells in proportion to ingested calories and response to nutrients, particularly carbohydrates. GLP-1 is an incretin hormone that modulates glucose control and provides negative feedback to the stomach by delaying gastric emptying and stimulating insulin secretion and inhibiting glucagon secretion along with gastric inhibitory peptide secretion (Chapman 2007). GLP-1 administration in humans reduces food intake and increases satiety. GLP-1 agonist liraglutide has been FDA approved for

426

weight loss in 2014. The effects of aging on satiating effects of GLP-1 and the plasma concentration of the GLP-1 are not completely understood (MacIntosh et al. 1999). (v) Peptide tyrosine-tyrosine (PYY): PYY is a 36-amino acid peptide secreted from enteroendocrine L cells of the distal GI tract, in response to fat and carbohydrate in the small intestine, which induces satiety by binding to the Y2R receptor. Neuropeptide Y receptor type 2 (Y2R) is a member of the neuropeptide Y receptor (family of G protein-coupled receptors). PYY has a role in central appetite regulation through vagal afferents which acts by reducing NPY secretion in the ARC (Simpson et al. 2012). The major physiologic function of PYY is to increase satiety and decrease food intake via gut-brain communication, inhibiting gastrointestinal motility and pancreatic hormone secretion. In addition, it plays an integral part in maintaining energy homeostasis (Cahill et al. 2014). PYY is involved in appetite control by activating ileal brake and other feedback control of regional motor function, and by delaying GE liquids, inhibiting gastric acid, pancreatic exocrine, and bile acid secretion. It is unclear whether PYY truly contributes to the development of AOA. (vi) Insulin: Insulin is secreted by pancreatic βcell. It initiates a satiety signal that decreases food intake by acting on the arcuate nucleus of the lateral hypothalamus. Fasting and postprandial insulin concentrations increase with aging (Fraze et al. 1987). Explained by increased adiposity with aging. Moreover, a higher glucose and insulin levels are noted after intraduodenal glucose infusion in older adults compared to the young and healthy (Atalayer and Astbury 2013). (vii) Amylin: Amylin is a peptide hormone cosecreted with insulin from the pancreatic βcell. It inhibits glucagon secretion, delays gastric emptying, and acts as a satiety agent (Schmitz et al. 2004). Amylin structurally

C. S. Pitchumoni and R. Chaudhari

related to the calcitonin family influences well-defined brain areas in controlling appetite (Lutz 2010, 2012; Woods et al. 2006). The role of amylin in AOA is not clear (Atalayer and Astbury 2013). Amylin may have a role as an anti-obesity agent as it reduces gastric emptying and energy intake by a direct effect on the feeding center in the hypothalamus (Brunetti et al. 2002). (viii) Oxyntomodulin (OXM): OXM is a 37amino acid peptide hormone produced by the oxyntic (fundic) cells of the oxyntic fundic mucosa. OXM reduces food intake, but the anorexigenic mechanism is not clear. Another action is the stimulation of acid secretion by the parietal cells. (ix) Glucagon: Glucagon is a 29-amino acid peptide secreted from pancreatic alphacells. It maintains blood glucose by activating gluconeogenesis and glycogenolysis and also affects energy expenditure and reduces meal size by retarding gastric emptying of liquids and inhibiting GI motility. It has a role in reducing meal size by increasing glucose oxidation for energy in rats, but no human research has been performed so far for its role in appetite control or AOA (Atalayer and Astbury 2013; Geary et al. 1993). Aging of peripheral appetite signaling molecules increases the satiety and anorectic hormones and reduced the amount of and sensitivity to hunger hormones. Older frail persons have an impaired response to hunger hormones like ghrelin and cholecystokinin (CCK) (Serra-Prat et al. 2009). A meal with 40% fat increases the glucagon-like peptide 1 (GLP-1) levels and reduces the acetylated-todeacetylated ghrelin ratio in the elderly but not in young adults (Di Francesco et al. 2010).

Hypothalamic Neuropeptides and Appetite Regulation (A) Orexigenic: (i) Melanin-concentrating hormone (MCH): MCH is an orexigenic peptide, expressed in neurons in the zona incerta

14

Anorexia, Appetite, Hunger, and Satiety in Older Adults

and lateral hypothalamus, which is supposed to work under the control of arcuate NPY and POMC neurons. It induces hyperphagia with significant weight gain in mice; however, its role in AOA remains unclear (Griffond and Risold 2009). (ii) Orexin (hypocretins 1 and 2): Orexins A and B (hypocretins 1 and 2), involved in eating and sleeping, are neuropeptides synthesized in the hypothalamus of the brain. As their name suggests, orexins are considered orexigenic; however, it is postulated that they affect the appetite directly as well as stimulate and increase arousal. Orexins are highly expressed in the lateral hypothalamus. Orexins A and B are orexigenic when injected intracerebroventricularly. There are two orexin receptors, OX1R and OX2R, to which orexin A binds with high affinity whereas orexin B binds preferentially to OX2R. Orexins along with MCH appear to influence the reward and motivational aspects of feeding. Moreover, orexins also act to modulate hindbrain satiety signaling (Parker and Bloom 2012). The levels of orexins are increased with aging in a healthy adult (Matsumura et al. 2002). (iii) Agouti gene-related peptide (AGRP): Agouti-related peptide is released by the arcuate nucleus and is a potent orexigenic neuropeptide that influences food intake mainly by the competitive antagonism of central melanocortin receptors. AgRP is expressed exclusively in the Arc (Parker and Bloom 2012). AgRP is more important during conditions of high energy requirements such as pregnancy and lactation under which it is more highly expressed. The role of AGRP in AOA is not clear (Aponte et al. 2011). (iv) Endocannabinoids: Endocannabinoids derived from membrane phospholipids stimulate appetite and promote weight

427

gain (Cota et al. 2003) by activating Gcoupled type 1 CB (CB-1) receptors in the brain (Williams and Kirkham 2002; Jamshidi and Taylor 2001). Aging is associated with reduced opioid feeding drive (Morley 1997). Lower plasma and CSF B-endorphin levels have been found in the aged population with idiopathic, senile AOA compared with normal weight age-matched controls (Martinez et al. 1993). (v) Neuropeptide Y: Neuropeptide Y, a major brain neurotransmitter, is expressed in neurons of the hypothalamic arcuate nucleus (ARC). Secreted by the peripheral nervous system and by the brain, NPY is a strong stimulant of feeding and plays a significant role in the development of AOA. An elevated level of neuropeptide Y has been found in the plasma and cerebrospinal fluid of the older adults with anorexia (Martinez et al. 1993). (vi) Galanin, galanin-like peptide (GALP), and alarin: Galanin is orexigenic, while GALP is anorectic. Alternative splicing of GALP gene produces a peptide called alarin which was initially considered orexigenic due to increasing food intake after intracerebroventricular injection of alarin; however, the physiological relevance of alarin to food intake remains unknown (Parker and Bloom 2012). Aging is associated with reduction in sensitivity of galanin, an orexigenic hormone abundantly present in the peripheral nervous system and brain, thought to be associated with AOA. (Baranowska et al. 2000) Galanin stimulates intestinal chloride secretion and inhibits gastric acid secretion and the release of glucagon-like peptide 1. (B) Anorectic: (vii) Cocaine and amphetamine-regulated transcript (CART): Cocaine- and amphetamine-related transcript is secreted in CART neurons located in ARC. CART mediates the anorexic effect of leptin. The effects of CART are

428

C. S. Pitchumoni and R. Chaudhari

mediated by the central release of GLP1. CART may be an important connection between food- and drug-related behaviors. (Vicentic and Jones 2007) It may form a part of both anorectic and orexigenic circuits. (Parker and Bloom 2012) CART mediates the anorectic effects. The role of CART in AOA is not clear. (Lau and Herzog 2014; Lau et al. 2018) (viii) Neuropeptide W (NPW): NPW is an anorectic peptide that activates proopiomelanocortin and inhibits neuropeptide Y neurons using a loose-patch extracellular recording of these neurons identified by promoter-driven green fluorescent protein expression. It may play an important role in the regulation of feeding and energy metabolism under the conditions of leptin insufficiency. It decreases the AgRP and increases the POMC expression without affecting the NPY expression in the ARC (Date et al. 2010). It binds to and activates two receptors: NPBWR1 and NPBWR2. It has a role in appetite regulation as evidenced by stimulation of a food intake by NPW neutralizing antibodies (Parker and Bloom 2012). (ix) α-Melanocyte-stimulating hormone (α-MSH): α-MSH is a post-translational cleavage product of the pro-opiomelanocortin (POMC) gene, and it is expressed in the anterior hypothalamus, DMH, PVN, and ARC and also in NTS in the brainstem. It acts through two different α-MSH receptors, namely, MC3R and MC4R. Though both of these receptors are involved in appetite regulation, MC4R is more widely distributed and is considered more important in appetite regulation (Parker and Bloom 2012). α-MSH has the ability to reduce food intake by direct action at the brainstem sites as evidenced by reduced food intake by activation of MC3R/

MC4R receptors in the NTS, parabrachial nucleus, and rostral ventrolateral medulla (Zheng et al. 2005). (x) Oxytocin: Oxytocin is expressed in the PVN and SON of the hypothalamus and is anorectic when injected intracerebroventricularly (ICV). Though NTS appears to be a likely site of action for oxytocin, the exact mechanism of oxytocin-induced anorexia is unknown; however, oxytocin receptor is expressed widely in the brain in relation to appetite regulation (Parker and Bloom 2012). It may affect food preferences as evidenced by selectively enhanced intake of carbohydrates but not fats, in the oxytocin knockout mice (Amico et al. 2005).

Fat-Derived Hormones (i) Leptin: Leptin, an anorexigenic hormone secreted by adipose tissue, opposes ghrelin’s effects on food intake, delays gastric emptying, and inhibits jejunal motility. The name leptin is derived from the Greek word “Leptos,” meaning “thin.” Plasma leptin levels increase with aging as its circulating levels are directly related to the amount of fat tissue in the body, and with aging, there is increased adiposity (Baumgartner et al. 1999). Another cause of increased leptin levels with aging is from a decline in testosterone levels in men. Testosterone therapy reduces, and inhibition of testosterone secretion increases leptin levels. However, leptin administration in obese people results only in minor weight loss. (Hislop et al. 1999) (ii) Adiponectin: Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. (Kubota et al. 2007) It has an unclear role in AOA. It is secreted by the fat tissue and involved in glucose regulation and fatty acid oxidation.

14

Anorexia, Appetite, Hunger, and Satiety in Older Adults

(iii) Resistin: Resistin is primarily secreted by peripheral blood mononuclear cells (PBMCs), macrophages, and bone marrow cells in humans and by the white adipose tissue in mice. It reduces energy intake by affecting NPY neurons and suppresses insulin-stimulated glucose uptake in the fat. The role of resistin in AOA remains unclear. (Acquarone et al. 2019)

Non-homeostatic Control of Appetite (Borer 2010) Edentulism and secondary chewing deficiency, delayed gastric emptying, gastroesophageal reflux, decline in the gastric and pancreatic exocrine function, and reduced testosterone levels in Table 6 Nutritional status assessment (Pilgrim et al. 2015a; Santos-Eggimann and Sirven 2016; Mattes et al. 2005; Morley and Silver 1988; Rolland et al. 2012)

men resulting in increased leptin levels all contribute to the pathogenesis of AOA.

Assessment of Anorexia of Aging Measurement of appetite. It is difficult to quantitate appetite. Assessing the degree of AOA is often by estimating the intake by checking the leftover food on the plate of the older adult after each meal. Other unvalidated approaches are visual analog scales or a single question such as “how hungry are you right now?.” The Simplified Nutritional Appetite Questionnaire (SNAQ) with four questions relating to appetite, satiety, taste, and meal frequency helps to predict >5% weight loss over 6 months in community-dwelling older people (Acar Tek and Karaçil-Ermumcu 2018).

SNAQ Short Nutritional Assessment Questionnaire Did you lose weight unintentionally? More than 6 kg in the last 6 months More than 3 kg in the last month Did you experience a decreased appetite over the last month? Did you use supplemental drinks or tube feeding over the last month? MUST Malnutrition Universal Screening Tool Have you/the patient lost weight recently without trying? No Unsure Yes; how much (kg)? 1–5 6–10 11–15 >15 Unsure Have you/the patient been eating poorly because of a decreased appetite? No Yes lost weight recently without trying? Do you feel you look frail or under your most comfortable weight? No Yes a

Severely malnourished; nutritional intervention and treatment dietician Moderately malnourished; nutritional intervention c No intervention b

429

a b c c

0 2 1 2 3 4 2

0 1

0 1

430

Patients identified as having poor appetite using the screening tool will need further investigation to identify the cause. The SNAQ and Malnutrition Universal Screening Tool (MUST) can be used by clinicians to identify patients with a poor appetite and at high risk for poor health outcomes, and they could be referred to a dietician for a full dietary assessment (Santos-Eggimann and Sirven 2016; Mederacke et al. 2009; Pilgrim et al. 2015a) (Table 6). The MUST is a validated screening tool suitable for adults in acute and community settings. There are various malnutrition screening and assessment tools. Malnutrition Screening Tool (MST) is a validated tool to screen patients for the risk of malnutrition. Mini Nutritional Assessment (MNA ®) is a quick and easy-to-use screening tool that takes less than 5 min to complete. Seniors in the Community: Risk Evaluation for Eating and Nutrition (SCREEN©) is a nutrition screening tool that caters to seniors living in different settings. It determines whether a senior has a potential nutritional problem or is at risk of developing one. In older adults, anorexia, sarcopenia, and frailty have significant overlap which, in combination with dementia, required a combined screening approach. Such an approach is more logical, as all conditions share common risk mitigation and management strategies. Rapid Geriatric Assessment (RGA) is the process that combines screening for four geriatric syndromes, namely, frailty, sarcopenia, anorexia of aging, and dementia. It is quick to administer and consists of (O’Keeffe et al. 2019) the FRAIL scale for frailty (Morley et al. 2012; Depoortere 2014), SARC-F for sarcopenia(Woo et al. 2014; Eggersdorfer et al. 2018) SNAQ for anorexia of aging (Wilson et al. 2005) and (Avelino-Silva and Jaluul 2017), the Rapid Cognitive Screen for dementia (Malmstrom et al. 2015). All of the screening tools identify risk and should lead to further assessment where risk has been identified (Morley and Adams 2015). Landi et al. recommended multistep screening/ assessment programs aimed at identifying and addressing risk factors for anorexia of aging. The first step involves the identification of subjects at risk for developing the condition by using secondand third-generation geriatric assessment tools. The minimum data set inter resident assessment

C. S. Pitchumoni and R. Chaudhari

suite represents a powerful suite of comprehensive geriatric assessment instruments that cover a wide spectrum of clinical, psychological, socioeconomic, and environmental factors across different healthcare settings. Independent of the assessment tool adopted, once an anorectic condition is identified, adjustments in feeding patterns may be enough in milder cases, whereas thorough dietary revision is required in more advanced cases. After an intervention has been implemented, follow-up assessments should be carried out to evaluate the efficacy of the treatment plan in future programming actions. Both quantitative and qualitative malnutrition, along with selective malnutrition, are strongly associated with AOA. Inadequate overall nutrient intake associated with aging is associated with a higher risk of quantitative malnutrition (for instance, protein-energy malnutrition). Suboptimal intake of single nutrients like protein and vitamins, in the early stages of anorexia, raises the possibility of qualitative anorexia (Muscaritoli et al. 2010)’. (Martone et al. 2013) Landi et al., in 2010a, demonstrated that selective malnutrition in older adults is associated with the development of sarcopenia and other adverse outcomes, comprising morbidity and mortality. Anorexia of aging is directly involved in the development of frailty as indicated by marked worsening of the 4-meter walk speed, short physical performance battery (SPPB), handgrip strength, and ADL scores among older adults (Fried et al. 2001; Landi et al. 2013b). The association between AOA and frailty may explain poor endurance, slow gait, and reduced mobility (Morley et al. 2012; Calvani et al. 2014). Anorexia was associated with impairment of physical performance and a significantly higher risk of incident disability after controlling for potential confounders (Landi et al. 2010b). Isolated nutritional deficiencies are more often missed. Inadequate dietary intake of leucine/vitamin D that frequently occurs during anorexia appears to be causally linked to sarcopenia and frailty (Landi et al. 2013b; Calvani et al. 2014). Supplementing essential amino acids, by countering such a deficiency of essential nutrition, improves muscle mass in old age (Rieu et al. 2006; Dreyer et al. 2008).

14

Anorexia, Appetite, Hunger, and Satiety in Older Adults

431

restrictions are prone to consume a semi-starvation regimen thinking that as age advances, one should restrict eating. Proper education is needed on age-related nutritional needs, and proper knowledge promotes better eating habits. Cigarette smoking and alcoholism reduce appetite and should be stopped. LacFrailty and tose intolerance may contribute to gastrointessarcopenia tinal symptoms reducing the intake of all foods. Another approach to improve nutritional intake in older adults is the use of flavor enhancers. The addition of flavor enhancers Cognitive over the cooked meal promotes food conimpairment Increased sumption and provides nutritional benefits hospitalization (Mathey et al. 2001; Best and Appleton 2011). Immunosuppression (b) Avoiding social isolation, endorsing conviviOsteomALACIA ality in the nursing home, avoiding monotony Osteopenia in food, and adding flavor enhancers in food. Premature death Premature death These are all measures that will impact the appetite and enhance adequate nutrition intake. With advancing age, the change in The impact of AOA on survival is difficult to sight, smell, and taste along with edentulous gums affect the appetite significantly. Improvassess and remains a complex but important issue. ing the flavor and texture of food can improve In a study by Landi et al., a direct correlation between mortality and anorexia was found in food palatability and acceptance and increase the overall quality of life and has the potential 1904 elderly nursing home residents of both gento reduce the risk of anorexia. Appropriate use ders. In the study, a twofold higher risk of mortality from all causes was found in subjects with of artificial dentures and appropriate help in feeding make a huge difference (Table 8). AOA compared with subjects without anorexia. Anorexia and unintentional weight loss are pow- (c) Manage comorbid conditions. Medical condierful risk factors of mortality, independent of age, tions and comorbidities that contribute to weight loss need evaluation and assessment. gender, and other potential confounders (Table 7). Treating these medical conditions is associated with improved outcomes. Swallowing disorder (dry mouth, tooth loss, sores or lesions in Management Options for Anorexia of mouth), dyspepsia (gastritis and ulcers), malabAging sorption syndrome (bacterial overgrowth, gluten enteropathy, pancreatic insufficiency), (a) General principles. Initial management neurologic causes (stroke with residual weakshould begin with a preliminary elimination of all potentially reversible contributing facness in muscles of mastication), endocrine disorder (hypercalcemia), psychiatric disorder tors. Any older person presenting with weight (depression, delirium), respiratory disease loss (particularly >5%) or low BMI (particularly 30 mg/mL (>75 nmol/L) Plasma thiamin: 4–15 nmol/L Thiamin, whole blood: 70–180 nmol/L Transketolase >150 nmol/L Erythrocyte trasketolase activity (ETKA)/activity coefficient < 1.15 Serum B12 (cobalamin) 200–1000 pg/mL

Comments

Intranasal B12 is available IfSIBO is suspected a course of antibiotics

Folate 340–1020 ng/mL Pyridoxal-50 phosphate: 5–24 ng/mL

Plasma retinol 20–80 mg/dL

Plasma alpha tocopherol

PT 10–13 sec

Serum iron: 60–170 mg/dL Transferrin 200–360 mg/dL Transferrin saturation: 20–50% Ferritin: 12– 300 ng/mL (male) Ferritin: 12– 150 ng/mL (females) (continued)

862

C. S. Pitchumoni

Table 1 (continued) Recommended daily intake Up to age 70 years: M, 1000 mg; F, 1200 mg 71+ years: M, 1200 mg; F, 1200 mg

Signs and symptoms of micronutrient deficiency Low bone density, Osteoporosis, Neuromuscular hyperexcitability, Muscle weakness, Paresthesia

Copper

900 μg

Anemia, Leukopenia, Optic polyneuropathy myelopathy

Zinc Absorbed in the duodenum

M, 11 mg; F, 8 mg

Magnesium

M: 420 mg F: 320 mg

Selenium

55 μg

Hypogeusia or ageusia, acrodermatitis enteropathica, diarrhea, poor Wound healing, hair loss, Recurrent infections Muscle cramps, arrythmias, increased irritability tremors, paresthesia, and palpitations Atrophy, degeneration, and necrosis of cartilage tissue, “Keshan disease.” Keshan disease is congestive cardiomyopathy caused by a combination of dietary deficiency of selenium and the presence of a mutated strain of coxsackievirus

Micronutrients Calcium

There are various forms of “dieting” (low-calorie diets, sodium-free diets, bland diets, and soft food diets), with different goals for the practice of eating and drinking in a coordinated fashion to achieve an objective. However, the word dieting has become synonymous with a quick fix solution to lose weight. Cyclic weight loss (and gain) is a feature of various diets practiced by millions of Americans who are overweight. According to Lupoli and associates, medical measures involving lifestyle modifications seldom provide longterm weight loss; an initial loss of 2–6% is not sustained. Nearly 90% of the patients return to their original weight or might even gain some weight for reasons not clear (Lupoli et al. 2017). There are various commercially popular named “diets” in the management of obesity. The long list includes “Weight Watchers diet,” “Atkins diet,” “Jenny Craig diet,” “vegan diet,” “flexitarian diet,”

Normal lab range Calcium (ionized) 4.4–5.2 mg/dL PTH (parathyroid hormone) 11–51 pg/mL Vitamin D 25, hydroxy 30–80 ng/mL Serum or plasma copper 11.8– 22.8 mmol/L Ceruloplasmin 75–145 mg/dL Plasma zinc 60–130 mg/dL

Comments

Essential for production of RBCs and for nervous system

Plasma magnesium 1.7–2.2 mg/dL Plasma selenium: 53.03–108.96 mg/L Whole blood selenium: 66.71–119.4 mg/L Plasma glutathione peroxidase: 196 to 477 U/L

Deficiency in post-BS in 14%–22%

“Ornish diet,” “Mayo Clinic diet,” “DASH diet,” “keto diet,” and many others promising weight loss, easy and fast. The challenge is to consume a significantly low-calorie diet while maintaining lean body mass (L.B.M.) and overall nutritional adequacy. The loss of L.B.M. impacts on health, ability to conduct activities of daily living (A.D.L.). An individual patient would have tried one or more of these diets periodically with only transient benefit. The “diets” are often unbalanced and restrict one or more of the calorie-containing macronutrients such as protein, fat, and carbohydrates, with no concern for micronutrients. The very low-calorie diet (V.L. C.D.) approach is typically instituted to achieve rapid weight loss and is centered on meal replacement powders and ready to drink beverages. A VLCD typically includes 400–800 kcalories (kcal)/day and is intended for rapid weight loss. The low-carbohydrate ketogenic diet is based on

36

Malnutrition in Obesity

the principle that low-carbohydrate conditions lead to skeletal muscle lipolysis and the subsequent release of fatty acids into the circulation, bound to albumin. Ketosis forces the body to burn fats rather than carbohydrates (Willoughby et al. 2018). The high-protein diet (
2 g protein/kg body weight/ day), 10–35% of total calories, is a strategy to offset the loss of L.B.M. experienced with caloric restriction (Trumbo et al. 2002; Stern et al. 2004). A highfiber diet is based on the concept that the type of carbohydrate in the diet promotes satiety. Chromium picolinate supplementation is promoted as a slimming aid in the USA and Europe and on the Internet (Tian et al. 2013). Social media always played a notable role in consumers’ eating behaviors. Garcinia cambogia (Malabar tamarind), a fruit native to Southeastern Asia, and Irvingia gabonensis, a tree indigenous to Africa, also known as bush mango, are recently promoted food items, but they are with unproven effects. What is common to all of these diets is that they work well in some, always only along with exercise and other lifestyle modifications, besides requiring careful evaluation for associated nutritional deficiencies of protein, vitamins, and/or trace elements. The success rates of maintaining weight loss with anyone of these commercially available diets are meager. In various trials, there is consistent weight loss with a combination of diet and exercise interventions, but on resuming to a normal lifestyle, nearly half of the weight lost during the intervention is regained within a year (Funk et al. 2019). The yo-yo effect of weight cycling is a pattern of cyclic weight loss and gain conducive to nutritional deficiencies.

Malnutrition in the Obese Older Adult Before and After Bariatric Surgery The onset, the degree, and type of deficiency of various trace elements and vitamins and their clinical manifestations widely vary (Lupoli et al. 2017; Sherf Dagan et al. 2017). The most common deficiencies in the obese adult are vitamin B12, folic acid, vitamin D, and thiamin and among trace elements iron and zinc. A broad spectrum of critical deficiency of vitamins, provitamins, and trace

863

elements are seen in pre-bariatric surgery patients. There are studies on nutritional deficiencies after bariatric surgery, but these are influenced by presurgery status of nutrition and the type of bariatric surgery in addition to the type of supplements taken by the patient. A single dose of multivitamin a day will not cover all the potential deficiencies of vitamins and minerals. The various BS procedures are classified as restrictive or malabsorptive based on mechanisms of weight loss. Both types cause nutritional deficiencies, the malabsorptive-type more than the restrictive-type procedures. Nutritional deficiencies are considered as expected side effects of BS that should be recognized early and managed appropriately. The degree of deficiency depends on the amount of weight loss, preexisting deficiencies, and the type of surgical procedure, increasing from gastric banding, vertical-banded gastroplasty, sleeve gastrectomy, Roux-en-Y gastric bypass, and partial biliopancreatic bypass (Ciangura and Corigliano 2012). BS procedures, despite their success, ease of performance, and popularity, are associated with nutritional deficiencies unless the procedure is carefully supervised in the setting of a team of professionals. Restrictive procedures such as LAGB (laparoscopic adjustable gastric banding) cause micronutrient deficiencies because of low nutrient intake of food in general. Vertical sleeve gastrectomy, another restrictive procedure, involves removal of the greater curvature of the stomach. Laparoscopic sleeve gastrectomy is performed by removing approximately 80% of the stomach in the greater curvature area (see Fig. 1. Physiology of nutrient absorption before and after BS and Fig. 2. Micronutrients before and after bariatric surgery). Because of the exclusion of the areas rich in parietal cells, there is the development of achlorhydria, impairing the absorption of iron. Intrinsic factor (IF) is also produced by the parietal cells; deficiency affects dietary vitamin B12 absorption. Decreased secretion of ghrelin, the appetite-stimulating hormone, decreases appetite, a welcome change. The endoscopic sleeve gastrectomy is a major advance in being incision-less and much less invasive. Malabsorptive procedures such as biliopancreatic bypass with duodenal switch

864

C. S. Pitchumoni

Fig. 2 Malnutrition of micronutrients before and after bariatric surgery

(BPDS) and Roux-en-Y gastric bypass (RYGB) are more effective in causing weight loss, but they also cause profound macronutrient malabsorption of protein and fat, with concomitant malabsorption of micronutrients. With the gastric bypass surgery, the newly created gastric pouch restricts food intake facilitating significantly smaller meals. Further, there are bypassed segments of the duodenum and proximal jejunum that are necessary to absorb calories as well as other nutrients. The bar diagram (Fig. 2) is a rough demonstration of malnutrition of vitamins and minerals in many overweight and obese individuals aggravated by bariatric surgical procedures. The degree and the frequency of deficiency of nutrients vary considerably in different population groups. As a rule, patients should benefit from careful nutritional follow-up with routine monitoring of micronutrients at 6 weeks and 3, 6, and 12 months post-op and then annually after surgery and multivitamin supplementation for life (Landais 2014) (Table 1). The goal of this chapter is not to underestimate the benefits of BS but to review the current knowledge of nutritional deficiencies in the obese older adult in order to institute proper preventive and remedial measures. After BS, all patients receive printed instructions for diets, exercise, and possible complications, but individual patients are primarily concerned about body weight changes

only. Often the relative neglect of the surgical service also follows when the patient had achieved the anticipated weight loss, which is the primary surgical goal. Primary care physicians (P.C.P.) and gastroenterologists are aware that there is often a significant disconnect between bariatric surgeons and the P.C.P. or gastroenterologists who may not understand the nature of the BS or the intricacies of the post-surgical care. The success of BS does not solely depend on the choice of the procedure or expertise of the surgeon but regular and efficient follow-up care by a P.C.P. in association with a nutritionist. There are potentially severe and fatal complications caused by nutritional deficiencies often reported in general medical journals. In the case of an older adult, the role of a clinical geriatrician who can differentiate the symptoms of older age from those secondary to those of post-BS cannot be underestimated. The guidance of a registered dietitian (R.D.) trained in bariatric procedures (BRD) is imperative in achieving success and in preventing nutritional deficiencies. The increasing number of BS procedures has expanded our knowledge on some of the rare clinical disorders caused by nutritional deficiencies of one or more micronutrients stressing the need for continued monitoring with regular laboratory testing to be performed by primary care providers and physician nutrition specialists over time (Gudzune et al. 2013) rather than

36

Malnutrition in Obesity

by the surgeon as is the case mostly. Evaluation should essentially be a team effort. The details of postoperative nutritional care are discussed in detail in a number of papers (Sherf Dagan et al. 2017; Parrott et al. 2016; Via and Mechanick 2017; Osland et al. 2020; Ledoux et al. 2020).

Protein Deficiency in Obese Adults Before and After BS Protein deficiency is mostly asymptomatic or manifested with weakness and detected only by serum testing. As the severity increases, there are decreased muscle mass and generalized edema. Albumin level is not a preferred assay in nutritional assessment due to its lack of specificity and long half-life (approximately 20 days). Prealbumin (transthyretin) is the precursor to albumin and has a half-life of 2–4 days, reflecting more rapid changes of the nutritional state (Keller 2019). Serum prealbumin concentrations less than 10 mg/dL are associated with malnutrition. However, prealbumin is unreliable in the presence of chronic kidney disease. And albumin is a negative acute phase reactant that declines in the presence of acute illness. Hypoproteinemia is associated with impairment of tissue growth and repair, immune response, and production of enzymes and hormones (Steenackers et al. 2018; Stroh et al. 2017; Bétry et al. 2017). There is a progressive decline of 1–2% of muscle mass in individuals aged 50 years and above that increases to approximately 50% among those aged >80 years (Kalyani et al. 2014; Kamel 2003; Keller and Engelhardt 2013). A poor protein intake, as is the case with the obesogenic diet, results in a decrease in lean muscle mass, limiting muscle protein synthesis and increasing oxidative damage of muscle tissue. Sarcopenic obesity is characterized by a loss of skeletal muscle mass and function in the presence of a high BMI Sarcopenia is considered a geriatric syndrome. The cause of sarcopenia is multifactorial influenced by the aging process, illness, or low intakes of or deficiencies in energy, protein, and vitamin D. Acute or chronic diseases exacerbate the development of sarcopenia (Santilli et al. 2014; CruzJentoft et al. 2010; Fielding et al. 2011).

865

The quick weight loss diets primarily focused on total body weight changes (as opposed to body composition) results in losses in both lean body mass (L.B.M.) and fat mass (F.M.), as well as changes in fluid status (Willoughby et al. 2018) unless carefully supervised. The Food and Nutrition Board recommends a recommended dietary allowance (R.D.A.) of 0.8 g/kg/day for all adults, including older adults over the age of 65. The protein requirements with aging are reported to be higher than many current dietary recommendations. Experts recommend a higher intake between 1.2 and 2.0 g/kg/day or higher for older adults (Wolfe et al. 2008; Baum et al. 2016), a goal not achieved by nearly 38% of adult men and 41% of adult women who have dietary protein intakes below the R.D.A. In a candidate for BS, the combination of obesity and protein deficiency is associated with increased surgical complications compared with healthy weight and normoalbuminuric patients (Dietch et al. 2015). An obese older adult invariably is protein deficient, which worsens after BS unless carefully assessed and supplemented. Severe protein malnutrition, with serum albumin ½ (18)

Ulcerated (24) Nonulcerated (2)

Traversed (7) Not traversed (10)

Small bowel is divided into tertiles according to transit time Core total (in worst-affected tertile): villous appearance x extent x descriptor + ulcers x extent x size + stenosis x ulcerated x traversed Short segment, < 10%; long segment, 11–50%; whole tertile, > 50% Ulcers: single (1), few (2–7), multiple (8) Ulcer descriptor (size): the proportion of capsule picture filled by largest ulcer Lewis score a)3 segments (diffuse disease)

Stricture score 0 1 2 3

None Single, traversed Multiple, traversed Obstruction

CECDAI: Proximal segment (Axb + C) + distal segment (Axb + C) Score range: 0–36 Clinical or endoscopic remission: CECDAI 1 cm), both have equal sensitivity (Postgate et al. 2009). SB screening is recommended every 3 years if polyps are found during the initial examination from the age of 8 years or earlier if the patient is symptomatic (Beggs et al. 2010).

975

Chronic Abdominal Pain Chronic abdominal pain (CAP) is a common gastrointestinal complaint, present in up to 21% of population (Quigley et al. 2006; Sandler et al. 2000; Townsend et al. 2005), is a common indication for gastroenterology clinic visits, and yet can be a diagnostic challenge due to varied etiologies ranging from benign and functional disorders to malignancy and inflammatory diseases (IBD) (Hulisz 2004; Middleton and Hing 2006; Myer et al. 2013). Patients with unexplained CAP undergo a series of examinations including ultrasound of abdomen, radiography, EGD, and colonoscopy. The role of WCE remains unclear. Studies evaluating the diagnostic yield of WCE in CAP patients are limited, inconsistent, performed mostly in tertiary care referral centers, and report a wide diagnostic yield (4–44%) (Makins and Blanshard 2006; Qvigstad et al. 2006; Xue et al. 2015). In a meta-analysis of 21 studies with 1520 patients, the yield of WCE for chronic abdominal pain is 21% with inflammatory (78%) and tumors (9%) being most common lesions (Xue et al. 2015). Overall, WCE is a noninvasive diagnostic tool in evaluating patients with unexplained CAP, with a limited diagnostic yield, and among patients with positive findings, change in management is likely limited to those with a history of CD (Egnatios et al. 2015).

Special Considerations of WCE in the Older Adult The most common indication for WCE in the older adult is obscure or occult gastrointestinal bleeding, whereas in the younger adult, it is used to evaluate suspected SB CD and chronic diarrhea of unknown origin (Papadopoulos et al. 2008). The failure rate of WCE in the general population is about 20%, similar to that observed in the older adult (Papadopoulos et al. 2008). A major difference between the younger (age < 65) and older age group (age > 65) is the SB transit time, which influences completion of the procedure (Papadopoulos et al. 2008). One way to overcome prolonged transit time or impaired swallowing in

976

the older adult is to place the capsule beyond the pylorus with the assistance of an upper gastrointestinal endoscope (Yachimski and Friedman 2008). Another consideration is the interference of signal transmission with the concomitant use of cardiac pacemakers or other implanted electromechanical devices (such as pacemaker), a common scenario in the older adult (Payeras et al. 2005) (Dirks et al. 2008). These problems appear to be more perception than reality (Moglia et al. 2009) (Liao et al. 2010) (Payeras et al. 2005) (Dirks et al. 2008). Furthermore, there is potential for inadequate visualization due to poor preparation in older adults with impairments and concern for capsule retention. Dysphagia and dementia can also be a hindrance to performing WCE in elderly.

Contraindications for WCE An important concern with WCE is the potential retention of the capsule within the gastrointestinal tract (Swain 2005) (Cheifetz and Lewis 2006) (Lewis 2005). Capsule retention may occur in patients with (a) prior abdominal surgery and (b) intestinal obstruction (Liao et al. 2010) (Lewis 2005) (Papadakis et al. 2005). In the event the capsule is not spontaneously excreted and cannot be removed endoscopically, surgery may be required (Cheifetz and Lewis 2006). The risk of capsule retention and impaction increases with the concerns above when the capsule gets lodged in a narrowed segment of SB and causes further obstruction. The retention rate is about 1%; most patients are asymptomatic and have a partial obstruction or symptomatic complete intestinal obstruction (Fleischer 2005). Capsule retention in Crohn’s disease can reach 8% (Eliakim 2010). Failure of the passage of the capsule is an acceptable outcome in patients if it demonstrates a site of obstruction when surgery to remove the capsule results in clinical improvement for which the WCE was originally performed (Cheifetz and Lewis 2006). Absolute contraindications include clinical or radiographic evidence of gastrointestinal

A. Dudekula and C. S. Pitchumoni

obstruction, active and extensive Crohn’s disease with or without the presence of strictures, and extensive intestinal diverticulosis (Liao et al. 2010).

Limitations of Capsule Endoscopy There are a few limitations for WCE. The expected life span of the battery is a maximum of 8 h and 45 min. About 10–20% of capsules do not reach the cecum; here battery failure can cause inadequate visualization of SB pathology (Tatar et al. 2006). Battery failure is more common in patients with delayed gastric emptying or when the capsule sits in the stomach for over 1.5 h (Liao et al. 2010). Image quality may be influenced by the presence of bile, poor bowel preparation, or residual barium from previous radiographic studies. Up to 40% of all lesions can be missed due to inability to control the velocity or direction of the capsule passage (Papadakis et al. 2005). Furthermore, the images are not in real time; therefore onthe-spot treatment and histopathologic confirmation of the findings are not possible (Papadakis et al. 2005).

Preparation Although WCE can be performed after an overnight fast and an empty stomach without intestinal cleansing, a bowel preparation enhances the visualization of the mucosa, increases the likelihood of a complete cecal examination, and prevents smudging of the camera lens (Eliakim 2010), (Gerson 2009). A half-day bowel preparation using polyethylene glycol (PEG) enhances the quality and diagnostic yield (Moglia et al. 2009). The ingested capsule passively travels through the gastrointestinal tract, while the cameras in the capsule capture images at two to three color frames per second (Moglia et al. 2009). The capsule is evacuated, usually 24–48 h later, with stool (Eliakim 2010). A complete examination of the SB is possible in over 80% of patients (Liao et al. 2010), (Van Gossum et al. 2009).

41

Wireless Capsule Endoscopy

Other Capsule Endoscopic Procedures Although esophageal and colon capsules are FDA approved, their usage is limited and is yet to gain widespread acceptance.

Esophageal WCE Esophageal WCE is a noninvasive unsedated imaging technique for visualization of the esophagus. In a meta-analysis, pooled sensitivity and specificity for the diagnosis of Barret’s esophagus were moderate, 77% and 86%, respectively (Bhardwaj et al. 2009). It can be utilized to detect esophageal varices (Karatzas et al. 2018) and esophagitis. Esophageal WCE has FDA approval for evaluation of esophageal varices and esophagitis but not for Barrett’s esophagus.

Colon Capsule Optical colonoscopy is still regarded as the gold standard test for CRC prevention as it allows for both diagnostic and therapeutic intervention for premalignant lesions and unequivocally demonstrated benefit in CRC screening/surveillance. Still, the acceptance of colonoscopy for CRC screening remains far from optimal due to concerns regarding adverse events, privacy, implications of workrelated absence, and invasive nature of the procedure. The PillCam colon capsule (PCCE) is minimially invasive, can be performed at patients’ homes without any privacy concerns, does not require sedation, and has significant potential to improve compliance for CRC screening. This is currently approved by the European Society for Gastrointestinal Endoscopy (ESGE) for averagerisk CRC screening and also for high-risk screening in patients who refuse colonoscopy or have a contraindication for colonoscopy (Spada et al. 2012). In the USA, FDA has approved it as an adjunctive test in those with a prior incomplete colonoscopy and in the evaluation of patients with suspected lower GI bleeding (Rex et al. 2017). The test is not yet approved as an option for average-risk CRC screening. Compared to colonoscopy, PCCE has similar

977

adenoma detection rate and colon completion rate but lower specificity (Spada et al. 2016) (Rex et al. 2015) (van Rijn et al. 2006). CT colonography is currently recommended as one of the options for average-risk CRC screening in patients who have a prior incomplete colonoscopy, as well as those with contraindications or unwilling to undergo colonoscopy. Studies comparing PCCE with CT colonography showed comparable results for sensitivity and specificity to polyp detection (Rondonotti et al. 2014). However, PCCE had a significantly higher reading time compared to CT colonography (62.8 30.8 mins vs. 18.5 7.3 min) (Rondonotti et al. 2014). Preliminary studies have showed PCCE as an effective tool for the assessment of disease activity and mucosal healing. But inability to biopsy and risk of retention are prohibiting its widespread usage (Hall et al. 2015) (Shi et al. 2015). PCCE requires a more rigorous bowel preparation compared to optical colonoscopy due to lack of ability to irrigate, suction, and insufflate. This may be the biggest limiting factory in patients’ acceptance of the procedure.

Elements of Capsule Report A good wireless capsule endoscopy report should include data on the following. Indication for the study, patient demographics, comorbidities, prior h/o abdominal surgery, h/o anticoagulant and NSAID use, capsule system used, duration of the study, quality of bowel preparation, identification key landmarks, and gastric emptying and oro-cecal transit time are optional findings of limited use, pertinent findings in SB, and incidental findings in the stomach and proximal colon (if observed), adverse effects, diagnosis, and potential recommendations.

Key Points Wireless Capsule Endoscopy (WCE) 1. WCE is a novel, noninvasive method of visualizing the entire small bowel (SB), which was considered inaccessible by routine endoscopy.

978

2. In contrast to other conventional endoscopies, WCE is solely a diagnostic procedure with no feasibility for biopsy or therapeutic capability. 3. WCE is a tool to detect bleeding sites in the small bowel as a cause of anemia in the older adults, tumors of the SB, Crohn’s disease (CD), and nonsteroidal ulcers. 4. WCE is helpful in patients with acute occult gastrointestinal bleeding where the bleeding site is not seen by conventional endoscopies. 5. Older adults with dysphagia may rarely encounter difficulty swallowing the capsule. 6. Previous gastric surgery and gastroparesis may pose a delay in the WCE exiting the stomach, and endoscopic placement of the capsule in the duodenum may be needed. 7. The complications are rare. Capsule retention may occur rarely and occasionally need for surgical removal of the retained capsule.

References Adler DG, Knipschield M, Gostout C. A prospective comparison of capsule endoscopy and push enteroscopy in patients with GI bleeding of obscure origin. Gastrointest Endosc. 2004;59(4):492–8. PubMed PMID: 15044884. Akin E, Demirezer Bolat A, Buyukasik S, Algin O, Selvi E, Ersoy O. Comparison between capsule endoscopy and magnetic resonance enterography for the detection of polyps of the small intestine in patients with familial adenomatous polyposis. Gastroenterol Res Pract. 2012;2012:215028. PubMed PMID: 22518115. Pubmed Central PMCID: 3296287. Annese V, Daperno M, Rutter MD, Amiot A, Bossuyt P, East J, et al. European evidence based consensus for endoscopy in inflammatory bowel disease. J Crohns Colitis. 2013;7(12):982–1018. PubMed PMID: 24184171. Bandorski D, Kurniawan N, Baltes P, Hoeltgen R, Hecker M, Stunder D, et al. Contraindications for video capsule endoscopy. World J Gastroenterol. 2016;22(45):9898–908. PubMed PMID: 28018097. Pubmed Central PMCID: 5143757. Bar-Meir S. Review article: capsule endoscopy – are all small intestinal lesions Crohn’s disease? Aliment Pharmacol Ther. 2006;24(Suppl 3):19–21. PubMed PMID: 16961739. Beggs AD, Latchford AR, Vasen HF, Moslein G, Alonso A, Aretz S, et al. Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut. 2010;59(7):975–86. PubMed PMID: 20581245.

A. Dudekula and C. S. Pitchumoni Bhardwaj A, Hollenbeak CS, Pooran N, Mathew A. A meta-analysis of the diagnostic accuracy of esophageal capsule endoscopy for Barrett’s esophagus in patients with gastroesophageal reflux disease. Am J Gastroenterol. 2009;104(6):1533–9. PubMed PMID: 19491867. Bresci G, Parisi G, Bertoni M, Tumino E, Capria A. The role of video capsule endoscopy for evaluating obscure gastrointestinal bleeding: usefulness of early use. J Gastroenterol. 2005;40(3):256–9. PubMed PMID: 15830284. Bulow S, Christensen IJ, Hojen H, Bjork J, Elmberg M, Jarvinen H, et al. Duodenal surveillance improves the prognosis after duodenal cancer in familial adenomatous polyposis. Color Dis: Off J Assoc Coloproctology G B Irel. 2012;14(8):947–52. PubMed PMID: 21973191. Carey EJ, Leighton JA, Heigh RI, Shiff AD, Sharma VK, Post JK, et al. A single-center experience of 260 consecutive patients undergoing capsule endoscopy for obscure gastrointestinal bleeding. Am J Gastroenterol. 2007;102(1):89–95. PubMed PMID: 17100969. Cellier C, Green PH, Collin P, Murray J. ICCE. ICCE consensus for celiac disease. Endoscopy. 2005;37(10): 1055–9. PubMed PMID: 16189790. Cheifetz AS, Lewis BS. Capsule endoscopy retention: is it a complication? J Clin Gastroenterol. 2006;40(8):688– 91. PubMed PMID: 16940879. Epub 2006/08/31. eng. Cheung DY, Kim JS, Shim KN, Choi MG. Korean gut image study G. the usefulness of capsule endoscopy for small bowel tumors. Clin Endoscopy. 2016;49(1):21–5. PubMed PMID: 26855919. Pubmed Central PMCID: 4743724. Choi M, Lim S, Choi MG, Shim KN, Lee SH. Effectiveness of capsule endoscopy compared with other diagnostic modalities in patients with small bowel Crohn’s disease: a meta-analysis. Gut liver. 2017;11(1):62–72. PubMed PMID: 27728963. Pubmed Central PMCID: 5221862. Chong J, Tagle M, Barkin JS, Reiner DK. Small bowel pushtype fiber optic enteroscopy for patients with occult gastrointestinal bleeding or suspected small bowel pathology. Am J Gastroenterol. 1994;89(12):2143–6. PubMed PMID: 7977230. Cobrin GM, Pittman RH, Lewis BS. Increased diagnostic yield of small bowel tumors with capsule endoscopy. Cancer. 2006;107(1):22–7. PubMed PMID: 16736516. Committee AT, Wang A, Banerjee S, Barth BA, Bhat YM, Chauhan S, et al. Wireless capsule endoscopy. Gastrointest Endosc. 2013;78(6):805–15. PubMed PMID: 24119509. Culliford A, Daly J, Diamond B, Rubin M, Green PH. The value of wireless capsule endoscopy in patients with complicated celiac disease. Gastrointest Endosc. 2005;62(1):55–61. PubMed PMID: 15990820. De Cruz P, Kamm MA, Prideaux L, Allen PB, Desmond PV. Postoperative recurrent luminal Crohn’s disease: a systematic review. Inflamm Bowel Dis. 2012;18 (4):758–77. PubMed PMID: 21830279.

41

Wireless Capsule Endoscopy

de Leusse A, Vahedi K, Edery J, Tiah D, Fery-Lemonnier E, Cellier C, et al. Capsule endoscopy or push enteroscopy for first-line exploration of obscure gastrointestinal bleeding? Gastroenterology. 2007;132(3):855–62; quiz 1164-5. PubMed PMID: 17324401. Dirks MH, Costea F, Seidman EG. Successful videocapsule endoscopy in patients with an abdominal cardiac pacemaker. Endoscopy. 2008;40(1):73–5.. PubMed PMID: 18161651. Epub 2007/12/29. eng. Dussault C, Gower-Rousseau C, Salleron J, VernierMassouille G, Branche J, Colombel JF, et al. Small bowel capsule endoscopy for management of Crohn’s disease: a retrospective tertiary care Centre experience. Dig Liver Dis: Off J Ital Soc Gastroenterolo Ital Assoc Study Liver. 2013;45(7):558–61. PubMed PMID: 23238033. Efthymiou A, Viazis N, Mantzaris G, Papadimitriou N, Tzourmakliotis D, Raptis S, et al. Does clinical response correlate with mucosal healing in patients with Crohn’s disease of the small bowel? A prospective, case-series study using wireless capsule endoscopy. Inflamm Bowel Dis. 2008;14(11):1542–7. PubMed PMID: 18521929. Egnatios J, Kaushal K, Kalmaz D, Zarrinpar A. Video capsule endoscopy in patients with chronic abdominal pain with or without associated symptoms: a retrospective study. PLoS One. 2015;10(4):e0126509. PubMed PMID: 25893440. Pubmed Central PMCID: 4404061. Eliakim R. The impact of wireless capsule endoscopy on gastrointestinal diseases. South Med J. 2007;100(3): 235–6. PubMed PMID: 17396720. Eliakim R. Video capsule endoscopy of the small bowel. Curr Opin Gastroenterol. 2010;26(2):129–33. PubMed PMID: 20145540. Epub 2010/02/11. eng. Ell C, Remke S, May A, Helou L, Henrich R, Mayer G. The first prospective controlled trial comparing wireless capsule endoscopy with push enteroscopy in chronic gastrointestinal bleeding. Endoscopy. 2002;34(9):685–9. PubMed PMID: 12195324. Enns RA, Hookey L, Armstrong D, Bernstein CN, Heitman SJ, Teshima C, et al. Clinical practice guidelines for the use of video capsule endoscopy. Gastroenterology. 2017;152(3):497–514. PubMed PMID: 28063287. Esaki M, Matsumoto T, Yada S, Yanaru-Fujisawa R, Kudo T, Yanai S, et al. Factors associated with the clinical impact of capsule endoscopy in patients with overt obscure gastrointestinal bleeding. Dig Dis Sci. 2010;55(8):2294–301. PubMed PMID: 19957038. Estevez E, Gonzalez-Conde B, Vazquez-Iglesias JL, de Los Angeles Vazquez-Millan M, Pertega S, Alonso PA, et al. Diagnostic yield and clinical outcomes after capsule endoscopy in 100 consecutive patients with obscure gastrointestinal bleeding. Eur J Gastroenterol Hepatol. 2006;18(8):881–8. PubMed PMID: 16825907. Flamant M, Trang C, Maillard O, Sacher-Huvelin S, Le Rhun M, Galmiche JP, et al. The prevalence and outcome of jejunal lesions visualized by small bowel

979 capsule endoscopy in Crohn’s disease. Inflamm Bowel Dis. 2013;19(7):1390–6. PubMed PMID: 23552764. Fleischer D. Capsule imaging. Clin Gastroenterol Hepatol. 2005;3(7 Suppl 1):S30–2. PubMed PMID: 16012992. Epub 2005/07/14. eng. Friedman S. Comparison of capsule endoscopy to other modalities in small bowel. Gastrointest Endosc Clin N Am. 2004;14(1):51–60. PubMed PMID: 15062380. Epub 2004/04/06. eng. Fry LC, Mönkemüller K, Neumann H, Von Arnim U, Bellutti M, Malfertheiner P. Capsule endoscopy (CE) increases the diagnostic yield of double balloon Enteroscopy (DBE) in patients being investigated for obscure gastrointestinal bleeding (OGIB). Gastrointest Endosc. 2009;69(5):AB190. Gastineau S, Viala J, Caldari D, Mas E, Darviot E, Le Gall C, et al. Contribution of capsule endoscopy to Peutz-Jeghers syndrome management in children. Dig Liver Dis: Off J Ital Soc Gastroenterolo Ital Assoc Study Liver. 2012;44(10):839–43. PubMed PMID: 22795616. Ge ZZ, Chen HY, Gao YJ, Hu YB, Xiao SD. Best candidates for capsule endoscopy for obscure gastrointestinal bleeding. J Gastroenterol Hepatol. 2007;22 (12):2076–80. PubMed PMID: 18031363. Gerson LB. Preparation before capsule endoscopy: the value of the purge. Gastroenterology. 2009;137 (3):1166–8; discussion 8. PubMed PMID: 19635602. Epub 2009/07/29. eng. Gerson LB, Fidler JL, Cave DR, Leighton JA. ACG clinical guideline: diagnosis and management of small bowel bleeding. Am J Gastroenterol. 2015;110 (9):1265–87; quiz 88. PubMed PMID: 26303132. Girelli CM, Porta P, Colombo E, Lesinigo E, Bernasconi G. Development of a novel index to discriminate bulge from mass on small-bowel capsule endoscopy. Gastrointest Endosc. 2011;74(5):1067–74; quiz 115 e1-5. PubMed PMID: 21907982. Guindi M, Riddell RH. Indeterminate colitis. J Clin Pathol. 2004;57(12):1233–44. PubMed PMID: 15563659. Pubmed Central PMCID: 1770507. Haanstra JF, Al-Toma A, Dekker E, Vanhoutvin SA, Nagengast FM, Mathus-Vliegen EM, et al. Prevalence of small-bowel neoplasia in lynch syndrome assessed by video capsule endoscopy. Gut. 2015;64(10):1578– 83. PubMed PMID: 25209657. Hall B, Holleran G, Chin JL, Smith S, Ryan B, Mahmud N, et al. A prospective 52 week mucosal healing assessment of small bowel Crohn’s disease as detected by capsule endoscopy. J Crohns Colitis. 2014;8(12):1601– 9. PubMed PMID: 25257546. Hall B, Holleran G, McNamara D. PillCam COLON 2((c)) as a pan-enteroscopic test in Crohn’s disease. World J Gastrointestinal Endoscopy. 2015;7(16):1230–2. PubMed PMID: 26566430. Pubmed Central PMCID: 4639745. Hartmann D, Schmidt H, Bolz G, Schilling D, Kinzel F, Eickhoff A, et al. A prospective two-center study

980 comparing wireless capsule endoscopy with intraoperative enteroscopy in patients with obscure GI bleeding. Gastrointest Endosc. 2005;61(7):826–32. PubMed PMID: 15933683. Hindryckx P, Botelberge T, De Vos M, De Looze D. Clinical impact of capsule endoscopy on further strategy and long-term clinical outcome in patients with obscure bleeding. Gastrointest Endosc. 2008;68 (1):98–104. PubMed PMID: 18291382. Hosoe N, Takabayashi K, Ogata H, Kanai T. Capsule endoscopy for small-intestinal disorders: current status. Dig Endosc: Off J Jpn Gastroenterological Endoscopy Soc. 2019;31(5):498–507. PubMed PMID: 30656743. Hulisz D. The burden of illness of irritable bowel syndrome: current challenges and hope for the future. J Manag Care Pharm : JMCP. 2004;10(4):299–309. PubMed PMID: 15298528. Hunt RH, Lanas A, Stichtenoth DO, Scarpignato C. Myths and facts in the use of anti-inflammatory drugs. Ann Med. 2009;41(6):423–37. PubMed PMID: 19430988. Jensen MD, Nathan T, Rafaelsen SR, Kjeldsen J. Diagnostic accuracy of capsule endoscopy for small bowel Crohn’s disease is superior to that of MR enterography or CT enterography. Clin Gastroenterol Hepatol. 2011;9(2):124–9. PubMed PMID: 21056692. Kaffes AJ, Siah C, Koo JH. Clinical outcomes after doubleballoon enteroscopy in patients with obscure GI bleeding and a positive capsule endoscopy. Gastrointest Endosc. 2007;66(2):304–9. PubMed PMID: 17643704. Karatzas A, Konstantakis C, Aggeletopoulou I, Kalogeropoulou C, Thomopoulos K, Triantos C. Non-invasive screening for esophageal varices in patients with liver cirrhosis. Ann Gastroenterol. 2018;31(3):305–14. PubMed PMID: 29720856. Pubmed Central PMCID: 5924853. Katsinelos P, Chatzimavroudis G, Terzoudis S, Patsis I, Fasoulas K, Katsinelos T, et al. Diagnostic yield and clinical impact of capsule endoscopy in obscure gastrointestinal bleeding during routine clinical practice: a single-center experience. Med Princ Pract: Int J Kuwait Univ, Health Sci Cent. 2011;20(1):60–5. PubMed PMID: 21160216. Kim Y, Jeon SR, Choi SM, Kim HG, Lee TH, Cho JH, et al. Practice patterns and clinical significance of use of capsule endoscopy in suspected and established Crohn’s disease. Intestinal Res. 2017;15(4):467–74. PubMed PMID: 29142514. Pubmed Central PMCID: 5683977. Koh SJ, Im JP, Kim JW, Kim BG, Lee KL, Kim SG, et al. Long-term outcome in patients with obscure gastrointestinal bleeding after negative capsule endoscopy. World J Gastroenterol. 2013;19(10):1632–8. PubMed PMID: 23539070. Pubmed Central PMCID: 3602481. Kopylov U, Yablecovitch D, Lahat A, Neuman S, Levhar N, Greener T, et al. Detection of small bowel mucosal healing and deep remission in patients with known small bowel Crohn’s disease using biomarkers, capsule endoscopy, and imaging. Am J Gastroenterol. 2015a;110(9):1316–23. PubMed PMID: 26215531.

A. Dudekula and C. S. Pitchumoni Kopylov U, Nemeth A, Koulaouzidis A, Makins R, Wild G, Afif W, et al. Small bowel capsule endoscopy in the management of established Crohn’s disease: clinical impact, safety, and correlation with inflammatory biomarkers. Inflamm Bowel Dis. 2015b;21(1):93– 100. PubMed PMID: 25517597. Kornbluth A, Colombel JF, Leighton JA, Loftus E. ICCE. ICCE consensus for inflammatory bowel disease. Endoscopy. 2005;37(10):1051–4. PubMed PMID: 16189789. Koulaouzidis A, Rondonotti E, Giannakou A, Plevris JN. Diagnostic yield of small-bowel capsule endoscopy in patients with iron-deficiency anemia: a systematic review. Gastrointest Endosc. 2012a;76(5):983–92. PubMed PMID: 23078923. Koulaouzidis A, Yung DE, Lam JH, Smirnidis A, Douglas S, Plevris JN. The use of small-bowel capsule endoscopy in iron-deficiency anemia alone; be aware of the young anemic patient. Scand J Gastroenterol. 2012b;47(8-9):1094–100. PubMed PMID: 22852553. Lai LH, Wong GL, Chow DK, Lau JY, Sung JJ, Leung WK. Long-term follow-up of patients with obscure gastrointestinal bleeding after negative capsule endoscopy. Am J Gastroenterol. 2006;101(6):1224–8. PubMed PMID: 16771942. Laine L, Sahota A, Shah A. Does capsule endoscopy improve outcomes in obscure gastrointestinal bleeding? Randomized trial versus dedicated small bowel radiography. Gastroenterology. 2010;138(5):1673–80 e1; quiz e11-2. PubMed PMID: 20138043. Epub 2010/02/09. eng. Lanas A, Garcia-Rodriguez LA, Polo-Tomas M, Ponce M, Alonso-Abreu I, Perez-Aisa MA, et al. Time trends and impact of upper and lower gastrointestinal bleeding and perforation in clinical practice. Am J Gastroenterol. 2009;104(7):1633–41. PubMed PMID: 19574968. Lazarev M, Huang C, Bitton A, Cho JH, Duerr RH, McGovern DP, et al. Relationship between proximal Crohn’s disease location and disease behavior and surgery: a cross-sectional study of the IBD genetics consortium. Am J Gastroenterol. 2013;108(1):106–12. PubMed PMID: 23229423. Pubmed Central PMCID: 4059598. Lepileur L, Dray X, Antonietti M, Iwanicki-Caron I, Grigioni S, Chaput U, et al. Factors associated with diagnosis of obscure gastrointestinal bleeding by video capsule enteroscopy. Clin Gastroenterol Hepatol. 2012;10(12):1376–80. PubMed PMID: 22677574. Leung WK, Graham DY. Obscure gastrointestinal bleeding: where do we go from here? Gastroenterology. 2010;138(5):1655–8. PubMed PMID: 20332043. Epub 2010/03/25. eng. Lewis B. How to prevent endoscopic capsule retention. Endoscopy. 2005;37(9):852–6. PubMed PMID: 16116537. Epub 2005/08/24. eng. Lewis BS, Swain P. Capsule endoscopy in the evaluation of patients with suspected small intestinal bleeding: results of a pilot study. Gastrointest Endosc. 2002;56 (3):349–53. PubMed PMID: 12196771.

41

Wireless Capsule Endoscopy

Li X, Chen H, Dai J, Gao Y, Ge Z. Predictive role of capsule endoscopy on the insertion route of doubleballoon enteroscopy. Endoscopy. 2009;41(9):762–6. PubMed PMID: 19662592. Liao Z, Gao R, Xu C, Li ZS. Indications and detection, completion, and retention rates of small-bowel capsule endoscopy: a systematic review. Gastrointest Endosc. 2010;71(2):280–6. PubMed PMID: 20152309. Epub 2010/02/16. eng. Loftus EV Jr. Capsule endoscopy for Crohn’s disease: ready for prime time? Clin Gastroenterol Hepatol. 2004;2(1):14–6. PubMed PMID: 15017627. Long MD, Barnes E, Isaacs K, Morgan D, Herfarth HH. Impact of capsule endoscopy on management of inflammatory bowel disease: a single tertiary care center experience. Inflamm Bowel Dis. 2011;17(9):1855– 62. PubMed PMID: 21830264. Pubmed Central PMCID: 3116981. Lorenzo-Zuniga V, de Vega VM, Domenech E, Cabre E, Manosa M, Boix J. Impact of capsule endoscopy findings in the management of Crohn’s disease. Dig Dis Sci. 2010;55(2):411–4.. PubMed PMID: 19255845. Ludvigsson JF, Bai JC, Biagi F, Card TR, Ciacci C, Ciclitira PJ, et al. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut. 2014;63(8):1210–28. PubMed PMID: 24917550. Pubmed Central PMCID: 4112432. Maiden L, Thjodleifsson B, Theodors A, Gonzalez J, Bjarnason I. A quantitative analysis of NSAID-induced small bowel pathology by capsule enteroscopy. Gastroenterology. 2005;128(5):1172–8. PubMed PMID: 15887101. Epub 2005/05/12. eng. Makins R, Blanshard C. Guidelines for capsule endoscopy: diagnoses will be missed. Aliment Pharmacol Ther. 2006;24(2):293–7. PubMed PMID: 16842455. Mark Feldman LSF, Brandt LJ. Sleisenger & Fordtran’s gastrointestinal and liver disease : pathophysiology, diagnosis, management. 10th ed. Philadelphia: Saunders; 2016. Mata A, Bordas JM, Feu F, Gines A, Pellise M, FernandezEsparrach G, et al. Wireless capsule endoscopy in patients with obscure gastrointestinal bleeding: a comparative study with push enteroscopy. Aliment Pharmacol Ther. 2004;20(2):189–94. PubMed PMID: 15233699. Maunoury V, Savoye G, Bourreille A, Bouhnik Y, Jarry M, Sacher-Huvelin S, et al. Value of wireless capsule endoscopy in patients with indeterminate colitis (inflammatory bowel disease type unclassified). Inflamm Bowel Dis. 2007;13(2):152–5. PubMed PMID: 17206697. May A, Wardak A, Nachbar L, Remke S, Ell C. Influence of patient selection on the outcome of capsule endoscopy in patients with chronic gastrointestinal bleeding. J Clin Gastroenterol. 2005;39(8):684–8. PubMed PMID: 16082277. McAlindon ME, Sanders DS, Sidhu R. Capsule endoscopy: 10 years on and in the frontline. Frontline Gastroenterolo. 2010;1:82–7.

981 Middleton KR, Hing E. National Hospital Ambulatory Medical Care Survey: 2004 outpatient department summary. Adv Data. 2006;23(373):1–27. PubMed PMID: 16841784. Min YW, Kim JS, Jeon SW, Jeen YT, Im JP, Cheung DY, et al. Long-term outcome of capsule endoscopy in obscure gastrointestinal bleeding: a nationwide analysis. Endoscopy. 2014;46(1):59–65. PubMed PMID: 24254387. Mitsui K, Tanaka S, Yamamoto H, Kobayashi T, Ehara A, Yano T, et al. Role of double-balloon endoscopy in the diagnosis of small-bowel tumors: the first Japanese multicenter study. Gastrointest Endosc. 2009;70 (3):498–504. PubMed PMID: 19555947. Moglia APA, Cuschieri A. Capsule endoscopy. BMJ. 2009;339:796–9. Moglia A, Menciassi A, Dario P, Cuschieri A. Capsule endoscopy: progress update and challenges ahead. Nat Rev Gastroenterol Hepatol. 2009;6(6):353–62. PubMed PMID: 19434097. Epub 2009/05/13. eng. Monteiro S, Boal Carvalho P, Dias de Castro F, Magalhaes J, Machado F, Moreira MJ, et al. Capsule endoscopy: diagnostic accuracy of Lewis score in patients with suspected Crohn’s disease. Inflamm Bowel Dis. 2015;21(10):2241–6. PubMed PMID: 26197449. Myer PA, Mannalithara A, Singh G, Singh G, Pasricha PJ, Ladabaum U. Clinical and economic burden of emergency department visits due to gastrointestinal diseases in the United States. Am J Gastroenterol. 2013;108 (9):1496–507. PubMed PMID: 23857475. Mylonaki M, Fritscher-Ravens A, Swain P. Wireless capsule endoscopy: a comparison with push enteroscopy in patients with gastroscopy and colonoscopy negative gastrointestinal bleeding. Gut. 2003;52(8):1122–6. PubMed PMID: 12865269. Pubmed Central PMCID: 1773749. Ooka S, Kobayashi K, Kawagishi K, Kodo M, Yokoyama K, Sada M, et al. Roles of capsule endoscopy and single-balloon Enteroscopy in diagnosing unexplained gastrointestinal bleeding. Clin Endosc. 2016;49(1):56–60. PubMed PMID: 26855925. Pubmed Central PMCID: 4743720. Oresland T, Bemelman WA, Sampietro GM, Spinelli A, Windsor A, Ferrante M, et al. European evidence based consensus on surgery for ulcerative colitis. J Crohns Colitis. 2015;9(1):4–25. PubMed PMID: 25304060. Papadakis KA, Lo SK, Fireman Z, Hollerbach S. Wireless capsule endoscopy in the evaluation of patients with suspected or known Crohn’s disease. Endoscopy. 2005;37(10):1018–22. PubMed PMID: 16189777. Epub 2005/09/29. eng. Papadopoulos AA, Triantafyllou K, Kalantzis C, Adamopoulos A, Ladas D, Kalli T, et al. Effects of ageing on small bowel video-capsule endoscopy examination. Am J Gastroenterol. 2008;103(10):2474–80. PubMed PMID: 18759823. Epub 2008/09/02. eng. Papay P, Ignjatovic A, Karmiris K, Amarante H, Milheller P, Feagan B, et al. Optimising monitoring in

982 the management of Crohn’s disease: a physician’s perspective. J Crohns Colitis. 2013;7(8):653–69. PubMed PMID: 23562672. Parikh DA, Mittal M, Leung FW, Mann SK. Improved diagnostic yield with severity of bleeding. J Dig Dis. 2011;12(5):357–63. PubMed PMID: 21955428. Park JJ, Cheon JH, Kim HM, Park HS, Moon CM, Lee JH, et al. Negative capsule endoscopy without subsequent enteroscopy does not predict lower long-term rebleeding rates in patients with obscure GI bleeding. Gastrointest Endosc. 2010;71(6):990–7. PubMed PMID: 20304392. Payeras G, Piqueras J, Moreno VJ, Cabrera A, Menendez D, Jimenez R. Effects of capsule endoscopy on cardiac pacemakers. Endoscopy. 2005;37 (12):1181–5.. PubMed PMID: 16329014. Epub 2005/ 12/06. eng. Pennazio M, Arrigoni A, Risio M, Spandre M, Rossini FP. Clinical evaluation of push-type enteroscopy. Endoscopy. 1995;27(2):164–70. PubMed PMID: 7601049. Pennazio M, Santucci R, Rondonotti E, Abbiati C, Beccari G, Rossini FP, et al. Outcome of patients with obscure gastrointestinal bleeding after capsule endoscopy: report of 100 consecutive cases. Gastroenterology. 2004;126(3):643–53. PubMed PMID: 14988816. Pennazio M, Spada C, Eliakim R, Keuchel M, May A, Mulder CJ, et al. Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders: European Society of Gastrointestinal Endoscopy (ESGE) clinical guideline. Endoscopy. 2015;47(4):352–76. PubMed PMID: 25826168. Petroniene R, Dubcenco E, Baker JP, Ottaway CA, Tang SJ, Zanati SA, et al. Given capsule endoscopy in celiac disease: evaluation of diagnostic accuracy and interobserver agreement. Am J Gastroenterol. 2005;100(3):685–94. PubMed PMID: 15743369. Petruzzelli M, Vacca M, Moschetta A, Cinzia Sasso R, Palasciano G, van Erpecum KJ, et al. Intestinal mucosal damage caused by non-steroidal anti-inflammatory drugs: role of bile salts. Clin Biochem. 2007;40 (8):503–10. PubMed PMID: 17321514. Pons Beltran V, Nos P, Bastida G, Beltran B, Arguello L, Aguas M, et al. Evaluation of postsurgical recurrence in Crohn’s disease: a new indication for capsule endoscopy? Gastrointest Endosc. 2007;66(3):533–40. PubMed PMID: 17725942. Postgate A, Hyer W, Phillips R, Gupta A, Burling D, Bartram C, et al. Feasibility of video capsule endoscopy in the management of children with Peutz-Jeghers syndrome: a blinded comparison with barium enterography for the detection of small bowel polyps. J Pediatr Gastroenterol Nutr. 2009;49(4):417–23. PubMed PMID: 19543117. Quigley EM, Locke GR, Mueller-Lissner S, Paulo LG, Tytgat GN, Helfrich I, et al. Prevalence and management of abdominal cramping and pain: a multinational survey. Aliment Pharmacol Ther. 2006;24(2):411–9. PubMed PMID: 16842469.

A. Dudekula and C. S. Pitchumoni Qvigstad G, Hatlen-Rebhan P, Brenna E, Waldum HL. Capsule endoscopy in clinical routine in patients with suspected disease of the small intestine: a 2-year prospective study. Scand J Gastroenterol. 2006;41(5): 614–8. PubMed PMID: 16638706. Raju GS, Gerson L, Das A, Lewis B, American Gastroenterological A. American Gastroenterological Association (AGA) institute medical position statement on obscure gastrointestinal bleeding. Gastroenterology. 2007a;133(5):1694–6. PubMed PMID: 17983811. Raju GS, Gerson L, Das A, Lewis B, American GA. American Gastroenterological Association (AGA) institute technical review on obscure gastrointestinal bleeding. Gastroenterology. 2007b;133 (5):1697–717. PubMed PMID: 17983812. Rex DK, Adler SN, Aisenberg J, Burch WC Jr, Carretero C, Chowers Y, et al. Accuracy of capsule colonoscopy in detecting colorectal polyps in a screening population. Gastroenterology. 2015;148(5):948–57 e2. PubMed PMID: 25620668. Rex DK, Boland CR, Dominitz JA, Giardiello FM, Johnson DA, Kaltenbach T, et al. Colorectal Cancer screening: recommendations for physicians and patients from the U.S. multi-society task force on colorectal cancer. Am J Gastroenterol. 2017;112(7):1016–30. PubMed PMID: 28555630. Robinson CA, Jackson C, Condon D, Gerson LB. Impact of inpatient status and gender on small-bowel capsule endoscopy findings. Gastrointest Endosc. 2011;74 (5):1061–6. PubMed PMID: 21924720. Rondonotti E, Borghi C, Mandelli G, Radaelli F, Paggi S, Amato A, et al. Accuracy of capsule colonoscopy and computed tomographic colonography in individuals with positive results from the fecal occult blood test. Clin Gastroenterol Hepatol. 2014;12(8):1303–10. PubMed PMID: 24398064. Rosa B, Moreira MJ, Rebelo A, Cotter J. Lewis score: a useful clinical tool for patients with suspected Crohn’s disease submitted to capsule endoscopy. J Crohns Colitis. 2012;6(6):692–7. PubMed PMID: 22398099. Sandler RS, Stewart WF, Liberman JN, Ricci JA, Zorich NL. Abdominal pain, bloating, and diarrhea in the United States: prevalence and impact. Dig Dis Sci. 2000;45(6):1166–71. PubMed PMID: 10877233. Saperas E, Dot J, Videla S, Alvarez-Castells A, PerezLafuente M, Armengol JR, et al. Capsule endoscopy versus computed tomographic or standard angiography for the diagnosis of obscure gastrointestinal bleeding. Am J Gastroenterol. 2007;102(4):731–7. PubMed PMID: 17397406. Epub 2007/04/03. eng. Scapa E, Jacob H, Lewkowicz S, Migdal M, Gat D, Gluckhovski A, et al. Initial experience of wirelesscapsule endoscopy for evaluating occult gastrointestinal bleeding and suspected small bowel pathology. Am J Gastroenterol. 2002;97(11):2776–9. PubMed PMID: 12425547. Schlag C, Menzel C, Nennstiel S, Neu B, Phillip V, Schuster T, et al. Emergency video capsule endoscopy in patients with acute severe GI bleeding and negative

41

Wireless Capsule Endoscopy

upper endoscopy results. Gastrointest Endosc. 2015;81(4):889–95. PubMed PMID: 25432532. Shahidi NC, Ou G, Svarta S, Law JK, Kwok R, Tong J, et al. Factors associated with positive findings from capsule endoscopy in patients with obscure gastrointestinal bleeding. Clin Gastroenterol Hepatol. 2012;10(12):1381–5. PubMed PMID: 22975384. Shi HY, Ng SC, Tsoi KK, Wu JC, Sung JJ, Chan FK. The role of capsule endoscopy in assessing mucosal inflammation in ulcerative colitis. Expert Rev Gastroenterol Hepatol. 2015;9(1):47–54. PubMed PMID: 24966092. Sidhu R, Sanders DS, Kapur K, Leeds JS, McAlindon ME. Factors predicting the diagnostic yield and intervention in obscure gastrointestinal bleeding investigated using capsule endoscopy. J Gastrointest Liver Dis: JGLD. 2009;18(3):273–8. PubMed PMID: 19795019. Sidhu R, Brunt LK, Morley SR, Sanders DS, McAlindon ME. Undisclosed use of nonsteroidal antiinflammatory drugs may underlie small-bowel injury observed by capsule endoscopy. Clin Gastroenterol Hepatol. 2010;8(11):992–5. PubMed PMID: 20692369. Singh A, Marshall C, Chaudhuri B, Okoli C, Foley A, Person SD, et al. Timing of video capsule endoscopy relative to overt obscure GI bleeding: implications from a retrospective study. Gastrointest Endosc. 2013;77 (5):761–6. PubMed PMID: 23375526. Spada C, Spera G, Riccioni M, Biancone L, Petruzziello L, Tringali A, et al. A novel diagnostic tool for detecting functional patency of the small bowel: the given patency capsule. Endoscopy. 2005;37(9):793–800. PubMed PMID: 16116528. Epub 2005/08/24. eng. Spada C, Hassan C, Galmiche JP, Neuhaus H, Dumonceau JM, Adler S, et al. Colon capsule endoscopy: European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy. 2012;44(5):527–36. PubMed PMID: 22389230. Spada C, Pasha SF, Gross SA, Leighton JA, SchnollSussman F, Correale L, et al. Accuracy of first- and second-generation Colon capsules in endoscopic detection of colorectal polyps: a systematic review and metaanalysis. Clin Gastroenterol Hepatol. 2016;14 (11):1533–43 e8. PubMed PMID: 27165469. Spigelman AD, Williams CB, Talbot IC, Domizio P, Phillips RK. Upper gastrointestinal cancer in patients with familial adenomatous polyposis. Lancet. 1989;2 (8666):783–5. PubMed PMID: 2571019. Swain P. Wireless capsule endoscopy and Crohn’s disease. Gut. 2005;54(3):323–6. PubMed PMID: 15710975. Pubmed Central PMCID: 1774425. Epub 2005/02/16. eng. Tai FWD, McAlindon ME. NSAIDs and the small bowel. Curr Opin Gastroenterol. 2018;34(3):175–82.. PubMed PMID: 29438118. Takeuchi K. Prophylactic effects of prostaglandin E2 on NSAID-induced enteropathy-role of EP4 receptors in its protective and healing-promoting effects. Curr Opin Pharmacol. 2014;19:38–45. PubMed PMID: 25063918.

983 Tanaka A, Hase S, Miyazawa T, Ohno R, Takeuchi K. Role of cyclooxygenase (COX)-1 and COX-2 inhibition in nonsteroidal anti-inflammatory drug-induced intestinal damage in rats: relation to various pathogenic events. J Pharmacol Exp Ther. 2002;303(3):1248–54. PubMed PMID: 12438549. Tatar EL, Shen EH, Palance AL, Sun JH, Pitchumoni CS. Clinical utility of wireless capsule endoscopy: experience with 200 cases. J Clin Gastroenterol. 2006;40(2):140–4. PubMed PMID: 16394875. Epub 2006/01/06. eng. Tee HP, Kaffes AJ. Non-small-bowel lesions encountered during double-balloon enteroscopy performed for obscure gastrointestinal bleeding. World J Gastroenterol. 2010;16(15):1885–9. PubMed PMID: 20397267. Pubmed Central PMCID: 2856830. Teshima CW, Kuipers EJ, van Zanten SV, Mensink PB. Double balloon enteroscopy and capsule endoscopy for obscure gastrointestinal bleeding: an updated metaanalysis. J Gastroenterol Hepatol. 2011;26(5):796–801. PubMed PMID: 21155884. Townsend CO, Sletten CD, Bruce BK, Rome JD, Luedtke CA, Hodgson JE. Physical and emotional functioning of adult patients with chronic abdominal pain: comparison with patients with chronic back pain. J Pain: Off J Am Pain Soc. 2005;6(2):75–83. PubMed PMID: 15694873. Triester SL, Leighton JA, Leontiadis GI, Fleischer DE, Hara AK, Heigh RI, et al. A meta-analysis of the yield of capsule endoscopy compared to other diagnostic modalities in patients with obscure gastrointestinal bleeding. Am J Gastroenterol. 2005;100(11):2407–18. PubMed PMID: 16279893. Epub 2005/11/11. eng. Tukey M, Pleskow D, Legnani P, Cheifetz AS, Moss AC. The utility of capsule endoscopy in patients with suspected Crohn’s disease. Am J Gastroenterol. 2009;104(11):2734–9. PubMed PMID: 19584828. Van Gossum A, Munoz-Navas M, Fernandez-Urien I, Carretero C, Gay G, Delvaux M, et al. Capsule endoscopy versus colonoscopy for the detection of polyps and cancer. N Engl J Med. 2009;361(3):264–70. PubMed PMID: 19605831. Epub 2009/07/17. eng. van Rijn JC, Reitsma JB, Stoker J, Bossuyt PM, van Deventer SJ, Dekker E. Polyp miss rate determined by tandem colonoscopy: a systematic review. Am J Gastroenterol. 2006;101(2):343–50. PubMed PMID: 16454841. Wadhwa V, Sethi S, Tewani S, Garg SK, Pleskow DK, Chuttani R, et al. A meta-analysis on efficacy and safety: single-balloon vs. double-balloon enteroscopy. Gastroenterolo Report. 2015;3(2):148– 55. PubMed PMID: 25698560. Pubmed Central PMCID: 4423464. Xin L, Liao Z, Jiang YP, Li ZS. Indications, detectability, positive findings, total enteroscopy, and complications of diagnostic double-balloon endoscopy: a systematic review of data over the first decade of use. Gastrointest Endosc. 2011;74(3):563–70. PubMed PMID: 21620401.

984 Xue M, Chen X, Shi L, Si J, Wang L, Chen S. Small-bowel capsule endoscopy in patients with unexplained chronic abdominal pain: a systematic review. Gastrointest Endosc. 2015;81(1):186–93. PubMed PMID: 25012561. Yachimski PS, Friedman LS. Gastrointestinal bleeding in the elderly. Nat Clin Pract Gastroenterol Hepatol. 2008;5(2):80–93. PubMed PMID: 18253137. Epub 2008/02/07. eng.

A. Dudekula and C. S. Pitchumoni Zallot C, Peyrin-Biroulet L. Clinical risk factors for complicated disease: how reliable are they? Dig Dis. 2012;30(Suppl 3):67–72. PubMed PMID: 23295694. Zhou Y, Boudreau DM, Freedman AN. Trends in the use of aspirin and nonsteroidal anti-inflammatory drugs in the general U.S. population. Pharmacoepidemiol Drug Saf. 2014;23(1):43–50. PubMed PMID: 23723142.

Part VI Imaging

Gastrointestinal Radiology: A Case-Based Presentation

42

Judith K. Amorosa and C. S. Pitchumoni

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appropriate Use of Imaging Modalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contrast Versus Noncontrast CT Abdomen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concern in Using IV Contrast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Magnetic Resonance Imaging (MRI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appropriate Use of Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

988 988 989 989 990 990

Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

991

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015

The chapter is a revision (Amorosa and Pitchumoni 2012). J. K. Amorosa (*) Robert Wood Johnson School of Medicine, Rutgers University, New Brunswick, NJ, USA Faculty Development and Academic Affairs, Department of Radiology, RUTGERS Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA University Radiology Group, East Brunswick, NJ, USA e-mail: [email protected]; [email protected] C. S. Pitchumoni (*) Department of Medicine, Robert Wood Johnson School of Medicine, Rutgers University, New Brunswick, NJ, USA Department of Medicine, New York Medical College, Valhalla, NY, USA Division of Gastroenterology, Hepatology and Clinical Nutrition, Saint Peters University Hospital, New Brunswick, NJ, USA e-mail: [email protected] © Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_36

987

988

Abstract

The utility of various endoscopic procedures to visualize the entire gastrointestinal tract (esophagogastroduodenoscopy, wireless capsule endoscopy, and colonoscopy) complements the value of many advanced imaging procedures such as abdominal ultrasound, computerized axial tomography (CT scan), and magnetic resonance imaging (MRI). When properly used, modern imaging techniques substantially help in the early diagnosis of intra-abdominal conditions and assess the severity of several gastrointestinal, pancreatic, and hepatobiliary emergencies. It is essential to be aware of the appropriate indications and the relatively small contraindications to minimize the abuse of the procedures, reduce the cost of care, and avoid overdiagnosis of incidental abnormalities related to an older age. The major contraindication for the techniques is the rare but occasionally life-threatening reaction and renal failure secondary to IV dye. To achieve a balance between the misuse and use with indications, one should be familiar with the American College of Radiology (ACR) guidelines. In this chapter, we have addressed some of the issues and provided images of educational value to the practicing physician. Keywords

Achalasia · Zenker’s diverticula · Carcinoma of the esophagus · Linitis plastica · Gastric cancer · Gastroparesis · GIST tumor · Enteritis · Small intestinal obstruction · Free air · Perforated viscus · Cecal cancer · Sigmoid cancer · Ischemic colitis · Pneumatosis intestinalis · Portal venous air · Diverticulitis · Hepatic metabolism · Intestinal distention · Acute cholecystitis · Gallstones · Porcelain gallbladder · Cystic tumor of the pancreas · Pancreatic cancer · Pancreatic pseudocyst · Walled-off necrosis (WON) · Necrotizing pancreatitis · Infected pancreatic necrosis ·

J. K. Amorosa and C. S. Pitchumoni

Hepatic abscess · Hepatic carcinoma · Computerized axial tomography (CT scan) magnetic resonance cholangiography · Magnetic resonance pancreaticcholangiography (MRCP) and abdominal ultrasound

Introduction Dramatic developments have occurred in gastrointestinal (GI) imaging in the past four decades. Two Nobel Prize–winning discoveries followed the discovery of abdominal ultrasound imaging of internal organs, the versatile computed tomography (CT) and magnetic resonance imaging (MRI). What was once a diagnostic imaging technique advanced to “interventional radiology” (IR), referring to a range of methods relying on radiological imaging to target therapy precisely. IR in many instances replaced not only traditional surgery but the minimally invasive procedures resulted in lower costs and better outcomes. During the same period, the field of gastrointestinal endoscopy also advanced. What was only an imaging procedure of the upper (esophagus, stomach, and duodenum) as well as the lower gastrointestinal tract (predominantly the colon) has introduced many endoscopic therapies. The two major fields of radiology and gastrointestinal endoscopy are currently well integrated; the specialties complement each other in early diagnosis and therapeutic choices.

Appropriate Use of Imaging Modalities In most cases, when appropriately used, the imaging techniques aid in early diagnosis, exclusion of critical disorders, and in assessing the severity of diseases (Iglehart 2006). The distinction between the two major diagnostic specialties, i.e., radiology or endoscopy is blurred. Older adults, in particular, are beneficiaries. Previously older adults were excluded from open or laparoscopic surgical procedures because of age or comorbidities but

42

Gastrointestinal Radiology: A Case-Based Presentation

currently benefit from the new IR therapeutic endoscopy approach (Ray et al. 2017). Along with the changes, traditional radiology using barium studies fell into disrepute and is currently replaced by the wide use of abdominal sonogram, CT scan, and MRI. The senior radiologists lament the near demise of barium studies. Many believe that barium studies still have a clear advantage over endoscopy for evaluating submucosal and extrinsic mass lesions and diagnosing several postoperative complications (e.g., perforation and obstruction). Fluoroscopic studies with water-soluble contrast material followed by barium are ideal for showing these leak sites and locations (Levine et al. 2008). Acute abdominal pain is a frequent presentation in older adults, severity ranging from benign to life threatening and is a common diagnostic dilemma. As discussed in another chapter in the book, abdominal pain is a significant diagnostic challenge because of the delay in older adult tending to seek medical attention, the atypical presentations, presence of coexisting diseases, and atypical physical examination findings (Marco et al. 1998). Although economists criticized the increasing cost of care, emergency medicine studies emphasize the importance of early, liberal imaging in the older population with undifferentiated abdominal pain (Marco et al. 1998). The indication for the study and the nature of the study chosen should be appropriate. The use of ultrasound over CT for right upper quadrant pain is emphasized by the American College of Radiology. In all other instances, CT abdomen has been widely accepted as a valuable imaging modality to evaluate patients with abdominal pain in the emergency department. In assessing any patient with abdominal pain, clinicians emphasize the need for a good history and physical examination before diagnostic tests. In many instances, older adults’ unique problems exclude the advantages of a good history and physical examination. Patients may have

989

dementia or anxiety states, precluding a good record. Physical examination in the older adult may be impossible or misleading with many preexisting conditions. Appropriate and prompt use of Imaging studies can be considered an extension of a physical examination that markedly improves diagnostic accuracy. The early use of CT scanning in evaluating abdominal pain has been accepted based on increased diagnostic certainty, and reduces morbidity and mortality and decreases hospital length of stay. It expedites the admission process (Brenton et al. 2014). The growth in medical imaging over the past few decades has yielded unquestionable benefits to older patients.

Contrast Versus Noncontrast CT Abdomen The two vexing questions of clinicians are whether to request a noncontrast or contrastenhanced CT, whether oral contrast will suffice, or IV contrast is essential. An oral contrast agent is used for bowel opacification and is generally a barium and water-soluble iodinated solution. Ingestion of a large volume of contrast material may be difficult or nearly impossible in many older adults and may delay a diagnosis and treatment (Anderson et al. 2009). That the patient has not finished drinking the oral contrast is a frustrating complaint of the ER nurse. However, current research studies support performing CT scans of the abdomen and pelvis without the need for positive oral contrast in most clinical situations (Kielar et al. 2016).

Concern in Using IV Contrast The concern with the use of IV contrast is the associated increased risk of nephrotoxicity (ACR – Manual on Contrast Media 2012. https://www. acr.org/-/media/ACR/Files/Clinical-Resources/ ContrastMedia). A history of multiple drug

990

allergies and asthma increases the risk. Whenever allergy is a consideration, ACR recommends administration of prednisone, 50 mg orally 13, 7, and 1 h before contrast administration; plus diphenhydramine, 50 mg intravenously, intramuscularly, or orally 1 h before contrast administration. A second concern is potential nephrotoxicity. In those with a history of mild to moderate reactions to intravenous contrast agents premedication with antihistamines and corticosteroids is required. The renal status is assessed by a baseline serum creatinine level obtained within a month before administering intravenous contrast agents. Metformin-associated nephrotoxicity and lactic acidosis (MALA) following intravenous contrast media is a concern. Many older adults may be on metformin for type 2 diabetes. Metformin use is likely to increase. Therefore, metformin use should be discontinued when IV contrast is administered and resumed only after careful reevaluation and monitoring of renal status (American College of Radiology. ACR manual on contrast media: version 8 2012. http://www. a c r. o r g / ~ / m e d i a / A C R / D o c u m e n t s / P D F / QualitySafety/Resources/Contrast%20Manual/ FullManual.pdf).

Magnetic Resonance Imaging (MRI) Despite many recent technical advances, the lengthy examination and interpretation times, as well as higher costs, represent barriers to the use (Canellas et al. 2019). The recent development of abbreviated, efficient, and precise MRI protocols represent a growing trend across radiology practices, but are useful for chronic problems. A serious problem is the danger of MRI in older adults with several cardiac implantable electronic devices. The electronic components of pacemakers or an implanted defibrillator can interact dangerously with a large magnet. Even patients forget that they have these devices implanted years earlier. Markedly obese persons may not fit comfortably inside a traditional MRI device. CT scans are cheaper, faster, do not cause claustrophobia, and thus may be a better choice in an

J. K. Amorosa and C. S. Pitchumoni

emergency. Older adults and their caregivers should be aware of their medical histories and provide information to imaging professionals related to any implanted devices.

Appropriate Use of Imaging There is a growing concern that medical technology advances are one of the primary drivers of the increase in health-care costs (Iglehart 2006,). The availability of many imaging studies coupled with the uncertainty in diagnosing the cause of abdominal pain in older adults results in overuse and even abuse of the studies. To achieve a balance between the overuse, misuse, and underuse of imaging studies, one should be familiar with the American College of Radiology (ACR) guidelines. Many clinicians request imaging procedures possess little knowledge about the techniques or possible alternative strategies that may yield the same or better information at a reduced cost or with less risk to the patient. Whenever possible, the examining physicians should obtain the history of previous imaging examinations the patients might have undergone to ensure that studies are not duplicated. Duplicate studies are frequent and contribute to medical imaging overutilization (Emanuel et al. 2008). Although appropriateness criteria are available for many imaging applications, knowledge about them is not widespread or the criteria are ignored. We emphasize the need to be familiar with the American College of Radiology (ACR) Appropriateness Criteria ® (AC) for imaging guidelines that rank the most appropriate test for multiple clinical conditions, based on the location of abdominal pain. The ACR Appropriateness Criteria (ACR AC) are evidence-based guidelines created by the American College of Radiology (American College of Radiology. ACR Appropriateness Criteria ®. [accessed April 21, 2018]. Available at: http:// bit.ly/2NDAbmN). The various guidelines are evidence based for specific clinical conditions reviewed annually by a multidisciplinary

42

Gastrointestinal Radiology: A Case-Based Presentation

expert panel). The practicing clinician should be familiar with the American College of Radiology Appropriateness Criteria and is well advised to refer to the guidelines when in doubt. A summary of the guidelines is provided here. The summary cites the relevant studies. In the original section by the ACR, there is a list of inappropriate reviews also. For the sake of brevity, we have excluded the list of problematic studies. The ACR guidelines cover various topics. They include: acute nonlocalized abdominal pain, acute pancreatitis, chronic liver disease, colorectal cancer screening, crohn disease, dysphagia, imaging of mesenteric ischemia, left lower quadrant pain–suspected diverticulitis, liver lesion – initial characterization, nonvariceal upper gastrointestinal bleeding, palpable abdominal mass-suspected neoplasm, pancreatic cyst, pretreatment staging of colorectal cancer, right lower quadrant pain–suspected appendicitis, right upper quadrant pain, staging of pancreatic ductal adenocarcinoma, suspected small-bowel obstruction, and jaundice. A few general principles in performing a CT examination of the abdomen in the older adult are as follows (Rawson et al. 2013). Although there is no direct interaction between metformin and IV radiologic contrast agents, the fact that metformin is actively excreted through the kidneys raises concerns of metformin clearance and metabolic acidosis. The US Food and Drug Administration advises that metformin therapy should be withheld for an IV contrast administration and 48 h afterward, and resumed only after reevaluation of renal status (i.e., return to baseline serum creatinine level) (Figs. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40). The following tables are adapted from the ACR criteria (American College of Radiology. ACR Appropriateness Criteria ®. [accessed April 21, 2018]. Available at: http://bit.ly/2NDAbmN); the information in the tables are summaries and not full guidelines. The readers are advised to refer to the full text (Tables 1, 2, 3, and 4).

991

Key Points 1. Modern imaging techniques such as abdominal ultrasound (AUS), computerized axial tomography (CT scan), magnetic resonance imaging (MRI) help in early diagnosis of intra-abdominal conditions, exclusion of critical disorders, and in assessing the severity of gastrointestinal, pancreatic, and hepatobiliary diseases. 2. Endoscopy and imaging studies are complementary. 3. Although traditional radiology using barium studies is replaced mainly by modern imaging techniques, there are limited indications for barium studies. Fluoroscopic studies with water-soluble contrast material are ideal for showing gastrointestinal leaks. 4. The concern with the use of IV contrast is because of the increased risk of nephrotoxicity (ACR 127 – Manual on Contrast Media 2012. https://www.128acr.org/-/media/ACR/ Files/Clinical-Resources/129Contrast Media). 5. A history of multiple drug allergies and asthma increases the risk for reaction to IV contrast agents. 6. A serious problem with the use of MRI in older adults is that many may use several cardiac implantable electronic devices. The electronic components can interact dangerously with a large magnet in the MRI machine. 7. To achieve a balance between the overuse, misuse, and underuse of imaging studies, one should be familiar with the American College of Radiology (ACR) guidelines. 8. Although there is no direct interaction between metformin and IV radiologic contrast agents, metformin is actively excreted through the kidneys and raises concerns of metformin clearance and metabolic acidosis. 9. The practicing clinician should be familiar with the American College of Radiology Appropriateness Criteria. 10. The pictures illustrate the most common gastrointestinal disorders with a few classic findings, but the examples are not complete.

992

J. K. Amorosa and C. S. Pitchumoni

Fig. 1 A 73-year-old woman is evaluated for progressive dysphagia, for solid foods and liquids. She has frequent episodes of regurgitation of undigested food and weight loss. (a) PA chest X-ray shows a mass density along the entire right mediastinum (white arrows). (b) Axial CT with

pulmonary window setting through the lower chest shows particulate material in a distended esophagus. (c) Barium esophagogram shows distended esophagus demonstrating beak like narrowing in its distal portion in the area of achalasia. Diagnosis: Achalasia (Vaezi et al. 2013)

Fig. 2 A 90-year-old man presents with halitosis and otherwise asymptomatic. (a) PA chest X-ray shows a large air- fluid (black arrow) containing structure (white arrows) in the upper chest. (b) Lateral chest X-ray shows

the air-fluid containing structure (black arrows) to be in the superior posterior portion of the chest. This is a large Zenker’s diverticulum filled with food. Diagnosis: Zenker’s diverticulum (Le Mouel and Fumery 2007)

42

Gastrointestinal Radiology: A Case-Based Presentation

a

993

b

Dilated proximal esophagus with partial obstruction by mass (arrow with dashes) Mass in esophagus: arrowheads Proximal mid-esophageal ulcerating mass (solid arrow)

Ulcerating mid-esophageal mass (arrow) Borders of the mass (arrowheads)

c

Ulcerating esophageal mass (arrow) Mass (arrowheads)

Fig. 3 (a–c) 82-year-old patient with dysphagia. (a) Sagittal reconstructed chest CT image through the mid-chest. Dilated proximal esophagus with partial obstruction by mass (arrow with dashes). Mass in esophagus: arrowheads. Proximal mid-esophageal ulcerating mass (solid arrow). (b) Coronal reconstructed CT scan Fig. 4 An 80-year-old man is evaluated for a 3-month history of progressive, dull, constant, non-radiating epigastric pain. The patient has had weight loss with early satiety and nausea. Axial oral contrastenhanced CT image at the level of the gastric fundus shows a thick infiltrating mass (white arrows) which surrounds the irregular contrast filled lumen. Diagnosis: Gastric cancer

of the Chest through the posterior mediastinum. Ulcerating mid-esophageal mass (arrow). Borders of the mass (arrowheads). (c) Axial CT chest image at the Level just above the carina (arrowheads). Ulcerating esophageal mass (arrow). Mass (arrowheads)

994 Fig. 5 A 70-year-old woman with long-standing, hard to control type 2 diabetes mellitus is evaluated for a 6-month history of nausea, vomiting, early satiety, and postprandial bloating. Supine abdominal image shows distended, air-filled stomach. Diagnosis: Gastroparesis (Camilleri et al. 2018)

Fig. 6 A 67-year-old man with left upper quadrant abdominal pain, early satiety, and vomiting. Axial oral contrast-enhanced CT image shows contrast in the fundus, a large mass displacing the fundus. The mass contains low density material (probably necrotic tumor. Gastrointestinal stromal tumor GIST

J. K. Amorosa and C. S. Pitchumoni

42

Gastrointestinal Radiology: A Case-Based Presentation

995

Fig. 7 A 74-year-old woman after returning from a trip developed severe diarrhea and crampy abdominal pain. (a, b) Axial oral contrast-enhanced CT images in the lower

abdomen/upper pelvis level shows diffuse small bowel, predominantly ileal wall thickening without definite obstruction. Diagnosis: Enteritis (Murphy et al. 2015)

Fig. 8 A 69-year-old man with a history of prior abdominal surgery presents with abdominal distention. (a) Supine abdominal image shows distended loops of bowel in the mid abdomen with circumferential markings (valvulae conniventes) indicating the presence of distended small

bowel loops. Some air is present in the colon, suggesting the diagnosis of partial small bowel obstruction (SBO). (b) Erect, upright abdominal image shows no free air, air fluid levels in the distended small bowel loops are present. Diagnosis: Partial small bowel obstruction

996 Fig. 9 A 68-year-old woman presents with acute abdominal pain. Supine abdominal image shows previous cholecystectomy and free air. Bowel loops are seen with air on both sides of the intestinal wall (termed the Rigler sign) (black arrow); the area of lucency depicts extra luminal air (asterisks). This is difficult to detect, warranting confirmation with a left lateral decubitus or erect image. Diagnosis: Free air in the peritoneal cavity

Fig. 10 A 77-year-old man with iron deficiency anemia. Axial oral and intravenous contrastenhanced CT image through the lower abdomen shows a mass in the cecum (white arrow). Diagnosis: Cecal carcinoma

J. K. Amorosa and C. S. Pitchumoni

42

Gastrointestinal Radiology: A Case-Based Presentation

Fig. 11 A 68-year-old woman with distended abdomen and severe constipation. (a) Axial oral and intravenous contrast-enhanced CT image through the upper abdomen shows the markedly distended colon. (b) Axial oral and intravenous contrast-enhanced CT image through the mid abdomen shows distended, fecal material filled colon. The

997

contrast filled normal caliber small bowel loops. (c) Axial oral and intravenous contrast-enhanced CT image through the lower pelvic level shows the distended sigmoid colon and the collapsed rectum. (d) Coronal reconstructed CT image through the mid abdomen shows the colonic distention. Diagnosis: Cancer, sigmoid colon, with obstruction

998

Fig. 12 A 72-year-old man on treatment for malignancy developed severe bloody diarrhea in the last 48 h. (a) Axial oral contrast-enhanced CT image through the mid abdomen demonstrates marked thickening of the ascending and descending colon. (b) Coronal reconstructed CT image through the anterior shows markedly thickened colonic wall; note that air is present in the nondependent portion

J. K. Amorosa and C. S. Pitchumoni

of the colon. (c) Coronal reconstructed CT image through the posterior abdomen (see vertebrae) shows colonic wall thickening, and of note, contrast in the dependent portion of the colon. (d) Axial oral contrast-enhanced CT image through the lower pelvis shows markedly thickened rectal mucosa. Diagnosis: Severe colitis C. difficle (Guerri et al. 2019)

42

Gastrointestinal Radiology: A Case-Based Presentation

999

Fig. 13 An 82-year-old man presents with bloody diarrhea. He has a history of coronary artery disease and hyperlipidemia. (a) Axial oral and intravenous contrastenhanced image through the upper abdomen shows at the level of the splenic flexure thick colonic wall suggestive of

ischemic colitis. (b) Coronal reconstructed image through the mid to posterior abdomen shows a thickened descending colonic wall, with a normal cecum. Diagnosis: Ischemic colitis (Demetriou et al. 2020)

Fig. 14 A 65-year-old woman presents with acute diffuse abdominal pain. (a) Supine abdominal image shows a markedly distended air-filled structure in the area of the stomach, with prominent haustral markings. (b) Axial oral and intravenous contrast-enhanced image through the upper abdomen shows contrast filled gastric fundus and

air and fecal material level in a more anterior structure (*fat containing right adrenal mass, reflecting an adenoma). (c) Coronal reconstructed image through the anterior abdomen shows markedly distended cecum filled with fecal material located in the mid to left upper abdomen. Diagnosis: Cecal volvulus (Hasbahceci et al. 2012)

1000

J. K. Amorosa and C. S. Pitchumoni

Fig. 15 An 83-year-old man with fever, leukocytosis, left lower quadrant (LLQ) abdominal pain, and tenderness. (a) Axial oral and intravenous contrast-enhanced CT image through the mid pelvis with enlargement (inset) shows abnormal sigmoid colon with multiple diverticula. An intramural abscess is apparent, with soft tissue density

and an air pocket. Adjacent to the abnormal sigmoid is in filtration of pericolic fat. (b) Coronal reconstructed CT image shows the abnormal sigmoid with an intramural abscess with air. Diagnosis: Diverticulitis with abscess (Bates et al. 2018)

Fig. 16 A 77-year-old man with anemia and RUQ abdominal pain. (a) Axial oral and intravenous contrastenhanced CT image through the upper abdomen shows multiple focal liver lesions. (b) Axial oral and intravenous

contrast-enhanced CT image through the lower abdomen shows a mass (white arrows) in the cecum. An enlarged mesenteric lymph node is visible (black arrow). Diagnosis: Cecal carcinoma with hepatic metastases

42

Gastrointestinal Radiology: A Case-Based Presentation

Fig. 17 A 73-year-old man presents with acute abdominal pain. Erect, upright PA (frontal) chest X-ray shows air (black arrow) under the diaphragms indicating free air in the peritoneal cavity, usually from a perforated viscus. Diagnosis: Perforated viscus

Fig. 18 A 65-year-old woman with prior colectomy now presents with abdominal pain and distension. Supine abdominal image shows surgical clips in the pelvis and distended small bowel loops. Diagnosis: Intestinal obstruction

1001

1002 Fig. 19 A 78-year-old woman with prior radiation therapy presents with foul smelling vaginal discharge. Lateral rectal image during gastrographin enema via rectal tube (T) shows a fistulous communication (black arrow) between the rectum (R) and vagina (V). Diagnosis: Rectovaginal fistula

Fig. 20 A 67-year-old woman with a history of previous cholecystectomy has recurrent symptoms of biliary colic. Right upper quadrant ultrasound sagittal image shows a dilated CBD (common bile duct) with two round confirming stones in the CBD (choledocholithiasis). Diagnosis: Choledocholithiasis

J. K. Amorosa and C. S. Pitchumoni

42

Gastrointestinal Radiology: A Case-Based Presentation

Fig. 21 A 72-year-old woman with RUQ abdominal pain. Hepatobiliary scan shows excretion of the radioactive tracer into the biliary tree and into the duodenum and more distal small bowel. Gallbladder is not seen, indicating occluded cystic duct due to inflammation. Diagnosis: Acute cholecystitis

Fig. 22 A 77-year-old woman known to have gallstones presents with RUQ abdominal pain for about 6 weeks; she is afebrile. Oral and intravenous contrastenhanced CT image through the gallbladder shows thick gallbladder wall (about 6 mm), intermittent gallbladder wall calcification (white arrows), two gallstones, and a mass (black arrows) protruding into the gallbladder lumen. Diagnosis: Gallstones and gallbladder cancer (Sharma et al. 2017)

Fig. 23 A 67-year-old woman presents with postprandial RUQ abdominal pain that radiates to her right shoulder accompanied by fever, nausea, and vomiting. Axial oral and intravenous contrast administration through the upper abdomen shows gallbladder wall thickening. Diagnosis: Acute cholecystitis

1003

1004

Fig. 24 A 79-year-old man with sepsis, severe RUQ abdominal pain, and tenderness. (a) Sagittal real-time ultrasound shows thick gallbladder wall (6 mm) (asterisks). Fig. 25 A 65-year-old woman with RUQ abdominal pain and tenderness. Right upper quadrant decubitus ultrasound image shows multiple echogenic foci with acoustic shadowing (black arrows) within the gallbladder; these are gallstones (white arrow). Diagnosis: Gallstones

J. K. Amorosa and C. S. Pitchumoni

(b) Transverse real-time ultrasound shows thick gallbladder wall (6 mm). Diagnosis: Acute cholecystitis

42

Gastrointestinal Radiology: A Case-Based Presentation

Fig. 26 Porcelain Gallbladder. A rare finding often seen more often in elderly females (Female to male preponderance of 5:1). In the past, it was believed to be associated with gallbladder malignancy. Recent studies have shown 6% increased risk of developing adenocarcinoma in patchy mucosal calcification type as compared with complete intramural type (Stephen and Berger 2001)

Fig. 27 A 65-year-old woman presents with jaundice. Spot image during ERCP shows catheter (white thin arrow) traversing biliary stricture; a dilated proximal CBD (thick arrow) is present. Diagnosis: CBD stricture. (Courtesy of Satya Kastuar, MD. Saint Peters University Hospital) (Nakai et al. 2020)

1005

1006 Fig. 28 A 75-year-old patient, incidental detection of a pedunculated gallbladder polyp (Wiles et al. 2017)

Fig. 29 A 68-year-old woman with a history of cholecystectomy, now status post-ERCP. Erect image of the upper abdomen demonstrates air in the biliary tree (solid black arrow), biliary stent in the CBD, surgical clips for cholecystectomy, and moderately distended stomach. Diagnosis: Air in the biliary tree; stent in place

J. K. Amorosa and C. S. Pitchumoni

42

Gastrointestinal Radiology: A Case-Based Presentation

1007

Fig. 30 A 70-year-old woman presents with RUQ abdominal pain and abnormal LFTs. Spot image during ERCP shows the endoscope through which a wire (black arrow) has been introduced into the biliary system. There are three stones (labeled 1, 2, 3) in the dilated CBD. Diagnosis: CBD stones. (Courtesy of Satya Kastuar, MD. Saint Peters, University Hospital)

Fig. 31 A 76-year-old asymptomatic man had a chest CT as part of evaluation to exclude lung cancer because of a long history of smoking. On a prior image of that CT a pancreatic mass was suspected, so a dedicated CT abdomen and pelvis was done. Axial intravenous contrastenhanced CT image at the level of the body and tail of

the pancreas shows a 3.5 cm multilobulated mass (white arrow) with low attenuation material (40 HU – soft tissue density, not fluid) with enhancing borders, suggesting a cystic tumor. Diagnosis: Cystic tumor, tail of pancreas (Abdelkader et al. 2020)

1008

J. K. Amorosa and C. S. Pitchumoni

Fig. 32 A 65-year-old man with a history of chronic pancreatitis and severe abdominal pain with vomiting. (a) Axial oral and intravenous contrast-enhanced CT image through the upper abdomen shows a large fluid collection anterior to the area of the pancreas; a definite normal pancreas is not identifiable. This collection is displacing

the stomach (white arrow). (b) Axial oral and intravenous contrast-enhanced CT image through the level of the kidneys demonstrates fluid beyond the tail of the pancreas in the retroperitoneal space; the collection is in the anterior pararenal space. Diagnosis: Pseudocyst of the pancreas (Foster et al. 2016)

Fig. 33 A 65-year-old man with LUQ abdominal pain. Axial oral and intravenous enhanced CT image through the upper abdomen shows subcapsular fluid collection in the spleen and a small fluid collection (asterisk) in the body of the pancreas with some inflammatory changes anteriorly.

Small amount of fluid (white circles) is noted around the head of the pancreas. The recent classification of acute pancreatitis redefines the nomenclature. Diagnosis: Pancreatic pseudocyst (Banks et al. 2013)

42

Gastrointestinal Radiology: A Case-Based Presentation

Fig. 34 A 69-year-old woman with severe upper abdominal pain and hypotension. (a) On day 1: axial oral and intravenous contrast-enhanced CT image through the upper abdomen shows relative lack of enhancement of the pancreas. There is peripancreatic fluid and ascites (solid black arrows). A gallstone is not visualized within the GB (gallbladder). (b) On day 9: axial oral and

1009

intravenous contrast-enhanced CT image through the upper abdomen shows necrosis of most of the pancreas; only small portions of the pancreas are identifiable (black arrows). Fluid density is seen in the pancreatic bed. There is splenic venous thrombosis (black arrowhead). On this image a gallstone is visible (black arrow). Diagnosis: Severe acute necrotizing pancreatitis

1010

Fig. 35 A 65-year-old woman with fever and RUQ abdominal pain. (a) Axial oral and intravenous contrastenhanced CT image through the mid abdomen shows a focal mass in the right lobe of the liver with low attenuation and slightly irregular border. (b) Coronal reconstructed CT image through the posterior abdomen shows a focal mass

J. K. Amorosa and C. S. Pitchumoni

in the right lobe of the liver. (c) Right upper quadrant ultrasound sagittal image shows a complex mass in the liver. (d) Magnetic resonance imaging was done to further clarify the nature of this mass and confirmed an enhancing mass suggestive of an abscess. Diagnosis: Hepatic abscess (Khim et al. 2019)

42

Gastrointestinal Radiology: A Case-Based Presentation

1011

Fig. 36 A 69-year-old man with hepatic encephalopathy. (a) Axial intravenous contrast-enhanced CT image through the upper abdomen shows a mass in the liver (black arrows). The liver is small and irregular-cirrhotic. There is splenomegaly; small amount of ascites and large right

pleural effusion (white circles), and varices (black circle). (b) Sagittal ultrasound image shows the liver mass (white arrows) to be complex consistent with hepatocellular carcinoma. Diagnosis: Hepatic carcinoma

Fig. 37 A 72-year-old man with severe abdominal pain and bloody diarrhea. Axial oral and intravenous contrastenhanced CT image through the level of the upper abdomen shows air in the portal venous system. Axial oral and intravenous contrast-enhanced CT image through the level of the portal vein shows air-contrast level in the portal vein (black arrow). Axial oral and intravenous contrast-

enhanced CT image through the level of the kidneys shows air in the superior mesenteric vein (black arrow). Axial oral and intravenous contrast-enhanced CT image with pulmonary window setting shows air in the bowel wall, suggesting pneumatosis intestinalis (black arrows). Diagnosis: Pneumatosis intestinalis and portal venous air

1012

J. K. Amorosa and C. S. Pitchumoni

Fig. 38 An 89-year-old man presents with fever, nausea, vomiting, and severe RLQ abdominal pain. (a, b) Axial and coronal oral and intravenous contrast-enhanced CT images in the lower abdomen demonstrate a soft tissue

mass with fluid and air (white arrow) adjacent to the cecum. The features suggest a perforated appendiceal abscess. Diagnosis: Appendiceal abscess

Fig. 39 An 89-year-old woman with RLQ abdominal pain and tenderness. (a, b) Axial and coronal oral and intravenous contrast-enhanced CT images through the

lower abdomen and pelvis show a dilated appendix, indicative of acute, but not perforated appendicitis (white arrows). Diagnosis: Acute appendicitis

42

Gastrointestinal Radiology: A Case-Based Presentation

Fig. 40 A 74-year-old man presents with chronic relapsing pancreatitis, weight loss, and steatorrhea. (a) Endoscopic view of the major papilla shows a fish mouth papilla secreting mucinous material. (b) Retroflexion reveals a deep ulcer in the fundus with mucous adherent to ulcer base. This is secondary to a direct extension to the gastric fold by a malignant intraductal papillary mucinous tumor (IPMT). (c) EUS: markedly expanded main

1013

pancreatic duct by a heterogeneous head of pancreas mass with irregular borders containing mucinous material. (d) EUS: head of pancreas with markedly dilated main pancreatic duct and echogenic material within the duct consistent with mucin. The duct does not manifest any strictures. Diagnosis: Malignant intraductal papillary mucinous tumor. (Courtesy of Hazar Michael, MD. Robert Wood Johnson University Hospital)

1014

J. K. Amorosa and C. S. Pitchumoni

Table 1 Acute nonlocalized abdominal pain and fever. No recent surgery. Initial imaging (Summarized from American College of Radiology ACR Appropriateness Criteria) Procedure CT abdomen and pelvis with IV contrast MRI abdomen and pelvis without and with IV contrast US abdomen CT abdomen and pelvis without IV contrast MRI abdomen and pelvis without IV contrast CT abdomen and pelvis without and with IV contrast

Appropriateness category Usually appropriate May be appropriate May be appropriate May be appropriate May be appropriate May be appropriate

Table 2 Acute nonlocalized abdominal pain and fever. Postoperative patient. Initial imaging (Summarized from American College of Radiology ACR Appropriateness Criteria) Procedure CT abdomen and pelvis with IV contrast MRI abdomen and pelvis without and with IV contrast US abdomen CT abdomen and pelvis without IV contrast MRI abdomen and pelvis without IV contrast CT abdomen and pelvis without and with IV contrast

Appropriateness category Usually appropriate May be appropriate May be appropriate May be appropriate May be appropriate May be appropriate

Table 3 Acute nonlocalized abdominal pain. Neutropenic patient. Initial imaging (Summarized from American College of Radiology ACR Appropriateness Criteria) Procedure CT abdomen and pelvis with IV contrast CT abdomen and pelvis without IV contrast MRI abdomen and pelvis without and with IV contrast US abdomen MRI abdomen and pelvis without IV contrast CT abdomen and pelvis without and with IV contrast

Appropriateness category Usually appropriate May be appropriate May be appropriate May be appropriate May be appropriate May be appropriate

Table 4 Acute nonlocalized abdominal pain. Not otherwise specified. Initial imaging (Summarized from American College of Radiology ACR Appropriateness Criteria) Procedure CT abdomen and pelvis with IV contrast CT abdomen and pelvis without IV contrast MRI abdomen and pelvis without and with IV contrast US abdomen MRI abdomen and pelvis without IV contrast CT abdomen and pelvis without and with IV contrast

Appropriateness category Usually appropriate Usually appropriate Usually appropriate May be appropriate May be appropriate May be appropriate

Usually appropriate: Indicated with a favorable risk-benefit ratio for patients, printed in Bold type May be appropriate. The specified clinical scenarios may be indicated as an alternative to imaging procedures or treatments with a more favorable risk-benefit ratio

42

Gastrointestinal Radiology: A Case-Based Presentation

References Abdelkader A, Hunt B, Hartley CP, et al. Cystic lesions of the pancreas: differential diagnosis and cytologic-histologic correlation. Arch Pathol Lab Med. 2020;144(1): 47–61. https://doi.org/10.5858/arpa.2019-0308-RA. Epub 2019 Sep 20. PMID: 31538798 American College of Radiology (2012) ACR manual on contrast media: version 8. http://www.acr.org/~/media/ ACR/Documents/PDF/QualitySafety/Resources/Contrast %20Manual/FullManual.pdf. Accessed 21 Nov 2012. American College of Radiology. ACR appropriateness criteria ®. Available at: http://bit.ly/2NDAbmN. Amorosa JK, Pitchumoni CS. Gastrointestinal radiology. In: Pitchumoni CS, Dharmarajan TS, editors. Geriatric gastroenterology. 1st ed. New York: Springer; 2012. p. 227–247. Anderson SW, Soto JA, Lucey BC, et al. Abdominal 64MDCT for suspected appendicitis: the use of oral and IV contrast material versus IV contrast material only. AJR Am J Roentgenol. 2009;193(5):1282–8. Banks PA, Bollen TL, Dervenis C. Classification of acute pancreatitis – 2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62:102–11. Bates DDB, Fernandez MB, Ponchiardi C, et al. Surgical management in acute diverticulitis and its association with multi-detector C.T., modified Hinchey classification, and clinical parameters. Abdom Radiol (NY). 2018;43 (8):2060–5. https://doi.org/10.1007/s00261-017-1422-y. Camilleri M, Chedid V, Ford AC. Gastroparesis. Nat Rev Dis Primers. 2018;4(1):41. https://doi.org/10.1038/ s41572-018-0038-z. PMID: 30385743 Canellas R, Rosenkrantz AB, Taouli B, et al. Radiographics. 2019;39(3):744–58. Demetriou G, Nassar A, Subramonia S. The pathophysiology, presentation and management of ischaemic colitis: a systematic review. World J Surg. 2020;44:927–38. Emanuel EJ, Fuchs VR. The perfect storm of overutilization. JAMA. 2008;299(23):2789–91. Foster BR, Jensen KK, Bakis G, Shaaban AM, Coakley FV. Revised Atlanta classification for acute pancreatitis: a pictorial essay. Radiographics. 2016;36(3):675– 87. https://doi.org/10.1148/rg.2016150097. Guerri S, Danti G, Frezzetti G, et al. Clostridium difficile colitis: CT findings and differential diagnosis. Radiol Med. 2019;124(12):1185–98. https://doi.org/10.1007/ s11547-019-01066-0. Hasbahceci M, Basak F, Alimoglu O. Cecal volvulus. Indian J Surg. 2012;74(6):476–9. https://doi.org/10. 1007/s12262-012-0432-9. Iglehart JK. The new era of medical imaging: progress and pitfalls. N Engl J Med. 2006;354(26):2822–8. Khim G, Em S, Mo S, Townell N. Liver abscess: diagnostic and management issues found in the low resource setting. Br Med Bull. 2019;132(1):45–52. https://doi.org/

1015

10.1093/bmb/ldz032. PMID: 31836890; PMCID: PMC6992887 Kielar A, Patlas MN, Katz DS. Oral contrast for C.T in patients with acute non-traumatic abdominal and pelvic pain: what should be its current role? Emerg Radiol. 2016;23(5):477–81. https://doi.org/10.1007/s10140016-1403-4. Levine MS, Rubesin SE, Laufer I. Barium esophagography: a study for all seasons. Clin Gastroenterol Hepatol. 2008;6:11–25. 2015 April 1;91 (7):452–9 Marco CA, Schoenfeld CN, Keyl PM, Menkes ED, Doehring MC. Abdominal pain in geriatric emergency patients: variables associated with adverse outcomes. Acad Emerg Med. 1998;5:1163–8. Mouel JL, Fumery M. Zenker’s diverticuum. N Engl J Med. 2007;377:e31. https://doi.org/10.1056/ NEJMicm1701620. Murphy KP, Twomey M, McLaughlin PD, et al. Imaging of ischemia, obstruction and infection in the abdomen. Radiol Clin N Am. 2015;53(4):847–69. https://doi. org/10.1016/j.rcl.2015.02.008. ix–x. PMID: 26046514 Nakai Y, Isayama H, Wang HP, et al. International consensus statements for endoscopic management of distal biliary stricture. J Gastroenterol Hepatol. 2020;35(6): 967–79. https://doi.org/10.1111/jgh.14955. Epub 2020 Jan 10. PMID: 31802537; PMCID: PMC7318125 Rawson JV, Pelletier AL. When to order contrast-enhanced CT. Am Fam Physician. 2013;88(5):312–6. Ray D, Srinivasan I, Tang, et al. Complementary roles of interventional radiology and therapeutic endoscopy in gastroenterology. World J Radiol. 2017;9(3):97–111. Sharma A, Sharma KL, Gupta A. Gallbladder cancer epidemiology, pathogenesis and molecular genetics: recent update. World J Gastroenterol. 2017;23(22): 3978–98. https://doi.org/10.3748/wjg.v23.i22.3978. PMID: 28652652; PMCID: PMC5473118 Stephen AE, Berger DL. Carcinoma in the porcelain gallbladder: a relationship revisited. Surgery. 2001;129(06): 699–703. Systermans BJ, Devitt PG. Computed tomography in acute abdominal pain: an overused investigation? ANZ J Surg. 2014;84:155–9. Vaezi MF, Pandolfino JE, Vela MF. ACG clinical guideline: diagnosis and management of achalasia. Am J Gastroenterol. 2013;108:1238–49. Wiles R, Thoeni RF, Barbu ST, et al. Management and follow-up of gallbladder polyps : joint guidelines between the European Society of Gastrointestinal and Abdominal Radiology (ESGAR), European Association for Endoscopic Surgery and other Interventional Techniques (EAES), International Society of Digestive Surgery - European Federation (EFISDS) and European Society of Gastrointestinal Endoscopy (ESGE). Eur Radiol. 2017;27(9):3856–66. https://doi.org/10. 1007/s00330-017-4742-y. Epub 2017 Feb 9

Imaging in Clinical Geriatric Gastroenterology

43

David Hirschl, Melanie Moses, and Rona Orentlicher

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1018 Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1018

Abstract

Medical imaging is a continuously evolving field which is increasingly utilized for the diagnosis, characterization, and follow-up of innumerable physiological processes. This chapter presents a selection of imaging findings frequently encountered in disease processes of the geriatric gastrointestinal tract. The cases are organized in anatomical order from the esophagus down the alimentary tract and also include a few entities of extraintestinal organs that could be confused with gastrointestinal diseases. The disorders included are those most commonly seen in the geriatric population. They are presented utilizing the imaging modality that most commonly and effectively aids in the diagnosis, along with the typical findings that can be seen. The chapter will help readers better understand the strengths of medical imaging, as well as the modalities that

D. Hirschl (*) · M. Moses · R. Orentlicher Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA e-mail: dhirschl@montefiore.org; mmoses@montefiore.org; rorentli@montefiore.org

should be considered for delineation of the diverse pathology of gastrointestinal tract disorders in older adults. In addition, key imaging findings that are illustrated in the chapter will help aid in the diagnosis of gastrointestinal disorders in the geriatric population, providing a means to guide subsequent therapy. Keywords

Imaging for gastrointestinal disorders · Radiology and GI disorders · Imaging for GI disorders · Geriatric imaging · Geriatric radiology · Ultrasound · Magnetic resonance imaging · X-ray · Ultrasound · CT · MRI · Fluoroscopy · Imaging for dysphagia · Isotope scan for gastric emptying · Barium swallow for esophageal disorder · CT scan of abdomen for diagnosis of GI disorders · Air under the diaphragm · Imaging for misplaced feeding tubes · Dislodged feeding tubes · Gastrointestinal stromal tumor · Gastric ulcer · Duodenal ulcer · Diverticular disease · Hepatic cysts · Ultrasound for cysts in the liver · CT abdomen for cystic disease · Hepatic cavernous angioma · Hepatic tumors · Hepatic metastases · Hepatobiliary scan · Gallbladder

© Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_104

1017

1018

stones · Choledocholithiasis · Biliary sludge · Porcelain gallbladder · Cysts of the liver · Jaundice · Abdominal pain · Abdominal aortic aneurysm · Perforated viscus · Mesenteric vascular ischemia · Perforated viscus · Pneumatosis · Pneumoperitoneum · Colon cancer

Introduction The diagnostic evaluation of older patients can be challenging. As people age there is a general increase in chronic illness and comorbidities. In addition, older adults may be more prone to acute illness due to infection, which could be more debilitating than in a younger patient. Initial evaluation in the older adult begins with history and physical exam that may be inconclusive or misleading. Communication barriers as a result of neurological disorders associated with aging, including cognitive decline, dementia, memory loss, or stroke, may hinder an adequate history. Furthermore, physical barriers such as immobility, combativeness, contracture, and movement disorders may complicate or confound a physical assessment. Infection can be difficult to diagnose. Characteristic fever and elevated white blood cell count may not always be present. Symptomatic presentations may be less specific due to change in mental status, or malaise. An added complexity is that older patients more often have medical devices such as percutaneous gastrostomy or suprapubic tubes that can be a source of infection or complication. Due to potential compromise of the patient history and physical examination, and even the decreased sensitivity of laboratory tests, radiological imaging is often essential to make the correct diagnosis in older adults. The images from multiple cases presented in this chapter include various common conditions throughout the gastrointestinal tract in anatomical order. A few disease entities of neighboring structures that can be mistaken for gastrointestinal

D. Hirschl et al.

disease are included. Diagnosis of gastrointestinal disorders in geriatric patients is often made radiographically, using computerized tomography, ultrasound, fluoroscopy, magnetic resonance imaging, and nuclear medicine imaging. The imaging modality used is the most effective for making the diagnosis. Characteristic imaging findings are delineated. Although fluoroscopy is essential to evaluate motility and often necessary to evaluate patency of bowel, as well as placement and position of tubes, CT is the most utilized modality due to its ready availability, rapid scan time, and ease of use, especially in patients in poor medical condition. In addition, CT is often optimal for evaluation because of its range of coverage, ability to evaluate vascular flow, and delineate structures due to its high contrast resolution, as well as mitigate motion artifact due to the rapid scan time. Additional modalities are often complementary, but can be the test of choice to make the diagnosis. As imaging technologies continue to evolve it may be challenging to choose the most appropriate examination for a particular clinical situation. The American College of Radiology has developed a set of evidence-based recommendations called Appropriateness Criteria to aid clinicians in imaging study decision making. It can be accessed at: https://www.acr.org/Clinical-Resour ces/ACR-Appropriateness-Criteria (Figs. 1–81).

Key Points • Imaging findings in common and uncommon pathologic processes affecting the gastrointestinal system are presented. • Images are acquired using the most appropriate imaging modality for the pathologic process being investigated. • Readers are urged to refer to the American College of Radiology appropriateness criteria when unsure of which imaging modality to use in various clinical scenarios.

43

Imaging in Clinical Geriatric Gastroenterology

1019

Fig. 1 Zenker’s diverticulum in a 91-year-old male with dysphagia and cough on thin liquids. Modified barium swallow demonstrates a posterior outpouching at the junction of the hypopharynx and esophagus (white arrow)

Fig. 3 Presbyesophagus in a 76-year-old female with difficulty swallowing. Barium swallow reveals severe dysmotility with poor stripping wave and extensive tertiary, nonpropulsive contractions (white arrow)

Fig. 2 Esophageal webs in an 86-year-old female with dysphagia. Barium swallow demonstrates two hypopharyngeal and cervical thin fold of tissues (white arrows)

1020

Fig. 4 Esophageal narrowing from ectatic aortic arch in a 90-year-old male with dysphagia. (a) Barium swallowesophageal narrowing at the level of a prominent, ectatic

D. Hirschl et al.

aortic arch (white arrow). (b) A barium pill is impacted just proximal to the narrowing (black arrow)

43

Imaging in Clinical Geriatric Gastroenterology

Fig. 5 Esophageal carcinoma in a 78-year-old male with severe dysphagia. Barium swallow demonstrates a 6 cm stricture along the mid esophagus with overhanging edges superiorly and mucosal irregularities (white arrow)

1021

1022

Fig. 6 Esophageal carcinoma in a 78-year-old male with dysphagia. (a) Esophagram – irregular stricture along the mid/distal esophagus (black arrow). (b, c) CT scan –

D. Hirschl et al.

sagittal and coronal projections: irregular mural thickening and overhanging edges with significant luminal narrowing

43

Imaging in Clinical Geriatric Gastroenterology

Fig. 7 Metastatic esophageal carcinoma in an 82-year-old female with dysphagia. Contrast enhanced abdominal CT scan: (a) soft tissue mass involving the distal esophagus and GE junction (white arrow). Hypodensity in the left

Fig. 8 Sliding hiatal and paraesophageal hernias in an 81year-old female with heartburn. Upper GI series utilizing barium reveals a portion of gastric body and antrum above the diaphragm (white arrows). A stricture at the gastroesophageal junction, may be result of instrumentation (black arrow)

1023

hepatic lobe consistent with esophageal metastatic disease (black arrow). (b) More inferior image demonstrates perigastric lymphadenopathy (clear arrow) and incidental layering gallbladder sludge (arrowhead)

1024

Fig. 9 Gastroparesis in a 66-year-old male with diabetes. Tc-99m labeled sulfur colloid liquid is administered through a gastrostomy tube. Sequential images obtained

D. Hirschl et al.

over the abdomen for 4 hours shows significant delay in gastric emptying, with calculated 81% of activity in the stomach at 4 h (Normal: 0–10%)

43

Imaging in Clinical Geriatric Gastroenterology

1025

Fig. 10 Bariatric surgery in a 67-year-old female with laparoscopic adjustable banding procedure. Fluoroscopic exam with ingested barium demonstrates band (white arrow) in good position. A small hiatal hernia is seen

Fig. 11 (a) Normal lap band procedure in a 66-year-old male with no symptoms. Coronal CT with lap band (black arrow) in normal position. (b) Lap band maladjustment in a

65-year-old female with vomiting and food intolerance. Coronal CT reveals dilatation of the distal esophagus (white arrow) proximal to a lap band that is too tight

1026

D. Hirschl et al.

Fig. 12 A 66-year-old female status post gastric bypass surgery. CT scan, coronal view, reveals a Roux- en-Y procedure with patent gastrojejunal and jejunal-jejunal anastomoses (arrows)

Fig. 13 Malpositioned feeding tubes: (a) Feeding tube tip within a right lower lobe bronchus (white arrow). Endotracheal tube in good position. Bilateral pneumonias (thin white arrows) with large left lower lobe consolidation (thin black arrow). (b) Feeding tube tip within the right

upper pleural space (black arrow). Tracheostomy tube present (arrowhead). Bilateral infiltrates and left pleural effusion (thin arrows). (c) Feeding tube tip coiled in a large hiatal hernia (clear arrow). Air and fluid within hernia seen along cardiac border (arrowhead)

43

Imaging in Clinical Geriatric Gastroenterology

1027

Fig. 14 Normal gastrostomy tube position in an 86-yearold male with dislodged tube which was replaced at the patient’s bedside. Frontal radiograph of the abdomen acquired after instilling contrast (Gastrografin) into gastrostomy tube to confirm appropriate positioning. Imaging shows the tip of the catheter to be in the pylorus (black arrow). Contrast is seen in the stomach and duodenum. No extraluminal extravasation is seen

Fig. 15 Free intraperitoneal air related to PEG leak in a 68-year-old male, status post lung transplant. (a) Air seen below the diaphragms causing a continuous diaphragm

sign (black arrows). (b) CT scan, axial view, demonstrates free air along the anterior abdomen (white arrows)

1028

Fig. 16 Dislodged feeding tube in an 86-year-old female. Contrast enhanced CT, coronal view, showing the feeding tube with bumper in the ascending colon (white arrow)

Fig. 17 Dislodged gastrostomy in a 72-yearold male. CT of the abdomen (axial bone windows) demonstrating a dislodged bumper style gastrostomy tube in the left anterior abdominal wall. Note the asymmetric thickening of the wall indicative of a collection (white arrow)

D. Hirschl et al.

43

Imaging in Clinical Geriatric Gastroenterology

Fig. 18 Invasive gastric adenocarcinoma in a 74-year-old female with vomiting. Abdominal CT with oral and IV contrast. (a) Axial view: large polypoid soft tissue mass Fig. 19 Gastrointestinal stromal tumor (GIST) in a 68-year-old with abdominal pain and bloating. Contrast enhanced CT scan, axial view, reveals a large hypodense mass arising from the stomach (white arrow)

1029

in the gastric fundus (white arrow). (b) Sagittal view: soft tissue mass occupying a large portion of the gastric lumen (black arrow)

1030

D. Hirschl et al.

Fig. 20 Malignant gastric ulcer with metastatic lymphadenopathy in a 77-year-old female with abdominal pain. Contrast enhanced CT scan, axial views, reveals (a) large

malignant ulcer along anterior gastric fundus with associated wall thickening (white arrow) and (b) a necrotic lymph node in the anterior mesentery (white arrow)

Fig. 21 Metastatic gastric adenocarcinoma in a 75-yearold male. CT scan of the abdomen shows (a) a distended partially obstructed stomach due to wall thickening in the distal body and antrum (white arrow) and (b) peritoneal

carcinomatosis in the gastrohepatic region (white arrow). A gastroduodenal stent was placed and demonstrates patency on (c) CT and (d) fluoroscopy (white arrows)

43

Imaging in Clinical Geriatric Gastroenterology

1031

Fig. 23 Chronic changes of peptic ulcer disease in a 74year-old male. Double contrast upper gastrointestinal series under fluoroscopic guidance reveals a cloverleaf shaped deformity of the duodenal bulb (white arrow) Fig. 22 Duodenal ulcer in an 88-year-old female with abdominal pain. Single contrast upper gastrointestinal series under fluoroscopic guidance reveals narrowing of the pyloric channel with small ulcer and deformity of the duodenal bulb (white arrow). Right upper quadrant surgical clips (black arrow), status post cholecystectomy

1032 Fig. 24 Gastric ulcer in a 75-year-old with abdominal pain. Upper GI series under fluoroscopic guidance reveals benign appearing ulcer at the antrum (white arrow) with a small leak of contrast (black arrow)

Fig. 25 Duodenal diverticulum in a 75-yearold female with abdominal pain. Upper GI series demonstrates a small diverticulum along the third portion of the duodenum (black arrow)

D. Hirschl et al.

43

Imaging in Clinical Geriatric Gastroenterology

1033

Fig. 26 Duodenal ulcer in an 84-year-old female from a nursing home admitted for an upper GI bleed. On endoscopy, a 2.5 cm ulcer crater with adherent clot was seen in the medial duodenal wall. The duodenum appears normal (white arrow) in Aug 2016 on a CT scan for abdominal

pain (a). A CT scan performed without IV contrast on Sept 16, 2019, (b) shows an air filled ulcer crater (white arrow). A CT scan with IV contrast on Sept 23, 2019, (c) shows a layering hypodensity compatible with fluid in the ulcer (white arrow)

Fig. 27 Gastrointestinal bleeding in a 70-year-old male with hematemesis. (a) Pre-contrast CT scan reveals no abnormality. (b) Post-intravenous contrast reveals active

extravasation of vascular contrast in third and fourth segments of duodenum (white arrow)

1034

Fig. 28 Hepatic cysts in a 79-year-old female. Contrast enhanced CT scan: (a) round low attenuation lesions are seen (white arrows). (b) An inferior hepatic cyst demonstrates thin septations (white arrow). Additional cysts in the uncinate process of the pancreas are stable compared to

D. Hirschl et al.

prior studies going back twelve years (black arrow). A cyst is also seen in the left kidney (arrowhead). (c) Abdominal ultrasound. An image of the largest cyst shows posterior acoustic enhancement. Internal echoes appear artifactual (white arrows)

43

Imaging in Clinical Geriatric Gastroenterology

Fig. 29 Fatty infiltration of the liver in a 69-year-old male with elevated liver enzymes. (a) Post-contrast CT scan, axial view. Low density liver consistent with fatty infiltration. Areas of focal fatty sparing seen as increased density along the periphery of the liver (white arrows). (b) Post-

1035

contrast CT scan, coronal view. Area of focal fatty sparing is seen in the region of the gallbladder fossa (black arrow). (c) RUQ ultrasound. Focal fatty sparing correlates with a hypoechoic area seen near the gallbladder two weeks earlier (arrowhead)

1036

D. Hirschl et al.

Fig. 30 Hepatic cavernous hemangioma in a 67-year-old female. Post-contrast CT scan: (a) Arterial phase- hemangioma reveals characteristic peripheral nodular

enhancement (white arrows). (b) Delayed venous phasehemangioma reveals characteristic filling in of contrast (black arrows)

Fig. 31 Right thigh sarcoma with single hepatic metastatic lesion in an 82-year-old male. Abdominal MRI: (a) the lesion is hypodense on non-contrast CT (white arrow), (c) hyperintense on T2 (white arrow), and (b) enhances on

contrast enhanced MR. Subtraction image (d) reveals internal enhancement. The imaging is characteristic of malignancy

43

Imaging in Clinical Geriatric Gastroenterology

Fig. 32 Enlarging cholangiocarcinoma in a 69-year-old female. (a) Abdominal MRI with contrast from July 2019 shows a central peripherally enhancing hypointense mass surrounding the intrahepatic IVC and portal veins (white

1037

arrow). (b, c) Abdominal CT without and with contrast from Nov 2019 again shows enhancement of the hypodense mass and interval enlargement (black arrows)

1038

Fig. 33 Progression of liver metastases from colon carcinoma in a 63-year-old male. Contrast enhanced CT scans, three years apart (a, b). On the earlier study (a), multiple hypoenhancing lesions are consistent with metastatic

D. Hirschl et al.

disease (examples-white arrows). On the later study (b), lesions have increased in size and number. Several lesions have calcified and retracted from the liver capsule (arrowheads)

43

Imaging in Clinical Geriatric Gastroenterology

Fig. 34 Hepatic abscess in a 74-year-old female with transaminitis. (a) Abdominal ultrasound shows a heterogeneous hepatic mass with ill-defined margins (arrowheads). (b) Liver MRI, post-gadolinium T1-weighted image, three

1039

days later, shows a complex mass with multiple enhancing septations (white arrow), compatible with an abscess. (c) The lesion is significantly smaller after treatment with a drainage catheter (black arrow)

1040

Fig. 35 Metastatic rectal cancer and prostate cancer in a 74-year-old male. Abdominal and pelvic CT scan: (a) Axial view of the pelvis shows a lobulated mass that replaces the prostate and seminal vesicles, invades the anterior rectal wall and bladder, and extends along the urogenital tract (white arrows). There is a suprapubic

D. Hirschl et al.

catheter (black arrow). (b) Axial view of the liver reveals faint hypodensities with vague rim enhancement consistent with metastases (clear arrows). (c) Axial view of the chest with lung windows reveals multiple round pulmonary metastases (black arrows)

43

Imaging in Clinical Geriatric Gastroenterology

Fig. 36 An 84-year-old male with multiple hepatic hypodense lesions with peripheral vascularity and capsular retraction (arrowheads), consistent with metastases (a). The CT scan also shows a small amount of loculated Fig. 37 Klatskin tumor in a 70-year-old male with abdominal pain. Coronal contrast enhanced CT of the abdomen shows a central hypodense mass (white arrows) in the liver causing ductal dilatation (black arrows) of both the right and left biliary tree

1041

perihepatic ascites (thin arrow). An ultrasound (c) shows a heterogeneous liver with a large hypoechoic mass (arrows) surrounding the intrahepatic IVC (arrowhead). The liver is normal on a prior CT scan from Dec 2010 (b)

1042

Fig. 38 Liver cirrhosis in a 74-year-old male with a history of alcoholism. The liver is nodular and shrunken (white arrows). There are abundant perigastric and perisplenic collaterals (black arrows). The spleen is enlarged (clear arrow). The main portal vein is attenuated and there Fig. 39 Gallstones in a 75year-old male with right upper quadrant pain. Abdominal ultrasound demonstrates highly reflective echogenic foci within the gallbladder lumen with prominent posterior acoustic shadowing consistent with stones (white arrow)

D. Hirschl et al.

are multiple peripancreatic collaterals, consistent with cavernous transformation (arrowhead). There is moderate ascites (black stars) and periportal adenopathy (thin black arrows)

43

Imaging in Clinical Geriatric Gastroenterology

Fig. 40 A 76-year-old female with multiple gallbladder stones and sludge seen on CT (a) and ultrasound (b) (white arrows). A hepatobiliary scan performed with Tc-99m labeled

1043

BRIDA (c) shows a patent cystic duct with no evidence of acute cholecystitis. There was, however, an abnormally low ejection fraction consistent with gallbladder dyskinesia

Fig. 41 Choledocolithiasis. Coronal CT (a) shows two small calculi (white arrow) in the common bile duct (CBD). Cholangiogram (b) shows a filling defect in the distal CBD (thin arrow)

1044

Fig. 42 A 76-year-old female with a mass in the gallbladder fundus consistent with gallbladder carcinoma. A contrast enhanced CT scan of the abdomen (a) shows an enhancing mass (white arrow). There is also irregularity and abnormal enhancement of the gallbladder wall.

D. Hirschl et al.

Ultrasound of the abdomen (b) from two months prior shows an echogenic mass in the gallbladder fundus, which correlates with the CT finding. Color Doppler (c) shows flow within the mass (white arrow), compatible with internal vascularity

43

Imaging in Clinical Geriatric Gastroenterology

Fig. 43 A 69-year-old female with an incidental porcelain gallbladder. The CT scan (a) shows peripheral calcification outlining the gallbladder (white arrow). There is relative increased density within the gallbladder lumen compatible with sludge. The ultrasound (b) shows an echogenic thin

1045

line in the gallbladder wall (white arrow) with posterior acoustic shadowing (arrowhead). Gallbladder sludge is better seen on the ultrasound. MRI (c) signal in the gallbladder wall is compatible with calcification. Signal within the gallbladder is compatible with sludge

1046

D. Hirschl et al.

Fig. 44 Acute cholecystitis. Axial contrast enhanced CT of the abdomen demonstrating a hydropically distended gallbladder with mucosal thickening and surrounding stranding indicating the presence of inflammation (white arrows)

Fig. 45 A 63-year-old female with acute pancreatitis. Contrast enhanced CT. There is enlargement of the gland and peripancreatic fluid, with thickening of the adjacent fascia (a, b) (arrows). Three years later, the pancreas is

normal in size and there are punctate calcifications in the head (arrow), compatible with chronic pancreatitis (c). There is also diffuse fatty infiltration of the liver (arrowhead)

43

Imaging in Clinical Geriatric Gastroenterology

Fig. 46 An 87-year-old male with acute pancreatitis. Ultrasound (a) showed mild dilatation of the pancreatic duct. Labs showed an elevated lipase. CT scan (b, c)

Fig. 47 Chronic pancreatitis. CT scan without oral or IV contrast – 65-year-old female with persistent abdominal pain. Extensive calcifications within the pancreatic body and tail (arrow)

1047

showed peripancreatic fluid (arrows) and mild pancreatic ductal dilatation

1048

D. Hirschl et al.

Fig. 48 Portal vein thrombosis in a 71-year-old female with abdominal pain. Contrast enhanced CT (a) shows a filling defect extending into the right portal vein (arrow)

with associated geographic hypoenhancement of the right hepatic lobe. Ultrasound (b) shows lack of color flow in the portal vein (arrow)

Fig. 49 A 79-year-old male with weight loss, epigastric pain, and hyperbilirubinemia. Ultrasound (a) shows pancreatic ductal dilatation (arrow). MRI (b, c) revealed a

hypointense pancreatic mass that proved to be malignant and pancreatic ductal dilatation (arrows). MRCP (d) shows biliary and pancreatic ductal dilatation (arrows)

43

Imaging in Clinical Geriatric Gastroenterology

1049

Fig. 50 A 73-year-old female with pancreatic neuroendocrine tumor. Contrast enhanced axial CT (a) and coronal CT (b) show a well-circumscribed heterogeneously enhancing mass in the mesentery (white arrows)

Fig. 51 A 74-year-old male with metastatic pancreatic cancer. (a) On a prior non-contrast CT scan from Sept 2012, the pancreas (white arrow) was normal. (b) A large mass is in the tail of the pancreas in Sep 2019, on a CT scan performed for RUQ pain and worsening liver function tests (white arrow). (c) Two months later on a contrast enhanced

CT scan, there is diffuse metastatic disease with peripancreatic and periportal adenopathy (thin white arrows), ascites, liver mets (black arrow), an enlarging heterogeneous necrotic pancreatic mass (white arrow), and peritoneal implants (arrowhead)

1050

Fig. 52 An 86-year-old female with abdominal pain, jaundice, and scleral icterus had a negative ERCP at an outside hospital and was transferred for further work up. CT scan, axial and coronal images (a, b), shows a

Fig. 53 Superior mesenteric artery (SMA) thrombus. Axial contrast enhanced CT of the abdomen shows a filling defect in the SMA (white arrow)

D. Hirschl et al.

hypodense mass in the head of the pancreas (white arrows). FNA revealed a well-differentiated adenocarcinoma in a background of intraductal papillary mucinous neoplasm

43

Imaging in Clinical Geriatric Gastroenterology

1051

Fig. 54 A 74-year-old female with a large splenic infarct. The patient presented with new atrial fibrillation and bilateral deep vein thrombosis. Axial contrast enhanced CT (a)

demonstrates diffuse hypoenhancement of the spleen (arrowheads). The spleen is lobulated and mildly atrophic five months later (b) (white arrow)

Fig. 55 Infrarenal abdominal aortic aneurysm (AAA) in a 74-year-old female. Ultrasound is the recommended screening method (a, b). The AAA in this patient measures 4.5 cm in greatest AP dimension (measured in a, b). There

is peripheral thrombus better seen on the CT scan, coronal view (c), performed with intravenous contrast for presurgical evaluation (white arrow)

1052

Fig. 56 Abdominal aortic aneurysm (AAA). A coronal image from a contrast enhanced CT (a) shows a dilated irregular abdominal aorta with mural thrombus (white arrow). Disease extends into the common iliac arteries

D. Hirschl et al.

bilaterally. Intraoperative angiogram (b) showing endovascular repair with placement of an aorto-bi iliac endograft

Fig. 57 A 78-year-old with an infrarenal abdominal aortic aneurysm. Coronal (a) and axial (b) images from a CTA show a tortuous and aneurysmal aorta (arrows)

43

Imaging in Clinical Geriatric Gastroenterology

1053

Fig. 58 Small bowel lymphoma: 76-year-old female with diffuse abdominal pain. Coronal (a) and axial (b) images from a CT scan demonstrate marked circumferential

thickening of the terminal ileal wall (arrow). The bowel is not obstructed

Fig. 59 Carcinoid in an 81-year-old male with abdominal pain. Coronal (a) and axial (b) images from a CT scan with oral and IV contrast show focal enhancing nodularity with

spiculated borders (white arrows) in the mesentery. The findings are characteristic for carcinoid which was diagnosed at surgery

1054

D. Hirschl et al.

Fig. 60 An 87-year-old with small bowel obstruction secondary to an incarcerated incisional hernia. An axial CT scan image demonstrates a fluid filled segment of bowel with wall thickening and submucosal edema within the subcutaneous soft tissues of the anterior abdominal wall (white arrow). There is an adjacent Richter’s hernia (arrowhead). Multiple small bowel loops are dilated

Fig. 61 Small bowel obstruction in an 85-year-old male with diabetes and dementia. The patient presented with vomiting and three days of abdominal pain. CT scan scout view (a) reveals multiple dilated small bowel loops

in a stepladder appearance (white arrows). A coronal image (b) shows multiple dilated fluid filled small bowel loops which resolved with conservative treatment. The stomach is distended (thin white arrow)

43

Imaging in Clinical Geriatric Gastroenterology

Fig. 62 An 82-year-old male with acute onset lower abdominal pain. Non-contrast CT, axial and coronal views (b, c), show mesenteric edema and ascites (white

Fig. 63 Acute appendicitis with microperforation in an 84-year-old female who presented with abdominal pain and rectal bleeding. A coronal CT scan image reveals a thick walled appendix with surrounding fatty infiltration and fluid (white arrow). Extraluminal air is consistent with focal perforation (arrowhead)

1055

arrows), and fluid filled loops of bowel (arrowhead). Prior axial CT (a) at a comparable level (top left image) shows normal appearing mesenteric fat

1056

Fig. 64 An 84-year-old female with acute appendicitis. CT scan, axial views (a, b), reveals multiple dilated, fluid filled small bowel loops (black arrows) secondary to an Fig. 65 A 74-year-old female with abdominal pain has splenomegaly (white arrow) and upper abdominal adenopathy (black arrows) on an axial CT scan image, consistent with known T-cell lymphoma

D. Hirschl et al.

inflammatory stricture (white arrow) from a fluid and air filled periappendicular abscess (arrowhead)

43

Imaging in Clinical Geriatric Gastroenterology

1057

Fig. 66 A 67-year-old presents with unexplained weight loss. A cecal mass is seen on colonoscopy. CT scan, axial and coronal views (a, b), demonstrates focal, irregular wall

thickening of the cecal wall, consistent with carcinoma (white arrows)

Fig. 67 Colonic pneumatosis with associated portal venous gas in a patient with ischemic bowel. Contrast enhanced axial CT (a) shows air on both dependent and nondependent aspects of the cecum (white arrows), consistent with pneumatosis

which can be seen with ischemic or infarcted bowel. Coronal reformats (b) show air in portal venous branches of segment 4B of the liver (arrowhead). There are multiple fluid filled small bowel loops compatible with an ileus

1058

D. Hirschl et al.

Fig. 68 Colo-colonic intussusception in a 75-year-old with acute abdominal pain. Coronal images from a contrast enhanced CT show a large intussusception of the descending colon (white arrow). Note bowel with surrounding fat, black on CT, surrounded again by bowel. Internal enhancement is suggestive of a colonic mass as a lead point (black arrow)

Fig. 69 Screening colonoscopy was incomplete due to severe sigmoid diverticulosis in this 69-year-old. 3D reformatted images from a CT colonography demonstrate

an 11 mm polyp in the mid transverse colon (white arrow, red circle). Multiple colonic diverticula are seen on the 3D reformats (e.g., thin white arrows)

43

Imaging in Clinical Geriatric Gastroenterology

1059

Fig. 70 Uncomplicated diverticulitis of the descending colon. Axial non-contrast CT of the abdomen showing stranding and haziness in the pericolonic fat of the descending colon (white arrow)

Fig. 71 Acute diverticulitis in a 71-year-old female with lower abdominal pain. CT scan with oral and IV contrast (a) demonstrates sigmoid wall thickening and mesenteric fat stranding and edema (white arrows). There is no

drainable collection. Follow-up CT scan (b) for recurrent abdominal pain 3 months later shows complete resolution of acute inflammatory changes

1060

D. Hirschl et al.

Fig. 72 An 85-year-old with MALToma (mucosa associated lymphoid tissue), a type of lymphoma on an axial image of a contrast enhanced CT scan (white arrow). There is mass effect on the bladder (black arrow)

Fig. 73 A 67-year-old female admitted with cardiac arrest, developed abdominal distension and projectile vomiting after 5 weeks in intensive care. CT scan, coronal view (a) and axial view with lung window (b), shows

pneumoperitoneum (black arrow), intestinal pneumatosis (white arrows), and portal venous air (arrowhead) consistent with bowel ischemia and, or infarction. There is also ascites

43

Imaging in Clinical Geriatric Gastroenterology

1061

Fig. 74 Pneumoperitoneum. Chest X-ray, frontal view, showing free air under the right hemidiaphragm (white arrow)

Fig. 75 A 69-year-old male with a history of a right colonic mass presents for evaluation. On a CT scan with oral and IV contrast, axial (a) and coronal (b) images, a right colonic mass (white arrow) is above the ileocecal

valve without obstruction. Pericolonic lymph nodes along the mesenteric border (arrowheads) are suspicious for local spread of disease

1062

Fig. 76 Enlarging cecal mass in a 91-year-old female. A small cecal polyp (black arrow) was seen on a CT scan in 2010 (coronal image: (a) nine years later, the patient presents with abdominal pain and a 4 cm soft tissue cecal mass (black arrow) (axial images: b, c). The mass obstructs the appendix which is distended with fluid and demonstrates wall thickening and enhancement (arrowhead). The mass

D. Hirschl et al.

extends outside of the cecum to involve the peritoneum and the iliacus muscle. Heterogeneous hypodensity and enhancement in the iliacus is compatible with an abscess (white arrow). A right internal iliac mass is consistent with adenopathy (thin arrow). An incidental slowly growing left adnexal mass measures 7 cm (clear arrow)

43

Imaging in Clinical Geriatric Gastroenterology

Fig. 77 A 69-year-old male with recurrent ischemic colitis involving the left colon. A coronal CT image shows diffuse wall thickening of the descending colon with mucosal enhancement (white arrows) compatible with colitis

1063

1064

Fig. 78 A 74-year-old male presented to the ER with acute diverticulitis. CT scan, axial (a, b) and coronal views (c), shows focal narrowing and wall thickening in

Fig. 79 A 78-year-old presents with lower abdominal pain. Contrast enhanced CT scan, axial view, reveals acute sigmoid diverticulitis with abscess formation (white arrow)

D. Hirschl et al.

the sigmoid colon, without obstruction. A contained abscess with air and fluid in the adjacent mesentery (thin arrows) formed secondary to local perforation

43

Imaging in Clinical Geriatric Gastroenterology

Fig. 80 A 69-year-old male with abdominal distention has a partial sigmoid volvulus. CT scan, scout view (a), reveals the classic coffee bean sign of sigmoid volvulus (white arrow). Coronal view (b) reveals distended sigmoid

1065

colon in a coffee bean appearance (white arrow). Coronal view of the upper abdomen (c) reveals an incidental large hiatal hernia (arrowhead)

1066

Fig. 81 A 65-year-old male presents to the emergency room with abdominal pain and no bowel movements for several days. CT scan, coronal and axial views (a, b), and an abdominal x-ray (c) show abundant stool throughout the

D. Hirschl et al.

colon and rectum (white arrows), compatible with constipation. There is wall thickening of the rectum and perirectal fat stranding consistent with stercoral colitis (thin arrows)

Advanced Imaging of Geriatric Gastrointestinal Pathology

44

Fernanda Samara Mazzariol

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1067 Magnetic Resonance Cholangiopancreatography (MRCP) . . . . . . . . . . . . . . . . . . . . . . . 1068 CT Colonoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1068 Acute Gastrointestinal (GI) Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radionuclide Imaging (Scintigraphy) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Catheter-Directed Angiography (CA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CT Angiography (CTA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1071 1071 1071 1072

Acute Mesenteric Ischemia and Chronic Mesenteric Insufficiency . . . . . . . . . . . . . . . 1073 Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1074 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1074

Abstract

Gastrointestinal disorders are common in the old; evaluation may utilize one of several available imaging modalities. These include plain abdominal radiographs, fluoroscopic exams, ultrasonography, computed tomography, nuclear medicine scans, and magnetic resonance imaging, each with its own specific applications. In this chapter, we will discuss the applications of magnetic resonance cholangiopancreatography (MRCP), CT

F. S. Mazzariol (*) Radiology, New York Presbyterian Hospital/Weill Cornell Medicine, New York, NY, USA e-mail: [email protected]; [email protected]

colonography, and the imaging of gastrointestinal hemorrhage. Keywords

CT colonography · MRCP · CT scan · Gastrointestinal bleeding · CT angiogram · Conventional angiography · Acute mesenteric ischemia · Chronic mesenteric ischemia

Introduction Gastrointestinal ailments in the elderly may affect any part of the gastrointestinal tract from the mouth to the anus and its associated glands.

© Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_37

1067

1068

While discussion of the appropriate imaging work up of all geriatric gastrointestinal diseases is beyond the scope of this chapter, it is important for the geriatric gastroenterologist to understand the available imaging modalities, their applicability, and pitfalls. The American College of Radiology provides evidence-based guidelines to assist the referring physician in making the most appropriate imaging or treatment decision for specific clinical conditions. Evaluation of biliary and pancreatic diseases may start with ultrasonography but often requires CT scan and MRI/MRCP for a comprehensive evaluation. CT colonography has emerged as alternative or replacement to optical colonoscopy for screening and diagnosis of colonic polyps and cancer due to its tolerability and noninvasive nature, and it is particularly suited to the elderly. The aging population is at an increased risk for gastrointestinal bleeding due to an increased incidence of chronic diseases and greater drug consumption. Timely imaging and image-guided therapy can help decrease geriatric gastrointestinal hemorrhage mortality. In this chapter, we will discuss the applications of magnetic resonance cholangiopancreatography (MRCP), CT colonography, and the imaging of gastrointestinal hemorrhage.

Fig. 1 A 75-year-old female presenting with elevated liver enzymes undergoes MRCP. (a) Thick slab MRCP and (b) axial T2WI MRI show large stones in the

F. S. Mazzariol

Magnetic Resonance Cholangiopancreatography (MRCP) MRCP imaging is the mainstay for diagnosis of biliary and pancreatic pathology and helps guide tissue sampling and interventions performed via endoscopic retrograde pancreatography (ERCP). The main indication for MRCP, with or without intravenous contrast, is evaluation of biliary obstruction. Biliary obstruction in the elderly can be caused by stone disease (Fig. 1a, b), malignant or benign strictures (Fig. 2a, b). MRCP is also used to evaluate patients presenting with cholangitis and acute pancreatitis, evaluate and follow-up pancreatic cystic lesions (Fig. 3) and tumors, and to assess exocrine pancreatic function (Palmucci et al. 2017; Manfredi and Pozzi 2016).

CT Colonoscopy The American Cancer Society (ACS) 2018 recommendation for colorectal cancer (CRC) screening for patients with average risk is high sensitivity stool-based test or visual examination starting at age 45 (qualified recommendation). The ACS strongly recommends CRC screening

gallbladder (long arrow) and common bile duct (short arrow) and biliary ductal dilatation (arrowheads)

44

Advanced Imaging of Geriatric Gastrointestinal Pathology

Fig. 2 A 67-year-old male presents with painless jaundice. (a) Thick slab MRCP shows intrahepatic biliary ductal dilatation with short segment of non-visualization of the ducts in the porta hepatis (long arrow) and marked intrahepatic biliary ductal dilatation. The normal common

Fig. 3 A 76-year-old diabetic female presents with abdominal pain. CT scan (not shown) showed atrophic pancreas and marked dilatation of main pancreatic duct. MRCP shows dilated pancreatic duct (arrows) most consistent with main duct intraductal papillary mucinous neoplasia (IPMN) of the pancreas. The patient underwent ERCP with sampling of duct fluid. Cytology identified mucin in the fluid without high-grade cellular dysplasia, confirming main duct IPMN

starting at age 50 and older. Average risk adults in good health and with life expectancy greater than 10 years should continue colorectal

1069

bile duct (short arrow) and pancreatic duct are visualized (arrowhead). (b) Axial post-contrast T1WI shows illdefined enhancing masses in the porta hepatis (between arrows) causing biliary obstruction consistent with cholangiocarcinoma, Klatskin tumor

screening until age 75. CRC screening options for stool based tests are: (a) fecal immunochemical test every year, (b) high-sensitivity guaiacbased fecal occult blood test every year, or (c) multitarget stool DNA test every 3 years. A positive fecal exam should be followed promptly by visual examination. CRC screening options for visual examinations are: (a) conventional optical colonoscopy (COC) every 10 years, (b) CT colonoscopy (CTC) every 5 years, or (c) flexible sigmoidoscopy every 5 years. Between ages 76 and 85, screening should be individualized based on patient’s preference, life expectancy, health status, and prior screening history. The ACS discourages CRC screening after age 85 (Wolf et al. 2018). COC limitations include need for sedation and potential risk of bleeding and perforation in 0.1–0.3% of patients. Failure to complete COC ranges from 5% to 10%. An incomplete COC exam can be followed by a same day or interval CTC. In the geriatric population, CTC can be the exam of choice as contraindications for sedation and instrumentation due to severe cardiopulmonary disease or use of anticoagulation medication may be more prevalent (Yucel et al. 2008; Kim et al. 2010).

1070

F. S. Mazzariol

Fig. 4 A 71-year-old morbidly obese female with contraindication for anesthesia underwent CTC. (a) 3-D cube view shows a 1.5 cm sessile sigmoid polyp (white arrow) and a tagged stool pellet (black arrow). (b) 2-D right lateral

decubitus view of the polyp (arrow). Patient underwent COC for polyp removal. (c) Endoscopic view of the polyp (arrow). Pathology revealed a tubular adenoma with focal villous architecture

Adequate colonic cleansing, fecal tagging, and colonic distention are prerequisites to a successful CTC. Bowel cleansing may be challenging in the elderly. A study found that limited colonic preparation is sufficient to exclude mass and polypoid lesions greater than 1 cm (Keeling et al. 2010) (Fig. 4a–c). The adenoma-carcinoma sequence and “de novo” carcinogenesis are two proposed pathways for colorectal cancer development, although controversial in importance (Bedenne et al. 1992). Most small polyps found on colonoscopy are

not adenomatous and the incidence of cancer in small polyps is rare (Aldridge and Simson 2001; Nusko et al. 1997). CTC cannot differentiate adenomatous from hyperplastic polyp. Small polyp measurement can vary slightly between CTC, COC, and pathology specimens with CTC measurement closest to the true dimension of the polyp (Summers 2010). Flat adenomas, lesions with height less than 50% of its width, and lesions less than 2 mm raised from the mucosa are more difficult and sometimes impossible to detect on CTC. CTC screening can also detect colonic and

44

Advanced Imaging of Geriatric Gastrointestinal Pathology

extra-colonic cancers in addition to other significant disease in one of 200 asymptomatic adults (Pickhardt et al. 2010). Early detection and treatment of cancers may contribute to favorable outcomes. COC is the gold standard for colorectal cancer screening allowing for immediate tissue sampling. CTC is the alternative visual exam when COC is incomplete or cannot be performed (Pickhardt et al. 2019; Johnson 2009).

1071

Diagnosis of bleeding is made by intraluminal manifestation of the radiotracer with increased intensity over time and demonstration of movement in the GI tract during dynamic acquisition of data (Holder 2000) (Fig. 5). Scintigraphy may be time consuming and precise anatomic localization of bleeding is not always possible. The reported accuracy varies from 40% to 100%, and therefore, surgical interventions, particularly segmental intestinal resections, are rarely performed on the basis of scintigraphy findings alone (Hammond et al. 2007).

Acute Gastrointestinal (GI) Bleeding In patients presenting with acute gastrointestinal bleeding, once hemodynamic instability is managed and achieved, radiographic exams can localize, characterize, and treat bleeding lesions. Endoscopy is the initial diagnostic and therapeutic modality in acute GI bleeding (Millward 2008), particularly upper GI bleeding, happening above the ligament of Treitz. Radiologic exams play a greater role in the diagnosis of lower GI bleeding. Bleeding must be active at the time of imaging for radiographic diagnosis. CT angiography (CTA) and conventional catheter angiography (CA) are the exams of choice in hemodynamically unstable patients because they can determine the precise location of bleeding and treat the bleeding lesion. Radionuclide imaging is often used for hemodynamically stable patients with slow intermittent bleeding.

Radionuclide Imaging (Scintigraphy) In this exam, a radioactive nuclide agent is bound to the patient’s red blood cells (RBC), injected in the patient and imaged with a gamma camera. Scintigraphy can detect bleeding rates as low as 0.04–0.1 ml/min, is noninvasive, and generally well tolerated. The imaging can be performed up to 18–24 h after injection of the labeled RBC. Positive scintigraphy increases the diagnostic yield of CA (Gunderman et al. 1998; Ng et al. 1997).

Catheter-Directed Angiography (CA) Bleeding rates as low as 0.5 ml/min can be detected with accurate anatomic localization and treatment can be performed with high success rates. In variceal or non-variceal upper GI bleeding, CA is used less frequently due to higher yield from EGD for diagnosis and treatment (Hastings 2000; Murata et al. 2006; Barkun et al. 2010). CA is used when EGD is not available, if bleeding cannot be controlled using EGD (Andersen and Duvnjak 2010) and for poor surgical candidates (Millward 2008). Most commonly, lower GI bleeding in the geriatric population is due to colonic diverticulosis and angiodysplasia. Treatment by superselective catheter embolization, usually with microcoils (Funaki et al. 2001; Funaki 2004), is effective and has low complication rates. Small bowel is a less frequent site of lower GI bleed, and angioectasia is the most common cause (Fig. 6). Sources of bleeding in the small bowel are more difficult to diagnose and patient outcomes can be poor (Prakash and Zuckerman 2003). If bowel resection is entertained, microcatheter infusion of methylene blue stain or a microcoil can be used to limit the extent of bowel resection. Extravasation of contrast into the bowel lumen is diagnostic of active bleeding. Indirect findings of bleeding are pseudoaneurysm, arterial venous fistula, hyperemia, neovascularity, and extravasation of contrast into a confined space.

1072

F. S. Mazzariol

Fig. 5 A 74-year-old male with GI bleeding of unknown location was evaluated with scintigraphy. Multiple sequential images show bleeding with activity localizing in the stomach (short arrow) and progressing to the small bowel (arrowhead)

Disadvantages of CA include, high cost, invasiveness, associated risk of catheter related and vascular access complications, utilization of iodinated contrast material and false negative exam related to intermittent bleeding, bleeding below detectable rates, and variant vascular anatomy.

CT Angiography (CTA)

Fig. 6 CT angiogram of a 76-year-old female with endstage renal disease presenting with massive GI bleeding. CT coronal reformatted image showing angioectasia of the small bowel evidenced by several focally dilated arteries along the small bowel wall (arrows). No active bleeding was demonstrated during CTA. Patient recovered with conservative treatment and the diagnosis was confirmed later with double-balloon endoscopy

CTA localization accuracy is comparable to CA (Wells et al. 2018; Yoon et al. 2006a; b; Zink et al. 2008; Kuhle and Sheiman 2000, 2003; Sabharwal et al. 2006). A noncontrast CT scan to detect preexisting hyperdense material in the bowel lumen is followed by contrast enhanced CTA. CTA diagnosis is made by detection of contrast material in the bowel lumen. Pitfalls include poor CTA technique, bowel mucosal enhancement, which can be interpreted as bleeding, and preexisting high attenuation material (often oral contrast) in the bowel lumen, which decreases CTA accuracy. Although CTA involves radiation

44

Advanced Imaging of Geriatric Gastrointestinal Pathology

1073

Fig. 7 An elderly patient with rectal bleeding. (a) Superselective angiography showing contrast extravasation into the rectal lumen (arrow). (b) Increased contrast pooling in

the rectal lumen (between arrows). (c) Microcoil embolization (arrow) of the rectal artery branches feeding the bleeding lesion

exposure and use of iodinated intravenous contrast material, it is less invasive than CA. The information obtained by CTA regarding etiology and site of bleeding, and delineation of vascular anatomy are important to plan patient management and are very helpful to guide CA interventions (Fig. 7). CTA is rapid, safe, sensitive, easy to perform, and readily available. Many institutions use CTA to triage patient presenting with lower GI bleeding (Laing et al. 2007; Lee et al. 2009; Artigas et al.

2013) to facilitate a focused CA intervention and spare an invasive intervention for patients without active bleeding (Fig. 8).

Acute Mesenteric Ischemia and Chronic Mesenteric Insufficiency Acute mesenteric ischemia is caused by arterial occlusive disease, venous occlusive disease, strangulation/obstruction, and hypoperfusion

1074

F. S. Mazzariol

due to interruption of peristalsis and may contain fluid particularly in venous occlusive disease and strangulation. Ascites and mesenteric fat stranding represent transudation of fluid (Furukawa et al. 2009; Ofer et al. 2009). Once the etiology of acute mesenteric ischemia and abdominal angina has been established, the treatment may be with open surgery or with catheter-directed thrombolysis, balloon angioplasty, and stent placement.

Key Points Fig. 8 CTA showing acute GI bleed in an elderly patient with diverticulosis. Axial image shows contrast pooling in the lumen of the left colon (arrow) from a bleeding diverticulum

associated with nonocclusive vascular disease. CT findings vary depending on the cause of ischemia. In patients with chronic arterial insufficiency of the intestines, known as abdominal angina, CTA is used to determine the degree of atherosclerotic stenosis of celiac and superior mesenteric arteries and evaluate collateral circulation and to exclude other cause of intestinal ischemia such as malignancy, median arcuate ligament syndrome, aneurysm, or dissection. CA is the preferred modality to treat abdominal angina. CTA evaluates the bowel wall, mesentery, and vessels in a single exam. The two main limitations of CTA are lack of dynamic visualization of the flow pattern and difficulty in determining degree of stenosis in heavily calcified vessels. Bowel wall is thickened when ischemia is caused by venous occlusion and reperfusion. In occlusive arterial ischemia with or without bowel infarction, the bowel wall may be paper thin due to lack of edema and may demonstrate hemorrhage. After contrast administration, poor enhancement is specific but not sensitive for bowel infarction. Hyperenhancement of the bowel can also be seen with ischemia. Gas in the bowel wall (pneumatosis intestinalis) and portomesenteric venous gas in the presence of mesenteric ischemia indicate transmural infarction. The bowel is often dilated

• MRCP imaging is the mainstay for diagnosis of biliary and pancreatic pathology and is also used for planning of ERCP or percutaneous guided interventions. • Conventional optical colonoscopy is the gold standard for colorectal cancer screening allowing for immediate tissue sampling. CT colonography is the alternative visual test and can be performed when optical colonoscopy is incomplete or cannot be performed due to contraindications for sedation or instrumentation. • In hemodynamically unstable patients with acute lower GI bleeding, CTA and CA are the exams of choice for diagnosis and treatment. Radionuclide imaging is the initial exam for hemodynamically stable patients with slow and/or intermittent bleeding. • CTA and CA are used for diagnosis of acute mesenteric ischemia and abdominal angina. CTA can evaluate the bowel wall, mesentery, and vessels in a single examination. • Percutaneous balloon angioplasty and stent placement are the preferred treatment of abdominal angina.

References Aldridge AJ, Simson JH. Histological assessment of colorectal adenomas by size: are polyps less than 10 mm in size clinically important? Eur J Surg. 2001;167:777–81.

44

Advanced Imaging of Geriatric Gastrointestinal Pathology

Andersen P, Duvnjak S. Endovascular treatment of non variceal acute arterial upper gastrointestinal bleeding. World J Radiol. 2010;2(7):257–61. Artigas J, Marti M, Soto J, et al. Multidetector CT angiography for acute gastrointestinal bleeding; technique and findings. Radiographics. 2013;33:1453–70. Barkun AN, Bardou M, Kuipers EJ, et al. International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med. 2010;152(2):101–13. Bedenne L, Faivre J, Boutron MC, Piard F, Cauvin JM, Hillon P. Adenoma-carcinoma sequence or “de novo” carcinogenesis. Cancer. 1992;69:883–8. Funaki B. Superselective embolization of lower gastrointestinal hemorrhage: a new paradigm. Abdom Imaging. 2004;29:434–8. Funaki B, Kostic J, Lornz J, Ha T, Yip D, Rosenblum J, Leef J, Straus C, Zaleski G. Superselective microcoil embolization of colonic hemorrhage. AJR. 2001;177: 829–36. Furukawa A, Kanasaki S, Naoaki K, et al. CT findings of acute mesenteric ischemia from various causes. AJR. 2009;192:408–16. Gunderman R, Leef J, Ong K, et al. Scintigraphic screening prior to visceral arteriography in acute lower gastrointestinal bleeding. J Nucl Med. 1998;39:1081–3. Hammond K, Beck D, Hicks T, Timmcke A, Whitlow C, Margolin D. Implications of negative technetium 99labeled red blood cell scintigraphy in patients presenting with lower gastrointestinal bleeding. Am J Surg. 2007;193:404–8. Hastings G. Angiographic localization and transcatheter treatment of gastrointestinal bleeding. Radiographics. 2000;20:1160–8. Holder L. Radionuclide imaging in the evaluation of acute gastrointestinal bleeding. Radiographics. 2000;20: 1153–9. Johnson C. CT colonography: coming of age. AJR. 2009;193:1239–42. Keeling A, Slattery M, Leong S, McCarthy E, Susanto M, Lee M, Morrin M. Limited-preparation CT colonography in frail elderly patients: a feasibility study. AJR. 2010;194:1279–87. Kim D, Pickhardt P, Hanson M, Hinshaw J. CT colonography: performance and program outcome measures in an older screening population. Radiology. 2010;254:493–500. Kuhle WG, Sheiman RG. The sensitivity of helical CT in detecting active colonic hemorrhage (abstr). J Vasc Interv Radiol. 2000;11(Suppl):208. Kuhle WG, Sheiman RG. Detection of active colonic hemorrhage with use of helical CT: findings in a swine model. Radiology. 2003;228(3):743–52. Laing C, Tobias T, Rosenblum D, Banker W, Tseng L, Tamrkin S. Acute gastrointestinal bleeding: emerging role of multidepector CT angiography and review of current imaging techniques. Radiographics. 2007; 27:1055–70.

1075

Lee S, Welman CJ, Ramsay D. Investigation of acute lower gastrointestinal bleeding with 16 and 64-slice multidetector CT. J Med Imaging Radiat Oncol. 2009; 53:56–63. Manfredi R, Pozzi R. Secretin enhanced MR imaging of the pancreas. Radiology. 2016;279:29–43. Millward S. ACR appropriateness criteria on treatment of acute nonvariceal gastrointestinal tract bleeding. J Am Coll Radiol. 2008;5(4):550–4. Murata S, Tajima H, Fukunaga T, Abe Y, Niggemann P, Onozawaga S, Kumazaki T, Kurramochi M, Kuramoto K. Management of pancreaticoduodenal artery aneurysms: results of superselective transcatheter embolization. AJR. 2006;187:290–8. Ng DA, Opelka FG, Beck DE, et al. Predictive value of Tc99m-labeled red blood cell scintigraphy for positive angiogram in massive lower gastrointestinal hemorrhage. Dis Colon Rectum. 1997;40: 471–7. Nusko G, Mansmann U, Altendorf-Hofmann A, Groitl H, Wittekind C, Hahn EG. Risk of invasive carcinoma in colorectal adenomas assessed by size and site. Int J Colorectal Dis. 1997;12:267–71. Ofer A, Abadi S, Nitechi S, et al. Multidetector CT angiography in the evaluation of acute mesenteric ischemia. Eur Radiol. 2009;19:24–30. Palmucci S, Roccasalva F, Piccoli M et al. Contrastenhanced magnetic resonance cholangiography: practical tips and clinical indication for biliary disease management. Gastroenterol Res Pract. 2017; Article ID 2403012, 11 pages. https://doi.org/10.1155/ 2017/2403012. Pickhardt P, Kim D, Meiners R, et al. Colorectal and extracolonic cancers detected at screening CT colonography in 10286 asymptomatic adults. Radiology. 2010;255:83–8. Pickhardt P, Correale L, Hassan C. Positive predictive value for colorectal lesions at CT colonography: analysis of factors impacting results in a large screening cohort. AJR. 2019;213:W1–8. Prakash C, Zuckerman G. Acute small bowel bleeding: a distinct entity with significant different economic implications compared with GI bleeding from other locations. Gastrointest Endosc. 2003;58: 330–5. Sabharwal R, Vladica P, Chou R, Law P. Helical CT in the diagnosis of acute lower gastrointestinal haemorrhage. Eur J Radiol. 2006;58:273–9. Summers R. Polyp size measurement at CT colonography: what do we know and what do we need to know? Radiology. 2010;255:707–20. Wells M, Hansel S, Bruining D, et al. CT for evaluation of acute gastrointestinal bleeding. Radiographics. 2018;38:1089–107. Wolf A, Fontham ETH, Church TR, et al. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin. 2018;68:250–81.

1076 Yoon W, Jeong YY, Kim JK. Acute gastrointestinal bleeding: contrast enhanced MDCT. Abdom Imaging. 2006a;31:1–8. Yoon W, Jeong Y, Shin S, Lim H, Song S, Jang N, Kim J, Kang H. Acute massive gastrointestinal bleeding: detection and localization with arterial phase multidetector row helical CT. Radiology. 2006b;239:160–7. Yucel C, Lev-Toaff A, Moussa N, Durrani H. CT colonography for incomplete or contraindicated

F. S. Mazzariol optical colonoscopy in older patients. AJR. 2008;190:145–50. Zink SI, Ohki SK, Stein B, Zambuto DA, Rosenberg RJ, Choi JJ, Tubbs DS. Noninvasive evaluation of active lower gastrointestinal bleeding: comparison between contrast-enhanced MDCT and 99mTc-labeled RBC scintigraphy. AJR. 2008;191:1107–14.

Part VII Pathology

Laboratory Testing in Older Adults: Indications, Benefits, and Harms

45

T. S. Dharmarajan and C. S. Pitchumoni

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1081 The Emergence of Laboratory Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1081 Is Old Age a Reason to Perform Laboratory Tests? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1082 Manifestations Must Determine the Need for Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1082 Unwanted Testing May Carry Risks More than Benefits . . . . . . . . . . . . . . . . . . . . . . . . . 1083 Common or Routine Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hemoglobin and Hematocrit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ferritin, Transferrin Saturation, B12, and Folate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Renal Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1084 1084 1084 1085

T. S. Dharmarajan (*) Department of Medicine, Division of Geriatrics, Montefiore Medical Center, Wakefield Campus, Bronx, NY, USA Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA Department of Medicine, New York Medical College, Valhalla, NY, USA e-mail: [email protected] C. S. Pitchumoni Department of Medicine, Robert Wood Johnson School of Medicine, Rutgers University, New Brunswick, NJ, USA Department of Medicine, New York Medical College, Valhalla, NY, USA Division of Gastroenterology, Hepatology and Clinical Nutrition, Saint Peters University Hospital, New Brunswick, NJ, USA e-mail: [email protected] © Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_38

1079

1080

T. S. Dharmarajan and C. S. Pitchumoni Liver Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085 Serum Albumin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1086 Serum Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1086 Specific or Individualized Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fecal Occult Blood Testing (FOBT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Screening for Celiac Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Screening for Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acute Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Testing for Bleeding and Coagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vitamin D Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Testing for Clostridium difficile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laboratory Testing in Rheumatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Homocysteine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1086 1087 1088 1088 1089 1089 1089 1090 1090 1090

Selecting Tests Prior to a Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1092 Preoperative Hematological Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1093 Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1095 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1095

Abstract

Laboratory testing trends have changed from a tendency to ordering numerous laboratory tests in the past to the current approach in requesting tests selectively and on an individualized basis. The number of tests ordered, the type of tests requested, the costs involved, and the value provided ultimately define in large measure the quality and cost of care provided. Multiple and repetitive laboratory testing is not proven to be of value and escalates costs of healthcare. Older adults manifest multi-morbidity and accordingly are subject to cumbersome and needless testing. Selective testing has value in the screening for disease, in evaluating the stage of disease, and in determining management strategies or their efficacy. Test results may yield a diagnosis, but there may be no specific treatment available for the disorder. The asymptomatic patient with abnormal test results is always an enigma. Test results may provide satisfaction in yielding a diagnosis, but there may be no specific treatment available for the disorder. Age by itself is not associated with significant alterations in laboratory test results. Marked deviations in test results usually indicate the presence of underlying disease or a response to therapy. Testing trends prior to a surgical procedure must be tailored to history, physical examination, comorbidity, and the

procedure. Results of laboratory testing may be influenced by several factors, including use of medications, both prescribed and over the counter. Routine repeat testing of common tests does not offer advantage over a single run. Discussing the indications and value of testing with the patient is the first step; decision for testing must relate to benefits outweighing any disadvantages. Keywords

Laboratory testing · Elective testing · Routine testing · Cost-effective testing · Value of testing · Preoperative testing · Needless testing · Benefits of testing · Harms of testing · False-positive results · False-negative results · Repeat testing · Homocysteine · Ferritin · Albumin · Liver function tests · Pancreatic function tests · Lipid levels · Prothrombin time · Vitamin D levels · Testing for Clostridium difficile · Testing for celiac disease · Antinuclear antibody · Thyroid function · B12 assay · Folate assay · Hemoglobin · Hematocrit · Creatinine · Blood urea nitrogen · Electrolytes · Fecal occult blood tests · Testing for celiac disease · Testing for diabetes mellitus · HbA1c measurements · Lipid levels · Vitamin D assay · Prothrombin time · PT · PTT · Platelet counts · INR · Analytical methods in the clinical laboratory

45

Laboratory Testing in Older Adults: Indications, Benefits, and Harms

Introduction The number of tests we order, the type of tests we order, the costs of testing, and the value provided ultimately define in large measure the quality and cost of care provided. In the era of escalating healthcare costs, every step taken in the provision of care, including laboratory tests both indicated and questionable, comes under scrutiny as part of the quality of care rendered. While we recognize the relevance and role of laboratory tests in healthcare, providers need to be cognizant of the benefits, risks, and costs of routine or standard batteries of tests. Caution needs to be exercised in solely utilizing age-based criteria as the reason to choose tests in the geriatric age group, especially in the asymptomatic older adult or prior to a minor surgical procedure. As stated in an editorial, “the tests that we order define us” (Mandell 2019). In general, it is more likely that test results may be abnormal as one ages and in particular in the very old population, who are more likely to have subclinical or apparent comorbidity (Hepner 2009). As more tests are performed, the odds of obtaining an abnormal result increases, posing implications for both patient and provider. False-positive tests contribute to further testing and escalation of costs (Fleisher 2001). The costs of paying for routine tests ordered based on age alone may no longer be paid for by insurance companies. In the past several years, there have been changes in the approach to ordering of tests (and diagnostic imaging procedures) due to economic pressures, with a trend toward “indicated” rather than routine testing (Fleisher 2001). Tests do not, often times, provide the information that the physician seeks; in many cases, the results may be irrelevant to diagnosis or management.

The Emergence of Laboratory Testing The sophistication of diagnostic testing has advanced substantially over centuries. From what was bedside medicine in the middle ages and the period when physicians made a

1081

diagnosis solely on observations based on visual and auditory approaches, the clinical laboratory has developed to modern, sophisticated methods that provide accurate information rapidly. The emergence of laboratory testing effectively used at primary healthcare level significantly improves diagnosis and treatment outcomes and is incorporated into routine clinical practice (Carter et al. 2012). At the same time many measures have been placed in the clinical laboratory to improve quality of testing; an example is the introduction of International Standards Organization (ISO) relating to the validation and verification of method performance; in fact, there are practical guides to validate and verify analytical laboratory methods (Pum 2019). As healthcare budgets are under constant pressure globally to lower costs of care, it is essential to ensure that efficiency gains are achieved by reducing laboratory error rate; thus quality indicators play a crucial role and allow for performance assessment; the indicators largely relate to laboratory errors (Tsai et al. 2019). Additionally, the benefits of point-of-care testing are being now evaluated. A point-ofcare testing program is helpful if it ensures that testing will result in an actionable management decision, which may confirm a diagnosis, referral, use of specific treatment, or some other action (Engel et al. 2015). A large study in India suggested rapid tests were not necessarily translated into practical treatment decisions, undermining the potential for benefit from the program (Engel et al. 2015). An example of testing for a common disorder is the utility of HbA1c for diabetes mellitus. Laboratory-based HbA1c testing is now recommended for diagnosing diabetes, a disorder common in older people, and for the monitoring of glycemic status, although it must be emphasized that there is wide variability in the performance of point-ofcare HbA1c testing devices and commercially available models, which limit their value (O’Brien and Sacks 2019). Thus, testing should not be used to establish a diagnosis of diabetes unless the test is validated as accurate (O’Brien and Sacks 2019).

1082

Is Old Age a Reason to Perform Laboratory Tests? It is generally accepted that advancing age is associated with increasing comorbidity. Does this alone justify routine screening, especially in the asymptomatic older adult? In a study of 544 surgical patients over age 70, the prevalence of abnormal electrolyte values and thrombocytopenia was small (0.5–5%); the prevalence of abnormal hemoglobin, creatinine, and glucose was higher at 12%, 10%, and 7% respectively, but did not predict adverse outcomes (Dzankic et al. 2001). The authors concluded that routine testing for hemoglobin, creatinine, glucose, and electrolytes, on the basis of age alone, may not be indicated (Dzankic et al. 2001). Laboratory values used for screening by insurers were not significantly influenced by age alone; most abnormalities arose from health impairments, rather than the age factor (Carter et al. 2012). However, the costeffectiveness is greater in older age, as there is a better likelihood of disease being detected (Pokorski 1990). These statements must be weighed against the probability that disease detected by testing will modify management (Fleisher 2001), justifying the test. Whether an inadequate history in a cognitively impaired person or an atypical presentation in an older person will justify the use of tests is debatable (Pokorski 1990). One often uses the rationale that more testing is attempted in older persons because of difficulties in obtaining a good history due to the presence of impaired cognition or sensorium; perhaps in such situations, it may be justifiable in ordering specific tests focused on an age-based presentation, as addressed below. Modified reference values exist for some tests in the over 65 age group (BourdelMarchasson et al. 2010). An example is the erythrocyte sedimentation rate, which increases minimally with age. It may be difficult to determine promptly, or ahead of time, the specific tests that will provide significant yield in older people with multi-morbidity, causing an increase in the number of tests ordered (Keiso 1990). A focused history on the use of prescribed and over-the-counter medications including supplement use may be relevant to

T. S. Dharmarajan and C. S. Pitchumoni

decision-making; the intake of supplements influences common laboratory test results such as platelet counts, hemoglobin, prothrombin time, vitamin D, and calcium levels, among others. Evaluating the medication list becomes relevant in the era of polypharmacy, a common, addressable issue encountered in the geriatric population. The National Health and Nutrition Examination Survey (NHANES) data indicates that about half the older adults consume an inappropriately excessive number of medications and supplements; several drugs and supplements influence laboratory result values (Kantor et al. 2015). For example, use of metformin or PPIs may cause B12 deficiency; protease inhibitors may increase triglyceride levels, and isoniazid may cause liver enzyme abnormalities.

Manifestations Must Determine the Need for Tests In general, tests are done on the basis of symptoms or signs, to rule out underlying disease, to understand the severity of a disorder, to monitor the progress or prognosis of the illness, and to assess the effectiveness of treatment. What constitutes normal or a range of accepted values is rarely an ideal scenario; laboratory values are determined by a reference population factoring age, gender, race and other variables (Pokorski 1990). Most laboratory values in older adults fall in the normal range; significant deviations or abnormal values must raise suspicion for disease (Coodley 1989). Among the common abnormalites noted in a study involving alkaline phosphatase, serum phosphorus, low creatinine clearance without an alteration of serum creatinine, abnormalities in glucose, and deficiencies in vitamins and albumin, many abnormalities indicated the presence of disease or the effect of a drug, rather than suggest a result of aging (Coodley 1989). Interestingly, data from common blood laboratory tests demonstrated that metabolic abnormalities are associated with global cognitive changes in older people, as evident by psychological testing; they included hyperglycemia, hypernatremia, hyperkalemia, low

45

Laboratory Testing in Older Adults: Indications, Benefits, and Harms

hemoglobin, and elevated creatinine, BUN, and white blood cell counts (Bruce et al. 2009). Additionally, several common test values are neglected. An example is a frequently ordered test, the complete blood cell count (CBC); underutilized components of the CBC include red blood cell distribution width, platelet volume, and nucleated red blood cell count (May et al. 2019). These results have much value for diagnosis, prognosis, and outcomes in older adults and may signify a serious underlying disorder (May et al. 2019). When a test is requested, it is incumbent on the provider to verify the entire results and take appropriate action. Yet, older adults in good health with mild anemia and a low MCV count but a high normal RBC count reflect a thalassemia trait but are extensively tested for chronic blood loss or the rare possibility of celiac disease in the older adult. And finally, a large number of tests ordered are often not verified or followed through, suggesting the questionable value of these tests in management.

Unwanted Testing May Carry Risks More than Benefits Three important questions should be asked before requesting a test. Is the test relevant to the patient’s health? Is there is a reason for the test? Does the test have potential to influence management? A screening program for the old in a rural practice found that although a few patients benefited from blood tests carried out during screening of older adults, and it was academically stimulating, the benefits were not worth the effort; and there was reservation of the impact of testing on the quality of life (Edwards 1991). Daily routine testing in the sick hospitalized older adult, a common practice without evidence for benefit, may lead to significant blood loss and iatrogenic anemia with hemodynamic changes; the results were higher transfusion requirements and a negative influence on mortality (Adiga et al. 2003). In a study, healthcare providers who were made aware of the costs of phlebotomy did order tests more appropriately and brought on savings for the hospital, leave alone benefits to the patient

1083

(Stuebing and Miner 2011). Clinicians should realize that there are diagnostic tests which will not change following therapy and return of prognostic markers. For example, in the evaluation of macrocytic anemia, intrinsic factor antibodies are diagnostic of pernicious anemia, but will not alter management with B12 administration, yet the antibody testing may be repeated multiple times. Similarly testing for serum amylase or lipase in a patient suspected to have acaute pancreatitis is not required on a daily basis. The ritualistic testing of stool samples for ova and parasites in all patients with diarrhea has the poorest diagnostic yield and yet is one of the most overused tests ordered with little understanding of the clinical utility in modern times (Mohapatra et al. 2018). Unfortunately laboratory test results are not always simple to interpret; results may be positive, negative, or inconclusive. A positive or abnormal test indicates that the disorder is present; a negative or normal test means that the disorder is not present; an inconclusive test is neither positive nor negative. A false-positive test suggests that a disorder is present, when in reality it is not; a falsenegative test does not detect the disorder when in reality it is present. Even in the healthy adult, there is a likelihood that 1 in 20 tests ordered may be abnormal (5%) in the absence of an evident underlying abnormality (Pokorski 1990). For a panel of 20 tests, the chances are that there is a 64% chance of at least one abnormal test (Macpherson 1993). This may lead to “labeling” of the patient with a disorder that may or may not be significant. Thus more testing has the potential to cause anxiety for the patient (and provider). Interestingly, if anesthesiologists ordered tests prior to a procedure, instead of primary physicians and surgeons, there appeared a significant reduction in costs without an increase in complications (Finegan et al. 2005). The question of an increase in liability for not requesting a test is a common consideration, at least in the minds of providers. Legal concerns are often sufficient reason for providers to request routine laboratory tests. Although there may be a legal risk for failure to order a test and make a diagnosis in the first place, the risk may be greater when ordering a laboratory test and not following

1084 Table 1 Factors that influence interpretation of test results Use of prescribed and “over-the-counter” drugs Supplements Herbals Fasting or fed state False-negative tests False-positive tests Reproduced from the original work by the same authors: Dharmarajan TS, Pitchumoni CS. Laboratory tests in older adults: Indications, interpretations, issues. In Pitchumoni CS, Dharmarajan TS eds. Geriatric Gastroenterology, First edition. Springer, New York, 2012; 261–269 Table 2 Additional concerns about laboratory testing in the elderly Costs of testing and willingness to undergo testing Repeat testing for inconsistent results Unwarranted repeated blood draws and resultant anemia Legal implications of overlooking an abnormal test result Fears and emotions associated with testing, especially dementia Hematomas, local injuries associated with fragile skin and veins Reproduced from the original work by the same authors: Dharmarajan TS, Pitchumoni CS. Laboratory tests in older adults: Indications, interpretations, issues. In Pitchumoni CS, Dharmarajan TS eds. Geriatric Gastroenterology, First edition. Springer, New York, 2012; 261–269

up in a timely fashion with required actions based on the abnormal results (Hepner 2009; Macpherson 1993). Laboratory test results must be acknowledged by the provider and reports attested in the medical record by the provider. Documentation must include normal and abnormal findings; critical test results warrant immediate action and appropriate, timely communication to the patient, along with documentation of results and actions taken. In summary, it is recommended and desirable that the provider who orders a test follows up with the test results in a timely manner (Tables 1 and 2). The following discussion arbitrarily divides laboratory tests into those commonly or routinely considered in all patients undergoing examination (or a procedure) irrespective of the history and physical examination, as opposed to those tests selected on the basis of a specific or individualized reason. The discussion does not cover every available test.

T. S. Dharmarajan and C. S. Pitchumoni

Common or Routine Tests Hemoglobin and Hematocrit Hemoglobin and hematocrit are among the useful routine tests. A study comparing two groups of men and women around 44  0.9 years to 63  0.9 years found significant differences with aging in hemoglobin levels, typically a decline, MCV (increase or decrease), and alterations in the indices; also observed were differences in ferritin values (Martin et al. 2001). The most common causes of microcytosis are iron deficiency and thalassemia trait. Anemia is a common multifactorial disorder in the geriatric age group. Based on the WHO definition, anemia is present in 10% of those over 65 years and in 20% of the over 85 year group in the community, increasing to 48–63% of nursing home patients (Patel 2008). Even more important, based on the National Health and Nutritional Examination Survey (NHANES) data, two thirds of anemia have a discernible cause from simple laboratory testing; a third of cases are due to a nutritional basis involving iron, B12, and folate deficiency in variable combinations, a third has anemia of chronic disease, and in the last third, routine tests do not provide an explanation (Guralnik et al. 2004). Thus laboratory tests provide a clue to the etiology of two thirds of older adults with anemia. The impact of anemia on organ dysfunction cannot be underestimated; it is an added risk factor component in heart disease, diabetes, and cerebrovascular disease and a predictor of mortality (Patel 2008; Dharmarajan and Dharmarajan 2007; Dharmarajan et al. 2005). A study of the 65+ age group revealed 12% to have iron deficiency anemia; many with unexplained anemia were “suspicious for myelodysplastic syndrome” (Price et al. 2011). There exists a strong association between anemia and gastrointestinal disease, a common disorder outlined in another chapter.

Ferritin, Transferrin Saturation, B12, and Folate While ferritin is a useful marker for body iron stores in the stable community patient, it tends to

45

Laboratory Testing in Older Adults: Indications, Benefits, and Harms

be elevated in the ill patient (acute phase reactant), when ferritin values require cautious interpretation (Knovich et al. 2009). Ferritin should be interpreted in conjunction with health status, along with serum iron levels, iron binding capacity, and transferrin saturation (Coyne 2006). At times the markers may be inadequate to guide iron therapy (Ferrari et al. 2011), especially in the setting of iron deficiency anemia coexisting with chronic disease or inflammation (Dharmarajan et al. 2005). In the NHANES I study, elevated transferrin saturation was associated with elevated mortality in over 2% of adults; but data from NHANES III suggested that ferritin and transferrin saturation are not associated with morality in those people not taking iron supplements and without a baseline history of cardiovascular disease or cancer (Menke et al. 2012). The need to evaluate folate and B12 status must be individualized based on clinical manifestations, history of prior illness, gastrointestinal resective surgical procedures (partial gastrectomy, bariatric surgery, and ileectomy), dietary habits (vegan or vegetarian), and chronic use of certain medications (e.g., PPIs, metformin) along with consideration for hematological indices (May et al. 2019). Both these nutrients can be low in older adults and in several gastrointestinal disorders affecting sites between the stomach and terminal ileum (detailed in another chapter). At this time testing for B12 and folate is not recommended among the routine initial panel of tests but may be indicated if the patient is anemic. An exception would be the older adult who has had a gastric surgical procedure (such as bariatric surgery), when iron and B12 deficiency follow invariably; in such patients, testing must also address ferrokinetics and B12 status (Dharmarajan et al. 2005).

Renal Function Serum creatinine by itself is an unreliable indicator of renal function in the old. Although the creatinine level would be commonly expected to rise with age or a disease-related decline in renal function, the value may nevertheless remain normal as a result of coexisting age-associated sarcopenia. Thus, instead of using the serum

1085

creatinine as a marker, a better approach would be to utilize an acceptable formula that estimates glomerular filtration rate (eGFR). Because of the high prevalence of CKD in geriatric age groups, precise estimates of renal function and staging are relevant, especially for appropriate dosing of drugs, when pharmacokinetics are dependent on renal function and further, to also assess stage of kidney disease. Particularly in the frail elderly, such estimates are invaluable. The choices of formulae include the Cockcroft-Gault equation, Modification of Diet in Renal Disease Study, and the newer Chronic Kidney Disease Epidemiology Collaboration Initiative Equation (Dharmarajan and Dharmarajan 2007). The three formulae do not provide identical values in older adults; in other words, they do not concur (Michels et al. 2010; Dharmarajan et al. 2012). It may be best to use a given formula in a particular patient to monitor renal function test results over time. Blood urea nitrogen (BUN) levels are influenced by multiple causes. Levels are elevated in acute and chronic kidney disease, volume depletion, heart failure, gastrointestinal bleeding, dietary factors, obstructive uropathy, and following the use of medications such as steroids and diuretics; on the other hand, low BUN levels occur in chronic liver disease. In the presence of renal disease, one must also routinely assess for electrolyte abnormalities.

Liver Function While the liver demonstrates much resilience with age, there are cellular hallmarks of aging that do occur through alterations of the genome and epigenome and dysregulation of mitochondrial function (Hunt et al. 2019). While the aging process of the liver is largely not clear, data from a Netherlands study suggest that liver function deteriorates with age (Cieslak et al. 2016). In a study of 1673 men aged over 70 years, alanine transaminase (ALT) was lower in older participants; older age, frailty, and low albumin were associated with reduced survival; low ALT was associated with frailty (Le Couteur et al. 2010a). Liver function tests (LFTs) include a panel of tests: liver enzymes, bilirubin, and hepatic

1086

synthetic measures (prothrombin time and albumin). About 1–4% of asymptomatic patients manifest abnormal tests (Krier and Ahmed 2009). As many as 14.7% of a Chinese population had abnormal LFTs, the most common causes being metabolic syndrome, nonalcoholic fatty liver disease, and alcoholism (Zhang et al. 2011). Nonalcoholic fatty liver disease is a common cause of abnormal AST and ALT worldwide, especially in affluent nations, increasing with the growing obesity epidemic (Vernon et al. 2011). Liver function tests are a panel, and not all are true tests of liver function; a better terminology is liver injury tests. True liver function tests are serum albumin levels and prothrombin time. Abnormalities may not reflect liver disease (Coates 2011; Coyne 2006). A focused history and physical examination are a foundation for appropriate testing (Hunt et al. 2019). Enzyme levels vary with gender, ethnicity, and age. Abnormal LFTs are commonly encountered in asymptomatic patients during routine visits and consultations; a cost-effective and systematic approach is recommended for their interpretation. Even the excessive use of certain vitamins, such as vitamin A may influence LFTs. Higher mortality was demonstrated in a study of 560,000 life insurance applicants, in those with higher levels of AST, ALT, and GGT (Pinkham and Krause 2009). On the other hand, low ALT activity was also a predictor of reduced survival, mediated by its association with frailty and increasing age (Le Couteur et al. 2010b).

Serum Albumin Screening for protein energy malnutrition at an early stage allows interventions to be more successful (Omran and Morley 2000). The value of serum albumin level is immense; levels reflect not only nutritional status but may also relate to renal and hepatic function, gastrointestinal disease, and catabolic states. In an orthogeriatric unit, nearly 450 elderly with hip fractures demonstrated better functional independence with normoalbuminemia at admission and at discharge (Mizrahi et al. 2007). Hypoalbuminemia is a predictor of poor outcome or mortality in many gastrointestinal disorders such

T. S. Dharmarajan and C. S. Pitchumoni

as C.difficile colitis, acute pancreatitis, ulcerative colitis, and other organ involvement such as decompensated heart failure or kidney disease with proteinuria (Uthamalingam et al. 2010) and colon cancer prior to surgery (Lai et al. 2011).

Serum Lipids Measurements of total cholesterol and its fractions (high density, low density, very low density) and triglycerides are now considered standard screening tests in adults. While they need to be repeated to monitor impact of therapy, multiple testing in the geriatric population appears associated with multiple providers, independent of indications and comorbidity, as demonstrated in a study of over 1.15 million Medicare beneficiaries (Goodwin et al. 2011). Hyperlipidemia is common in older people and undoubtedly a treatable risk factor for vascular disease. Measurements of serum cholesterol fractions and triglycerides are indicated for screening; repeat testing is indicted to monitor the response to therapy and for adjusting dosage of medications used in management (Grundy et al. 2018). Unfortunately, although the tests are repeated, the results are not always acted upon to titrate statin medication dosage, which negate the value of the testing (Table 3). The frequency of ordering unnecessary routine tests in a hospital (or other) setting was reduced by imparting education to those in training regarding indications for testing and costs involved, in conjunction with frequent reminders (Faisal et al. 2018). The study demonstrated a drop in testing by 50% and was associated with a shorter length of hospital stay (Faisal et al. 2018). Practicing physicians stand to benefit by using a similar strategy.

Specific or Individualized Tests On the other hand, specific testing may be indicated based on an individual’s history and physical examination. Specific tests are not requested in all patients and are best tailored to each individual.

45

Laboratory Testing in Older Adults: Indications, Benefits, and Harms

Table 3 Common or “routine” tests (Fleisher 2001; Pokorski 1990; Coodley 1989; May et al. 2019; Macpherson 1993; Martin et al. 2001; Dharmarajan et al. 2012; Krier and Ahmed 2009) Hemoglobin Anemia: prevalence 10% of community adults over age 65, 20% over 85 Laboratory tests can delineate an etiology in two thirds of anemics Creatinine and BUN Renal function declines with age; but serum creatinine may remain normal in spite of decline in kidney function (effect of sarcopenia) Calculate eGFR to assess renal function, using an acceptable formula BUN: non-specific and increased by several causes: renal failure, volume depletion, heart failure, gastrointestinal bleeding, dietary causes, medication effect (steroids), and obstructive uropathy BUN may be lower in liver disease Electrolytes Abnormal in the presence of renal disease, gastrointestinal volume losses, heart failure, and medication effect Abnormalities may result from hepatic or pulmonary disease Albumin and pre-albumin: Lower levels in liver disease, gastrointestinal or renal protein losses, and malnutrition Are acute negative phase reactant; deconditioning or illness associated with lower albumin levels Cholesterol, total and fractions, triglycerides Considered as standard screen in all adults Frequency of testing relates to levels, cardiovascular risk and to determine management Liver function Abnormal tests are common, even in asymptomatic adults Interpretation may need specialist consultation Medication history is helpful Prothrombin time and APTT Dictated by bleeding or clotting history and presence of liver disease Use of anticoagulants, antiplatelet agents, herbals, and alcoholism Erythrocyte sedimentation rate Marginal increase with age, more in females than in males Non-specific and increases with many illnesses Reproduced from the original work by the same authors: Dharmarajan TS, Pitchumoni CS. Laboratory tests in older adults: Indications, interpretations, issues. In Pitchumoni CS, Dharmarajan TS eds. Geriatric Gastroenterology, First edition. Springer, New York, 2012; 261–269

1087

Fecal Occult Blood Testing (FOBT) Colorectal cancer (CRC) is the fourth most common cancer diagnosed among adults and the second leading cause of death from cancer (Wolf et al. 2018). CRC screening is detailed in a separate chapter. The American Cancer Society 2018 guideline update suggests that adults aged 45 years and older with an average risk for CRC undergo regular screening with either a high-sensitivity stool-based test or a structural visual examination, based on patient preference and test availability (Wolf et al. 2018). Regular screening of adults aged 50 years and older is currently a strong recommendation. Options for laboratory testing include fecal immunochemical test annually; high-sensitivity, guaiac-based fecal occult blood test annually; and multi-target DNA test every 3 years (Wolf et al. 2018). All positive screening tests are required to be followed by colonoscopy. The stool occult blood test has been utilized for reasons other than CRC screening; in a study most patients were not suitable candidates due to contraindications for testing, leading to further needless investigations (Soin et al. 2019). The use of a single dose of oral aspirin prior to fecal immunochemical testing did not increase test sensitivity for detecting colorectal neoplasms (versus placebo) in a study of 2422 patients, mean age 59.6 years (Brenner et al. 2019). Anticoagulant or aspirin therapy, commonly used in older adults, does not affect the positive predictive value of an immunological fecal occult blood test in those undergoing CRC screening, as noted in a cohort case-controlled study (Mandelli et al. 2011). Even immunochemical FOBT appears associated with falsenegative results. Improvements in stool DNA tests relating to sensitivity for CRC and the use of fecal immunochemical tests have evolved over the years. Data from a longitudinal cohort of patients over age 70 suggests that the net burden could be decreased by better targeting FOBT screening and follow-up to healthy older adults; those with the best life expectancy were less likely to experience a net burden (Kistler et al. 2011).

1088

A guidance statement from the American College of Physicians suggests the following approach to screening for CRC in asymptomatic average risk adults (Qaseem et al. 2019). Clinicians must screen for CRC in average risk adults between 50 and 75 years. They must select the screening test based on a discussion of benefits, harms, costs, and patient preferences; screening intervals are fecal immune-chemical testing or high-sensitivity guaiac-based fecal occult bleed testing every 2 years, colonoscopy every 10 years, or flexible sigmoidoscopy every 10 years plus fecal immunochemical testing every 2 years. Discontinue screening for CRC in average risk adult older than 75 years or those with a life expectancy of less than 10 years (Qaseem et al. 2019). Additional details are provided in the chapter on colon cancer.

Screening for Celiac Disease Celiac disease (CD) is not uncommon, yet is an under-recognized disorder in older adults. It is an inflammatory disease triggered by dietary gluten in those with a genetic tendency; the best noted genetic susceptibilities are class II human leucocyte antigen (HLA) genes HLADQ2 and DQ8 (Brown et al. 2019). Genetic testing is possible through laboratories to evaluate a patient or identify family members at risk. HLA genetic testing carries a low positive predictive value but a high negative predictive value, which suggests the need for appropriate testing and proper test result interpretation (Brown et al. 2019). In the appropriate patient, if HLA typing and clinical presentation favor the diagnosis of celiac disease, a biopsy may not be necessary (Gulseraen et al. 2019). The European Society for the Study of Coeliac Disease guideline has provided recommendations; there appears to be a marked increase in the prevalence of CD, and many are undiagnosed (AlToma et al. 2019). Testing must be performed on a gluten-containing diet. Most CD patients (90–95%) carry the HLA-DQ2.5 heterodimers, encoded by the DQA105 and DQB102 alleles; the rest carry HLA-DQ8.

T. S. Dharmarajan and C. S. Pitchumoni

Testing for IGA-antigliadin antibodies has been used for a long time and is reasonably accurate (sensitivity 85% and specificity 90%), when there is a high pretest prevalence of CD, but not a good test for the general population (Al-Toma et al. 2019). Serum IgA antibodies to tissue transglutaminase (TG2) are increased in active disease (except when IgA deficient); a related anti-endomysial IgA antibody is similar in sensitivity and specificity at around 95% (Al-Toma et al. 2019; van der Windt et al. 2010). The following should be tested: adults with symptoms, signs, and malabsorption; first-degree relatives of a patient with celiac disease; HLA-matched siblings, parents, and children especially; a lower likelihood for second-degree relatives; and type 1 diabetes mellitus (Al-Toma et al. 2019); they may be screened through a blood test or cheek swab for HLA DQ2 or HLA DQ8, by polymerase chain reaction; their absence makes celiac disease highly unlikely (negative predictive value 100%) (van der Windt et al. 2010; Rostom and Dube 2005). Because of the high incidence of CD in association with type 1 diabetes mellitus (7%), Down syndrome (16%), autoimmune diseases, inflammatory bowel diseases, and those with unexplained elevation of liver enzymes, besides first-degree relatives with the disease, screening for CD is highly recommended (Al-Toma et al. 2019). On the other hand, the US Preventive Services Task Force has concluded that that current evidence is insufficient to assess the balance of benefits and harms of screening for celiac disease in asymptomatic patients (Bibbibns-Domingo 2017).

Screening for Diabetes With an increase in life expectancy and the prevalence of obesity, there is a higher likelihood that older patients will have type 2 diabetes (T2D). The 2019 American Diabetes Association guidelines suggest that screening for T2D is indicated at age 45 years and additionally in the presence of overweight or obese status, history of T2D in a first-degree relative, presence of cardiovascular

45

Laboratory Testing in Older Adults: Indications, Benefits, and Harms

disease or hypertension, and other settings (Riddle 2019). The major difference of note is in management, where less stringent HbA1c targets are set for older people; targets are tailored to patient setting (community versus institutions), coexisting morbidity, and remaining years of life expectancy (Riddle 2019). HbA1c has largely replaced the glucose tolerance test and is the mainstay for monitoring glucose control. Fundamental to good diagnostic testing is standardization with defined reference materials and measurement procedures (Wilson et al. 2009; English and Lenters-Westera 2018). Frequency of monitoring is important; based on the degree of control (good versus poor), the guidelines suggest every 3 or 6 months (Riddle 2019). However, testing every 6 months may be as effective as quarterly testing and compared to four tests a year; more than four tests were associated with lower likelihood of achieving targets, with two or three tests giving similar likelihoods as 4 per year (Duff et al. 2018). HbA1c testing at the point of care offers an opportunity for improvement of diabetes care but needs to be conducted with stringent quality assurance processes (Kenealy et al. 2019). HbA1c testing is currently used less frequently than glucose testing for screening but is far more likely to result in a clinical diagnosis of prediabetes and diabetes (Evron et al. 2019).

Acute Pancreatitis Data covering 1996–2005 suggests an increase in the incidence of acute pancreatitis, in part because of the increased testing for pancreatic enzymes; the proportion of ED visits resulting in an inpatient discharge diagnosis of acute pancreatitis appears to be going up (Yadav et al. 2011). Serum amylase and lipase are relevant in this context, although both are non-specific especially when the elevations are less than three times the upper normal (Yadav et al. 2002). Amylase levels rise and decline rapidly and may not be helpful in those patients who have delay in getting to the hospital; presently serum lipase is preferred in view of its high sensitivity and specificity (Muniraj et al. 2015). Overdiagnosis of acute pancreatitis is likely in view of false-positive

1089

elevations in many patients with diabetes. Underdiagnosis is also likely if proper diagnostic testing is not done when the history of abdominal pain is unclear as is the case of older adults with dementia. C-reactive protein is a non-specific acute phase reactant and is useful in older people when diagnosis is not readily apparent. The approach to testing is detailed in the chapter of acute pancreatitis.

Testing for Bleeding and Coagulation Routine coagulation testing may have a higher yield if based on a perceived risk of coagulopathy in those on warfarin or heparin or with liver disease (Martin and Beardsell 2012; Thachil 2008). In complex situations such as disseminated intravascular coagulation, when several bleeding and clotting parameters are abnormal, not a single test appears sufficiently accurate to establish or reject the diagnosis (Levi and Meijers 2011). For coagulation monitoring, an initial history for clotting or bleeding history should be obtained, followed by appropriate testing should the history be suggestive (Kistler et al. 2011). The change in paradigm is the increasing use of an evidence-based approach based on bleeding history and awareness of limitations of routine coagulation tests to guide management in the event of massive bleeding (Kozek-Langenecker 2010). It is prudent to obtain a history of herbal and supplement use, as several of these products influence bleeding and clotting parameters; the simultaneous use of medications with herbal supplements such as garlic, ginger, ginkgo biloba, feverfew, saw palmetto, and ginseng can influence the INR (Abad et al. 2010; Wittkowsky 2008).

Vitamin D Status Status of vitamin D (25-hydroxy D) appears relevant in older adults who are vulnerable to deficiency, based on the many predispositions such as restricted mobility to indoors; poor intake of supplements, fish, and fortified products such as dairy; malabsorption and malnutrition; use of medications that influence metabolism of vitamin D (e.g., anticonvulsants);

1090

chronic liver disease; chronic kidney disease; inflammatory bowel disease; gait abnormalities and falls; and generalized unexplained musculoskeletal or bone pain with or without fractures. For vitamin D measurement to add value, the test may be used in conjunction with calcium, phosphorus, and alkaline phosphatase levels (Rosen 2011). Laboratory testing for vitamin D has increased dramatically in the USA since 2008 largely due to an awareness of vitamin D status and its links to health (Kennel et al. 2010; Manson et al. 2017). This has reached such an extent that the government and laboratories have placed stringent requirements or indications for testing, as opposed to routine screening in most patients. There is considerable disagreement regarding the interpretations of serum concentrations of 25(OH)D and as to what is normal or optimal good health versus deficiency; cutoff points have not been developed by a scientific consensus process. Based on its review of data regarding vitamin D requirements, the Institute of Medicine concluded that 25 (OH) D levels 20 ng/ml are generally considered adequate for bone and overall health in healthy individuals (NIH office of Dietary Supplements 2019).

Testing for Clostridium difficile The topic is detailed in a separate chapter. An appropriate selection of tests must be made between enzyme immunoassays for toxin A and B, which are less sensitive than either glutamate dehydrogenase immunoassays (GDH) or the nucleic acid amplification test (NAATs). Tests vary in sensitivity and specificity and are associated with overdiagnosis (owing to detection of C. difficile carriers) or underdiagnosis due to lower sensitivity; multistep testing may be an option (Collins and Riley 2018; Gupta et al. 2018).

Laboratory Testing in Rheumatology Autoimmune diseases are common with no age group exempt. However, the tests lack sensitivity and standardization and include false positives and negatives (Meroni and Schur 2010). In

T. S. Dharmarajan and C. S. Pitchumoni

fact, false-positive antinuclear antibodies (ANA) without disease are far more common than systemic lupus, particularly in older age. Besides low titer positivity that is common in the geriatric patient, medications such as hydralazine, anticonvulsants, and isoniazid give a positive test, as also non-viral hepatitis and primary biliary cirrhosis; drug-induced lupus is not uncommon, and in such cases the ANA testing must be followed by additional tests (Hossain et al. 2019). Laboratory tests in rheumatology are useful but have limitations; it is necessary to be practical and select evidencebased guidance on requesting and interpreting selected tests including rheumatoid factor, ANA, human leukocyte antigen-B27, anti-neutrophil cytoplasmic antibody, and others (Suresh 2019). Often, the negative test provides far more value in rheumatological diagnosis (Suresh 2019).

Homocysteine Homocysteine levels are increased in several settings including aging, chronic kidney disease, hypothyroidism, and vitamin B12, folate, and B6 deficiencies, suggesting that the test is far from specific. Routine testing for homocysteine is not warranted including in inflammatory bowel disease; although 13% of all inflammatory bowel disease patients had elevated levels, the authors concluded that routine testing is not warranted and there was no correlation between levels and disease activity (Vagianos and Berstein 2012). Providers need to be knowledgeable about the application and interpretation of elevated homocysteine levels and that although levels are elevated in B12 and folate deficiency, the values are not specific to the nutrient status (Fei et al. 2017). On the other hand, the assessment of vitamin B12 and folate status is frequently indicated in patients with cognitive impairment and gait speed abnormalities and in the presence of anemia of nutrient deficiency in older people (Fei et al. 2017; Vidoni et al. 2017). The B vitamins have been detailed in other chapters (Table 4).

45

Laboratory Testing in Older Adults: Indications, Benefits, and Harms

Table 4 Individualized or “specific” tests (Knovich et al. 2009; Coyne 2006; Ferrari et al. 2011; Soin et al. 2019; Qaseem et al. 2019; Al-Toma et al. 2019; Riddle 2019;

1091

Muniraj et al. 2015; Heindl 2010; Kennel et al. 2010; Collins and Riley 2018; Meroni and Schur 2010; Vidoni et al. 2017)

Antinuclear antibody Is positive with illnesses, e.g., systemic lupus, scleroderma, etc. Can be drug-induced (anticonvulsants, hydralazine, isoniazid) Positive ANA in low titers common in the old Ferrokinetics Serum iron, total iron binding capacity, ferritin Used in conjunction with transferrin saturation, indicator of iron availability Ferritin is an acute phase reactant, falsely elevated in inflammation B12 and folic acid: Deficiencies are common and occur in up to 25% of the older adults B12 levels in borderline range are hard to interpret and may require homocysteine and methylmalonic acid assays to confirm Additional tests help determine the specific etiology of B12 deficiency: such as intrinsic factor antibodies for pernicious anemia Vitamin D status: 25 hydroxy D levels are index of vitamin D status Predisposition: diet, restricted mobility, lack of sun exposure, age Low calcium levels may be suggestive of vitamin D deficiency Guidelines regarding screening vary; they do not call for routine screening Tests for pancreatic function Amylase levels rise and decline rapidly, unhelpful in delayed presentations Serum lipase preferred in view of its high sensitivity and specificity Tests for celiac disease, an entity that is generally underdiagnosed Serum IgA antibodies to tissue transglutaminase (TG2) (except when IgA deficient); a related anti-endomysial IgA antibody is similar in sensitivity and specificity at around 95% Select patients screened through a blood test or cheek swab for HLA DQ2 or HLA DQ8 by PCR; their absence makes celiac disease unlikely (negative predictive value 100%) Thyroid function Tests are commonly abnormal from thyroid and non-thyroid illness Initial screen: thyroid-stimulating hormone, free thyroxine (T4) Guidelines regarding screening and frequency vary C-reactive protein Non-specific marker of inflammation Homocysteine and methylmalonic acid assays do not provide a specific diagnosis in most situations but are helpful where B12 levels are borderline Urinalysis and/or culture In those with diabetes, renal disease, polyuria, infection, abdominal pain, etc. Fecal tests: Fecal immunochemical tests High-sensitivity guaiac-based fecal occult blood tests Multi-targeted DNA test Clostridium difficile infection-associated disease Tests for malabsorption Tests for parasitic or bacterial infection Reproduced from the original work by the same authors: Dharmarajan TS, Pitchumoni CS. Laboratory tests in older adults: Indications, interpretations, issues. In Pitchumoni CS, Dharmarajan TS eds. Geriatric Gastroenterology, First edition. Springer, New York, 2012; 261–269

1092

Selecting Tests Prior to a Procedure As a general rule, the best approach to choosing tests prior to an elective surgical or gastrointestinal (GI) procedure is to make the selection based on a comprehensive history, physical examination, morbidity, type of procedure, and an awareness of the current and recently prescribed medications, including over-the-counter preparations, herbals, and ophthalmic preparations. History is targeted to relevant aspects of the procedure to be performed; for example, is the procedure just endoscopy or endoscopy plus biopsy and excision of lesions? Is there likely to be significant blood loss? Is there an available prior history of outcomes following previous surgery? There is an ongoing trend toward less testing and obtaining only relevant tests in contrast to the past when several tests were routinely ordered in all patients. As an example, an electrocardiogram and urinalysis were requested in all patients in the past even for minor procedures, in contrast to selectively ordering tests today based on the patient profile and procedure involved. In a study of 19,557 older adults, over 9000 patients underwent cataract surgery without routine testing, compared to a similar number on routine testing. Routine medical testing did not measurably increase the safety of surgery (Schein et al. 2000). Although it was not pertinent to a gastrointestinal procedure, valuable lessons were provided from the study. Far more was expected from the physician’s physical assessment compared to the yield of laboratory testing (Roizen 2000). The results may be extrapolated to several low risk procedures. More than 30 years of evidence suggests that a focused history and physical examination and minimal selective laboratory tests may be the best approach, with costs optimized by this approach (Richman 2010). A healthy older adult in good functional state, undergoing evaluation for inguinal hernia surgery, requires little by way of testing; in such cases there is minimal need for prothrombin time and partial thromboplastin time, as they are clinically insignificant for the concerned procedure, unless the patient is on medications that alter the values or there is evidence of abnormal liver function or

T. S. Dharmarajan and C. S. Pitchumoni

history of a bleeding or clotting disorder (Richman 2010). After adjustment for age and comorbidities, serum albumin level was a predictor of postoperative complications in the elderly with hip fracture (Lee et al. 2009). Although a predictor, little can be done to substantially change low albumin levels prior to impending surgery. In a study, hypoalbuminemia, acute renal injury, and a high white cell count were nevertheless present in 11%, 24%, and 33% of 70+-year-old persons tested prior to surgery, where only 47% had all the tests performed (Achuthan et al. 2011). Routine repeat testing of critical values of hemoglobin, platelet count, white blood cell count, prothrombin time, and activated partial thromboplastin time do not offer advantage over a single run (Toll et al. 2011). If repeating testing has limited value, does timing matter? Timing of endoscopic retrograde cholangiopancreatography and association of laboratory values with clinical outcomes (death or organ failure) was evaluated in a Japanese study (Schwed et al. 2016). White blood cell count over 20,000 cells/μl and elevated bilirubin were independent prognostic factors for adverse outcomes (Schwed et al. 2016). Erythrocyte sedimentation rate is a useful nonspecific test in some illnesses, with higher values typically seen in anemia and inflammatory states; however, low sedimentation rates are noted in heart failure, a common disorder in older adults. Marginal increase in the sedimentation rates also occur with age (Keiso 1990). Thus, requesting the sedimentation rate routinely does not add value prior to a procedure. Data does not provide an optimal strategy on improving the diagnostic tests used in intensive care units (ICU) and their impact on outcomes. An open-label prospective study indicated that a decrease in the overall number of tests per ICUpatient-days was possible after an educational approach; the total costs of the tests decreased, and no secondary effect from the intervention was observed; thus senior committed physicians can effectively contribute to this quality improvement process (Clouzeau et al. 2019). While laboratory testing is an integral tool in the management of patients in the ICU, there is a trade-off in the

45

Laboratory Testing in Older Adults: Indications, Benefits, and Harms

selection and timing of lab tests and utility of clinical decision-making at a specific time; Table 5 Pre-procedure testing (Pokorski 1990; BourdelMarchasson et al. 2010; Keiso 1990; Kantor et al. 2015; Coodley 1989; Bruce et al. 2009; May et al. 2019; Martin and Beardsell 2012; Thachil 2008; Levi and Meijers 2011; Heindl 2010; Kozek-Langenecker 2010) General: The approach must be to individualize tests based on a comprehensive history and physical examination Review all medications: prescribed, topical, ophthalmic, herbals, and supplements; include over-thecounter medications Laboratory tests do not require repeat testing if performed in the recent past and the patient’s clinical status remains unchanged In the healthy, asymptomatic older adult Hematological Hemoglobin level if anemic and/or blood loss is expected Complete blood count generally not required Platelet counts if indicated by history, examination, or medication intake Renal, electrolyte, and metabolic Serum creatinine and blood urea nitrogen Blood glucose; screen if warranted for prediabetes and diabetes Electrolytes generally indicated (e.g., in CKD, diuretic, laxative, ACE inhibitor, and other medication use) Coagulation parameters, if suggested by history and/or examination In the older adult with comorbidity: Chest radiographs, electrocardiogram, and additional tests based on age and comorbidity; individualize accordingly CKD: tests for renal function and electrolytes Diabetes type 2: evaluate for end organ damage Heart disease: specialized cardiac testing as indicated Liver function, with a history of alcoholism or chronic liver disease Bleeding history: history of medication use (anticoagulants, aspirin, herbals) and alcohol intake; individualize tests for liver function, platelet counts, bleeding, and clotting parameters Blood type and cross match: in anemia and anticipated blood loss Reproduced from the original work by the same authors: Dharmarajan TS, Pitchumoni CS. Laboratory tests in older adults: Indications, interpretations, issues. In Pitchumoni CS, Dharmarajan TS eds. Geriatric Gastroenterology, First edition. Springer, New York, 2012; 261–269

1093

experiments show that a policy can reduce frequency of lab tests and optimize timing to minimize information redundancy (Cheng et al. 2019) (Table 5).

Preoperative Hematological Assessment Preoperative hematological assessment has changed over the years. The 2018 Frankfurt Consensus Conference on Blood Management made several clinical recommendations, regarding the diagnosis and management of preoperative anemia; key points are outlined in Table 6 (Mueller et al. 2019). Mild anemia, a marker of most gastrointestinal diseases, is not an indication for blood transfusion. Preoperative blood transfusion is potentially lifesaving in specific circumstances, but inappropriate blood transfusion can also be an independent risk factor for adverse patient outcomes. The key recommendations from the conference are that the diagnosis and management of preoperative anemia are crucial and iron-deficient anemia must be treated with iron supplementation; the red blood cell transfusion threshold for critically ill, clinically stable patients is 4 mg/dL and dilated CBD on US/CT (>6 mm or 8 mm postcholecystectomy) Abnormal liver test or Dilated CBD (6 mm or 8 mm postcholecystectomy)

Table 8 Indications for MRI of liver (ACR 2020) and MRCP (Griffin et al. 2012) MRI of liver Detection of focal hepatic lesions Characterization of focal hepatic lesions Evaluation of vascular patency Evaluation and noninvasive quantification of iron, fat, fibrosis in chronic liver disease such as hemochromatosis, hemosiderosis, NASH, and hepatitis Evaluation of cirrhotic liver and HCC surveillance Evaluation of infection Clarification of findings from laboratory anomalies and other imaging studies Alternative imaging for contraindication to CT scan MRCP Congenital anomalies of cystic and hepatic ducts Choledochal cyst Choledocholithiasis Biliary strictures (benign and malignant) Pancreas division Chronic pancreatitis Pancreatic tumors Postsurgical biliary anatomy and complications

by the kidney, but deposits can occur in the brain, bone, and skin. A variety of conditions (neurological, musculoskeletal, dermal, pancreatitis, hepatotoxicity, and nephrotoxicity) have been reported (Rogosnitzky and Branch 2016). Other drawbacks of MRI are cost of procedure, patient size, availability, claustrophobia, and presence of metal implants. Fibrosis Evaluation. While most NAFLD patients have simple steatosis, only a minority (10–20%) have NASH that can progress to severe

Proposed investigation ERCP

MRCP, EUS, laparoscopic IOC, or intra operative US

fibrosis and complications of chronic liver disease. A critical issue is to identify those with NASH and to differentiate those with advanced hepatic fibrosis (Castera et al. 2019; Younossi et al. 2018). Numerous scores that utilize commonly checked tests including aminotransferases, GGT, bilirubin, INR, and platelets have been proposed to indirectly assess fibrosis. Most studied are AST to platelet ratio index (APRI), AST to ALT ratio, Fibrosis-4 score (FIB-4), FibroTest, and NAFLD fibrosis score. Among these, the FIB-4 (uses age, AST, ALT, platelets) and NAFLD fibrosis score (uses age, ALT, AST, albumin, platelets, BMI, and diabetes) are the most accurate with a high negative predictive value of >90% for ruling out advanced fibrosis and thereby identify patients who do not need further assessment. Only in case of a positive test, further diagnostic workup is required for confirming advanced fibrosis (Castera et al. 2019). The scores have been developed and validated in patients aged 35–65 years old. The specificity for detecting advanced fibrosis in patients >65 years old with the NAFLD fibrosis score and FIB4 has been shown to be low resulting in high false positive rates. This is not surprising as age is utilized in the calculation. It has been suggested to modify cutoffs for patients >65 years, in order to reduce the false positive rate (McPherson et al. 2017). Direct serum biomarkers measure components of the fibrosis pathway: procollagen peptides I/III, type IV collagen, cytokines interleukin-10, and transforming growth factor alpha. ELF (Enhanced

57

Aging Liver and Interpretation of Liver Tests

Liver Fibrosis Test uses hyaluronic acid, PIIINP, and TIMP-1) has been recommended as the next testing for those patients with intermediate FIB-4 or NAFLD fibrosis score (Newsome et al. 2018) as they are limited in distinguishing intermediate stages of fibrosis (Castera 2020). The ELF test does not utilize age in the calculation model. However, a study suggested that the test has a reduced accuracy in patients >45 years old (Fagan et al. 2015). Vibration Controlled Transient Elastography: Vibration Controlled Transient Elastography (FibroScan; Echosens, Paris, France) is an ultrasound-based technique that permits rapid, painless, noninvasive measurement of liver fibrosis with high accuracy and no potential complications. It has been validated with high intraand interobserver reproducibility and can be performed quickly at bedside. An ultrasound transducer probe is placed between two ribs in the intercostal space and measures the generated elastic shear wave and velocity. This gives a liver stiffness measurement expressed in kilopascals that correlates with fibrosis stage. To improve reliability, a minimum of ten valid readings are taken. The limiting factors are that it is operator dependent ( 30). Older age (>50 years) has also been identified as a possible limiting factor for reliable results (Castera et al. 2010). It has an accuracy of approximately 80% and 90% for diagnosing advanced fibrosis and cirrhosis, respectively (Castera et al. 2019, Younossi et al. 2018). While there is considerable overlap in distinguishing mild and moderate degree of fibrosis, its greatest value is the negative predictive value of 90% whereby it can exclude both advanced fibrosis/cirrhosis in approximately 90% of the patients and avoid the need for a liver biopsy. It is therefore recommended as the second line radiologic test in the American (Chalasani et al. 2018), British (Newsome et al. 2018), and European (EASL 2016) guidelines for management of patients with NAFLD. Liver Biopsy. Despite availability of extensive serologic workup and noninvasive measurements

1345 Table 9 Liver biopsy (Pandey et al. 2020; Neuberger et al. 2020) Purpose Diagnosis

Prognosis

Management

Indications Differentiate complex conditions Autoimmune hepatitis (AIH) from NASH AIH/primary biliary cholangitis overlap Drug induced liver injury Posttransplant rejection from underlying Pathology Determine etiology and grade of mass lesions Determine severity of damage NASH: advanced fibrosis from cirrhosis Hemochromatosis: presence of cirrhosis Treatment decisions Monitor treatment efficacy

of fibrosis, liver biopsy is the gold standard in the management of several complex liver conditions for diagnosis, prognosis, and management (Table 9). Liver biopsy is relatively safe. The few relative contraindications are the uncooperative patient, increased risk of bleeding, vascular tumors of the liver, ascites, morbid obesity, extrahepatic biliary obstruction, bacterial cholangitis, and amyloidosis (Neuberger et al. 2020; Pandey et al. 2020). Percutaneous liver biopsy is usually performed with or without or under ultrasound guidance; image guidance increases the safety and yield. Transvenous (trans-jugular or trans-femoral) liver biopsy is another option for the high-risk patients (ascites, obesity, and coagulopathy). Endoscopic ultrasound guided (EUS) or laparoscopic liver biopsy are other options. The most frequent complication is pain in 84% (Pandey et al. 2020). The incidence of serious complication is approximately 1% with a mortality of only 0.2%. Bleeding occurs in 70 years than patients 20– 29 years (Sotaniemi et al. 1997). The distribution of medications is also altered because of decreased albumin levels. Water soluble drug distribution can be altered because of change in ratio of body fat to water in older patients. Polypharmacy also impacts risk of drug-drug interactions. Elderly patients are more likely to take multiple medications because of multiple comorbidities. In a prospective study from Netherlands, 94.2% of elderly patients, mean age 82.3 years, were taking more than one medication and 73.3% were prescribed four or more medications (Tulner et al. 2009). Older patients are more likely to present with cholestatic pattern of drug induced liver injury, whereas younger patients are more prone to hepatocellular injury. (Lucena et al. 2009; Chalasani et al. 2015). It is unclear if there is a biological explanation for this or simply a reflection that older patients may be more likely to be prescribed medications such as antibiotics, cardiovascular medications, and analgesics/antipyretics medications that are more prone to cholestatic injury. Table 11 Most frequent medications and type of druginduced liver injury (Adapted from Chalasani et al. 2015) Medication AmoxicillinClavulanate Isoniazid Nitrofurantoin TMP-SMZ Minocycline Cefazolin Azithromycin Ciprofloxacin Levofloxacin Diclofenac Phenytoin Methyldopa Azathioprine

Phenotype Cholestatic or mixed Hepatitis Acute hepatocellular hepatitis Acute or chronic hepatocellular hepatitis Mixed hepatitis Acute or chronic hepatocellular hepatitis Cholestatic Hepatitis Hepatocellular, mixed or cholestatic hepatitis Hepatocellular, mixed or cholestatic hepatitis Hepatocellular, mixed or cholestatic hepatitis Acute or chronic hepatocellular hepatitis Hepatocellular or mixed hepatitis Hepatocellular or mixed hepatitis Cholestatic hepatitis

57

Aging Liver and Interpretation of Liver Tests

Patients >75 years old require significantly longer hospitalization for DILI (Onji et al. 2009). However, the prospective study of DILI in the USA did not observe older patients (¼>65 years) to have higher frequency of liver transplant or death (Chalasani et al. 2015). Cirrhosis in the Elderly. There is increasing prevalence of cirrhosis in older adults. The etiology of cirrhosis due to NAFLD is increasing while that due to chronic viral hepatitis is decreasing. Other causes in the elderly are autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and idiopathic (Carrier et al. 2019). However, cirrhosis is often underdiagnosed in older persons. Possible explanations are fewer clinical signs on presentation and infrequent use of diagnostic modalities (Carrier et al. 2019). An autopsy study revealed that 23.7% of elderly with liver cirrhosis had not been diagnosed as having cirrhosis before death (Fujimoto et al. 2008). Similarly, in a study of 135 patients aged 80 years or above with chronic liver disease, 54.1% were found to have cirrhosis. Cirrhosis was a major risk factor affecting the prognosis in this study (Hoshida et al. 1999). Cirrhosis increases risk of perioperative morbidity and mortality depending on the severity of liver dysfunction. Perioperative mortality is 2–10 times higher in patients with cirrhosis compared to patients without cirrhosis (Newman et al. 2020). The two commonly used predictors of perioperative mortality in patients with cirrhosis are the Child-Turcotte-Pugh (CTP) score and Model for End Stage Liver Disease (MELD) score. The components of CTP score are serum albumin, bilirubin, PT-INR, encephalopathy, and ascites. Patients are categorized as class A (5–6 points), class B (7–9 points), and Class C (10–15 points). Overall surgical mortality for various nonhepatic abdominal surgeries is enflurane > isoflurane > desflurane > sevoflurane (Rajan et al. 2019). Regional anesthesia (spinal or epidural anesthesia and nerve blocks) and total intravenous anesthesia are safer alternatives to inhalation anesthetics. Fentanyl is considered the opioid drug of choice as it does not decrease hepatic oxygen and blood supply (Rahimzadeh et al. 2014). Wang et al. (2013) in their randomized control study of older patients undergoing laparoscopic colon or rectal resections have demonstrated that combined general and regional anesthesia is more conducive to the protection of perioperative liver function than general anesthesia alone. Liver Enzymes in Critical Illness. The liver has a critical role in the systemic response during critical illness (Bernal 2016). It serves a role in clearance of pathogenic microorganisms and toxins from circulation. In response to systemic inflammation, the liver releases cytokines, inflammatory mediators, and coagulation cascade components. Hepatic dysfunction occurs in approximately 11–31% of critically ill patients (Kluge and Tacke 2019) and up to 41% in patients with intraabdominal infections (Guo et al. 2015) is associated with worst outcomes (Kramer et al. 2007; Jager et al. 2012; Kluge and Tacke 2019; Yang 2020). Kramer and associates in their prospective multicenter study of 4146 critically ill patients observed that early hepatic dysfunction

was associated with a twofold increase in mortality (30.4% versus 16.4%) (Kramer et al. 2007). Similarly, one-year survival rate was significantly lower (8% vs 25%) in patients with hypoxic hepatitis (Jager et al. 2012). Hepatic dysfunction in critical illness can be classified into ischemic hepatitis and cholestasis of sepsis. Ischemic hepatitis seen in 5–10% occurs because of decreased hepatic blood flow in the setting of cardiac, respiratory, or circulatory failure (Kluge and Tacke 2019). It often impacts older patients with underlying cardiac disease. It clinically presents as an acute rise in serum transaminases with the exclusion of other causes of acute liver injury such as viral or drug induced liver injury. Transaminase elevation is rapid and profound (often in thousands) and peaks in 48–72 h after a drop in cardiac output or blood pressure. It is typically accompanied by rise in bilirubin, which may have a delayed peak. Mild coagulopathy can also be present which is reflective of compromised hepatic synthetic function. Liver enzymes improve after hemodynamic status has been restored. Cholestasis of sepsis seen in approximately 20% presents with progressive rise in bilirubin, ALP, and GGT (Kluge and Tacke 2019; Jenniskens et al. 2016). It is usually not due to obstruction but is thought to be secondary to inflammation induced alterations in the transport of bile acids which appear to drive bile acids and bilirubin towards the systemic circulation. This is usually defined as total bilirubin >2 mg/dl (Guo et al. 2015). Management entails treating underlying infection, minimizing inflammation, and hypoxia in the liver, preventing hyperglycemia, avoiding early use of parenteral nutrition and reducing the administration of avoidable drugs (Jenniskens et al. 2018). Hepatocellular carcinoma (HCC). The incidence of HCC increases with age. Elderly patients with HCC are more likely to be women, suffer from hepatitis C virus infection and NAFLD (Brunot et al. 2016). Although prognosis is poor, surveillance in high risk patients is associated with early detection and improved survival. Surveillance for HCC in 363 elderly Italian patients >¼70 years of age with cirrhosis using both

57

Aging Liver and Interpretation of Liver Tests

ultrasound and AFP determinations every 6–12 months reduced risk of dealing with an advanced cancer and improved survival as the cancers were amenable to effective treatments (Trevisani et al. 2004). In a single center study of 1530 patients diagnosed with HCC, older patients ¼>65 years (n ¼ 318, 21%) were compared to younger patients 9.8 indicates advanced hepatic fibrosis and is influenced by age, steatosis and histological activity. Liver Int. 2015;35:1673–81. Fleming KM, et al. Abnormal liver tests in people aged 75 and above: prevalence and association with mortality. Aliment Pharmacol Ther. 2011;34:324–34. Frossard JL, Morel PM. Detection and management of bile duct stones. Gastrointest Endosc. 2010;72:808–16. Fujimoto K, Sawabe M, Sasaki M, et al. Undiagnosed cirrhosis occurs frequently in the elderly and requires periodic follow ups and medical treatments. Geriatr Gerontol Int. 2008;8(3) https://doi.org/10.1111/j.14470594.2008.00470.x. Gilmore I, Burroughs A, Murray-Lyon I, et al. Indications, methods and outcomes of percutaneous liver biopsy in England and Wales: an audit by the British Society of Gastroenterology and the Royal College of Physicians of London. Gut. 1995;36:437–41. Griffin N, Charles-Edwards G, Grant L. Magnetic resonance cholangiopancreatography: the ABC of MRCP. Insights Imaging. 2012;3:11–21. Guo K, Ren J, Wang G, et al. Early liver dysfunction in patients with intra-abdominal infections. Medicine. 2015;94(42):e1782. Guo H, Wu T, Lu Q, et al. Hepatocellular carcinoma in elderly: clinical characteristics, treatments and outcome compared with younger adults. PLoS One. 2017;12(9):

R. Agarwal e 0184160. https://doi.org/10.1371/journal.phone. 0184160. Harrison MF. The misunderstood coagulopathy of liver disease: a review for the acute setting. West J Emerg Med. 2018;19:863–71. Hartman M, Szalai C, Saner F. Hemostasis in liver transplantation: pathophysiology, monitoring and treatment. World J Gastroenterol. 2016;22:1541–50. Hatipoglu S, Akbulut S, Hatipoglu F, Abdullayev R. Effect of laparoscopic abdominal surgery on splanchnic circulation: Historical developments. World J Gastroenterol. 2014;20:18165–76. Hernaez R, Lazo M, Bonekamp S, et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver : a meta-analysis. Hepatology. 2011;54: 1082–90. Hirode G, Saab S, Wong R. Trends in the burden of chronic liver disease among hospitalized US adults. JAMA Netw Open. 2020;3(4):e201997. Hoofnagle J, Bjornsson E. Drug induced liver injury – types and phenotypes. N Engl J Med. 2019;381: 264–73. Hoshida Y, Ikeda K, Kobayashi M, et al. Chronic liver disease in the extremely elderly of 80 years or more: clinical characteristics, prognosis and patient survival analysis. J Hepatol. 1999;31:860–6. Hundt M, Basit H, John S. Physiology, bile secretion. StatPearls [Internet]. Treasure Island: StatPearls Publishing; 2020. PMID: 29262229. Hunt N, McCourt P, Le Couteur D, Cogger V. Novell targets for delaying aging: the importance of the liver and advances in drug delivery. Adv Drug Deliv Rev. 2018;135:39–49. Hunt N, Kang S, Lockwood G, et al. Hallmarks of aging in the liver. Comput Struct Biotechnol J. 2019;17: 1151–61. Jager B, Drolz A, Michl B, et al. Jaundice increases the rate of complications and one-year mortality in patients with hypoxic hepatitis. Hepatology. 2012;56: 2297–304. Jain S, Gautam V, Naseem S. Acute-phase proteins: as diagnostic tool. J Pharm Bioallied Sci. 2011;3: 118–27. Jenniskens M, Langouche L, Vanmijngaerden Y, et al. Cholestatic liver dysfunction during sepsis and other critical illness. Intensive Care Med. 2016;42:16–27. Jenniskens M, Langouche L, Van den Berghe G. Choleestatic alterations in the critically ill: some new light on an old problem. Chest. 2018;153:733–43. Jeong H, Kim D. Bone diseases in patients with chronic liver disease. Int J Mol Sci. 2019;20:4270. https://doi. org/10.3390/ijms20174270. Kasarala G, Tillmann H. Standard liver tests. Clin Liver Dis. 2016;8:13–8. Keane J, Eleangovan H, Stokes R, Gunton J. Vitamin D and the liver – correlation or cause? Nutrients. 2018;10: 496. https://doi.org/10.3390/nu10040496. Keller F, Maiga M, Neumayer H, et al. Pharmacokinetic effect of altered plasma protein binding of drugs in

57

Aging Liver and Interpretation of Liver Tests

renal disease. Eur J Drug Metab Pharmacokinet. 1984;9:275–82. Khalil R, Al-Humadi N. Types of acute phase reactants and their importance in vaccination (review). Biomed Rep. 2020;12:143–52. Kim H, Kisseleva T, Brenner D, et al. Aging and liver disease. Curr Opin Gastroenterol. 2015;31:184–91. Kluge M, Tacke F. Liver impairment in critical illness and sepsis: the dawn of new biomarkers? Ann Transl Med. 2019;7(Suppl 8) https://doi.org/10.21037/atm2019. 12.79. Koenig G, Seneff S. Gama glutamyl transferase: a predictive biomarker of cellular antioxidant inadequacy and disease risk. Dis Markers. 2015:818570. https://doi. org/10.1155/2015/818570. Kramer L, Jordan B, Drumi W, et al. Incidence and prognosis of early hepatic dysfunction in critically ill patients – a prospective multicenter study. Crit Care Med. 2007;35:1099–104. Kubes P, Jenne C. Immune response in the liver. Annu Rev Immunol. 2018;36:247–77. Kwo P, Cohen S, Lim J. ACG clinical guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol. 2017;112:18–35. Labori KJ, Raeder MG. Diagnostic approach to the patient with jaundice following trauma. Scand J Surg. 2004;93:176–83. Leise M, Poterucha J, Talwalkar J. Drug-induced liver injury. Mayo Clin Proc. 2014;89:95–106. Levitt D, Levitt M. Human serum albumin homeostasis: a new look at the role of synthesis, catabolism, renal and gastrointestinal excretion, and the clinical value of serum albumin measurements. Int J Gen Med. 2016;9: 229–55. Lilford R, Bentham L, Girling A, et al. Birmingham and Lambeth liver evaluation testing strategies (BALLETS): a prospective cohort study. Health Technol Assess. 2013;17:1–307. Limdi JK, Hyde GM. Evaluation of abnormal liver function test. Postgrad Med J. 2003;79:307–12. Liu Y, Cao W, Liu Y, et al. Changes in duration of action of rocuronium following decrease in hepatic blood flow during pneumoperitoneum for laparoscopic gynaecological surgery. BMC Anaesthesiol. 2017;17:45. Lock RJ, Unsworth DJ. Immunoglobulins and immunoglobulin subclasses in the elderly. Ann Clin Biochem. 2003;40:143–8. Lucena MI, Spanish Group for the Study of Drug Induced Liver Disease, et al. Phenotypic characterization of idiosyncratic drug induced liver injury: the influence of age and sex. Hepatology. 2009;49:2001–9. McPherson S, Hardy T, Dufour J, et al. Age as a confounding factor for the accurate non-invasive diagnosis for advanced NAFLD fibrosis. Am J Gastroenterol. 2017;112:740–51. Midia M, Odedra D, Shuster A, et al. Predictors of bleeding complications following percutaneous image-guided liver biopsy: a scoping review. Diagn Interv Radiol. 2019;25:71–80.

1351 Mohamad M, Mitchell S, Wu L, et al. Ultrastructure of the liver microcirculation influences hepatic and systemic insulin activity and provides a mechanism for age related insulin resistance. Aging Cell. 2016;15:706–15. Morsiani C, Bacalini M, Santoro A, et al. The peculiar aging of human liver: a geroscience perspective within transplant context. Aging Res Rev. 2019;51:24–34. Mukaiyama K, Kamimura M, Uchiyama S, et al. Evaluation of serum alkaline phosphatase (alp) level in post-menopausal woman is caused by high bone turnover. Aging Clin Exp Res. 2015;27:413. Nemeth E, Ganz T. The role of hepcidin in iron metabolism. Acta Haematol. 2009;122:78–86. Neuberger J, Patel J, Caldwell H, et al. Guidelines on the use of liver biopsy in clinical practice from the British Society of Gastroenterology, the Royal College of Radiologists and the Royal College of Pathology. Gut. 2020;69:1382–403. Newman K, Johnson K, Cornia P, et al. Perioperative evaluation and management of patients with cirrhosis: risk assessment, surgical outcomes and future directions. Clin Gastroenterol Hepatol. 2020;18:2398–414. Newsome P, Cramb R, Davison S, et al. Guidelines on the management of abnormal liver blood tests. Gut. 2018;67:6–19. Noh C, Lee M, Kim B, Chung Y. A case of nutritional osteomalacia in young adult male. J Bone Metab. 2013;20:51–5. Northup PG, Wanamaker RC, Lee VD, et al. Model for End Stage Liver Disease (MELD) predicts nontransplant surgical mortality in patients with cirrhosis. Ann Surg. 2005;242:244–51. O’Leary J, Greenberg C, Patton H, Caldwell S. AGA clinical practice update: coagulation in cirrhosis. Gastroenterology. 2019;157:34–43. Oh R, Hustead T, Ali S, Pantsari M. Mildly elevated liver transaminase levels: causes and evaluation. Am Fam Physician. 2017;96:709–15. Onji M, et al. Clinical characteristics of drug induced liver injury in the elderly. Hepatol Res. 2009;39:546–52. Ortega-Rivera M, Hunt N, Garcia-Sancho J, Cogger V. The hepatic sinusoid in aging and disease: update and advances from the 20th liver sinusoid meeting. Hepatol Commun. 2020;4:1087–98. Paik J, Golabi P, Biswas R, et al. Nonalcoholic fatty liver disease and alcoholic liver disease are major drivers of liver mortality in the United States. Hepatol Commun. 2020;4:890–903. Palmer M, Regev A, Lindor K, et al. Consensus guidelines: best practices for detection, assessment and management of suspected acute drug-induced liver injury occurring during clinical trials in adults with chronic cholestatic liver disease. Aliment Pharmacol Ther. 2020;51:90–109. Pandey N, Hoilat G, John S. Liver biopsy. StatPearls Intranet. Treasure Island: StatPearls Publishing; 2020. Pant A, Kopec A, Luyendyk J, et al. Role of blood coagulation cascade in hepatic fibrosis. Am J Physiol Gastrointest Liver Physiol. 2018;315:G171–6.

1352 Patel T. Surgery in patients with liver disease. Mayo Clin Proc. 1999;74:593–9. Petersen K, Befroy D, Shulman G. Mitochondrial dysfunction in the elderly: possible role of insulin resistance. Science. 2003;300:1140–2. Poynard T, Imbert-Bismut F. Laboratory testing for liver disease. In: Thomas D Boyer, Michael P Manns and Arun J Sanyal, editors. Zakim and Boyer’s Hepatology. 6th ed. Science Direct, 2012;201–215. https://doi.org/ 10.1016/B978-1-4377-0881-3.00072-3. Pratt D, Kaplan M. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med. 2000;342:1266–71. Rahimzadeh P, Safari S, Faiz SHR, Alavian M. Anesthesia for patients with liver disease. Hepat Mon. 2014;14(7): e19881. Rajan S, Garg D, Cummings K III, Krishnaney A. Hepatotoxity after sevoflurane anaesthesia: a new twist to an old story. Br J Anaesth. 2019;122(4): e63–71. Rogosnitzky M, Branch S. Gadolinium-based contrast agent toxicity: a review of known and proposed mechanisms. Biometals. 2016;29:365–76. Salizzoni M, Amoroso A, Lupo F, et al. Centenarian livers: very long-term outcomes of old grafts. Transplantation. 2017;101:e292. Sanchez J, Corey K. Interpretation of abnormal liver chemistries in the hospitalized patient. Clin Liv Dis. 2016;7: 132–4. Sangkhae V, Nemeth E. Regulation of the iron homeostatic hormone hepcidin. Adv Nutr. 2017;8:126–36. Sato K, Kawamura T, Wakusawa R. Hepatic blood flow and function in elderly patients undergoing laparoscopic cholecystectomy. Anesth Analg. 2000;90: 1198–202. Schmucker D. Age related changes in liver structure and function: implications for disease? Exp Gerontol. 2005;40:650–9. Schmucker D, Sachs H. Quantifying dense bodies and a lipofuscin during aging: a morphologist’s perspective. Arch Gerantol Geriatr. 2002;34:249–61. Segal J, Dzik W, Transfusion medicine/ Hemostasis Clinical Trials network. Paucity of studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: an evidence based review. Transfusion. 2005;45:1413–25. Sheedfar F, Di Biase S, Koonen D, Vinciguerra M. Liver diseases and aging: friends or foe? Aging Cell. 2013;12:950–4. Shetty S, Lalor P, Adams D. Liver sinusoidal endothelial cells – gatekeepers of hepatic immunity. Nature Rev: Gastroenterol Hepatol. 2018;15:555–67. Singal RS, Singal RP, Sandhu K, et al. Evaluation and comparison of post-operative levels of serum bilirubin,

R. Agarwal serum transaminases and alkaline phosphatase in laparoscopic cholecystectomy versus open cholecystectomy. J Gastrointest Oncol. 2015;6:479–86. Sotaniemi EA, et al. Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions. Clin Pharmacol Ther. 1997;61:331–9. Tajiri K, Shimizu Y. Liver physiology and liver disease in the elderly. World J Gastroenterol 2013; 19: 84598467. Tietz N, Shuey D, Wekstein D. Laboratory values in fit and aging individuals – sexagenarians through centenarians. Clin Chem. 1992;38:1167–85. Trevisani F, Cantarini M, Labate A, et al. Surveillance of hepatocellular carcinoma in elderly Italian patients with cirrhosis: effects of cancer staging and patient survival. Am J Gastroenterol. 2004;99:1470–6. Tulner LR, et al. Discrepancies in reported drug use in geriatric outpatients: relevance to adverse events and drug-drug interactions. Am J Geriatr Pharmacother. 2009;7:93–104. Valdivieso V, Palam R, Wunkhaus R, et al. Effect of aging on biliary lipid composition and bile acid metabolism in normal Chilean women. Gastroenterology. 1978;74: 871–4. Volk ML. Burden of cirrhosis on patients and caregivers. Hepatol Commun. 2020;4:1107–11. Wang P, Wang H, Zhong T. Influence of different anesthesia on liver and renal function in elderly patients undergoing laparoscopic colon or rectal resection. HepatoGastroenterology. 2013;60:79–82. Wynne H, Cope L, Mutch E, et al. The effect of age upon the liver volume and apparent liver blood flow in healthy man. Hepatology. 1989;9:297–301. Xu F, Hua C, Tautenhahn H, et al. The role of autophagy for the regeneration of the aging liver. Int J Mol Sci. 2020;21:3606. Yang JH. Hepatic dysfunction in critically ill patients. Acute Crit Care. 2020;35:44. Younossi Z, Loomba R, Anstee Q, et al. Diagnostic modalities for nonalcoholic fatty liver disease, nonalcoholic steatohepatitis and associated fibrosis. Hepatology. 2018;68:349–60. Younossi Z, Stepanova M, Younossi Y, et al. Epidemiology of chronic liver diseases in the USA in the past three decades. Gut. 2020;69:564–8. Zhao E, Carruthers M, Li C, et al. Conditions associated with polyclonal hypergammaglobulinemia in the IgG-4 related disease era: a retrospective study from a hematology tertiary care center. Hema. 2020;105(3):e121–3. Zhu C, Ikemoto T, Utsunomiya T, et al. Senescence related genes possibly responsible for poor liver regeneration after hepatectomy in elderly patients. J Gastroenterol Hepatol. 2014;29:1102–8.

Viral Liver Diseases

58

Satheesh Nair and Rajanshu Verma

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1354 Hepatitis A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1354 1355 1356 1356

Hepatitis E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1357 Hepatitis C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mode of Transmission and Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HCV Genotypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Extrahepatic Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1357 1358 1358 1358 1358 1359

Hepatitis B (HBV) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HBV Genotypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reactivation of HBV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment of HBV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1361 1361 1362 1362 1362

Hepatitis Delta (HDV) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1363 Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1363 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1364

Abstract S. Nair (*) Medical Director of Liver Transplantation, Endowed Chair of Excellence in Transplant Medicine, University of Tennessee Health Science Center, Memphis, TN, USA e-mail: [email protected] R. Verma Division of Transplant Hepatology, University of Tennessee Health Science Center, Memphis, TN, USA e-mail: [email protected]

Hepatitis A, hepatitis B, and hepatitis C are the most common types of viral hepatitis. Other types include hepatitis E and hepatitis D. Hepatitis A virus (HAV) infection can produce a significant illness in adults with severity increasing with advancing age. Once acute HAV infection resolves, patients develop lifelong immunity. Hepatitis E virus (HEV) is

© Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_50

1353

1354

S. Nair and R. Verma

similar to HAV, but acute infection causes higher mortality in older adults. Hepatitis B virus (HBV) is one of the most common infections in the world and a leading cause of liver cancer. Majority of adult patients with acute HBV spontaneously clear the infection. Five percent of patients, however, progress into chronic hepatitis B. Chronic HBV is a dynamic disease with four phases: HBe antigen positive immune tolerance and immune clearance phases; and HBe antigen negative inactive and reactivation phases. Most chronic HBV encountered in older patients are “E antigen” negative/E antibody positive chronic HBV. Treatment of chronic HBV is indicated when there is evidence of liver injury based on elevated ALT and advanced fibrosis on liver biopsy. Entecavir or tenofovir are the currently approved treatments and both have excellent safety and efficacy. HCV is the one of the leading indications for liver transplant in the United States and Europe. Most patients, who get infected with HCV, develop chronic HCV with many eventually progressing to cirrhosis. Screening is recommended for people born between 1945 and 1965 irrespective of risk factors; this screening recommendation may be expanded further to all adults in the near future. Specific drugs targeting HCV replication can cure most patients and hence treatment is recommended if there is detectable HCV RNA.

HEV HIV IgG IgM NS3A/4 NS5A NS5B PCR RAS RNA SVR

Hepatitis E virus Human immunodeficiency virus Immunoglobulin G Immunoglobulin M Nucleoside 3A/4 Nucleoside 5A Nucleoside 5B Polymerase chain reaction Resistance-associated substitutions Ribonucleic acid Sustained virologic response

Introduction Viral hepatitis (hepatitis A–E) affect millions of people in the world. The World Health Organization estimates that in 2015, 257 million people were living with chronic hepatitis B infection (defined as hepatitis B surface antigen positive). Acute liver failure, end-stage liver disease, and hepatocellular carcinoma from viral hepatitis are leading causes of mortality in the world. Hepatitis A and E cause acute infection, while hepatitis B and C mostly present as chronic infections (Fig. 1). Tremendous progress has been made in the treatment of viral hepatitis, especially with hepatitis C over the last few years. This chapter highlights the recent advances in the field of viral hepatitis. The key diagnosis criteria and treatment recommendations based on the current data and practice guidelines are summarized with easy to read tables (Table 1).

Keywords

Hepatitis A · HBV · HCV · Cirrhosis · Liver transplantation · HEV · HDV · Hepatocellular carcinoma · Interferon · Hepatitis B · Hepatitis C · Hepatitis E · Viral liver diseases · Viral hepatitis Abbreviations

HAV HBV HCC HCV HDV

Hepatitis A virus Hepatitis B virus Hepatocellular carcinoma Hepatitis C virus Hepatitis D virus

Hepatitis A According to the World Health Organization, approximately 1.5 million clinical cases of hepatitis A occur worldwide annually (Daniels et al. 2009), but seroprevalence data indicate that tens of millions of hepatitis A virus (HAV) infections occur each year. Even though the prevalence of anti-HAV antibody is high among the older population (75%) (Bell et al. 2005), those who are not immune and acquire the infection are at increased risk of complications and higher likelihood of hospitalization.

58

Viral Liver Diseases

1355

Fig. 1 Viral hepatitis: clinical presentations and outcomes Table 1 Viral hepatitis serology and interpretation IgM anti HAV antibody IgG anti HAV antibody IgM HEV antibody Ig G HEV HCV antibody HCV RNA HB surface antigen(HBsAg) Anti HB surface antibody (HBsAb) IgM Anti HB core Ab IgG HB core Ab Anti HBs Ab (+) and IgG HBcore Ab (+) Anti HBs Ab (+) and IgG HBcore Ab (
) Anti HBs Ab (
) IgG HBcore (+) HBsAg (
) HBe antigen Anti-HBe antibody HBV DNA HDV antibody HDV PCR

Acute hepatitis A Previous exposure; immunity Acute hepatitis E infection Prior infection Chronic hepatitis C or prior infection – no immunity Active HCV infection Active HBV infection (>6 months indicates chronic HBV infection) No active HBV and Immunity Acute HBV (rarely seen in reactivation phase) Prior exposure to HBV Resolved HBV infection Vaccination Prior infection (small % can have DNA in serum/liver-occult infection- risk of reactivation with immunosuppression) Active replication (early phases of infection) Late phases of infection or resolved HBV Active infection and for treatment monitoring Infection/exposure Active infection

Clinical Features and Diagnosis Clinical illness varies from a mild flu-like sickness to fulminant hepatic failure. The average incubation period is 28 days (range: 15–50 days), after which symptoms include nausea, abdominal pain, fatigue,

fever, dark urine, and jaundice along with abnormal liver function including high transaminases and bilirubin. The illness is usually self-limited with most symptoms resolving within 2–4 weeks (Fig. 2). Rarely, HAV infection can cause a relapsing or cholestatic form of hepatitis lasting several

1356

S. Nair and R. Verma

Fig. 2 Clinical and serological features of acute viral hepatitis A and E. (Modified from CDC website)

months before eventual recovery. However, unlike hepatitis B and C, hepatitis A does not cause chronic infection and only rarely leads to fulminant hepatic failure. Acute liver failure from HAV is seen more commonly in patients with chronic liver disease, particularly when it is secondary to chronic hepatitis C virus infection (Vento et al. 1998). The diagnosis of acute HAV infection is established by the detection of IgM antibodies to HAV (IgM anti-HAV). Following resolution, IgM antibody is replaced by immunoglobulin G (IgG) anti-HAV, which remains detectable for life, and affords lifelong immunity (Fig. 2). People who have received hepatitis A vaccine will also have detectable total anti-HAV antibodies (Table 2).

Treatment HAV infection is usually self-limited and treatment is therefore supportive. The majority recover without sequelae. However, fatalities associated with the infection and the rate of hospitalization are more common with advancing age (Daniels

et al. 2009; Vento et al. 1998; Forbes and Williams 1988). Thus, special care is indicated for the elderly with acute infection.

Prevention There are two kinds of vaccine available in the United States (HARVIX, VAQTA). Two doses of the vaccine elicit good immune response in almost 100% of recipients (antibody titer of >20 mIU/ ml). HAV vaccination is recommended for everyone with chronic liver disease including those with fatty liver disease and those with persistently elevated ALT (more than two times upper limit of normal). However, the older population and immunocompromised patients may have a suboptimal immune response to vaccination. International travel remains the most commonly identified risk factor for acquiring HAV for US citizens. Travel to endemic areas is common among older adults who now have increased life expectancy and mobility. Therefore, all older travelers lacking naturally acquired immunity should be vaccinated as soon as travel is planned. The

58

Viral Liver Diseases

1357

Table 2 Treatment for viral hepatitis Hepatitis A Acute HBV supportive chronic hepatitis Ba Hepatitis D HBV cirrhosis with liver failure or HCC Acute liver failure (HBV, HEV, HAV) HCV HCV cirrhosis with no liver failure HCV cirrhosis with liver failure or HCC a

Supportive Entecavir or tenofovir in prolonged acute HBV Entecavir, tenofovir (TDF/TAFa) PEGylated interferon α (contraindicated in cirrhosis) Pegylated interferon α Liver transplantation is the best treatment (treat HBV before transplant to prevent recurrence in the allograft) Liver transplant/supportive Glecaprevir/pibrentasvir (Mavyret) or Sofosbuvir/velpatasvir, (Epclusa) Treat with antiviral agents as above Liver transplantation is the best treatment; treat Epclusa if patient is not a candidate for transplant

treat only if advanced fibrosis, high ALT, and high DNA; tenofovir alafenamide has less bone and renal toxicity than TDF

HAV prophylaxis guidelines depend on the underlying health condition of the traveler, endemicity of the area one is traveling to, and the timing of the travel. If travelling to an area with high or intermediate risk of HAV endemicity within 2 weeks, administration of immunoglobulin is also recommended in addition to the vaccine. Detailed guidelines can be accessed on the CDC site (https://www.cdc.gov/mmwr/volumes/67/wr/ mm6743a5.htm).

diagnosing HEV, but IgM anti-HEVantibody testing is available commercially. Like HAV, detection of IgM anti-HEV indicates acute infection and IgG anti-HEV becomes positive when the infection resolves. HEV PCR assays are also available and usually positive during the acute illness. These commercial assays are not well standardized and false positive results are possible. Vaccine against HEV (HEV 239, Hecolin ®) has been developed and licensed in China with limited availability outside Chinese mainland (Li et al. 2015; World Health Organization).

Hepatitis E Hepatitis E resembles HAV in mode of transmission, clinical presentation, and natural history. HEV causes approximately 20 million infections worldwide each year; however, it is rare in the United States, although sporadic cases have been reported (Rein et al. 2012). HEV in endemic areas of the world is caused by genotype 1 and 2 and results in maternal mortality by affecting pregnant women. In the industrial world, HEV infection is caused by genotypes 3 and 4, possibly acquired as a zoonotic infection. There are several reports of HEV evolving into a chronic infection in severely immunocompromised patients and solid organ recipients. Acute hepatitis due to HEV is a self-limited disease but is known to be more serious in the older people. There are no FDA approved tests for

Hepatitis C It is estimated that more than 170 million persons are infected with hepatitis C worldwide with an incidence of 3–4 million new cases annually. According to the US National Health and Nutrition Examination Survey (NHANES) 2003–2010 data, 1.3% of US population (3.6 million individuals) have anti-HCV antibodies (Denniston et al. 2014). The prevalence of HCV in the geriatric population is projected to increase in the next two to three decades. Because of the longer duration of infection, older adults with hepatitis C are more likely to have advanced disease. HCV is one of the leading indications for liver transplant in the United States and Europe. Twenty-five to 30% of those chronically infected will progress to

1358

S. Nair and R. Verma

HCV is transmitted primarily through exposure to infected blood and blood products. Most patients with HCV in a geriatric practice probably acquired the infection from the use of unsterilized syringes and needles or from blood transfusion prior to 1992 (Thabut et al. 2006).

assay. The presence of HCV antibody indicates exposure but testing for HCV RNA is required to diagnose active infection. The HCV RNA levels are reported as IU/ml. Since the degree of fibrosis determines the prognosis and risk of hepatocellular carcinoma, assessment of fibrosis is an important part of evaluation of the patients with chronic hepatitis C (and HBV). Fibrosis is typically classified from I–IV (METAVIR system, stage IV ¼ cirrhosis). Several noninvasive tests (FIB-4, APRI from online calculators) and imaging modalities (transient elastography FibroScan ®, shear wave elastography, MR elastography) are now available to estimate the degree of fibrosis. Hence, liver biopsy is no longer indicated in most patients with HCV infection. However, liver biopsy is useful if concomitant diseases such as hemochromatosis, alcoholic hepatitis, and hepatic sarcoidosis are suspected.

Clinical Features and Diagnosis

HCV Genotypes

Majority of patients (80%) infected with HCV evolve into chronic hepatitis C, without presenting with an acute phase, with the remaining 20% spontaneously clearing the virus. Hence acute HCV is rarely encountered in clinical practice. Factors including younger age, female gender, certain major histocompatibility complex genes, white race, and interleukin 28 gene polymorphism (IL 28 CC genotype) are associated with spontaneous clearance of HCV infection. Chronic HCV infection is asymptomatic and is routinely diagnosed during evaluation for elevated transaminases or by birth cohort-based screening. In many instances, however, the initial presentation can be with symptoms and signs of liver failure, especially in geriatric patients, who may have acquired the infection 30–40 years earlier. Serum ALT and AST are typically elevated up to five times the upper limit of normal. Serum ALT is higher than AST in the milder stages of HCV, but as the disease evolves into cirrhosis, AST/ALT ratio is reversed (serum AST > ALT). The diagnosis is established by HCV RNA assay in the serum using polymerase chain reaction

HCV viral genome exhibits substantial genetic variations; six major types of HCV, called genotypes, are identified worldwide. About 75% of patients in the United States have genotype 1 and 25% have genotype 2 and 3. Within these genotypes, there are several subtypes and quasispecies. The current treatment of HCV is effective for all genotypes.

cirrhosis in 20–25 years after acquiring the infection. The rate of progression depends on the age at which infection was acquired; when contracted at an older age, the disease progression is more rapid (Thabut et al. 2006). Once cirrhosis is established, the risk of liver failure is 5% every year and the risk of hepatocellular carcinoma is 1–3% per year. Several other factors have been linked with higher rate of disease progression (Poynard et al. 1997, 2001).

Mode of Transmission and Risk Factors

Extrahepatic Manifestations HCV infection is well known to be associated with membranous glomerulonephritis, porphyria cutanea tarda, and mixed cryoglobulinemia, whereas its association with B cell lymphoma is not proven. There are reports of higher incidence of diabetes and increased insulin resistance in patients with HCV, even in the absence of cirrhosis. It is not unreasonable to screen patients with diabetes for HCV and cirrhosis (Eslam et al. 2011). Insulin resistance is also associated with higher rate of progression of fibrosis and is known to improve with HCV

58

Viral Liver Diseases

1359

Table 3 Extrahepatic manifestation of viral hepatitisa Condition 1. Polyarteritis nodosa 2. Membranous nephropathy 3. Membranoproliferative nephropathy 4. Essential mixed cryoglobulinemia 5. B-cell non-Hodgkin’s lymphoma

6. Elevated gamma globulin 7. Porphyria cutanea tarda

8. Lichen planus 9.Thyroid disorder 10. Diabetes mellitus 11. Autoantibodies

Comments HBV, HBV treatment may be indicated HBV (Rx effect not known) HBV (Rx effect not known) and HCV 90% have HCV; HCV cure may not decrease Cryoglobulin levels or its manifestation Treatment is similar to other lymphoma All lymphoma patients be tested for HCV HCV treatment may cause regression Reported with HCV but not very conclusive Elevated IG levels are seen in chronic liver disease 50% patients have HCV HCV treatment may not affect skin lesions HIV and hemochromatosis need to be ruled out Test for HCV in patients with lichen planus HCV patients are at risk of hypothyroidism TSH and T4 should be checked at diagnosis of HCV HCV increases insulin resistance HCV cure may improve glycemic control Rheumatoid factor antinuclear antibodies are seen in HCV-may lead to false diagnosis

a

Lower mortality from cardiovascular and neurological diseases has been observed in HCV patients who achieved SVR compared to those without SVR

treatment (Conjeevaram et al. 2011; Patel et al. 2011). HCV antibody is frequently seen in patients with rheumatoid arthritis, and HCV PCR is required to confirm the diagnosis of active infection. Conversely, rheumatoid factor is present in many patients with HCV, but without any other evidence of rheumatoid arthritis. A detailed review of extrahepatic manifestations of HCV was recently published (Jacobson et al. 2010) (Table 3).

Treatment Treatment of chronic hepatitis C is truly one of the miracles of modern medicine. Within the last decade, its treatment has transformed from, yearlong treatment with multiple injections with interferon with suboptimal response, multiple side effects to simple tablet-based treatment that effectively cures nearly 100% of patients. The end point of HCV therapy is defined as sustained virologic response (SVR), meaning undetectable HCV RNA by a sensitive assay,

12 weeks after stopping the treatment. Once SVR is achieved, HCV RNA remains undetectable (durability of response), and hence clinicians use the term “cure” in patients who achieve SVR (Swain et al. 2010). In addition to reducing liver complications, in achieving SVR in HCV-infected patients, there is a decrease in nonliver-related mortality. Moreover, several studies have shown that fibrosis is reversible in those who achieve sustained viral suppression in both HCV and HBV. However, patients with cirrhosis need hepatocellular carcinoma screening every 6 months even after achieving SVR (Morgan et al. 2010). HCV was first discovered in 1989. Interferonalpha was the first drug used to treat HCV which resulted in treatment response in up to a third of patients; however, it led to significantly high relapse rates and thus a low true SVR of 6% (Davis et al. 1989). Addition of ribavirin to interferon helped increase SVR rates to 34–42% (McHutchison et al. 1998). Subsequently, it was found that use of pegylated form of interferon when used with ribavirin helped achieve higher

1360

SVR rates (Zeuzem et al. 2000). The development of HCV replicon in 2006 has made it possible to develop many direct acting agents that target the key enzymes (NS3, NS 5B, and NS 5A) involved in the HCV replication. A NS5B polymerase inhibitor, sofosbuvir (Sovaldi®, Gilead Sciences), was approved in 2013 (FDA approves Sovaldi for chronic hepatitis C). Sofosbuvir in combination of N5A inhibitors (Ledipasvir (Harvoni) and velpatasvir (Epclusa) have led the way in HCV treatment during the last few years (Feld et al. 2015; Foster et al. 2015). In 2017, another combination regimen with NS5a inhibitor, pibrentasvir and NS3 inhibitor, glecaprevir (Mavyret, Abbvie Inc.) was approved to treat HCV (Forns et al. 2017). The two recommended regimens for HCV patients, who have not failed previous treatment, are either sofosbuvir + velpatasvir (Epclusa), 1 tablet/per day with or without food for 12 weeks, or pibrentasvir and glecaprevir (Mavyret), 3 tablets/day with food for 8 weeks. Both regimens are highly effective with near 100% cure rate and are effective for all genotypes (Zeuzem et al. 2018; FDA approves Mavyret). Cirrhosis, genotype 3, and baseline NS5A resistance-associated substitutions (RAS) may lower the response by 5–10%. Age, race, gender, BMI, and baseline viral RNA levels do not affect response to treatment. The safety of both regimens is well established in patients with decreased renal function and those with ESRD on hemodialysis. There is no need for dose adjustment. The current simplified treatment regimen encourages primary care physicians and physician extenders to treat HCV. Liver biopsy is not required before treatment. There is no need for follow-up or laboratory testing during treatment in majority of patients. However, SVR need to be documented. Cirrhosis can be diagnosed with reasonable accuracy by using APRI (https://www.mdcalc.com/astplatelet-ratio-index-apri) or FIB-4 score (https:// www.mdcalc.com/fibrosis-4-fib-4-index-liverfibrosis). If cirrhosis is suspected or patient had failed treatment in the past or has coinfection with HBV, closer follow-up and a referral to a specialist are indicated. The most updated guidelines for treatment of HCV are jointly published

S. Nair and R. Verma

by Infectious Diseases Society of America (IDSA) and American Association for the Study of Liver Diseases (AASLD) on https:// www.hcvguidelines.org. The HCV treatment regimen is safe and effective in patients over 65 years. The phase 3 clinical trials included several patients over 65 years and the SVR rate is similar to younger patients. These regimens were also equally well tolerated. Age by itself should not be consideration for eligibility of HCV treatment but treatment should not be offered to patents with life expectancy of less than 1 year. Protease inhibitor (NS3 inhibitor) containing regimens such as pibrentasvir and glecaprevir (Mavyret) are contraindicated in patients with decompensated liver disease (Child-Pugh score 7 or more) or in patients who had a decompensating event in the past. An FDA update in September 2019 reported several deaths in patients taking protease inhibitor drugs. Hence patients with cirrhosis need careful assessment before protease inhibitors are prescribed. Since patients over 65 are likely to be on multiple cardiovascular drugs for metabolic syndrome, drug–drug interaction (DDI) is an important consideration. For example, sofosbuvir (Epclusa) is contraindicated in patients taking amiodarone due to life-threatening bradyarrhythmias. Statins also have significant drug interactions with these drugs; dose adjustment or discontinuation may be required. Epclusa has lower efficacy when used in patients taking high dose of proton pump inhibitors as the absorption of velpatasvir is reduced at higher pH. Interactions with warfarin and hypoglycemic agents may require closer monitoring. All drugs have lower efficacy in patients taking CYP3A inducers such as phenytoin sodium and carbamazepine. There are app-based services one can use to verify DDI (Liverpool HEP1Chart: http://www.hepdruginteraction.org). It is very rare for HCV treatment to fail; failure is often due to inadequate exposure to the drugs either because of nonadherence or drug interactions as mentioned above. Rarely treatment emergent resistance-associated substitutions (RAS) lead to virologic failure. Sofosbuvir, velpatasvir, and voxilaprevir combination (Vosevi) is effective

58

Viral Liver Diseases

1361

in treating most patients who have failed treatment (Jacobson et al. 2017). Resistance testing is not indicated for HCV. On basis of these highly effective treatments, World Health Organization (WHO) has set a goal to eliminate hepatitis C by 2030 (WHO 2016). Effective HCV treatment has also helped expand the donor pool by allowing use of HCV positive organs in solid organ transplantation where there is always a scarcity of suitable donors and demand outstrips the supply of available organs by manyfold (WHO 2016).

Hepatitis B (HBV) The incidence of hepatitis B infection in the United States is increasing due to immigration from endemic areas. The Center for Disease Control recommends screening for all individuals from endemic countries (Far East, sub-Saharan Africa). HBV is parenterally transmitted and hence screening is recommended for individuals with high risk behavior or those with exposure to blood products or contaminated needles.

Clinical Features and Diagnosis HBV can present as acute HBV, with a clinical presentation very similar to acute HAV (Fig. 3). Almost 90–95% patients with acute HBV spontaneously clear the infection and develop immunity. Five percent of patients, however, progress into chronic hepatitis B as evidenced by persistence of HBV surface antigen (HBsAg) beyond 6 months. Once chronic infection is established, HBV infection evolves through different stages based on the interaction with the immune system of the host (Fig. 2). Most chronic HBV encountered in adults over 65 years will be “e antigen” negative chronic HBV and have “pre-core mutant HBV” (HBV loses the ability to produce HBV e antigen) and hence the typical serological pattern will be HBsAg antigen positive, HBV e antibody positive (anti-HBe), and HBV e antigen negative (HBeAg). The HBV DNA and the serum ALT levels will depend on whether the patient is in the inactive phase or the reactivation phase of chronic HBV disease (Fig. 3). It is important to note that unlike hepatitis C, HBV can cause hepatocellular carcinoma (HCC)

Phases of CHB Infection: Clinical/Histology same as Previous slide: Details in a Table format

Duration of Infection

ALT

HBV DNA

Liver Histology

Immune-tolerant Normal phase

Elevated, typically >1 million IU/mL

Minimal inflammation and fibrosis

HBeAg-positive immune-active phase

Elevated TREAT

Elevated ≥20,000 IU/mL

Moderate-tosevere inflammation or fibrosis

Inactive CHB phase

Normal

Low or undetectable 14 standard drinks per week in women over a 2-year period preceding baseline liver histology (Kleiner et al. 2005) b Amiodarone, methotrexate, tamoxifen, corticosteroids c Valproate, antiretroviral medications

a

prevalence between 2003 and 2011. Other studies corroborate this increase in prevalence in NAFLD between 1994 and 2008 (Younossi et al. 2011). Moreover, prevalence increased regardless of sex, age, or race (Kanwal et al. 2016). The prevalence of NAFLD after age 75 actually decreases, likely due to mortality from comorbid conditions (Clark 2006). NAFLD affects all age groups, races, and both sexes. However, there are populations that have a higher prevalence of NAFLD and NASH. Higher risk demographics include: Latin Americans, patients with metabolic risk factors, and men (Saab et al. 2016; Chalasani et al. 2012). Hispanics have been demonstrated to have higher risks of NAFLD compared to Blacks (Rich et al. 2017). South Asians represent a growing population with NAFLD, although many do not have the traditional risk factor of elevated BMI (Chitturi et al. 2011). Any level of obesity increases the prevalence of NAFLD in patients with diabetes mellitus (Wanless and Lentz 1990; Silverman et al. 1990). It is estimated that in those individuals with both obesity and diabetes, the prevalence of NAFLD reaches 70% (Kim et al. 2018). Nonalcoholic steatohepatitis is estimated to affect 19% of the obese American population (Wanless and Lentz 1990; Silverman et al. 1990). In the morbidly obese, the prevalence of NAFLD is as high as 95%, with NASH

1383

close to 25% (Dixon and Bhathal 2001). Moreover, the metabolic syndrome (Table 2) and all its components are widely known to be associated with the development of NAFLD and NASH. Clinically, its recognition is vital, as the allcause mortality rate of patients with NAFLD is at least 34% higher than that of the general population (Marengo et al. 2016). NASH is a more aggressive condition that is associated with inflammation, hepatocyte injury with progressive fibrosis, and ultimately cirrhosis. Cirrhosis is largely irreversible resulting in multiple systemic sequelae and can lead to hepatocellular carcinoma and death. Even more concerning is growing evidence that HCC can even develop in the absence of cirrhosis in the NAFLD/NASH population (Mittal et al. 2016).

Diagnosis of NAFLD and NASH Clinical Evaluation The goals in diagnosis are to confirm the etiology of liver disease, to evaluate the specific type of fatty liver (Table 1), and to stage the disease (to establish clinical severity). The definition of nonalcoholic fatty liver disease (NAFLD) requires that (a) there is evidence of hepatic steatosis and (b) there are no causes for secondary hepatic fat accumulation such as significant alcohol consumption or use of steatogenic medication; and other liver diseases including hepatitis C (especially genotype 3), hemochromatosis, alpha-1 antitrypsin deficiency, and Wilson’s disease are adequately ruled out (Chalasani et al. 2018). It is possible to have NALFD in conjunction with the abovementioned diseases. Most people with NAFLD are asymptomatic. Fatigue, weight loss, weakness, and right upper quadrant abdominal pain are rare; and signs including jaundice, ascites, gynecomastia, and spider angiomata are noted only in advanced stages of the disease. This leads many individuals to present with more advanced disease at the time of diagnosis. In 15–50% of cases, liver fibrosis or cirrhosis is seen as the initial presentation (Falchuk et al. 1980).

1384

S. Krawitz and N. Pyrsopoulos

Table 2 Components of metabolic syndrome Criteria Waist circumference Fasting glucose Triglycerides HDL cholesterol Blood pressure

Variable >102 cm men; >88 cm women 100 mg/dL 150 mg/dL 50 mg was associated with a shorter latency to DILI, but drug properties were not helpful in determining outcomes (Vuppalanchi et al. 2014). While idiosyncratic DILI is not dose-related, there may be a threshold dose of 50–100 mg/day for DILI to be more likely (Andrade et al. 2019). However, it is not clear how to apply information about biochemical properties or dose, other than to note that idiosyncratic DILI can occur even when drugs are taken according to standard dosing.

Patterns of Liver Injury DILI is a pattern of injury with characteristics that encompass a range of biochemical, histologic, and other clinical features (such as fever or rash,

1395

which may signal an allergic-based reaction). The “R” value (Table 1), the ratio of ALT/ULN to alkaline phosphatase/ULN, is used to categorize the pattern of presenting biochemistries as reflective of injury that is hepatocellular (R > 5), cholestatic (R < 2), or mixed (R = 2–5). Irrespective of what is “classically” expected in terms of a biochemical profile from a particular drug, older adults appear to be more likely to exhibit a cholestatic or mixed biochemical pattern of injury in response to a given drug, when compared to younger adults who may exhibit a hepatocellular pattern (Bjornsson et al. 2013; Chalasani et al. 2015; Onji et al. 2009) (Andrade et al. 2019; Hunt et al. 2014; Lucena et al. 2009) (Table 1). There are a variety of histologic patterns that may be seen in the setting of DILI, including acute or chronic hepatocellular or cholestatic injury, granuloma formation, steatosis, macroand micro-vesicular steatohepatitis, necrosis, vascular injury, and nodular regenerative hyperplasia. Regarding histologic patterns, in a large cohort, there were five patterns that were seen in the majority of cases: acute hepatitis, chronic hepatitis, acute cholestasis, chronic cholestasis, and cholestatic hepatitis. There was limited correlation between histologic and biochemical patterns at the time of injury when it came to classification into hepatocellular, cholestatic, or mixed patterns of injury based on the “R” value (Kleiner et al. 2014). Caution is urged in predicting the pattern of histologic changes based on the pattern of biochemistries. Age may be a risk factor for the development of chronic DILI, but findings have not been consistent. Defining chronic DILI as persistently abnormal biochemistries, histology, or imaging lasting a year or more after drug withdrawal, older age was a risk factor in one study (MedinaCaliz et al. 2016). However, using abnormal biochemistries, imaging, or exam findings noted at least 6 months after drug withdrawal to define chronicity, a separate study found that older patients are actually less likely to have chronic DILI compared to other age groups (Chalasani et al. 2015).

1396

E. D. Miller et al.

Table 1 Patterns of liver injury in drug induced liver injury R-value 5

Hepatocellular

22x ULN in the setting of AST or ALT >3x the upper limit of normal have an approximately 10–50% risk of DILI-related mortality or need for liver transplant (Temple 2006). This rule, in fact, is the basis for the model used by the US Federal Drug Administration in drug development, to determine whether a compound proceeds through the drug approval process (Senior 2014), highlighting its importance in considering DILI. A liver biopsy is useful in certain circumstances but is by no means a required element in the evaluation of any possible DILI. Histologic findings of DILI, as mentioned, are diverse and not pathognomonic. However, a biopsy may be needed for one of several reasons. First, it can help diagnostically to identify a pattern of injury when one or more possible causes of liver injury are being considered, usually to rule out a cause.

1402

Second, it can help to establish the severity of injury. This information is often needed, particularly to serve as a baseline if serial biopsies are being considered, or when the patient already has a known chronic liver disease, or if re-challenge with the suspected or known cause of DILI is being considered.

Management When DILI is suspected, the first step is to discontinue the causative drug(s). Most cases improve upon withdrawal of the suspected medication(s) with no long-term sequelae (Hayashi et al. 2017). Normalization of liver function may take days to months, and some develop chronic DILI, with an incidence of 5–10% (Hayashi and Bjornsson 2018). Regular monitoring of labs and, when relevant, signs or symptoms of possible persistence or progression of DILI is advised (Bessone et al. 2019; Reuben et al. 2010; Andrade et al. 2019; European Association for the Study of the Liver 2016; Martin et al. 2014) Sometimes steroids are needed, especially when there may be an autoimmune-like reaction (Stine and Chalasani 2015), including for immune checkpoint inhibitors which are increasingly being used for a variety of cancers (Brahmer et al. 2018). Steroid use should be limited to situations in which they are specifically indicated, and not as part of the general management of DILI. N-acetylcysteine is a well-known treatment of acetaminophen-related DILI (Ramachandran and Jaeschke 2019). Its use for other causes of liver failure in DILI is controversial, largely due to lack of clear evidence of efficacy. There is some evidence that it can improve survival if administered to adults with acute liver failure not due to acetaminophen (Lee et al. 2009). USA and European guidelines recommend its use in ALF due to idiosyncratic DILI early on (e.g., coma grade I–II) (Chalasani et al. 2014; Andrade et al. 2019). With its low side-effect profile and lack of other definitive and safe treatments of DILI, its administration is encouraged when available.

E. D. Miller et al.

Prior history of DILI increases the risk of injury on re-exposure to the same or structurally similar agents. Re-challenge is not advisable, since recurrent injury may be more severe than the initial insult, especially with immunologic injury. Ideally, re-challenge should be avoided. It is essential to closely monitor hepatic function in those with a prior history of DILI if re-exposure is necessary. The presence of jaundice, coagulopathy, newonset fluid retention, and encephalopathy or coma is evidence of DILI-related acute liver failure (Reuben et al. 2010). DILI can be associated with significant mortality, and is one of the most common causes of liver failure leading to death or liver transplant (Bessone et al. 2019). Compared to other causes of acute liver failure, it leads to a lower transplant-free survival (Andrade et al. 2019). When there are features concerning for liver failure, it is important to consider whether liver transplant is an option, based on patient factors and access to a transplant center. It is important to recognize that older age is not a contraindication to liver transplantation based on the most recent USA (Martin et al. 2014) and European guidelines (European Association for the Study of the Liver 2016), with liver transplants having been successfully performed in older adults. However, for this population, assessment of comorbidities is essential due to the risk of posttransplant cardiovascular complications.

Next Steps: Future Goals The prediction and monitoring of the course of DILI remains a challenge. Novel biomarkers are needed and have been the subject of recent work (Barnhill et al. 2018; Church et al. 2018). There is also a computer-based modeling system, DILIsym, used to characterize the effects of drugs on a selected patient population by mathematically simulating its mechanism of injury (Church and Watkins 2018). Another model incorporates lab values and comorbidities to estimate 6-month mortality in DILI. The study that led to this model was also novel in providing insight into the context in which DILI occurs:

61

Drug-Induced Liver Injury in Older Adults

higher burden of comorbid illness (particularly for older males) was an independent risk factor for 6month mortality in DILI (Ghabril et al. 2019). This observation merits additional investigation into the role comorbid diseases play in DILI, especially in older patients. Finally, better data for elderly patients and inclusion in clinical trials are needed (Mitchell and Hilmer 2010). Older adults are often underrepresented in clinical trials (Stine et al. 2013; van Riet-Nales et al. 2016). There is an initiative by the NIH in the USA that trials include patients across the life span, with the goal of requiring expanded age criteria in new grants (https:// grants.nih.gov/grants/guide/notice-files/NOT-OD18-116.html). It is also essential for registries, worldwide, to include cases of DILI among older patients (Haugen et al. 2019).

Key Points • Older adults are not, in general, at higher risk of drug-induced liver injury compared to other age groups. • A few medications, including antibiotics (amoxicillin-clavulanate, erythromycin, flucloxacillin, isoniazid) and diclofenac, may be more likely to cause DILI in older adults. • DILI may present more commonly with a cholestatic biochemical pattern in the elderly age group compared to younger adults or children. • Although statins can cause DILI, they are not riskier to use as age increases. • Cessation of the offending agent and clinical monitoring are needed when DILI is suspected.

References Ahmad J, Odin JA. Epidemiology and genetic risk factors of drug hepatotoxicity. Clin Liver Dis. 2017;21:55–72. https://doi.org/10.1016/j.cld.2016.08.004. Andrade RJ, et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology. 2005;129:512–21. https://doi.org/10.1016/j.gastro.2005.05.006. Andrade RJ, et al. EASL clinical practice guidelines: druginduced liver injury. J Hepatol. 2019;70:1222–61. https://doi.org/10.1016/j.jhep.2019.02.014.

1403 Banks AT, Zimmerman HJ, Ishak KG, Harter JG. Diclofenac-associated hepatotoxicity: analysis of 180 cases reported to the Food and Drug Administration as adverse reactions. Hepatology. 1995;22:820–7. Barnhill MS, Real M, Lewis JH. Latest advances in diagnosing and predicting DILI: what was new in 2017? Expert Rev Gastroenterol Hepatol. 2018;12:1–11. https://doi.org/10.1080/17474124.2018.1512854. Barry PJ, Gallagher P, Ryan C, O’Mahony D. START (screening tool to alert doctors to the right treatment) – an evidence-based screening tool to detect prescribing omissions in elderly patients. Age Ageing. 2007;36:632–8. https://doi.org/10.1093/ ageing/afm118. Begriche K, Massart J, Robin MA, Borgne-Sanchez A, Fromenty B. Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver. J Hepatol. 2011;54:773–94. https://doi.org/10.1016/j.jhep.2010. 11.006. Bell LN, Chalasani N. Epidemiology of idiosyncratic druginduced liver injury. Semin Liver Dis. 2009;29:337–47. https://doi.org/10.1055/s-0029-1240002. Bessone F, Robles-Diaz M, Hernandez N, Medina-Caliz I, Lucena MI, Andrade RJ. Assessment of serious acute and chronic idiosyncratic drug-induced liver injury in clinical practice. Semin Liver Dis. 2019. https://doi. org/10.1055/s-0039-1685519. Bjornsson ES, Bergmann OM, Bjornsson HK, Kvaran RB, Olafsson S. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144:1419–25, 1425.e1411–3; quiz e1419–20. https://doi.org/10.1053/j.gastro.2013.02.006. Brahmer JR, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36:1714–68. https://doi.org/10.1200/jco.2017.77.6385. Bratton H, Alomari M, Al Momani LA, Aasen T, Young M. Prolonged jaundice secondary to amiodarone use: a case report and literature review. Cureus. 2019;11:e3850. https://doi.org/10.7759/cureus.3850. Bunchorntavakul C, Reddy KR. Review article: herbal and dietary supplement hepatotoxicity. Aliment Pharmacol Ther. 2013;37:3–17. https://doi. org/10.1111/apt.12109. Chalasani N, Bjornsson E. Risk factors for idiosyncratic druginduced liver injury. Gastroenterology. 2010;138:2246–59. https://doi.org/10.1053/j.gastro. 2010.04.001. Chalasani N, et al. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135:1924–34., 1934.e1921-1924. https://doi.org/ 10.1053/j.gastro.2008.09.011. Chalasani NP, Hayashi PH, Bonkovsky HL, Navarro VJ, Lee WM, Fontana RJ. ACG clinical guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014;109:950–66. https:// doi.org/10.1038/ajg. 2014.131.

1404 Chalasani N, et al. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterology. 2015;148:1340–1352.e1347. https://doi.org/10.1053/j.gastro.2015.03.006. Chen M, Borlak J, Tong W. High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury. Hepatology. 2013;58:388–96. https://doi.org/10.1002/hep.26208. Chen M, Suzuki A, Borlak J, Andrade RJ, Lucena MI. Drug-induced liver injury: interactions between drug properties and host factors. J Hepatol. 2015;63:503–14. https://doi.org/10.1016/j.jhep.2015.04.016. Church RJ, Watkins PB. In silico modeling to optimize interpretation of liver safety biomarkers in clinical trials. Exp Biol Med. 2018;243:300–7. https://doi.org/ 10.1177/1535370217740853. Church RJ, et al. Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury: an international collaborative effort. Hepatology. 2018. https:// doi.org/10.1002/hep.29802. Corsini A, Bortolini M. Drug-induced liver injury: the role of drug metabolism and transport. J Clin Pharmacol. 2013;53:463–74. https://doi.org/10.1002/jcph.23. Cotreau MM, von Moltke LL, Greenblatt DJ. The influence of age and sex on the clearance of cytochrome P450 3A substrates. Clin Pharmacokinet. 2005;44:33–60. https://doi.org/10.2165/00003088200544010-00002. Crabb DW, Im GY, Szabo G, Mellinger JL, Lucey MR. Diagnosis and treatment of alcohol-related liver diseases: 2019 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019. https://doi.org/10.1002/hep.30866. Dakhoul L, Ghabril M, Gu J, Navarro V, Chalasani N, Serrano J. Heavy consumption of alcohol is not associated with worse outcomes in patients with idiosyncratic drug-induced liver injury compared to non-drinkers. Clin Gastroenterol Hepatol. 2018;16:722–729.e722. https://doi.org/10.1016/j. cgh.2017.12.036. Daly AK, Day CP. Genetic association studies in drug-induced liver injury. Semin Liver Dis. 2009;29:400–11. https://doi. org/10.1055/s-0029-1240009. Daly AK, et al. HLA-B5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet. 2009;41:816–9. https://doi. org/10.1038/ng.379. Danan G, Benichou C. Causality assessment of adverse reactions to drugs – I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol. 1993;46:1323–30. de Boer YS, et al. Features of autoimmune hepatitis in patients with drug-induced liver injury. Clin Gastroenterol Hepatol. 2017;15:103. https://doi.org/ 10.1016/j.cgh.2016.05.043. de Lemos AS, et al. Amoxicillin-clavulanate-induced liver injury. Dig Dis Sci. 2016;61:2406–16. https://doi.org/ 10.1007/s10620-016-4121-6.

E. D. Miller et al. De Martin E, et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol. 2018;68:1181–90. https://doi. org/10.1016/j.jhep.2018.01.033. European Association for the Study of the Liver. EASL clinical practice guidelines: liver transplantation. J Hepatol. 2016;64:433–85. https://doi.org/10.1016/j. jhep.2015.10.006. Fontana RJ. Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives. Gastroenterology. 2014;146:914–28. https://doi.org/10.1053/j.gastro. 2013.12.032. Fontana RJ, et al. Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology. 2014;147:96–108.e104. https://doi.org/10.1053/j. gastro.2014.03.045. Fredriksson L, et al. Diclofenac inhibits tumor necrosis factor-alpha-induced nuclear factor-κB activation causing synergistic hepatocyte apoptosis. Hepatology. 2011;53:2027–41. https://doi.org/10.1002/hep.24314. Geller AI, et al. Emergency department visits for adverse events related to dietary supplements. N Engl J Med. 2015;373:1531–40. https://doi.org/10.1056/ NEJMsa1504267. Ghabril M, et al. Development and validation of model consisting of comorbidity burden to calculate risk of death within 6 months for patients with suspected drug-induced liver injury. Gastroenterology. 2019. https://doi.org/10.1053/j.gastro.2019.07.006. Haugen CE, et al. Assessment of trends in transplantation of liver grafts from older donors and outcomes in recipients of liver grafts from older donors, 2003–2016. JAMA Surg. 2019. https://doi.org/ 10.1001/jamasurg.2018.5568. Hautekeete ML, et al. HLA association of amoxicillinclavulanate–induced hepatitis. Gastroenterology. 1999;117:1181–6. Hayashi PH, Bjornsson ES. Long-term outcomes after drug-induced liver injury. Curr Hepatol Rep. 2018;17:292–9. https://doi.org/10.1007/s11901-0180411-0. Hayashi PH, et al. Death and liver transplantation within 2 years of onset of drug-induced liver injury. Hepatology. 2017;66:1275–85. https://doi. org/10.1002/hep.29283. Ho RH, Kim RB. Transporters and drug therapy: implications for drug disposition and disease. Clin Pharmacol Ther. 2005;78:260–77. https://doi.org/ 10.1016/j.clpt.2005.05.011. Hoofnagle JH, Serrano J, Knoben JE, Navarro VJ. LiverTox: a website on drug-induced liver injury. Hepatology. 2013;57:873–4. https://doi.org/10.1002/ hep.26175. Hunt CM, Yuen NA, Stirnadel-Farrant HA, Suzuki A. Age-related differences in reporting of drug-associated liver injury: data-mining of WHO safety report database. Regul Toxicol Pharmacol. 2014;70:519–26. https://doi.org/10.1016/j.yrtph.2014.09.007.

61

Drug-Induced Liver Injury in Older Adults

Kleiner DE, et al. Hepatic histological findings in suspected drug-induced liver injury: systematic evaluation and clinical associations. Hepatology. 2014;59:661–70. https://doi.org/10.1002/hep.26709. Lammert C, Einarsson S, Saha C, Niklasson A, Bjornsson E, Chalasani N. Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals. Hepatology. 2008;47:2003–9. https://doi.org/10.1002/hep.22272. Lammert C, Bjornsson E, Niklasson A, Chalasani N. Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events. Hepatology. 2010;51:615–20. https://doi.org/10.1002/hep.23317. Lang C, et al. Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury. Pharmacogenet Genomics. 2007;17:47–60. https:// doi.org/10.1097/01.fpc.0000230418.28091.76. Lee WM, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage nonacetaminophen acute liver failure. Gastroenterology. 2009;137:856–64, 864.e851. https://doi.org/10.1053/j. gastro.2009.06.006. Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clin Proc. 2014;89:95–106. https://doi. org/10.1016/j.mayocp.2013.09.016. Lewis JH, et al. Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients. Hepatology. 1989;9:679–85. Lucena MI, et al. Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex. Hepatology. 2009;49:2001–9. https://doi.org/ 10.1002/hep.22895. Lucena MI, et al. Susceptibility to amoxicillin-clavulanateinduced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology. 2011;141:338–47. https://doi.org/10.1053/j.gastro. 2011.04.001. Malatjalian DA, Ross JB, Williams CN, Colwell SJ, Eastwood BJ. Methotrexate hepatotoxicity in psoriatics: report of 104 patients from Nova Scotia, with analysis of risks from obesity, diabetes and alcohol consumption during long term follow-up. Can J Gastroenterol. 1996;10:369–75. https://doi.org/ 10.1155/1996/213596. Manns MP, Czaja AJ, Gorham JD, Krawitt EL, MieliVergani G, Vergani D, Vierling JM. Diagnosis and management of autoimmune hepatitis. Hepatology. 2010;51:2193–213. https://doi.org/ 10.1002/hep.23584. Martin P, DiMartini A, Feng S, Brown R Jr, Fallon M. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology. 2014;59:1144–65. Medina-Caliz I, et al. Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury. J Hepatol. 2016;65:532–42. https://doi.org/ 10.1016/j.jhep.2016.05.003.

1405 Mitchell SJ, Hilmer SN. Drug-induced liver injury in older adults. Ther Adv Drug Saf. 2010;1:65–77. https://doi. org/10.1177/2042098610386281. Navarro VJ, et al. Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network. Hepatology. 2014;60:1399–408. https://doi. org/10.1002/hep.27317. Navarro VJ, Khan I, Bjornsson E, Seeff LB, Serrano J, Hoofnagle JH. Liver injury from herbal and dietary supplements. Hepatology. 2017;65:363–73. https:// doi.org/10.1002/hep.28813. Nicoletti P, et al. Association of liver injury from specific drugs, or groups of drugs, with polymorphisms in HLA and other genes in a genome-Wide Association Study. Gastroenterology. 2017;152:1078–89. https://doi.org/ 10.1053/j.gastro.2016.12.016. Noe J, et al. Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis. J Hepatol. 2005;43:536–43. https://doi.org/10.1016/j.jhep.2005.05.020. O’Connor N, Dargan PI, Jones AL. Hepatocellular damage from non-steroidal anti-inflammatory drugs QJM: monthly. J Assoc Physicians. 2003;96:787–91. Onji M, Fujioka S, Takeuchi Y, Takaki T, Osawa T, Yamamoto K, Itoshima T. Clinical characteristics of druginduced liver injury in the elderly. Hepatol Res. 2009;39:546–52. https://doi.org/10.1111/j.1872034X.2009.00492.x. Overman MJ, et al. The addition of bevacizumab to oxaliplatin-based chemotherapy: impact upon hepatic sinusoidal injury and thrombocytopenia. J Natl Cancer Inst. 2018;110:888–94. https://doi.org/10.1093/jnci/djx288. Pan HJ, Chang HT, Lee CH. Association between tamoxifen treatment and the development of different stages of nonalcoholic fatty liver disease among breast cancer patients. J Formos Med Assoc. 2016;115:411–7. https://doi.org/10.1016/j.jfma.2015.05.006. Pauli-Magnus C, Meier PJ. Hepatobiliary transporters and drug-induced cholestasis. Hepatology. 2006;44:778–87. https://doi.org/10.1002/hep.21359. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378:158–68. https:// doi.org/10.1056/NEJMra1703481. Qato DM, Wilder J, Schumm LP, Gillet V, Alexander GC. Changes in prescription and over-the-counter medication and dietary supplement use among older adults in the United States, 2005 vs 2011. JAMA Intern Med. 2016;176:473–82. https://doi.org/ 10.1001/jamainternmed.2015.8581. Ramachandran A, Jaeschke H. Acetaminophen hepatotoxicity. Semin Liver Dis. 2019;39:221–34. https://doi. org/10.1055/s-0039-1679919. Reuben A, Koch DG, Lee WM, Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U. S. multicenter, prospective study. Hepatology. 2010;52:2065–76. https://doi.org/10.1002/hep.23937. Schmidt LE, Dalhoff K, Poulsen HE. Acute versus chronic alcohol consumption in acetaminophen-induced

1406 hepatotoxicity. Hepatology. 2002;35:876–82. https:// doi.org/10.1053/jhep.2002.32148. Senior JR. Evolution of the Food and Drug Administration approach to liver safety assessment for new drugs: current status and challenges. Drug Saf. 2014;37(Suppl 1): S9–17. https://doi.org/10.1007/s40264-014-0182-7. Sgro C, et al. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology. 2002;36:451–5. https://doi.org/10.1053/jhep.2002. 34857. Sisti E, et al. Age and dose are major risk factors for liver damage associated with intravenous glucocorticoid pulse therapy for graves’ orbitopathy. Thyroid. 2015;25:846–50. https://doi.org/10.1089/ thy.2015.0061. Sonawane KB, Cheng N, Hansen RA. Serious adverse drug events reported to the FDA: analysis of the FDA adverse event reporting system 2006–2014 database. J Manag Care Spec Pharm. 2018;24:682–90. https:// doi.org/10.18553/jmcp.2018.24.7.682. Stine JG, Chalasani N. Chronic liver injury induced by drugs: a systematic review. Liver Int. 2015;35:2343–53. https://doi.org/10.1111/liv.12958. Stine JG, Sateesh P, Lewis JH. Drug-induced liver injury in the elderly. Curr Gastroenterol Rep. 2013;15:299. https://doi.org/10.1007/s11894-012-0299-8. Stricker BH, Blok AP, Claas FH, Van Parys GE, Desmet VJ. Hepatic injury associated with the use of nitrofurans: a clinicopathological study of 52 reported cases. Hepatology. 1988;8:599–606. Suk KT, et al. A prospective nationwide study of drug-induced liver injury in Korea. Am J Gastroenterol. 2012;107:1380–7. https://doi.org/ 10.1038/ajg.2012.138. Tan JL, Eastment JG, Poudel A, Hubbard RE. Age-related changes in hepatic function: an update on implications

E. D. Miller et al. for drug therapy. Drugs Aging. 2015;32:999–1008. https://doi.org/10.1007/s40266-015-0318-1. Temple R. Hy’s law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006;15:241–3. https:// doi.org/10.1002/pds.1211. Tujios S, Fontana RJ. Mechanisms of drug-induced liver injury: from bedside to bench. Nat Rev Gastroenterol Hepatol. 2011;8:202–11. https://doi.org/10.1038/ nrgastro.2011.22. van Riet-Nales DA, Hussain N, Sundberg KA, Eggenschwyler D, Ferris C, Robert JL, Cerreta F. Regulatory incentives to ensure better medicines for older people: From ICH E7 to the EMA reflection paper on quality aspects. Int J Pharm. 2016;512:343–51. https:// doi.org/10.1016/j.ijpharm.2016.05.001. Vincenzi B, et al. The use of SAMe in chemotherapyinduced liver injury. Crit Rev Oncol Hematol. 2018;130:70–7. https://doi.org/10.1016/j.critrevonc. 2018.06.019. Vuppalanchi R, et al. Relationship between characteristics of medications and drug-induced liver disease phenotype and outcome. Clin Gastroenterol Hepatol. 2014;12:1550–5. https://doi.org/10.1016/j.cgh.2013. 12.016. Walgren JL, Mitchell MD, Thompson DC. Role of metabolism in drug-induced idiosyncratic hepatotoxicity. Crit Rev Toxicol. 2005;35:325–61. Wilke RA, et al. Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Nat Rev Drug Discov. 2007;6:904–16. https:// doi.org/10.1038/nrd2423. Wing K, et al. Quantification of the risk of liver injury associated with flucloxacillin: a UK population-based cohort study. J Antimicrob Chemother. 2017;72:2636–46. https://doi.org/10.1093/jac/dkx183.

Gallstones and Benign Gallbladder Disease

62

C. S. Pitchumoni and Nishal Ravindran

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1409 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Age and Gender . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethnicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1409 1410 1411 1411

Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1412 Clinical Features of Gallstone Disease (Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biliary Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acute Calculous Cholecystitis and its Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Common Bile Duct (CBD) Stones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ascending Cholangitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biliary Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chronic Cholecystitis (See Fig. 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1413 1413 1413 1415 1416 1416 1416

C. S. Pitchumoni (*) Department of Medicine, Robert Wood Johnson School of Medicine, Rutgers University, New Brunswick, NJ, USA Department of Medicine, New York Medical College, Valhalla, NY, USA Division of Gastroenterology, Hepatology and Clinical Nutrition, Saint Peters University Hospital, New Brunswick, NJ, USA e-mail: [email protected] N. Ravindran Robert Wood Johnson School of Medicine, Rutgers University, New Brunswick, NY, USA Saint Peters University Hospital, New Brunswick, NY, USA © Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_54

1407

1408

C. S. Pitchumoni and N. Ravindran Porcelain Gallbladder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1417 Pyogenic Liver Abscess . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1417 Diagnostic Studies for Biliary Disease (See Table 9) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . US Abdomen (See Fig. 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cholescintigraphy (HIDA) Scan (See Figs. 4 and 5) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Computerized Tomography Scan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Magnetic Resonance Cholangiopancreatogram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endoscopic Retrograde Cholangiopancreatogram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endoscopic Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1417 1417 1418 1418 1420 1420 1421

Management of Gallstones and Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Asymptomatic Gallstones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uncomplicated Acute Cholecystitis in a Good Surgical Candidate . . . . . . . . . . . . . . . . . . . Management of Complicated Gallbladder Disease in the Elderly . . . . . . . . . . . . . . . . . . . . CBD Stones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acute Cholangitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DVT Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1421 1421 1422 1423 1425 1427 1427

Acute Acalculous Cholecystitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1428 Functional Gallbladder Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1428 Biliary Strictures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1429 Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1429 Key Points 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1430 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1430

Abstract

The prevalence of gallstones progressively increases as age advances. Although asymptomatic in most, the clinical manifestations depend on the location of the stone in the biliary system. Gallstones, when in the gallbladder, may be painless or cause a postprandial biliary type of pain in the right upper quadrant related to a meal. When a stone migrates to the cystic duct and causes obstruction, it results in acute cholecystitis. Between 5% and 30% of cholelithiasis patients have concurrent choledocholithiasis. Gallstones obstructing the common bile duct (CBD) cause ascending cholangitis and acute biliary pancreatitis when the stone blocks the ampulla of Vater. Other complications include cholecystoduodenal or choledocho-duodenal fistula and gallstone ileus. Older adults are more likely to present with complications such as acute cholecystitis, gallstone pancreatitis, and common bile-duct stones than the young.

Tokyo guidelines are useful. There is an increase in the number of emergency and elective surgical cases involving older patients. Elective instead of emergency and a laparoscopic approach is the preferred method of surgery. In the management of CBD stones, endoscopic retrograde cholangiography, and stone extraction and stent placement are safe and effective in advanced age groups. Keywords

Cholelithiasis · Gallstone disease · Gallbladder disease · Cholesterol stones · Pigment stones · Acute cholecystitis · Chronic cholecystitis · Common bile duct stones · Ascending cholangitis · Mirizzi’s syndrome · Bouveret’s syndrome · Gallstone ileus · Biliary fistulas · Magnetic resonance cholangiopancreatography · Endoscopic retrograde chloangiopancreatography · Stent placements · Laparoscopic cholecystectomy · Post cholecystectomy pain · Biliary drainage · Biliary fistula · Functional gallbladder disorder

62

Gallstones and Benign Gallbladder Disease

Introduction Among the biliary diseases, gallstones and gallbladder cancer increase with age, with gallstones affecting 33% of older adults (McSherry et al. 1985; Sugiyama and Atomi 1997). Other biliary disorders are polyps, biliary dyskinesia, and biliary cancers. Gallstones (GS) have been found in Chinese and Egyptian mummies from more than 3500 years ago. The modern history of GS perhaps began in the eighteenth century with Morgagni, who made a number of observations based on autopsy studies, the findings being still relevant today (Moore 1937). He noted that the prevalence of gallstone disease increased with age and hypothesized that obesity could be a risk factor and that gallstones can remain asymptomatic for a lifetime. GS form in the biliary system and may be cholesterol, the more common type, or pigment stones, the less common form. Along with diverticulitis, cholecystitis is also a principal gastrointestinal diagnosis for inpatients in the United States. The frequency of hospital admissions and surgery for cholelithiasis is steadily increasing in Western countries since the 1950s and more rapidly since the advent of minimally invasive laparoscopic cholecystectomy (Lam et al. 1996; Shaffer 2005). About 20–25 million Americans have gallstones, predominantly of cholesterol, (see Fig. 1) with more than 700,000 cholecystectomies done annually in the United States (Shaffer 2006). Fig. 1 Gallbladder specimen with cholesterol gallstones

1409

Symptomatic gall stone disease has a low mortality rate of 0.6%, which has fallen dramatically since 1979 but can be still significant in older people (Everhart and Ruhl 2009a). With the advent of laparoscopic cholecystectomy, there has been an increase in surgery in the United States by 28% (Nenner et al. 1994). The cost of biliary tract disease in the United States in 2015 was $10.3 billion (Peery et al. 2019). Epidemiological data suggests higher risk of cardiovascular disease and mortality associated with gallstones (Zheng et al. 2018; Upala et al. 2017). The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) recommended cholecystectomy in most symptomatic patients. Despite this recommendation, older adults are often excluded from cholecystectomy. The low rate of surgery reflects concerns and uncertainty about the risk and benefits of cholecystectomy in the elderly (Overby et al. 2010). Recent demographic changes of increasing older population, coupled with the fact that the prevalence of gallstones progressively increases with age, predict a dramatic increase in the incidence of all types of gallstone disease – asymptomatic, symptomatic, and complicated.

Epidemiology Risk factors for cholesterol gallstones include non-modifiable factors like ethnicity, family history, female sex, increasing age, and modifiable

1410

C. S. Pitchumoni and N. Ravindran

Table 1 Risk factors for cholesterol stones Modifiable High-calorie diet/ high-carbohydrate diet Low-fiber diet (“Western diet”) Sedentary lifestyle Obesity/metabolic syndrome (MS) Diabetes mellitus/insulin resistance Low HDL, high TG NAFLD Rapid weight loss /weight cycling Bariatric surgery/gastrectomy Pregnancy and parity Total parenteral nutrition Drugs Crohn’s disease Spinal cord injury Solid organ transplant Liver cirrhosis Chronic hepatitis C Non-modifiable Increasing age Female sex Family history

Ethnicity

Comment High-carb diets noted to increase risk (Tsai et al. 2005) Cholesterol stones now are majority of stones in East Asia (Shaffer 2005) Exercise reduces lithogenic risk (Banim et al. 2010) BMI more than 45 increases risk sevenfold (Stampfer et al. 1992) T2DM (Nervi et al. 2006), insulin resistance (Chapman et al. 1996), increased risk Increased risk (Petitti et al. 1981; Ahlberg 1979) Insulin resistance and MS (Loria et al. 2005) Weight loss > 1.5 kg/week increased risk (Erlinger 2000) Most likely in first 6 weeks (Melmer et al. 2015; Liang et al. 2017) Increased sludge, gallstones in 5% (Maringhini et al. 1993) Sludge formation after 4 weeks (Roslyn et al. 1983) Ceftriaxone, octreotide, thiazides, estrogen, progesterone (Stinton and Shaffer 2012) Two- to threefold increase (Whorwell et al. 1984) Threefold increase (Apstein and Dalecki-Chipperfield 1987) Increased in the first 2 years (Spes et al. 1990) (Except liver transplant as cholecystectomy done) Mostly pigment but also cholesterol stones Higher in child B C (Conte et al. 1999) More in hepatitis C (Acalovschi et al. 2009) 4–10 times more after 40 (Everhart and Ruhl 2009b) In 80 year old risk 40–50% 2:1 Difference in risk disappears in elderly (Everhart et al. 1999) Higher in twins 5 times higher in families (Sarin et al. 1995) Lith genes Lith genes include ABC cholesterol transporter (Krawczyk et al. 2013) Highest in Pima Indians, south and Central America parts of North India Lowest in Sub-Saharan Africa (Shaffer 2005)

Adapted from “The Growing Global Burden of Gallstone disease” Acalovschi and Lammert

factors like diet, drugs, rapid weight loss, low physical activity, total parenteral nutrition, and spinal cord injury (Shaffer 2006). Solid organ transplantation, except liver transplant (as gallbladder is removed) is associated with increased risk of gallstones in the first 2 years (Kao et al. 2003). In 1999, Everhart JE et al. published a landmark paper which was the first large US population-based estimate of the prevalence of gallstones and gallbladder disease. It included 14,000 participants who underwent screening

ultrasonography, as part of the Third National Health and Nutrition Examination Survey (NHANES III) (Everhart et al. 1999). Risk factors for gallstones, cholesterol, and pigment stones are tabulated in Tables 1 and 2.

Age and Gender Prevalence of gallstones increases with age. The risk of gallstones after 40 years rises by

62

Gallstones and Benign Gallbladder Disease

1411

Table 2 Risk factors for pigment stones Modifiable Chronic hemolysis – sickle cell disease Thalassemia Crohn’s disease Extensive ileal resection Cystic fibrosis Liver cirrhosis Biliary infection

Non-modifiable Increasing age Asian ethnicity

Comment Black pigment stones (Haley 2017) Consider prophylactic cholecystectomy Both cholesterol and black stones (Brink et al. 1999) Black pigment stones (Pitt et al. 1984) Mostly black pigment stones (Angelico et al. 1991) Mostly black pigment stones (Alvaro et al. 1990) Brown stones (Maki 1966) Form in bile ducts More common in East Asia Infestation with Clonorchis Opisthorchis Increase in black pigment stones in the elderly (Everhart and Ruhl 2009b) Brown pigment stones (Shoda et al. 2003)

Adapted from “The Growing Global Burden of Gallstone disease” Acalovschi and Lammert

4–10 times (Stinton and Shaffer 2012). The prevalence of gallstones in women at age 70 was 24% in the MICOL study and about 40% in the 80-year-old and near 50% in the above 90 group in a study from Dundee (Festi et al. 2008; Bateson 2000). Women are twice as likely as men to form gallstones, related to the effect of female sex hormones on cholesterol. Multiparous women have increased likelihood for gallstones. The female and male prevalence rates are nearly similar in the older age groups.

Ethnicity There is a wide variation in occurrence of gallstones in relation to ethnicity. Gallstone disease affects at least 10–15% of the Caucasian population but is a disease of epidemic proportions in Native Americans with a prevalence of 60–70% in Pima Indians of North America (Comess et al. 1967; Sampliner et al. 1970). Gallstones affect over 35–50% of the Hispanic population in Central and South America. A higher incidence is seen among Northern Europeans, 4–25% compared to Southern Europeans, 6–14% (Barbara et al. 1987; Aerts and Penninckx 2003). In Northern India, the rate is 6–21% (Singh et al. 2001). Frequency is lower in African Americans, East

Asia, and Sub-Saharan Africa, 5–13% (Everhart et al. 1999; Nomura et al. 1988). The propensity of North American Indians to develop obesity and diabetes, the two risk factors associated with cholelithiasis is a growing trend in most population groups. Familial incidence of gallstones is seen in nearly 1/3 of all patients (Hemminki et al. 2017).

Obesity Obesity is a risk factor for the formation of cholesterol gallstones (Amaral and Thompson 1985; Maclure et al. 1989). Stampfer et al. evaluated the effect of obesity in 90,000 women in the Nurses Health Study which showed a sevenfold rise in gallstones in those with a BMI more than 45 (Stampfer et al. 1992). Metabolic syndrome and diabetes mellitus are risk factors for gall stone formation. Complex metabolic pathways are thought to link gallstones to metabolic syndrome. Insulin resistance leads to altered cholesterol and bile salt metabolism (Ruhl and Everhart 2000). There are also more stone-related complications in the obese (Ata et al. 2011). Metabolic obesity associated with insulin resistance is being recognized as a risk factor in addition to insulin resistance in the non-obese non-diabetic in the prevalence of gallstone disease (Chang et al. 2008). The alarming rise in attempts to lose

1412

weight rapidly by medical treatment or by bariatric surgery increases the risk. Women who had a rapid weight loss of more than 4 kg had 44% increased risk of gallstones compared to an equal weight loss of 4 kg over a 2 year period. Women who lost more than10 kg had more than 94% risk for gallstones when other risk factors were controlled (Everhart 1993). Ehrlinger observed that the prevalence of new gallstones increases by 10– 12% after 8–16 weeks of a low-calorie diet and more than 30% about 12–18 months after gastric bypass, with 1/3 of stones becoming symptomatic. Risk factors that were identified were a relative loss of weight greater than 24% of the initial body weight, rate of weight loss more than 1.5 kg per week, a very low-calorie diet without fat, long overnight fasting period, and high serum triglycerides. Ursodeoxycholic acid (UDCA) decreases lithogenicity by lowering cholesterol saturation of bile (Erlinger 2000). TPN is a rare risk factor for microlithiasis and gallstones (Guglielmi et al. 2006; Roslyn et al. 1983). Drugs known to increase the risk of gallstones are octreotide, cephalosporins, and thiazides (Trendle et al. 1997; Lopez et al. 1991; Angelin 1989). Octreotide reduces motility and leads to biliary stasis. Ceftriaxone is secreted in high concentrations and crystallizes in bile, resulting in sludge.

Pathogenesis Gallstones are divided based on chemical composition into cholesterol, pigment, and mixed stones, depending on location as intrahepatic, gallbladder stones or choledocholithiasis. Most stones are cholesterol stones comprising 37–68%, pigment stones account for 2–27%, mixed stones 4–16%, and calcium stones 1–17%. Mixed stones are a combination of cholesterol and pigment stones (Tazuma 2006; Johnston and Kaplan 1993; Gurusamy and Davidson 2014). This classification is not of much practical use since composition can be determined only after surgery and chemical analysis of stones. Cholesterol stones form in the gallbladder mostly, but about 10% may form in the bile ducts.

C. S. Pitchumoni and N. Ravindran

Pigment stones are seen in patients with chronic hemolytic anemias such as sickle cell disease and thalassemia. Hemolysis leads to increased bilirubin and stone formation. These are black pigment stones consisting of calcium bilirubinate and form in the gallbladder or sometimes in the common bile duct (Trotman 1991). They contain less than 20% cholesterol. Sickle cell disease, although not a major problem in older people, frequently requires prophylactic cholecystectomy, in order to distinguish clinical features of sickle cell crisis from infarction of viscera (Bonatsos et al. 2001). Brown pigment stones are composed of unconjugated bilirubin, calcium salts and cholesterol and are intrahepatic. In East Asians brown pigment stones develop secondary to biliary infections due to bacteria or parasites or inflammation. There is changing epidemiology in that currently cholesterol stones are now more common than pigment stones in East Asia. Pigment stones can be seen in older adults as well (Van Erpecum et al. 1988). Although the discussion on the pathogenesis that follows here pertains to cholesterol stones, the clinical manifestations are the same. The pathogenesis of gallstones represents a failure of biliary cholesterol homeostasis (Wang et al. 2017). In bile, cholesterol, phospholipids, and bile acids are three major lipids, and bile pigments are minor lipids. Five primary defects in the pathogenesis are (i) genetic factors and Lith genes; (ii) hypersecretion of biliary cholesterol leading to supersaturated bile; (iii) rapid phase transitions of cholesterol in bile; (iv) impaired gallbladder motility associated with hypersecretion of mucins; and (v) increased amounts of cholesterol of intestinal origin (Dowling 2000; Wang et al. 2010, 2018). Bile salts are important to keep cholesterol in solution. Bile salts in critical micellar concentration aggregate to form simple micelles which can solubilize cholesterol (Somjen and Gilat 1985). Bile salts incorporate phospholipids to form mixed micelles that can solubilize triple the amount of cholesterol in simple micelles. The relative proportion of these three main components plays a critical role in determining the maximal solubility of cholesterol. Cholesterol gallstones are a polygenic disorder with

62

Gallstones and Benign Gallbladder Disease

several underlying mechanisms, but the main factor is excess biliary cholesterol (Venneman and van Erpecum 2010). Genes that contribute to cholesterol gallstones are those that encode for membrane transporters, regulatory enzymes, transcription factors, lipoprotein receptors, hormone receptors, and biliary mucins (Wang et al. 2018; Wang and Afdhal 2004). The complex genetic relationship to gallstone disease is still evolving. Gallstones form as microcrystals in the biliary system. Sludge is an intermediate stage in stone formation (Lee et al. 1988; Carey and Cahalane 1988). Sludge is a particulate matter composed of cholesterol, calcium bilirubinate, and mucin. Sludge may contain larger particles seen under microscopy called microliths (1–3 mm in size) which may lead to gallstones. Biliary sludge is reversible in most situations but may persist in 12–20% and cause complications like acute cholecystitis, cholangitis, or acute pancreatitis (Lee et al. 2015).

Clinical Features of Gallstone Disease (Table 3) Gallstones are asymptomatic in most people and only about 20% develop symptoms, necessitating removal of the gallbladder in 1–2% yearly (Gibney 1990; Portincasa et al. 2016).

1413

Because of the high prevalence of gallstones in older adults, cause of pain may falsely be attributed to the presence of gallstones, and although we call this entity symptomatic disease, the source of pain is not biliary in etiology. When symptomatic, the classic symptoms are sudden and rapidly intensifying pain in the right upper quadrant, radiating to the right scapula or shoulder, lasts several minutes to a few hours, associated with nausea and vomiting. In the geriatric population, however, similar to many other conditions, biliary disease may also present atypically, with atypical pain or no pain, associated with a confused state of mind and without leukocytosis. The clinical presentations depend on the site in the biliary system where the stone has lodged.

Biliary Pain Biliary pain is a consequence of transient obstruction of the cystic duct by a stone and is often erroneously called biliary colic. The term is a misnomer as the pain is steady and not colicky. Abdominal pain occurs in epigastrium or RUQ and may last for 1–5 h. The pain starts, gradually progresses to plateau, and stays constant for several hours prior to gradual resolution. It may be associated with dyspepsia. Right upper quadrant tenderness may be present. Laboratory tests are usually normal.

Table 3 Summarizes the clinical presentations Clinical presentation of gallstones Asymptomatic gallstones Biliary pain Acute cholecystitis Empyema of gallbladder Choloenteric fistula Gallstone Ileus Mirizzi’s syndrome Bouveret’s syndrome Chronic cholecystitis Asymptomatic choledocholithiasis Obstructive jaundice Acute cholangitis Acute pancreatitis Pyogenic liver abscess

Acute Calculous Cholecystitis and its Complications Gallstones cause more than 90% of acute cholecystitis. Acalculous cholecystitis accounts for the remaining 5–10% of acute cholecystitis. Acute calculous cholecystitis (ACC) occurs when a gallstone gets impacted in the cystic duct leading to acute inflammation of the gallbladder (Gurusamy and Davidson 2014). In 75% of patients, this is preceded by biliary pain. Initially there is epigastric pain that lasts more than 6 h, followed by right upper quadrant (RUQ) pain, which may be accompanied by nausea and vomiting. Patients

1414

C. S. Pitchumoni and N. Ravindran

Table 4 Tokyo guidelines TG18/TG13 diagnostic criteria for acute cholecystitis (Yokoe et al. 2018)

Table 5 Tokyo guidelines TG18/13 severity of acute cholecystitis (Yokoe et al. 2018)

A. Local signs of inflammation, etc. (1) Murphy’s sign, (2) RUQ mass/pain/tenderness B. Systemic signs of inflammation, etc. (1) Fever, (2) elevated CRP, (3) elevated WBC count C. Imaging findings Imaging findings characteristic of acute cholecystitis Suspected diagnosis: one item in A + one item in B Definite diagnosis: one item in A + one item in B + C

Grade III acute cholecystitis “Grade III” acute cholecystitis is associated with dysfunction of any one of the following organs/systems: 1. Cardiovascular dysfunction: hypotension requiring treatment with dopamine
5 μg/kg per min, or any dose of norepinephrine 2. Neurological dysfunction: decreased level of consciousness 3. Respiratory dysfunction: PaO2/FiO2 ratio < 30 4. Renal dysfunction: oliguria, creatinine >2.0 mg/dl 5. Hepatic dysfunction: PT-INR >1.5 6. Hematological dysfunction: platelet count 18,000/mm3) 2. Palpable tender mass in the right upper abdominal quadrant 3. Duration of complaints >72 h 4. Marked local inflammation (gangrenous cholecystitis, pericholecystic abscess, hepatic abscess biliary peritonitis, emphysematous cholecystitis Grade I acute cholecystitis

may have RUQ tenderness on palpation (Murphy’s sign) which is highly sensitive and specific (Trowbridge et al. 2003). Serum bilirubin may be mildly elevated; serum alkaline phosphatase and aminotransferases may be elevated as well. These classic findings may be obscure in the elderly, and clinical findings may not always be reliable. Complications like empyema or gallbladder perforation can occur if untreated in about 10% (Morris et al. 2007). Gangrenous cholecystitis is a rare but severe condition associated with intramural hemorrhage, mucosal ulcers, intraluminal purulent debris, hemorrhage, and fibrinous exudate (Bennett and Balthazar 2003; Morfin et al. 1968). Emphysematous cholecystitis (EC), also rare, is a rapidly progressive condition due to bacteria like Clostridia and E. coli with gas formation within the gallbladder. EC is seen more in men, in those with diabetes and bowel ischemia, with a fivefold increase in perforation and may be fatal (Gill et al. 1997). Tokyo guidelines 2013/2018 suggest guidelines for management of acute cholangitis and acute cholecystitis (see Tables 4 and 5). “Grade I” acute cholecystitis does not meet the criteria of “Grade III” or “Grade II” acute cholecystitis. It can also be defined as acute cholecystitis in a healthy patient with no organ dysfunction and mild inflammatory changes in the gallbladder, making cholecystectomy a safe and low-risk operative procedure. Gallbladder perforation is a rare complication occurring in 2–5% of acute cholecystitis (Jansen et al. 2018; Roslyn et al. 1987). It is more common in the elderly and can be associated with increased morbidity and mortality. Gallbladder

perforation may be of three types: type 1 into the peritoneal cavity, type 2 localized perforation, and type 3 cholecystoenteric fistula (Roslyn et al. 1987). Biliary fistulas are a rare complication of gallstone disease (Crespi et al. 2016). The primary fistulas are spontaneous complication, while the secondary ones are related to surgical complications. The incidence of primary biliary fistulas range from 1% to 2% and may be as high as 5% in endemic areas. The types of fistulas may be cholecystoduodenal, cholecystogastric, or cholecystocolic. Large stones, recurrent cholangitis, female sex, and in particular old age are risk factors for bilio-enteric fistulas. Gallbladder wall erosion and fistula formation can occur with gallstones causing obstruction when lodged in narrow parts of the GI tract, the ileocecal valve being the commonest area (gallstone ileus). Proximal migration or direct invasion to the stomach can result in the stone, usually of more than 2.5 cm size, causing gastric outlet obstruction (Bouveret syndrome).

62

Gallstones and Benign Gallbladder Disease

Table 6 Cesendes classification of Mirizzi’s syndrome (Csendes et al. 1989) Type of Mirizzi’s Type I

Type II

Type III Type IV

Description External compression of the common bile duct by stone impacted in the gallbladder or cystic duct Cholecystobiliary fistula present with erosion of less than one-third of the circumference of the bile duct Cholecystobiliary fistula involves up to two-thirds of the bile duct circumference Cholecystobiliary fistula with complete destruction of the bile duct

When a gallstone in the cystic duct causes compression on the bile duct or fistulizes into the bile duct and is associated with jaundice, it is termed Mirizzi’s syndrome (Zaliekas and Munson 2008). There are four types of Mirizzi’s syndrome as classified by Cesendes depending on the location (Table 6). Pathology in Mirizzi’s syndrome is due to impaction of stone and obstruction by direct mass effect or development of stricture due to inflammation and pressure necrosis which leads to fistula formation (Clemente et al. 2018). ERCP and MRCP help in diagnosis, but often this is only recognized during surgery (Alemi et al. 2019). A few authors include cholecystoenteric fistulas in the types of Mirizzi’s syndrome (Beltran et al. 2008). A discussion on secondary fistulas is discussed in major surgical textbooks.

Common Bile Duct (CBD) Stones The incidence/prevalence of choledocholithiasis is not known but estimated to be 10–20% in patients with gallstones and the incidence increases with age (Chen et al. 2015). Recent studies have demonstrated that the clinical presentation of CBD stones may vary with age (Hu et al. 2016). Unlike in younger adults who present with classic biliary colic symptoms, older adults may be asymptomatic with no apparent clinical features or present with biliary colic and jaundice (Rosseland and Glomsaker 2000). There are

1415

reports of cases of CBD stones impacted in the CBD that were asymptomatic for years. CBD stones may be classified as primary, secondary, residual, or recurrent. Primary CBD stones form in the bile ducts in setting of biliary ductal dilatation. Secondary stones form in the gallbladder and escape into the CBD. Residual stones are those stones in the CBD that are missed at the time of cholecystectomy but present within 2 years of cholecystectomy. Recurrent stones develop in the biliary ducts and occur longer than 2 years after cholecystectomy. CBD stones can cause intermittent obstruction of the bile duct, with transient increase in bilirubin, alkaline phosphatase, aminotransferases, and pancreatic enzymes. Younger adults with CBD stones were significantly more likely to have abnormal liver function tests than those without. The sensitivity and accuracy of transabdominal ultrasound scans in screening for CBD stones increases with age (Hu et al. 2016). Unless removed, CBD stones can cause acute pancreatitis, obstructive jaundice, acute ascending cholangitis, and hepatic abscess. ASGE criteria that stratify the risk of having choledocholithiasis are used in patients with intact gallbladder (Maple et al. 2010). Although CBD dilatation is not a predictive factor for choledocholithiasis post cholecystectomy, ASGE criteria are applicable similar to non-cholecystomized patients based on a retrospective study of 327 patients by Sousa et al. (2019). ASGE criteria have been shown to have a sensitivity varying from 55% to 89% (Gouveia et al. 2018; Suarez et al. 2016; Magalhaes et al. 2015). The criteria suggests high probability for CBD stones requiring further evaluation with ERCP. ASGE criteria for risk stratification for CBD stones suggest: Very strong predicators are the presence of a CBD stone on transabdominal US, clinical features of acute cholangitis, and serum bilirubin greater than 4 mg/dL. Dilated CBD was defined as > 6 mm in adults and > 8 mm post cholecystectomy. Intermediate risk (10–50%) patients had abnormal liver biochemical tests or age more than 55 or dilated CBD on imaging. Low-risk patients (< 10%) had no predictors.

1416

Ascending Cholangitis Ascending cholangitis can occur with distal CBD obstruction (see Tables 7 and 8). This presents as Charcot’s triad with RUQ abdominal pain, fever, and jaundice (Attasaranya et al. 2008; Kimura et al. 2007). Charcot’s triad has high specificity but low sensitivity as older adults with cholangitis may not manifest all the findings. More than 1/3 of patients, in particular older people, may not present with Charcot’s triad. In a prospective study assessing the diagnostic power of Charcot’s triad only 22% of patients documenting suppurative bile on surgical choledochotomy demonstrated all three criteria, indicating the suboptimal utility of the triad. However the triad has high specificity. Reynold’s pentad (Charcot’s triad with septic shock and altered mental status) is present only in 30–45% adults with cholangitis but with elderly patients, delirium, or dementia may confound the clinical picture. Bile cultures are positive in 80–100% of patients and blood cultures in 70% (Tanaka et al. 2007). Bacteria most frequently cultured are E. coli, Klebsiella, and Enterococcus (Gomi et al. 2013). Anaerobes and Clostridia may also occur. Staphylococcal infections are rare. Resistance to quinolones, ceftriaxone, ampicillinsulbactam, and piperacillin-tazobactam has been reported from 30% to 52% (Reuken et al. 2017). “Grade I” acute cholangitis does not meet the criteria of “Grade III” or “Grade II (moderate)” acute cholangitis at initial diagnosis.

Biliary Pancreatitis Acute biliary pancreatitis occurs as a result of CBD obstruction by gallstones at the ampullary region. Additional details on biliary pancreatitis are discussed in another chapter.

Chronic Cholecystitis (See Fig. 2) Chronic cholecystitis occurs with recurrent attacks of biliary pain associated with gallstones (Nesland 2004). Chronic cholecystitis is seen in the setting of cholelithiasis.

C. S. Pitchumoni and N. Ravindran Table 7 Tokyo guidelines 2018 TG18/13 criteria cholangitis (Kiriyama et al. 2018) A. Systemic inflammation A-1. Fever and/or shaking chills A-2. Laboratory data: evidence of inflammatory response B. Cholestasis B-1. Jaundice B-2. Laboratory data: abnormal liver function tests C. Imaging C-1. Biliary dilatation C-2. Evidence of the etiology on imaging (stricture, stone, stent, etc.) Suspected diagnosis: one item in A + one item in either B or C Definite diagnosis: one item in A, one item in B and one item in C

Table 8 Tokyo 2018 TG18/13 severity of acute cholangitis (Kiriyama et al. 2018) Grade III acute cholangitis “Grade III” acute cholangitis is defined as acute cholangitis that is associated with the onset of dysfunction at least in any one of the following organs/ systems: 1. Cardiovascular dysfunction: hypotension requiring dopamine
5 μg/kg per min, or any dose of norepinephrine 2. Neurological dysfunction: disturbance of consciousness 3. Respiratory dysfunction: PaO2/FiO2 ratio < 300 4. Renal dysfunction: oliguria, serum creatinine >2.0 mg/dl 5. Hepatic dysfunction: PT-INR >1.5 6. Hematological dysfunction: platelet count 12,000/mm3, 60 years, diabetes, acute colic within 30 days of operation, jaundice, acute cholecystitis, or cholangitis) (Table 11) (Level I, Grade B). Among papers suggesting that antibiotic prophylaxis is helpful is a recent randomized study finding fewer wound infections in patients on ampicillin sulbactam versus cefuroxime particularly in enterococcal infections in high risk patients undergoing elective cholecystectomy. If

Table 11 High risk acute cholecystitis patient requiring antibiotics Risk factors Age > 60 years Diabetes mellitus Acute colic within 30 days of operation Jaundice Acute cholecystitis Cholangitis

C. S. Pitchumoni and N. Ravindran

given, they should be limited to a single preoperative dose given within one hour of skin incision and re-dosed if the procedure is more than 4 h long (Dervisoglou et al. 2006). Laparoscopic cholecystectomy (LC) is the standard of care in most patients with symptomatic gallstones and is a safe procedure in the older adult although outcomes may not be as good as younger patients (Nielsen et al. 2014). Parmar et al. used a large population-based cohort to describe the trajectory of care specifically in older patients presenting with an initial episode of symptomatic cholelithiasis who did not undergo elective cholecystectomy. The authors developed the PREOP-Gallstones model, a nomogram that reliably predicted patients with an over 40% 2-year risk of developing gallstone-related complications (approximately 10% of the cohort) and an additional 50% of patients with less than 10% 2-year risk. Older age, white race, male sex, initial visit to the emergency room department, and a diagnosis of complicated gallstone disease (gallstone pancreatitis, common bile duct stones, and acute cholecystitis) at initial presentation need urgent surgery. The PREOP-Gallstones model enables clinicians to use readily identifiable patient characteristics to quantify an individualized risk score requiring emergent biliary care. Active treatment of coexisting diseases, appropriate selection of surgical procedures, improvements in perioperative therapy, and timely management of postoperative complications are key factors in enhancing therapeutic efficacy in elderly patients with biliary diseases (Zhang et al. 2017). Despite the proven safety of laparoscopic cholecystectomy, older patients with gallstone disease are less likely to undergo cholecystectomy than younger patients (Riall et al. 2010). However the super-elderly patients (>90 years) have a mortality of 3.7% after laparoscopic cholecystectomy and 12% after open cholecystectomy according to Irojah et al. (2017). Unsurprisingly in their study, postop myocardial infarction, pneumonia, sepsis, SIRS, pre-operative delirium, history of cigarette smoking, and corticosteroid use were predictive of poor outcome and death. In symptomatic gallstone disease, cholecystectomy should be done as

62

Gallstones and Benign Gallbladder Disease

early as possible, if no major contraindications exist, preferably in the same admission (Thangavelu et al. 2018; Oppenheimer and Rubens 2019). Gurusamy et al. (2010) in a metaanalysis compared early laparoscopic cholecystectomy (ELC 1 week of onset of symptoms) with delayed laparoscopic cholecystectomy (DLC at least 6 week after symptoms resolve) in patients with ACC (Gurusamy et al. 2010). The results were similar with regard to bile duct injury and conversion rate, but the hospital stay was shorter by 4 days for early LC (Gomes et al. 2017; Gurusamy et al. 2013). Mortality rates in the elderly undergoing emergency cholecystectomy are reported to range from 6% to 22% (Uecker et al. 2001; Glenn 1981; Harness et al. 1986). The conversion rate to open cholecystectomy is 7–32% in older patients. Patients with mild cholecystitis should have early surgery, within 7 days. The role of medical therapy with ursodeoxycholic acid (UDCA) with or without extracorporeal shock wave lithotripsy is limited due to low rates of cure, ineffectiveness in preventing complications and high recurrence rates (O’Donnell and Heaton 1988; Carrilho-Ribeiro et al. 2006). Arguably UDCA can be considered in patients with non-calcified stones less than 1.5 mm and if the patient does not want surgery, although the benefit is disputed (Venneman et al. 2006). However, there is an indication for UDCA therapy in patients after bariatric surgery who have gallstones prior to surgery or are at high risk (Magouliotis et al. 2017).

Management of Complicated Gallbladder Disease in the Elderly Supportive treatment like IV fluids and antibiotics are advisable. Antibiotic therapy should be instituted taking into consideration severity, hospitalized status, and cultures. Multi-specialty input including infectious disease may be needed in severely ill patients. Gallbladder disease is the most common cause of acute abdominal pain in older patients and accounts for a third of abdominal operations in

1423

patients older than 65 years (Hendrickson and Naparst 2003; Riall et al. 2015; Bugliosi et al. 1990; Ansaloni et al. 2016). Age is an independent risk factor for mortality related to surgery, and older age is a negative predictor for undergoing cholecystectomy (Bergman et al. 2011). The 2017 WSES guidelines on ACC considered the relationship between old age and surgery (Ansaloni et al. 2016). Laparoscopic cholecystectomy (LC) is the standard approach of treatment for symptomatic gallstone disease with few relative or absolute contraindications, but elderly patients with gallstone complications are less likely to undergo surgery (Maple et al. 2010; Williams et al. 2008). Laparoscopic approach should always be attempted at first except in the case of absolute anesthetic contraindications and septic shock in older patients with acute cholecystitis (see Table 12). Most geriatric patients today undergo laparoscopic cholecystectomy without increased morbidity or mortality even though obesity and other comorbid conditions would affect the outcome. LC was shown to be safe and feasible in octogenarians (De la Serna et al. 2019). However, another study based on a large number of adults aged 60 or older, age was associated negatively with complications. Older age however is not a major factor in conversion of LC to open surgery. The rate of complications between older and younger patients is not different (Nassar and Richter 2019). The mortality for the super-elderly (90 year and older) after laparoscopic or open Table 12 Contraindications cholecystectomy

for

laparoscopic

ASGE guidelines – contraindications for LC include but are not limited to Generalized peritonitis Septic shock from cholangitis Severe acute pancreatitis Untreated coagulopathy Lack of surgeon expertise Previous abdominal operations which prevent safe abdominal access or progression of the procedure Advanced cirrhosis with failure of hepatic function Gallbladder cancer

1424

cholecystectomy is 3.7% and 12%, respectively, significantly higher than the mortality in the general population of 0.3% to 3.8% (Irojah et al. 2017; Ingraham et al. 2010). Other factors increasing the risk further were reported to be Hispanic race, emergent procedures, open surgical approaches, poor preoperative functional status, postoperative myocardial infarction, delirium, and septic shock (Irojah et al. 2017). Management of gallbladder disease varies according to complications and comorbidities. A reliable prognostic score in assessing frailty that can guide the management in ACC is necessary but can consider using ASA APACHE II Charlson Comorbidity Index (CCI) or P-POSUM score (Portsmouth Physiological and Operative Severity Score for the enUmeration of Mortality.) POSUM score is useful in assessing mortality and morbidity in elderly patients undergoing laparoscopic cholecystectomy (Tambyraja et al. 2005). POSUM score accurately predicts morbidity in emergency surgery in nonagenarians (Imaoka et al. 2017). CCI is a method to categorize a patient’s comorbidities based on the International Classification of Diseases (ICD) codes used in regulatory data such as hospital summary data. There is agreement that the decision is based on comorbid conditions and risk stratification criteria like American Society of Anesthesiology (ASA) criteria. The above perceptions are to be critically reviewed with other options. Older individuals do better with elective surgery, so it is necessary to weigh the decision regarding surgery with great care. Patients on chronic anticoagulation on bridging heparin therapy had more bleeding in several studies and caution is needed in these patients (Ercan et al. 2010). The Tokyo 2013 guidelines recommended surgery within 72 h and in the 2018 update early cholecystectomy was still advised in low risk patients beyond 72 h (Yokoe et al. 2018). Tokyo Guidelines 2018 are summarized as follows (see Fig. 6). The ASA score or Charlson Comorbidity Index (CCI) can be used to stratify patients with high risk. Patients with moderate cholecystitis should have surgery early if the patient can withstand surgery, but if the patient is high risk for surgery, conservative treatment and biliary

C. S. Pitchumoni and N. Ravindran

drainage should be considered. In patients with severe cholecystitis, after the patient has been resuscitated, with favorable organ system failure factors and negative predictive factors, early surgery can be considered in specialist centers. Cholecystectomy should be performed as early as possible as it has less complications and shorter hospital stay but can be done within 10 days of onset of symptoms. There are no specific studies evaluating early versus delayed laparoscopic cholecystectomy for elderly patients. Conversion to open surgery may be predicted by fever, leucocytosis, elevated serum bilirubin, and extensive upper abdominal surgery. Laparoscopic or open subtotal cholecystectomy can be considered as an alternative for older patients with advanced inflammation, gangrenous gallbladder, and if gallbladder anatomy makes it difficult and main bile duct injuries are likely. In individuals who may not withstand surgery, including the elderly, conservative treatment including early biliary drainage should be performed and surgery should be done once factors are favorable. Studies looking at the need for cholecystectomy after percutaneous cholecystostomy in high-risk patients are scant. The role of cholecystostomy as a bridging therapy until cholecystectomy or as definitive treatment in elderly patients is uncertain due to lack of studies in the age group, but in high risk patients, a number of options are available like emergency ultrasonographic percutaneous cholecystostomy and interval laparoscopic cholecystectomy (Fleming et al. 2019; Radosa et al. 2019; Park et al. 2019). Endoscopic techniques are an alternate in older patients who are acutely ill and are at high risk for surgery (discussed in another chapter) (Mori et al. 2018; Siddiqui et al. 2019). Endoscopic US-guided gallbladder drainage is an emerging alternative as it provides highly effective drainage without the need for a percutaneous catheter via either a trans-ampullary or a transmural approach (Balmadrid 2018). Endoscopic gallbladder drainage is reported to have a high success rate with an acceptable rate of adverse events and can be considered in nonsurgical patients to avoid long term percutaneous catheter (Adler 2019). Percutaneous transhepatic

62

Gallstones and Benign Gallbladder Disease

1425

Fig. 6 Adaptation of Tokyo guidelines 2018 for treatment of cholecystitis (Ref Management of acute cholecystitis Tokyo guidelines 2018)

gallbladder aspiration though not a recommended standard procedure, is a simple and easy decompression method with a low complication rate (Itoi et al. 2017; Komatsu et al. 2016). It may also be reasonable to wait in high risk patients as about 30% of patients may not have recurrent biliary colic.

CBD Stones The presence of biliary stones in patients with symptomatic gallbladder disease is about 10– 20%, but in the absence of abnormal liver biochemical tests and CBD dilatation, risk of choledocholithiasis may be as low as 5% (Collins

1426

C. S. Pitchumoni and N. Ravindran

Table 13 ASGE risk stratification and management Probability for CBD stone High

Intermediate

Low

Predictors for choledocholithiasis CBD stone on imagingor Clinical ascending cholangitis or Total bilirubin>4 mg/dl and dilated CBD stone on imaging Abnormal liver biochemical tests or age > 55 years or Dilated CBD on imaging No predictors present

et al. 2004; Nebiker et al. 2009). The management of CBD stones is endoscopic or by surgery or by a combined approach. The general principles in the management of CBD stones were recently revised (Williams et al. 2017; Buxbaum et al. 2019). The ASGE 2019 guidelines should be used in older patients to risk stratify for CBD stones to reduce unnecessary ERCP (Buxbaum et al. 2019) (see Table 13). Direct ERCP was advised only in patients with confirmed CBD stones on abdominal ultrasound or high risk of choledocholithiasis (total bilirubin > 4 mg/dl, dilated bile duct and cholangitis) to allow immediate clearance of the duct. There was no conclusive superior outcome with ERCP done preoperatively, intraoperatively, or postoperatively. In patients undergoing cholecystectomy, timing of ERCP is advised based on available surgical and endoscopic expertise. The British Society of Gastroenterology recommends laparoscopic bile duct exploration in patients undergoing cholecystectomy to reduce the number of interventions needed for biliary stones, as there was no difference in mortality or morbidity compared to perioperative ERCP. Laparoscopic biliary duct exploration was comparable to ERCP and associated with shorter hospital stay (Williams et al. 2017; Dasari et al. 2013). ERCP and intraoperative cholangiography (IOC) have showed excellent and comparable results (Dasari et al. 2013). Intraoperative cholangiogram is limited by its availability but is an option where available in patients with intermediate to high probability of gallstones

Recommended strategy Proceed to ERCP

EUS MRCP laparoscopic IOC or intraoperative US

Cholecystectomy with/without IOC or intraoperative US

and where diagnosis has not been confirmed by other modalities. CBD stone removal with ERCP is associated with high efficiency (about 90%) and only a negligible rate of adverse events of about 5% including ERCP pancreatitis, bleeding, perforation, and death (less than 1%). ERCP leads to complications (pancreatitis, cholangitis, duodenal perforations, hemorrhage, contrast media allergy) in 1% to 2% of patients which increases to 10% in case of sphincterotomy (Sousa et al. 2019; Cotton et al. 2009). Endoscopic sphincterotomy (ES) followed by large balloon dilation over ES alone was advised in patients with large or difficult to remove bile duct stones. Intraductal therapy with electrohydraulic or laser lithotripsy was suggested for large intrahepatic and extrahepatic bile ducts stones that cannot be removed by conventional methods (Watson et al. 2018). Stent maintenance with exchange or removal is essential to reduce the risk for adverse events in patients who have stents placed. MRCP, EUS, intraoperative cholangiography, or laparoscopic US can be done in older patients with moderate risk for choledocholithiasis depending on local availability and expertise. Evaluation with tests including intraoperative cholangiogram was not felt to be necessary in the EASL 2016 guidelines in patients at low risk for CBD stones as small stones would pass spontaneously, while ASGE guidelines recommend cholecystectomy with or without IOC or intraoperative US in these patients (EASL 2016).

62

Gallstones and Benign Gallbladder Disease

Primary CBD stones can occur in patients with risk factors for gallstones. CBD stones may recur in patients treated with ERCP+ES without cholecystectomy. Risk is high in patients with periampullary type A diverticulum and dilated CBD (Nzenza et al. 2018).

Acute Cholangitis Acute cholangitis is a serious complication associated with significant morbidity and mortality especially in the geriatric population (Sugiyama and Atomi 1997). Presence of RUQ pain with fever and jaundice is highly suggestive of cholangitis. Abdominal US may show CBD dilatation but is less sensitive than EUS or MRCP. Treatment includes IV fluids and antibiotics alone in mild cholangitis and biliary drainage procedure usually ERCP+ES in moderate and severe cholangitis or if there is failure to improve in mild cholangitis (Lai et al. 1992). Antibiotic treatment should be guided by local microbial susceptibility patterns. ERCP +ES are procedures of choice in management of ascending cholangitis and has the additional benefit of obtaining bile cultures which are a reliable mechanism to evaluate ascending cholangitis and check sensitivity of organisms (Chandra et al. 2019). In the Tokyo guidelines 2018, recommendations include treating mild community acquired infection with ampicillin sulbactam (unless local resistance is more than 20%), second- or thirdgeneration cephalosporins, and quinolones with metronidazole. In patients with severe communityacquired infections or hospital acquired infections piperacillin tazobactam, third- or fourth-generation cephalosporins +/- metronidazole, and broadspectrum carbapenems were recommended (Gomi et al. 2018; Pisano et al. 2019). High rate of multidrug-resistant bacteria and polymicrobial culture is seen in patients who have had previous biliary stenting, especially those patients with multiple prior interventions (Schneider et al. 2014). Additional details on antimicrobial therapy in biliary infections are provided in another chapter. In patients with septic shock or deterioration despite antibiotic therapy biliary decompression

1427

needs to be done urgently after adequate resuscitation, within 24 h of presentation although evidence on optimal timing is not clear. Early ERCP is associated with reduced hospital stay, while in patients who had ERCP after 72 h, increased vasopressor requirement was seen. If ERCP is not feasible then percutaneous drainage or surgical intervention may be required. Endoscopic therapy was seen to be superior to surgical treatment in patients needing biliary decompression for cholangitis due to gallstones, especially in the old, with lesser mortality and morbidity (Leese et al. 1986). Among older patients including those with serious comorbidities early ERCP+ES followed by laparoscopic cholecystectomy is associated with a significant and clinically important reduction in complications compared to sphincterotomy alone. Patient’s family members as well as physicians are often reluctant to proceed with cholecystectomy in elderly patients with cholangitis. Cholecystectomy followed by endoscopic intervention does not appear to increase surgical complications (Elmunzer et al. 2017; Tohda et al. 2016). Older age does not influence incidence or severity of post ERCP pancreatitis (Katsinelos et al. 2018). Biliary pancreatitis has been discussed in another chapter. Urgent ERCP was not recommended in patients with gallstone pancreatitis without cholangitis or biliary obstruction; this was a strong recommendation with low quality of evidence in the recent ASGE guidelines. Same admission cholecystectomy was advised in mild gallstone pancreatitis.

DVT Prophylaxis The American College of Chest Physicians (ACCP) guidelines for deep vein thrombosis (DVT) prophylaxis utilizing the venous thromboembolism (VTE) risk stratification systems were endorsed by the SAGES guidelines committee although they are not specifically directed at laparoscopic surgery patients (Gould et al. 2012; Richardson et al. 2017). There was a statistically significant reduction in VTE risk in laparoscopic procedures as seen in a study comparing the

1428

incidence of VTE following laparoscopic versus open surgery in 138,595 patients (Vedovati et al. 2014). Based on a meta-analysis on laparoscopic cholecystectomy patients routine use of VTE chemoprophylaxis showed no significant benefit and suggested its use only in higher risk patients based on risk stratification (Rondelli et al. 2013). Risk of bleeding should be considered when evaluating for chemoprophylaxis postoperatively. Although the optimal agent, dosing, duration, and timing of pharmacologic prophylaxis was not determined in the SAGES guidelines, ACCP guidelines recommend heparin and mechanical prophylaxis with elastic stockings or intermittent pneumatic compression in high-risk patients.

Acute Acalculous Cholecystitis See Table 14. Acute acalculous cholecystitis (AAC) is acute cholecystitis in the absence of gallstones, a rare but lethal condition, with a mortality rate of 30% (Kalliafas et al. 1998). A high index of suspicion is needed as it has no typical presentation, so diagnosis can be challenging and is a serious problem as can progress rapidly with a high prevalence of gangrene and perforation. It is usually seen in patients hospitalized for serious illnesses like trauma and burns but is not limited to critical illness. It can occur after gastrointestinal surgery and in the postoperative period is a devastating condition. It is seen more often in males (80%), especially elderly (Ryu et al. 2003). Diagnosis of AAC can be made with use of US or CT abdomen accurately (Crichlow et al. 2012). US features for AAC are GB wall thickness of Table 14 Risk factors for AAC Risk factors Burns Trauma Prolonged parenteral nutrition Uncontrolled diabetes Congestive heart failure Vascular disease Acquired immune deficiency syndrome Drugs like hormonal agents and thiazides

C. S. Pitchumoni and N. Ravindran

more than 3.5 mm, subseroral edema or pericholecystic fluid, distention of more than 5 cm (without associated ascites or hypoalbuminemia) intramural gas and mucosal sloughing (Barie and Eachempati 2010). E. coli and other gram-negative enteric bacteria are most frequently isolated. HIV-infected patients may have CMV, Cryptosporidium, Mycobacterium TB, MAI, or fungal infection as the agent (Elwood 2008). Bile stasis is implicated in its pathogenesis. Bile compounds like lysophosphatidyl choline and β glucuronidase may have a role, leading to inflammation of the gallbladder wall (Neiderhiser 1986; Kouroumalis et al. 1983). Infection with bacteria is a secondary event. Increasing rates of AAC is attributed to obesity and fat in the gallbladder wall. Traditionally cholecystectomy has usually been the treatment but percutaneous cholecystostomy with antibiotics is emerging as an alternative (Glenn and Becker 1982; Horn et al. 2015). Percutaneous cholecystostomy is adequate in 85–90% of patients (Park et al. 2019; Akhan et al. 2002). Cholecystectomy may be performed after the resolution of cholecystitis and optimization of associated medical illnesses to prevent recurrent cholecystitis.

Functional Gallbladder Disorder Functional disorders of the gallbladder include acalculous biliary pain or biliary dyskinesia or dysmotility and Sphincter of Oddi dysfunction (SOD). Functional gallbladder disorder is biliary pain which is not due to structural disease. A previous classification (Milwaukee) defined type 1 as biliary type pain associated with abnormal liver/pancreatic chemistries in association with biliary or pancreatic changes. Type 2 refers to either abnormal liver or pancreatic chemistries, with either biliary or pancreatic ductal dilatation. Type 3 was based only on symptoms. Rome IV has eliminated type 3 (Geenen et al. 1989). According to the Rome IV criteria, Sphincter of Oddi disorders are now classified as functional biliary sphincter disorder and functional pancreatic sphincter disorder (Cotton et al. 2016).

62

Gallstones and Benign Gallbladder Disease

According to the Rome IV criteria, biliary pain is defined as pain in the epigastrium or RUQ that meets the following criteria: Builds up to a steady level and lasts at least 30 min Occurs at different intervals Is severe enough to interrupt daily activities or lead to an emergency department visit Is not significantly related to bowel movements (< 20%) or relieved by postural change or acid suppression It is more common in women and young to middle age. Pathophysiology is poorly understood, but dysmotility and crystal formation have been suggested. These patients should be evaluated with liver enzymes, pancreatic enzymes, and abdominal ultrasound. Cholecystokinin cholescintigraphy may be used to measure gallbladder ejection fraction. Normal GB EF is 35%. A low gallbladder EF is supportive of diagnosis. There is insufficient evidence on the role of cholecystectomy in patients with normal EF. In a recent study looked at the utility of scintigraphic studies in evaluation of chronic GB disease by reviewing 366 hepatobiliary scintigraphic studies the authors noted that the findings like small bowel delayed transit, GB filling time, and reversal of normal GB and small bowel filling sequence on HB scanning are not associated with GB EF. GB EF according to the authors should continue to be used as a diagnostic tool for chronic gallbladder disease (Christensen et al. 2018). Chronic pain after laparoscopic cholecystectomy is not as common as with open cholecystectomy and appears to be associated with the intensity of acute postoperative pain (Bisgaard et al. 2005; Ahmed et al. 2008). This is a difficult issue for the patient and physician, and there is not much literature on its prevalence. Usually no clear etiology is found.

Biliary Strictures Biliary strictures may be benign or malignant (Kapoor et al. 2018). Causes of benign biliary strictures include iatrogenic causes like biliary or

1429

hepatic surgery, chronic pancreatitis, parasites, and primary sclerosing cholangitis (Ferreira et al. 2016). Patients may present with abnormal liver biochemistry or obstructive jaundice. Differentiation whether stricture is benign or malignant maybe difficult especially in older people. The diagnosis of biliary lesions and strictures, and differentiating benign from malignant is important in the precise diagnosis of inflammatory activity and in management (Rey et al. 2014). The accurate assessment of bile duct stenosis may require MRCP, ERCP, EUS, and or spyglass technique of cholangioscopy. Brush cytology is the preferred investigation method for strictures. Cholangioscopy allows direct visualization, therapeutic maneuvers of the biliary ductal system and opportunity for obtaining sample for cytology (Ayoub et al. 2018). Cholangioscopyguided biopsy appears to have the potential to overcome the problems associated with inadequate tissue sampling.

Key Points The burden of gallstone disease is impressive because of its high frequency, relationship to advancing age, and the rising cost of care. • Over 700,000 cholecystectomies are performed in the United States annually. • With increasing obesity and aging populations, there is rising incidence and severity of gallstone disease. • Gallstones are formed in the gallbladder or bile ducts, of cholesterol or bile pigments. Most gallstones are cholesterol stones. • The risk of gallstones at age 80 years is near 50%. • Asymptomatic in most people; about 20% develop symptoms, necessitating cholecystectomy in 1–2% yearly. • Abdominal ultrasound is the preferred initial imaging technique in suspected acute cholecystitis, because of low cost, easy availability, non-invasive nature and high accuracy for gallbladder stones. • Ultrasound abdomen has low sensitivity in detecting microlithiasis (50%).

1430

• The combination of sonographic Murphy sign, gallbladder wall thickening > 3 mm, pericholecystic fluid are major criteria for diagnosis of acute cholecystitis. Biliary dilation and gallbladder hydrops are minor criteria. • Hepatobiliary iminodiacetic acid scan (HIDA scan) has the highest sensitivity and specificity for acute cholecystitis, but the long time required to perform the test and exposure to ionizing radiation limit its use. • Acute cholecystitis is an inflammatory process at the beginning. • The use of antibiotics may be restricted to those likely to develop sepsis. • Laparoscopic cholecystectomy for acute cholecystitis is safe and feasible and has a low complication rate in the older adult.

Key Points 2 • The incidence of choledocholithiasis in patients with cholelithiasis is 5–20%, of which 5% are asymptomatic. • Charcot’s triad had low sensitivity but high specificity. • The complication of CBD stones are acute cholangitis acute pancreatitis and biliary cirrhosis. • Sensitivity of abdominal US in detection of CBD stones is only 65–70%; however specificity is 90%. • Endoscopic US has a sensitivity of 90% and a higher specificity. • CT scan has variable accuracy for choledocholithiasis but lower than MRCP and EUS. • ERCP should only be performed for therapeutic purposes and not as a diagnostic test. • Ascending cholangitis should be treated with early biliary drainage.

References Acalovschi M, Buzas C, Radu C, Grigorescu M. Hepatitis C virus infection is a risk factor for gallstone disease: a prospective hospital-based study of patients with chronic viral C hepatitis. J Viral Hepat. 2009;16(12):860–6. Acosta JM, Katkhouda N, Debian KA, Groshen SG, TsaoWei DD, Berne TV. Early ductal decompression versus

C. S. Pitchumoni and N. Ravindran conservative management for gallstone pancreatitis with ampullary obstruction: a prospective randomized clinical trial. Ann Surg. 2006;243(1):33–40. Adler DG. Endoscopic gallbladder drainage. Endosc. 2019;114(5):700–2. Aerts R, Penninckx F. The burden of gallstone disease in Europe. Aliment Pharmacol Ther. 2003;18(s3):49–53. Ahlberg J. Serum lipid levels and hyperlipoproteinaemia in gallstone patients. Acta Chir Scand. 1979;145(6):373–7. Ahmed BH, Ahmed A, Tan D, Awad ZT, Al-Aali AY, Kilkenny J 3rd, et al. Post-laparoscopic cholecystectomy pain: effects of intraperitoneal local anesthetics on pain control – a randomized prospective doubleblinded placebo-controlled trial. Am Surg. 2008;74(3):201–9. Akhan O, Akıncı D, Özmen MN. Percutaneous cholecystostomy. Eur J Radiol. 2002;43(3):229–36. Alemi F, Seiser N, Ayloo S. Gallstone disease: cholecystitis, Mirizzi syndrome, Bouveret syndrome, gallstone ileus. Surg Clin North Am. 2019;99(2):231–44. Alvaro D, Angelico M, Gandin C, Ginanni Corradini S, Capocaccia L. Physico-chemical factors predisposing to pigment gallstone formation in liver cirrhosis. J Hepatol. 1990;10(2):228–34. Amaral JF, Thompson WR. Gallbladder disease in the morbidly obese. Am J Surg. 1985;149(4):551–7. Angelico M, Gandin C, Canuzzi P, Bertasi S, Cantafora A, De Santis A, et al. Gallstones in cystic fibrosis: a critical reappraisal. Hepatology (Baltimore, Md). 1991;14(5):768–75. Angelin B. Effect of thiazide treatment on biliary lipid composition in healthy volunteers. Eur J Clin Pharmacol. 1989;37(1):95–6. Ansaloni L, Pisano M, Coccolini F, Peitzmann AB, Fingerhut A, Catena F, et al. WSES guidelines on acute calculous cholecystitis. World J Emerg Surg. 2016;11(1):25. Apstein MD, Dalecki-Chipperfield K. Spinal cord injury is a risk factor for gallstone disease. Gastroenterology. 1987;92(4):966–8. Ata N, Kucukazman M, Yavuz B, Bulus H, Dal K, Ertugrul DT, et al. The metabolic syndrome is associated with complicated gallstone disease. Can J Gastroenterol ¼ J Can de Gastroenterol. 2011;25(5):274–6. Attasaranya S, Fogel EL, Lehman GA. Choledocholithiasis, ascending cholangitis, and gallstone pancreatitis. Med Clin North Am. 2008;92(4):925–60, x. Ayoub F, Yang D, Draganov PV. Cholangioscopy in the digital era. Transl Gastroenterol Hepatol. 2018;3:82. Balmadrid B. Recent advances in management of acalculous cholecystitis. F1000Research. 2018;7:1660. Banim PJ, Luben RN, Wareham NJ, Sharp SJ, Khaw KT, Hart AR. Physical activity reduces the risk of symptomatic gallstones: a prospective cohort study. Eur J Gastroenterol Hepatol. 2010;22(8):983–8. Barbara L, Sama C, Morselli Labate AM, Taroni F, Rusticali AG, Festi D, et al. A population study on the prevalence of gallstone disease: the Sirmione study. Hepatology (Baltimore, Md). 1987;7(5):913–7.

62

Gallstones and Benign Gallbladder Disease

Barie PS, Eachempati SR. Acute Acalculous cholecystitis. Gastroenterol Clin. 2010;39(2):343–57. Bateson MC. Gallstones and cholecystectomy in modern Britain. Postgrad Med J. 2000;76(901):700–3. Beltran MA, Csendes A, KSJWJoS C. The relationship of Mirizzi syndrome and cholecystoenteric fistula: validation of a modified classification. World J Surg. 2008;32(10):2237–43. Bennett GL, Balthazar EJ. Ultrasound and CT evaluation of emergent gallbladder pathology. Radiol Clin. 2003;41(6):1203–16. Bergman S, Sourial N, Vedel I, Hanna WC, Fraser SA, Newman D, et al. Gallstone disease in the elderly: are older patients managed differently? Surg Endosc. 2011;25(1):55–61. Bisgaard T, Rosenberg J, Kehlet H. From acute to chronic pain after laparoscopic cholecystectomy: a prospective follow-up analysis. Scand J Gastroenterol. 2005;40(11):1358–64. Boender J, Nix GA, de Ridder MA, Dees J, Schutte HE, van Buuren HR, et al. Endoscopic sphincterotomy and biliary drainage in patients with cholangitis due to common bile duct stones. Am J Gastroenterol. 1995;90(2):233–8. Bonatsos G, Birbas K, Toutouzas K, Durakis N. Laparoscopic cholecystectomy in adults with sickle cell disease. Surg Endosc. 2001;15(8):816–9. Brink MA, Slors JF, Keulemans YC, Mok KS, De Waart DR, Carey MC, et al. Enterohepatic cycling of bilirubin: a putative mechanism for pigment gallstone formation in ileal Crohn’s disease. Gastroenterology. 1999;116(6):1420–7. Bugliosi TF, Meloy TD, Vukov LF. Acute abdominal pain in the elderly. Ann Emerg Med. 1990;19(12):1383–6. Buxbaum JL, Abbas Fehmi SM, Sultan S, Fishman DS, Qumseya BJ, Cortessis VK, et al. ASGE guideline on the role of endoscopy in the evaluation and management of choledocholithiasis. Gastrointest Endosc. 2019;89(6):1075–105. Carey MC, Cahalane MJ. Whither biliary sludge? Gastroenterology. 1988;95(2):508–23. Carrilho-Ribeiro L, Pinto-Correia A, Velosa J, Carneiro De Moura M. A ten-year prospective study on gallbladder stone recurrence after successful extracorporeal shockwave lithotripsy. Scand J Gastroenterol. 2006;41(3):338–42. Chandra S, Klair JS, Soota K, Livorsi DJ, Johlin FC. Endoscopic retrograde Cholangio-Pancreatographyobtained bile culture can guide antibiotic therapy in acute cholangitis. Dig Dis. 2019;37(2):155–60. Chang Y, Sung E, Ryu S, Park Y-W, Jang YM, Park M. Insulin resistance is associated with gallstones even in non-obese, non-diabetic Korean men. J Korean Med Sci. 2008;23(4):644–50. Chapman BA, Wilson IR, Frampton CM, Chisholm RJ, Stewart NR, Eagar GM, et al. Prevalence of gallbladder disease in diabetes mellitus. Dig Dis Sci. 1996;41(11):2222–8. Chen W, Mo JJ, Lin L, Li CQ, Zhang JF. Diagnostic value of magnetic resonance cholangiopancreatography in choledocholithiasis. World J Gastroenterol. 2015;21(11):3351–60.

1431 Christensen CT, Peacock JG, Vroman PJ, Banks KP. Scintigraphic findings beyond ejection fraction on hepatobiliary scintigraphy: are they correlated with chronic gallbladder disease? Clin Nucl Med. 2018;43(10):721–7. Clemente G, Tringali A, De Rose AM, Panettieri E, Murazio M, Nuzzo G, et al. Mirizzi syndrome: diagnosis and Management of a Challenging Biliary Disease %J Canadian journal of gastroenterology and. Hepatology. 2018;2018:6. Collins C, Maguire D, Ireland A, Fitzgerald E, O’Sullivan GC. A prospective study of common bile duct calculi in patients undergoing laparoscopic cholecystectomy: natural history of choledocholithiasis revisited. Ann Surg. 2004;239(1):28–33. Comess LJ, Bennett PH, Burch TA. Clinical gallbladder disease in pima Indians. N Engl J Med. 1967;277(17):894–8. Conte D, Fraquelli M, Fornari F, Lodi L, Bodini P, Buscarini L. Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey. Arch Intern Med. 1999;159(1):49–52. Cotton PB, Garrow DA, Gallagher J, Romagnuolo J. Risk factors for complications after ERCP: a multivariate analysis of 11,497 procedures over 12 years. Gastrointest Endosc. 2009;70(1):80–8. Cotton PB, Elta GH, Carter CR, Pasricha PJ, Corazziari ES. Gallbladder and sphincter of Oddi disorders. Gastroenterology. 2016;150(6):1420–9.e2. Crespi M, Montecamozzo G, Foschi D. Diagnosis and treatment of biliary fistulas in the laparoscopic era. Gastroenterol Res Pract. 2016;2016:6293538. Crichlow L, Walcott-Sapp S, Major J, Jaffe B, Bellows CF. Acute acalculous cholecystitis after gastrointestinal surgery. Am Surg. 2012;78(2):220–4. Csendes A, Diaz JC, Burdiles P, Maluenda F, Nava O. Mirizzi syndrome and cholecystobiliary fistula: a unifying classification. Br J Surg. 1989;76(11): 1139–43. Dasari BVM, Tan CJ, Gurusamy KS, Martin DJ, Kirk G, McKie L, et al. Surgical versus endoscopic treatment of bile duct stones. Cochrane Database Syst Rev. 2013;9: CD003327. De la Serna S, Ruano A, Perez-Jimenez A, Rojo M, Avellana R, Garcia-Botella A, et al. Safety and feasibility of cholecystectomy in octogenarians. Analysis of a single center series of 316 patients. HPB (Oxford). 2019;21(11):1570–6. Dervisoglou A, Tsiodras S, Kanellakopoulou K, Pinis S, Galanakis N, Pierakakis S, et al. The value of chemoprophylaxis against Enterococcus species in elective cholecystectomy: a randomized study of cefuroxime vs ampicillin-sulbactam. Arch Surg (Chicago, Ill: 1960). 2006;141(12):1162–7. Dowling RH. Review: pathogenesis of gallstones. Aliment Pharmacol Ther. 2000;14(Suppl 2):39–47. EASL. Clinical practice guidelines on the prevention, diagnosis and treatment of gallstones. J Hepatol. 2016;65(1):146–81. Elmunzer BJ, Noureldin M, Morgan KA, Adams DB, Cote GA, Waljee AK. The impact of cholecystectomy after

1432 endoscopic Sphincterotomy for complicated gallstone disease. Am J Gastroenterol. 2017;112(10):1596–602. Elwood DR. Cholecystitis. Surg Clin North Am. 2008;88(6):1241–52, viii. Ercan M, Bostanci EB, Ozer I, Ulas M, Ozogul YB, Teke Z, et al. Postoperative hemorrhagic complications after elective laparoscopic cholecystectomy in patients receiving long-term anticoagulant therapy. Langenbeck’s Arch Surg. 2010;395(3):247–53. Erlinger S. Gallstones in obesity and weight loss. Eur J Gastroenterol Hepatol. 2000;12(12):1347–52. Everhart JE. Contributions of obesity and weight loss to gallstone disease. Ann Intern Med. 1993; 119(10):1029–35. Everhart JE, Ruhl CE. Burden of digestive diseases in the United States part III: liver, biliary tract, and pancreas. Gastroenterology. 2009a;136(4):1134–44. Everhart JE, Ruhl CE. Burden of digestive diseases in the United States part I: overall and upper gastrointestinal diseases. Gastroenterology. 2009b;136(2):376–86. Everhart JE, Khare M, Hill M, Maurer KR. Prevalence and ethnic differences in gallbladder disease in the United States. Gastroenterology. 1999;117(3):632–9. Ferreira R, Loureiro R, Nunes N, Santos AA, Maio R, Cravo M, et al. Role of endoscopic retrograde cholangiopancreatography in the management of benign biliary strictures: what’s new? World of J Gastrointest Endosc. 2016;8(4):220–31. Festi D, Dormi A, Capodicasa S, Staniscia T, Attili AF, Loria P, et al. Incidence of gallstone disease in Italy: results from a multicenter, population-based Italian study (the MICOL project). World J Gastroenterol. 2008;14(34):5282–9. Fleming CA, Ismail M, Kavanagh RG, Heneghan HM, Prichard RS, Geoghegan J, et al. Clinical and survival outcomes using percutaneous cholecystostomy tube alone or subsequent interval cholecystectomy to treat acute cholecystitis. J Gastrointest Surg. 2019;21(2):302–11. Geenen JE, Hogan WJ, Dodds WJ, Toouli J, Venu RP. The efficacy of endoscopic sphincterotomy after cholecystectomy in patients with sphincter-of-Oddi dysfunction. N Engl J Med. 1989;320(2):82–7. Gibney EJ. Asymptomatic gallstones. Br J Surg. 1990;77(4):368–72. Giljaca V, Gurusamy KS, Takwoingi Y, Higgie D, Poropat G, Stimac D, et al. Endoscopic ultrasound versus magnetic resonance cholangiopancreatography for common bile duct stones. Cochrane Database Syst Rev. 2015;2:Cd011549. Gill KS, Chapman AH, Weston MJ. The changing face of emphysematous cholecystitis. Br J Radiol. 1997;70(838):986–91. Glenn F. Surgical management of acute cholecystitis in patients 65 years of age and older. Ann Surg. 1981;193(1):56–9. Glenn F, Becker CG. Acute acalculous cholecystitis. An increasing entity. Ann Surg. 1982;195(2):131–6. Gomes CA, Junior CS, Di Saverio S, Sartelli M, Kelly MD, Gomes CC, et al. Acute calculous cholecystitis: review

C. S. Pitchumoni and N. Ravindran of current best practices. World J Gastrointest Surg. 2017;9(5):118–26. Gomi H, Solomkin JS, Takada T, Strasberg SM, Pitt HA, Yoshida M, et al. TG13 antimicrobial therapy for acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2013;20(1):60–70. Gomi H, Solomkin JS, Schlossberg D, Okamoto K, Takada T, Strasberg SM, et al. Tokyo guidelines 2018: antimicrobial therapy for acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2018;25(1): 3–16. Gould MK, Garcia DA, Wren SM, Karanicolas PJ, Arcelus JI, Heit JA, et al. Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e227S–e77S. Gouveia C, Loureiro R, Ferreira R, Oliveira Ferreira A, Santos AA, Santos MPC, et al. Performance of the Choledocholithiasis diagnostic score in patients with acute cholecystitis. GE Port J Gastroenterol. 2018;25(1):24–9. Grand D, Horton KM, Fishman EK. CT of the gallbladder: spectrum of disease. AJR Am J Roentgenol. 2004;183(1):163–70. Guglielmi FW, Boggio-Bertinet D, Federico A, Forte GB, Guglielmi A, Loguercio C, et al. Total parenteral nutrition-related gastroenterological complications. Dig Liver Dis. 2006;38(9):623–42. Gurusamy KS, Davidson BR. Gallstones. BMJ. 2014;348: g2669. Gurusamy K, Samraj K, Gluud C, Wilson E, Davidson BR. Meta-analysis of randomized controlled trials on the safety and effectiveness of early versus delayed laparoscopic cholecystectomy for acute cholecystitis. Br J Surg. 2010;97(2):141–50. Gurusamy KS, Davidson C, Gluud C, Davidson BR. Early versus delayed laparoscopic cholecystectomy for people with acute cholecystitis. Cochrane Database Syst Rev. 2013;6:Cd005440. Haley K. Congenital hemolytic anemia. Med Clin North Am. 2017;101(2):361–74. Harness JK, Strodel WE, Talsma SE. Symptomatic biliary tract disease in the elderly patient. Am Surg. 1986;52(8):442–5. Hemminki K, Hemminki O, Forsti A, Sundquist K, Sundquist J, Li X. Familial risks for gallstones in the population of Sweden. BMJ Open Gastroenterol. 2017;4(1):e000188. Hendrickson M, Naparst TR. Abdominal surgical emergencies in the elderly. Emerg Med Clin North Am. 2003;21(4):937–69. Holzman RS, Oram V, Rahimian J, Wilson T. Pyogenic liver abscess: recent trends in etiology and mortality. Clin Infect Dis. 2004;39(11):1654–9. Horn T, Christensen SD, Kirkegård J, Larsen LP, Knudsen AR, Mortensen FV. Percutaneous cholecystostomy is an effective treatment option for acute calculous cholecystitis: a 10-year experience. HPB. 2015;17(4):326–31.

62

Gallstones and Benign Gallbladder Disease

Hu KC, Chu CH, Wang HY, Chang WH, Lin SC, Liu CC, et al. How does aging affect presentation and Management of Biliary Stones? J Am Geriatr Soc. 2016;64(11):2330–5. Imaoka Y, Itamoto T, Nakahara H, Oishi K, Matsugu Y, Urushihara T. Physiological and operative severity score for the enUmeration of mortality and morbidity and modified physiological and operative severity score for the enUmeration of mortality and morbidity for the mortality prediction among nonagenarians undergoing emergency surgery. J Surg Res. 2017;210:198–203. Ingraham AM, Cohen ME, Ko CY, Hall BL. A current profile and assessment of North American cholecystectomy: results from the American college of surgeons national surgical quality improvement program. J Am Coll Surg. 2010;211(2):176–86. Irojah B, Bell T, Grim R, Martin J, Ahuja V. Are they too old for surgery? safety of cholecystectomy in superelderly patients (
age 90). Perm J. 2017;21:16–013. Itoi T, Takada T, Hwang TL, Endo I, Akazawa K, Miura F, et al. Percutaneous and endoscopic gallbladder drainage for acute cholecystitis: international multicenter comparative study using propensity score-matched analysis. J Hepatobiliary Pancreat Sci. 2017;24(6):362–8. Jansen S, Stodolski M, Zirngibl H, Godde D, Ambe PC. Advanced gallbladder inflammation is a risk factor for gallbladder perforation in patients with acute cholecystitis. World J Emerg Surg. 2018;13:9. Johnston DE, Kaplan MM. Pathogenesis and Treatment of Gallstones. N Engl J Med. 1993;328(6):412–21. Kalliafas S, Ziegler DW, Flancbaum L, Choban PS. Acute acalculous cholecystitis: incidence, risk factors, diagnosis, and outcome. Am Surg. 1998;64(5):471–5. Kao LS, Kuhr CS, Flum DR. Should cholecystectomy be performed for asymptomatic cholelithiasis in transplant patients? J Am Coll Surg. 2003;197(2):302–12. Kapoor BS, Mauri G, Lorenz JM. Management of Biliary Strictures: state-of-the-art review. Radiology. 2018;289(3):590–603. Katsinelos P, Lazaraki G, Chatzimavroudis G, Terzoudis S, Gatopoulou A, Xanthis A, et al. The impact of age on the incidence and severity of post-endoscopic retrograde cholangiopancreatography pancreatitis. Ann Gastroenterol. 2018;31(1):96–101. Khan ZS, Livingston EH, Huerta S. Reassessing the need for prophylactic surgery in patients with porcelain gallbladder: case series and systematic review of the literature. Arch Surg (Chicago, Ill: 1960). 2011;146(10):1143–7. Kiewiet JJ, Leeuwenburgh MM, Bipat S, Bossuyt PM, Stoker J, Boermeester MA. A systematic review and meta-analysis of diagnostic performance of imaging in acute cholecystitis. Radiology. 2012;264(3):708–20. Kimura Y, Takada T, Kawarada Y, Nimura Y, Hirata K, Sekimoto M, et al. Definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis: Tokyo guidelines. J Hepato-Biliary-Pancreat Surg. 2007;14(1):15–26.

1433 Kiriyama S, Kozaka K, Takada T, Strasberg SM, Pitt HA, Gabata T, et al. Tokyo guidelines 2018: diagnostic criteria and severity grading of acute cholangitis (with videos). J Hepatobiliary Pancreat Sci. 2018;25(1):17–30. Knab LM, Boller AM, Mahvi DM. Cholecystitis. Surg Clin North Am. 2014;94(2):455–70. Komatsu S, Tsuchida S, Tsukamoto T, Wakahara T, Ashitani H, Ueno N, et al. Current role of percutaneous transhepatic gallbladder aspiration: from palliative to curative management for acute cholecystitis. J Hepatobiliary Pancreat Sci. 2016;23(11):708–14. Kouroumalis E, Hopwood D, Ross PE, Milne G, Bouchier IA. Gallbladder epithelial acid hydrolases in human cholecystitis. J Pathol. 1983;139(2):179–91. Krawczyk M, Miquel JF, Stokes CS, Zuniga S, Hampe J, Mittal B, et al. Genetics of biliary lithiasis from an ethnic perspective. Clin Res Hepatol Gastroenterol. 2013;37(2):119–25. Lai EC, Mok FP, Tan ES, Lo CM, Fan ST, You KT, et al. Endoscopic biliary drainage for severe acute cholangitis. N Engl J Med. 1992;326(24):1582–6. Lam CM, Murray FE, Cuschieri A. Increased cholecystectomy rate after the introduction of laparoscopic cholecystectomy in Scotland. Gut. 1996;38(2):282–4. Lee SP, Maher K, Nicholls JF. Origin and fate of biliary sludge. Gastroenterology. 1988;94(1):170–6. Lee YS, Kang BK, Hwang IK, Kim J, Hwang JH. Longterm outcomes of symptomatic gallbladder sludge. J Clin Gastroenterol. 2015;49(7):594–8. Leese T, Neoptolemos JP, Baker AR, Carr-Locke DL. Management of acute cholangitis and the impact of endoscopic sphincterotomy. Br J Surg. 1986;73(12):988–92. Liang TJ, Liu SI, Chen YC, Chang PM, Huang WC, Chang HT, et al. Analysis of gallstone disease after gastric cancer surgery. Gastric Cancer: Off J Int Gastric Cancer Assoc and Jpn Gastric Cancer Assoc. 2017;20(5):895–903. Loozen CS, Kortram K, Kornmann VN, van Ramshorst B, Vlaminckx B, Knibbe CA, et al. Randomized clinical trial of extended versus single-dose perioperative antibiotic prophylaxis for acute calculous cholecystitis. Br J Surg. 2017;104(2):e151–e7. Lopez AJ, O’Keefe P, Morrissey M, Pickleman J. Ceftriaxone-induced Cholelithiasis. Ann Intern Med. 1991;115(9):712–4. Loria P, Lonardo A, Lombardini S, Carulli L, Verrone A, Ganazzi D, et al. Gallstone disease in non-alcoholic fatty liver: prevalence and associated factors. J Gastroenterol Hepatol. 2005;20(8):1176–84. Maclure KM, Hayes KC, Colditz GA, Stampfer MJ, Speizer FE, Willett WC. Weight, diet, and the risk of symptomatic gallstones in middle-aged women. N Engl J Med. 1989;321(9):563–9. Magalhaes J, Rosa B, Cotter J. Endoscopic retrograde cholangiopancreatography for suspected choledocholithiasis: from guidelines to clinical practice. World J Gastrointest Endosc. 2015;7(2):128–34. Magouliotis DE, Tasiopoulou VS, Svokos AA, Svokos KA, Chatedaki C, Sioka E, et al. Ursodeoxycholic

1434 acid in the prevention of gallstone formation after bariatric surgery: an updated systematic review and metaanalysis. Obes Surg. 2017;27(11):3021–30. Maki T. Pathogenesis of calcium bilirubinate gallstone: role of E. coli, beta-glucuronidase and coagulation by inorganic ions, polyelectrolytes and agitation. Ann Surg. 1966;164(1):90–100. Maple JT, Ben-Menachem T, Anderson MA, Appalaneni V, Banerjee S, Cash BD, et al. The role of endoscopy in the evaluation of suspected choledocholithiasis. Gastrointest Endosc. 2010;71(1):1–9. Maringhini A, Ciambra M, Baccelliere P, Raimondo M, Orlando A, Tine F, et al. Biliary sludge and gallstones in pregnancy: incidence, risk factors, and natural history. Ann Intern Med. 1993;119(2):116–20. McSherry CK, Ferstenberg H, Calhoun WF, Lahman E, Virshup M. The natural history of diagnosed gallstone disease in symptomatic and asymptomatic patients. Ann Surg. 1985;202(1):59–63. Melmer A, Sturm W, Kuhnert B, Engl-Prosch J, Ress C, Tschoner A, et al. Incidence of gallstone formation and cholecystectomy 10 years after bariatric surgery. Obes Surg. 2015;25(7):1171–6. Moore SW. Intramural formation of gallstones. Arch Surg. 1937;34(3):410–23. Morfin E, Ponka JL, Brush BE. Gangrenous cholecystitis. Arch Surg (Chicago, Ill: 1960). 1968;96(4):567–73. Mori Y, Itoi T, Baron TH, Takada T, Strasberg SM, Pitt HA, et al. Tokyo guidelines 2018: management strategies for gallbladder drainage in patients with acute cholecystitis (with videos). J Hepatobiliary Pancreat Sci. 2018;25(1):87–95. Morris BS, Balpande PR, Morani AC, Chaudhary RK, Maheshwari M, Raut AA. The CT appearances of gallbladder perforation. Br J Radiol. 2007;80(959):898–901. Nassar Y, Richter S. Management of complicated gallstones in the elderly: comparing surgical and non-surgical treatment options. Gastroenterol Rep. 2019;7(3):205–11. Nebiker CA, Baierlein SA, Beck S, von Flue M, Ackermann C, Peterli R. Is routine MR cholangiopancreatography (MRCP) justified prior to cholecystectomy? Langenbeck’s Arch Surg. 2009;394(6):1005–10. Neiderhiser DH. Acute acalculous cholecystitis induced by lysophosphatidylcholine. Am J Pathol. 1986;124(3): 559–63. Nenner RP, Imperato PJ, Rosenberg C, Ronberg E. Increased cholecystectomy rates among Medicare patients after the introduction of laparoscopic cholecystectomy. J Community Health. 1994;19(6):409–15. Nervi F, Miquel JF, Alvarez M, Ferreccio C, García-Zattera MJ, González R, et al. Gallbladder disease is associated with insulin resistance in a high risk Hispanic population. J Hepatol. 2006;45(2):299–305. Nesland JM. Chronic cholecystitis. Ultrastruct Pathol. 2004;28(3):121. Nielsen LB, Harboe KM, Bardram L. Cholecystectomy for the elderly: no hesitation for otherwise healthy patients. Surg Endosc. 2014;28(1):171–7. Nomura H, Kashiwagi S, Hayashi J, Kajiyama W, Ikematsu H, Noguchi A, et al. Prevalence of gallstone

C. S. Pitchumoni and N. Ravindran disease in a general population of Okinawa, Japan. Am J Epidemiol. 1988;128(3):598–605. Nzenza TC, Al-Habbal Y, Guerra GR, Manolas S, Yong T, McQuillan T. Recurrent common bile duct stones as a late complication of endoscopic sphincterotomy. BMC Gastroenterol. 2018;18(1):39. O’Donnell LD, Heaton KW. Recurrence and re-recurrence of gall stones after medical dissolution: a longterm follow up. Gut. 1988;29(5):655–8. Oppenheimer DC, Rubens DJ. Sonography of acute cholecystitis and its mimics. Radiol Clin. 2019;57(3):535–48. Overby DW, Apelgren KN, Richardson W, Fanelli R. SAGES guidelines for the clinical application of laparoscopic biliary tract surgery. Surg Endosc. 2010;24(10):2368–86. Park JK, Yang JI, Wi JW, Park JK, Lee KH, Lee KT, et al. Long-term outcome and recurrence factors after percutaneous cholecystostomy as a definitive treatment for acute cholecystitis. J Gastroenterol Hepatol. 2019;34(4):784–90. Peery AF, Crockett SD, Murphy CC, Lund JL, Dellon ES, Williams JL, et al. Burden and cost of gastrointestinal, liver, and pancreatic diseases in the United States: update 2018. Gastroenterology. 2019;156(1):254–72. e11. Petitti DB, Friedman GD, Klatsky AL. Association of a history of gallbladder disease with a reduced concentration of high-density-lipoprotein cholesterol. N Engl J Med. 1981;304(23):1396–8. Pisano M, Ceresoli M, Cimbanassi S, Gurusamy K, Coccolini F, Borzellino G, et al. 2017 WSES and SICG guidelines on acute calcolous cholecystitis in elderly population. World J Emerg Surg. 2019;14(1):10. Pitt HA, Lewinski MA, Muller EL, Porter-Fink V, DenBesten L. Ileal resection-induced gallstones: altered bilirubin or cholesterol metabolism? Surgery. 1984;96(2):154–62. Portincasa P, Di Ciaula A, de Bari O, Garruti G, Palmieri VO, Wang DQ. Management of gallstones and its related complications. Expert Rev Gastroenterol Hepatol. 2016;10(1):93–112. Radosa C, Schaab F, Hofmockel T, Kuhn JP, Hoffmann RT. Percutaneous biliary and gallbladder interventions. Radiologe. 2019;59(4):342–7. Ralls PW, Colletti PM, Lapin SA, Chandrasoma P, Boswell WD Jr, Ngo C, et al. Real-time sonography in suspected acute cholecystitis. Prospective evaluation of primary and secondary signs. Radiology. 1985;155(3):767–71. Reuken PA, Torres D, Baier M, Loffler B, Lubbert C, Lippmann N, et al. Risk factors for multi-drug resistant pathogens and failure of empiric first-line therapy in acute cholangitis. PLoS One. 2017;12(1):e0169900. Rey JW, Hansen T, Dumcke S, Tresch A, Kramer K, Galle PR, et al. Efficacy of SpyGlass(TM)-directed biopsy compared to brush cytology in obtaining adequate tissue for diagnosis in patients with biliary strictures. World of J Gastrointest Endosc. 2014;6(4):137–43. Riall TS, Zhang D, Townsend CM Jr, Kuo YF, Goodwin JS. Failure to perform cholecystectomy for acute

62

Gallstones and Benign Gallbladder Disease

cholecystitis in elderly patients is associated with increased morbidity, mortality, and cost. J Am Coll Surg. 2010;210(5):668–77–9. Riall TS, Adhikari D, Parmar AD, Linder SK, Dimou FM, Crowell W, et al. The risk paradox: use of elective cholecystectomy in older patients is independent of their risk of developing complications. J Am Coll Surg. 2015;220(4):682–90. Richardson WS, Hamad GG, Stefanidis D. SAGES VTE prophylaxis for laparoscopic surgery guidelines: an update. Surg Endosc. 2017;31(2):501–3. Rondelli F, Manina G, Agnelli G, Becattini C. Venous thromboembolism after laparoscopic cholecystectomy: clinical burden and prevention. Surg Endosc. 2013;27(6):1860–4. Roslyn JJ, Pitt HA, Mann LL, Ament ME, DenBesten L. Gallbladder disease in patients on long-term parenteral nutrition. Gastroenterology. 1983;84(1):148–54. Roslyn JJ, Thompson JE Jr, Darvin H, DenBesten L. Risk factors for gallbladder perforation. Am J Gastroenterol. 1987;82(7):636–40. Rosseland AR, Glomsaker TB. Asymptomatic common bile duct stones. Eur J Gastroenterol Hepatol. 2000;12(11):1171–3. Ruhl CE, Everhart JE. Association of diabetes, serum insulin, and C-peptide with gallbladder disease. Hepatology (Baltimore, Md). 2000;31(2):299–303. Ryu JK, Ryu KH, Kim KH. Clinical features of acute acalculous cholecystitis. J Clin Gastroenterol. 2003;36(2):166–9. Sampliner RE, Bennett PH, Comess LJ, Rose FA, Burch TA. Gallbladder disease in pima Indians. N Engl J Med. 1970;283(25):1358–64. Sarin SK, Negi VS, Dewan R, Sasan S, Saraya A. High familial prevalence of gallstones in the first-degree relatives of gallstone patients. Hepatology (Baltimore, Md). 1995;22(1):138–41. Schneider J, De Waha P, Hapfelmeier A, Feihl S, Rommler F, Schlag C, et al. Risk factors for increased antimicrobial resistance: a retrospective analysis of 309 acute cholangitis episodes. J Antimicrob Chemother. 2014;69(2):519–25. Schnelldorfer T. Porcelain gallbladder: a benign process or concern for malignancy? J Gastrointest Surg. 2013;17(6):1161–8. Seeto RK, Rockey DC. Pyogenic liver abscess. Changes in etiology, management, and outcome. Medicine. 1996;75(2):99–113. Shaffer E. Epidemiology and risk factors for gallstone disease: has the paradigm changed in the 21st century? Curr Gastroenterol Rep. 2005;7(2):132–40. Shaffer EA. Gallstone disease: epidemiology of gallbladder stone disease. Best Pract Res Clin Gastroenterol. 2006;20(6):981–96. Shoda J, Tanaka N, Osuga T. Hepatolithiasis – epidemiology and pathogenesis update. Front Biosci. 2003;8: e398–409. Siddiqui A, Kunda R, Tyberg A, Arain MA, Noor A, Mumtaz T, et al. Three-way comparative study of endoscopic ultrasound-guided transmural gallbladder drainage using lumen-apposing metal stents versus endoscopic transpapillary drainage versus

1435 percutaneous cholecystostomy for gallbladder drainage in high-risk surgical patients with acute cholecystitis: clinical outcomes and success in an international. Multicenter Study Surg Endosc. 2019;33(4):1260–1270. https://doi.org/10.1007/s00464-018-6406-7 Singh V, Trikha B, Nain C, Singh K, Bose S. Epidemiology of gallstone disease in Chandigarh: a community-based study. Eur J Gastroenterol Hepatol. 2001;16(5):560–3. Somjen GJ, Gilat T. Contribution of vesicular and micellar carriers to cholesterol transport in human bile. J Lipid Res. 1985;26(6):699–704. Sousa M, Pinho R, Proença L, Rodrigues J, Silva J, Gomes C, et al. ASGE high-risk criteria for choledocholithiasis – are they applicable in cholecystectomized patients? Dig Liver Dis. 2019;51(1):75–8. Spes CH, Angermann CE, Beyer RW, Schreiner J, Lehnert P, Kemkes BM, et al. Increased incidence of cholelithiasis in heart transplant recipients receiving cyclosporine therapy. J Heart Transplant. 1990;9(4):404–7. Stampfer MJ, Maclure KM, Colditz GA, Manson JE, Willett WC. Risk of symptomatic gallstones in women with severe obesity. Am J Clin Nutr. 1992;55(3):652–8. Stephen AE, Berger DL. Carcinoma in the porcelain gallbladder: a relationship revisited. Surgery. 2001;129(6):699–703. Stinton LM, Shaffer EA. Epidemiology of gallbladder disease: cholelithiasis and cancer. Gut and Liver. 2012;6(2):172–87. Suarez AL, LaBarre NT, Cotton PB, Payne KM, Cote GA, Elmunzer BJ. An assessment of existing risk stratification guidelines for the evaluation of patients with suspected choledocholithiasis. Surg Endosc. 2016;30(10):4613–8. Sugiyama M, Atomi Y. Treatment of acute cholangitis due to choledocholithiasis in elderly and younger patients. Arch Surg (Chicago, Ill: 1960). 1997;132(10): 1129–33. Tambyraja AL, Kumar S, Nixon SJ. POSSUM scoring for laparoscopic cholecystectomy in the elderly. ANZ J Surg. 2005;75(7):550–2. Tanaka A, Takada T, Kawarada Y, Nimura Y, Yoshida M, Miura F, et al. Antimicrobial therapy for acute cholangitis: Tokyo guidelines. J Hepato-BiliaryPancreat Surg. 2007;14(1):59–67. Tazuma S. Gallstone disease: epidemiology, pathogenesis, and classification of biliary stones (common bile duct and intrahepatic). Best Pract Res Clin Gastroenterol. 2006;20(6):1075–83. Thakrar R, Thomson S, Monib S, Pakdemirli E. Calcified gallbladder cancer: is it preventable? J Surg Case Rep. 2019;2019(3):rjz069. Thangavelu A, Rosenbaum S, Thangavelu D. Timing of cholecystectomy in acute cholecystitis. J Emerg Med. 2018;54(6):892–7. Tohda G, Ohtani M, Dochin M. Efficacy and safety of emergency endoscopic retrograde cholangiopancreatography for acute cholangitis in the elderly. World J Gastroenterol. 2016;22(37):8382–8. Trendle MC, Moertel CG, Kvols LK. Incidence and morbidity of cholelithiasis in patients receiving chronic

1436 octreotide for metastatic carcinoid and malignant islet cell tumors. Cancer. 1997;79(4):830–4. Trotman BW. Pigment gallstone disease. Gastroenterol Clin N Am. 1991;20(1):111–26. Trowbridge RL, Rutkowski NK, Shojania KG. Does this patient have acute cholecystitis? JAMA. 2003;289(1):80–6. Tsai CJ, Leitzmann MF, Willett WC, Giovannucci EL. Dietary carbohydrates and glycaemic load and the incidence of symptomatic gall stone disease in men. Gut. 2005;54(6):823–8. Uecker J, Adams M, Skipper K, Dunn E. Cholecystitis in the octogenarian: is laparoscopic cholecystectomy the best approach? Am Surg. 2001;67(7):637–40. Upala S, Sanguankeo A, Jaruvongvanich V. Gallstone disease and the risk of cardiovascular disease: a systematic review and meta-analysis of observational studies. Scand J Surg. 2017;106(1):21–7. Van Erpecum KJ, Van Berge Henegouwen GP, Stoelwinder B, Stolk MFJ, Eggink WF, Govaert WHA. Cholesterol and pigment gallstone disease: comparison of the reliability of three bile tests for differentiation between the two stone types. Scand J Gastroenterol. 1988;23(8):948–54. Vedovati MC, Becattini C, Rondelli F, Boncompagni M, Camporese G, Balzarotti R, et al. A randomized study on 1-week versus 4-week prophylaxis for venous thromboembolism after laparoscopic surgery for colorectal cancer. Ann Surg. 2014;259(4):665–9. Venneman NG, van Erpecum KJ. Pathogenesis of gallstones. Gastroenterol Clin N Am. 2010;39(2):171–83, vii. Venneman NG, Besselink MG, Keulemans YC, VanbergeHenegouwen GP, Boermeester MA, Broeders IA, et al. Ursodeoxycholic acid exerts no beneficial effect in patients with symptomatic gallstones awaiting cholecystectomy. Hepatology (Baltimore, Md). 2006;43(6):1276–83. Wang DQ, Afdhal NH. Genetic analysis of cholesterol gallstone formation: searching for Lith (gallstone) genes. Curr Gastroenterol Rep. 2004;6(2):140–50. Wang HH, Portincasa P, Afdhal NH, Wang DQ. Lith genes and genetic analysis of cholesterol gallstone formation. Gastroenterol Clin N Am. 2010;39(2):185–207, vii–viii.

C. S. Pitchumoni and N. Ravindran Wang HH, Li T, Portincasa P, Ford DA, NeuschwanderTetri BA, Tso P, et al. New insights into the role of Lith genes in the formation of cholesterol-supersaturated bile. Liver Res. 2017;1(1):42–53. Wang TY, Portincasa P, Liu M, Tso P, Wang DQ. Mouse models of gallstone disease. Curr Opin Gastroenterol. 2018;34(2):59–70. Watson RR, Parsi MA, Aslanian HR, Goodman AJ, Lichtenstein DR, Melson J, et al. Biliary and pancreatic lithotripsy devices. VideoGIE. 2018;3(11):329–38. Whorwell PJ, Hawkins R, Dewbury K, Wright RJDD. Ultrasound survey of gallstones and other hepatobiliary disorders in patients with Crohn’s disease. Dig Dis Sci. 1984;29(10):930–3. Williams EJ, Green J, Beckingham I, Parks R, Martin D, Lombard M. Guidelines on the management of common bile duct stones (CBDS). Gut. 2008;57(7): 1004–21. Williams E, Beckingham I, El Sayed G, Gurusamy K, Sturgess R, Webster G, et al. Updated guideline on the management of common bile duct stones (CBDS). Gut. 2017;66(5):765–82. Yarmish GM, Smith MP, Rosen MP, Baker ME, Blake MA, Cash BD, et al. ACR appropriateness criteria right upper quadrant pain. J Am Coll Radiol. 2014;11(3):316–22. Yokoe M, Hata J, Takada T, Strasberg SM, Asbun HJ, Wakabayashi G, et al. Tokyo guidelines 2018: diagnostic criteria and severity grading of acute cholecystitis (with videos). J Hepatobiliary Pancreat Sci. 2018;25(1):41–54. Zaliekas J, Munson JL. Complications of gallstones: the Mirizzi syndrome, gallstone ileus, gallstone pancreatitis, complications of “lost” gallstones. Surg Clin North Am. 2008;88(6):1345–68, x. Zhang ZM, Liu Z, Liu LM, Zhang C, Yu HW, Wan BJ, et al. Therapeutic experience of 289 elderly patients with biliary diseases. World J Gastroenterol. 2017;23(13):2424–34. Zheng Y, Xu M, Heianza Y, Ma W, Wang T, Sun D, et al. Gallstone disease and increased risk of mortality: two large prospective studies in US men and women. J Gastroenterol Hepatol. 2018;33(11):1925–31.

Biliary Neoplasms

63

C. S. Pitchumoni and Nishal Ravindran

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1438 Gallbladder Polyps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1438 Gallbladder Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1440 Cholangiocarcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1443 Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1445 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1445

Abstract

Gallbladder polyps are mostly benign but may progress to cancer. In older age, single polyps and large and sessile polyps are more likely to undergo malignant transformation. Adenomyomatosis is a benign hyperplastic lesion due to the excessive proliferation of the

C. S. Pitchumoni (*) Department of Medicine, Robert Wood Johnson School of Medicine, Rutgers University, New Brunswick, NJ, USA Department of Medicine, New York Medical College, Valhalla, NY, USA Division of Gastroenterology, Hepatology and Clinical Nutrition, Saint Peters University Hospital, New Brunswick, NJ, USA e-mail: [email protected] N. Ravindran Robert Wood Johnson School of Medicine, Rutgers University, New Brunswick, NJ, USA

surface epithelium, which invaginates into the muscularis. Gallbladder cancer is extremely rare in the USA and many Western countries. The incidence is high in certain ethnic groups such as Native Americans and Mexican Americans and some geographic areas including Chile, Bolivia, and Northern parts of India. Other risk factors include older age, history of chronic cholecystitis, the larger size of stones, gallbladder polyps, and certain types of porcelain gallbladder disease with patchy calcification of the wall of the gallbladder. Typhoid carrier state is an association in some countries. Gallbladder cancer has a poor prognosis as it is usually detected late because symptoms are non-specific and cancer spreads early. The prognosis is good when the disease is incidentally detected in routine cholecystectomy.

Saint Peters University Hospital, New Brunswick, NJ, USA e-mail: [email protected] © Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_105

1437

1438

Keywords

Gallbladder polyps · Cholesterolosis · Adenomyomatosis · Adenomas · Inflammatory polyps · Porcelain gallbladder · Typhoid carrier state · Malignant polyps · Gallbladder cancer · Cholangiocarcinoma

Introduction Biliary neoplasms may be benign or malignant, with the vast majority being benign polyps found incidentally. Both benign and malignant lesions are seen more often in women and increase with age. Biliary malignancies are rare in most parts of the Western world but are seen more often in certain parts of the world, such as in the Andes region of Chile and Bolivia, Eastern Europe, East Asia, and Northern parts of India as well as in certain populations like Native Americans (Malhotra et al. 2017; Hundal and Shaffer 2014). There has been a rise in incidentally detected malignancy in cholecystectomy specimens with the increase in laparoscopic cholecystectomy. Biliary malignancies can arise in the bile ducts or gallbladder and are divided, based on location, into intra- or extrahepatic, gallbladder malignancies, and ampullary lesions. They have different genetics, risk factors, and clinical presentation (Benavides et al. 2015). Gallbladder cancer is the commonest biliary malignancy. Estimates for cancer of the gallbladder and large bile ducts in the USA for 2019 by the American Cancer Society are about 12,360 new cases, 5,810 in men and 6,550 in women, and about 3,960 deaths from these cancers. About four in ten of these will be gallbladder cancers. Only 25% of patients with gallbladder cancer are detected early enough for curative surgery with a 5-year survival rate of 16%.

Gallbladder Polyps Polyps in the gallbladder (GB) are mucosal projections into the lumen. Gallbladder polyps are formed as a result of a heterogeneous group of changes in the GB that result in the formation of cholesterol polyps, inflammatory polyps, adenomas, lipomas, and leiomyomas. Adherent

C. S. Pitchumoni and N. Ravindran

sludge or gallstones may give the appearance of polyps on imaging. Interestingly one study found a high number of gallstones in patients thought to have polyps initially (Kratzer et al. 2008). While nearly 5% of all adults have gallbladder polyps, the majority (95%) are pseudopolyps with no neoplastic potential. Polyps due to cholesterolosis are the commonest (60% of gallbladder polyps), while adenomyomas are 25%, inflammatory are 10%, and adenomas are less than 5% (Hundal and Shaffer 2014; McCain et al. 2018; Christensen and Ishak 1970). No consistent risk factors have been identified for polyps in most studies except presence of gallbladder polyps in familial polyposis syndrome-like Peutz-Jeghers and Gardener’s syndrome and hepatitis B in the Chinese (Lin et al. 2008; Wada et al. 1987; Komorowski et al. 1986). In a recent metaanalysis from East Asia (China, Korea, and Japan), Yamin et al. identified additional risk factors for gallbladder polyps. According to the authors, the additional risk factors are male gender, higher BMI, higher waist circumference, higher LDL, low HDL, and higher diastolic BP and HBsAg in this population (Yamin et al. 2019). There is a trend toward an increase in gallbladder polyps with age, mostly in 40–59 years old with a drop in the above 65 age group (Heitz et al. 2019). Gallbladder polyps are usually found incidentally on abdominal ultrasound (US) examination. The prevalence of gallbladder polyps based on abdominal US studies ranges from 0.3% to 26%. A follow-up study in a random population observed that nearly 80% of polyps did not significantly change in size (Moriguchi et al. 1996). GB polyps may disappear in a large number of patients (Heitz et al. 2019). The majority of polyps are hyperechoic on the abdominal US exam. Imaging findings like polyp size, shape, wide base, wall thickening, and coexistent gallstones aid in diagnosis (Mellnick et al. 2015). Histology is necessary to confirm the diagnosis through radiographic appearance may be suggestive. Age, risk factors for gallbladder cancer, and radiological appearance are useful in clinical decision-making. In cholesterolosis, the lamina propria is infiltrated with lipid-laden macrophages and can be

63

Biliary Neoplasms

diffuse or form polyps. It is characterized by villous mucosal hyperplasia with excessive accumulation of cholesterol esters within epithelial macrophages (Owen and Bilhartz 2003). In the diffuse form of cholesterolosis, the bright red mucosa with interposed areas of yellow lipid gives a characteristic appearance, “strawberry gallbladder.” Cholesterol polyps are pedunculated, are multiple, and are usually less than 10 mm in size (Owen and Bilhartz 2003; Gallahan and Conway 2010). They may be solitary in about 20%. They are generally benign and do not cause symptoms but rarely can cause acute pancreatitis, often attributed as idiopathic (Parrilla Paricio et al. 1990). Adenomyomatosis is a benign hyperplastic lesion due to the excessive proliferation of the surface epithelium, which invaginates into the muscularis. Increased intraluminal pressure in the gallbladder from mechanical obstruction is thought to lead to cystic dilatation of the Rokitansky sinuses and results in hyperplasia of the muscularis. The incidence increases after 50 years of age (Golse et al. 2017). Adenomyomatosis may resemble more serious and emergent gallbladder disease in the US (Mariani and Hsue 2011). It is reported to have a twinkling or comet tail appearance in the US. Adenomyomatosis may be segmental, fundal, or diffuse. They are usually seen in the fundus, are solitary, and range in size from 10 to 20 mm (Gallahan and Conway 2010; Ram and Midha 1975). Segmental adenomyomatosis may coexist with gallbladder cancer (Ootani et al. 1992). Segmental adenomyomatosis has a high risk of gallbladder cancer in elderly patients (Nabatame et al. 2004). Asymptomatic adenomyomatosis is not an indication for surgery. In older adults especially those from the gallbladder cancer (GBC) belt with increased risk of GBC, cholecystectomy is justified when in doubt (Golse et al. 2017) (Fig. 1). Inflammatory polyps resulting from chronic inflammation are typically less than 10 mm (Gallahan and Conway 2010). They are made up of granulation and fibrous tissue and are small sessile lesions.

1439

Fig. 1 The US showing adenomyomatosis

Adenomas are usually solitary, are pedunculated masses, and vary in size from 5 to 20 mm (Persley 2005). They may be papillary or non-papillary. They are often associated with gallstones. Although adenomas are neoplastic, they are mostly benign. The progression from adenoma to carcinoma has been reported but is not thought to be the predominant pathway (Albores-Saavedra et al. 2012). There is an increased risk of malignant polyps noted with age above 50, history of primary sclerosing cholangitis, Northern Indian population, large polyps, and sessile polyps (McCain et al. 2018). Several studies have shown that large polyps (more than 10 mm) have increased the probability of adenomas and 50% may have carcinoma (Park et al. 2008). Gallbladder polyps were reported to be associated with colorectal adenomas in Taiwanese men (Liu et al. 2018). Usually, polyps are asymptomatic, but there are reports of biliary colic, obstruction, cholecystitis, and hemobilia. The sonographic findings suggestive of a polyp on the abdominal US are immobility of the shadow with changes in patient position and lack of acoustic shadowing. Sonographic features suggestive of malignancy are solitary lesions, size above 1 cm, increased vascularity, sessile shape, rapid growth noted on serial studies, and invasion into the liver but are unreliable (Li et al. 2018). Although EUS is more accurate, there is no evidence to support its use as a more definitive diagnostic test but could be

1440

considered in centers that have availability. In a retrospective study of 2290 cholecystectomies, malignancy was seen only in 0.4%; risk factors identified were age more than 40 and polyp size more than 10 mm (Li et al. 2018). Cholecystectomy is advised for gallbladder polyps with symptoms or if more than 10 mm or if 6–9 mm with risk factors. If the polyp is less than 6 mm or if 6–9 mm without risk factors, serial follow-up imaging is recommended in 6 months, 1 year, and yearly for 5 years (Wiles et al. 2017). A predictive model based on older age, single lesion, sessile polyp, and size showed statistical significance for neoplastic potential (probability of 7.4%) and could guide the decision for cholecystectomy (Yang et al. 2018). Open cholecystectomy is advisable if there is a high suspicion of malignancy, but laparoscopic cholecystectomy should be adequate in most patients (Gallahan and Conway 2010; Persley 2005).

Gallbladder Cancer Gallbladder cancer is the most common malignancy of the biliary tract, representing 80–95% of biliary tract cancers worldwide. The prevalence of gallbladder cancer and mortality rates tends to increase with advancing age. In the USA, where GB cancer is not so common, data from 2016 reveals that age-adjusted incidence rates were 1.2/100,000 with 28% in 65–74 age group and 26% in 75–84 age group. The highest mortality rate was in individuals over the age of 75 at 5.05/100,000, according to the SEER data (2013). Risk factors are similar to gallstones like increasing age, female gender, ethnicity, family history, smoking, obesity, and diet and much less often attributed to gallstones, chronic inflammation, congenital abnormalities, and polyps (Malhotra et al. 2017; Randi et al. 2006). GBC is more often diagnosed in women, Hispanics, Native Alaskans, and Natives Americans. The highest incidence of GBC is seen in those above 65, with an average age of 72 years. Women have a risk of two to eight times that of men and are

C. S. Pitchumoni and N. Ravindran

more common in older women (Kiran et al. 2007). The high incidence in women suggests that female sex hormones play a role in the pathogenesis. In a majority of patients with gallbladder cancer, Chen and Huminer found high levels of estrogen and its receptor (ER) in the gallbladder (Chen and Huminer 1991). Chronic infection with Salmonella Typhi is associated with an increased risk of gallbladder cancer, up to a 12-fold increase (Caygill et al. 1994; Nath et al. 1997). High incidence areas include parts of Andean regions of South America (Peru, Chile, Bolivia), Eastern Europe (Hungary, Poland), Northern India, Southern Pakistan, and Korea, with the highest rates in Korean males (Randi et al. 2006; Batra et al. 2005; Bhattacharjee and Nanda 2019; Barreto et al. 2018; Nagaraja and Eslick 2014). The incidence of gallbladder cancer in North and Central India is very high. It is the most common gastrointestinal cancer in women there (Kapoor and McMichael 2003). Population-based data reveals that while the incidence of gallbladder cancer in Northern Indian cities is 5–7 per 100,000 women, it is low in Southern India, 0–0.7 per 100,000 women (Dhir and Mohandas 1999). The prevalence of gallbladder cancer is especially high along the banks of the Ganga, two to three times higher than other parts of India. The possibility of heavy metal poisoning in this area was studied by Shukla, who found high concentrations of cadmium and chromium in drinking water and gallbladder specimens (Shukla et al. 1998) (Fig. 2 and Table 1). A genetic role is possible in gallbladder cancer but is not clear. The expression of p53 in gallbladder dysplasia suggests that the p53 mutation could be an early event in the evolution of some gallbladder cancers (Wee et al. 1994) (Fig. 3). Larger stones (more than 3 cm) have a higher risk of malignancy (Diehl 1983). Porcelain gallbladder occurs in chronic cholecystitis with mural calcification of the gallbladder, and incomplete calcification of gallbladder is a risk factor (Gore et al. 2002; Patel et al. 2011). Traditional teaching is that porcelain gallbladder is strongly associated with gallbladder cancer with older reports quoting the prevalence of 12–61%. However, the risk is much lower than previously reported. It is prudent

63

Biliary Neoplasms

1441

Fig. 2 Map showing the incidence of gallbladder cancer worldwide Table 1 Gallbladder cancer rates worldwide in both sexes Rank 1 2 3 4 5

Country Bolivia Chile Thailand South Korea Nepal

Age-standardized rate per 100,000 14.0 9.3 7.4 6.8 6.7

Bolivia had the highest rate of gallbladder cancer in 2018, followed by Chile Source: Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global Cancer Statistics 2018 Fig. 3 Gallbladder cancer histopathology

to do prophylactic cholecystectomy in young, healthy, and symptomatic patients, but surveillance in those patients who are poor surgical candidates is a reasonable approach (DesJardins et al. 2018) (Table 2). The presenting symptoms that occur in patients with GBC are similar to symptoms seen in a benign disease like biliary colic, right upper quadrant pain, or obstructive jaundice. In general, patients found to have obstructive jaundice are more likely to have metastatic disease and

unresectable GBC. Other factors that influence survival are gastric outlet obstruction, nodal involvement and extension to adjacent organs, and higher cancer staging (Hickman and Contreras 2019; Mishra et al. 2017). Gallbladder cancer has a poor prognosis as is usually detected late because symptoms are non-specific, and also the anatomy of the gallbladder leads to cancer spreading early (Chan et al. 2008). It is usually advanced when it causes symptoms. Only about one of five gallbladder

1442

C. S. Pitchumoni and N. Ravindran

Table 2 Risk factors for gallbladder cancer Risk factors Increasing age Female gender

Obesity Ethnicity/geography Genetic predisposition

Cholelithiasis

Porcelain gallbladder

Gallbladder polyps

Choledochal cysts Anomalous junction of the pancreaticobiliary ductal system

Typhoid carrier state Environmental risk factors

Mean age at diagnosis is 65 years Incidence increases with age Female to male ratio of 2:1 Higher risk in females is independent of gallstone disease Risk increases after menopause Mortality rate higher in females The relative risk of 1.66 Stronger association in women Native Americans, Indian, Pakistani, Japanese, and Korean Eastern Europe, Andes region of South America Genetic predisposition to lithogenic bile in certain ethnicities suggests a possible genetic link Familial risk in Swedish, Italian, and American reports relative risk range 2.1–13.9 for first-degree relatives Gallstones in 70–88% of GBC patients but the incidence of gallbladder cancer 0.3–3.0% with gallstones Increased risk with larger gallstones Stones larger than 3 cm increases risk tenfold Increased number, weight, and volume of gallstones increase risk 12–60% incidence of gallbladder cancer with GB calcification in older literature Current consensus weak association 2–3% and only in patchy calcification Size >1 cm increases risk Especially those older than 50–60 years with polyps larger than 1 cm Incidence of malignancy 11% Higher risk of cholangiocarcinoma Reflux of pancreatic secretions into the biliary tree Seen more in Asia especially Japanese Seen in 10% of patients with gallbladder cancer Seen more in younger women Chronic salmonellosis – a 12-fold increase Exposure to industrial chemicals Cigarette smoking

Hickman and Contreras (2019) Wernberg and Lucarelli (2014)

Larsson and Wolk (2007) Hundal and Shaffer (2014) Wernberg and Lucarelli (2014)

Wernberg and Lucarelli (2014)

Hundal and Shaffer (2014)

Hundal and Shaffer (2014) Sastry et al. (2015) Hundal and Shaffer (2014)

Koshiol et al. (2016) Wernberg and Lucarelli (2014)

Data from Hickman and Contreras (2019), Kanthan et al. (2015), Koshiol et al. (2016), and Hundal and Shaffer (2014)

cancers is found in the early stages. Incidental identification of gallbladder cancer occurs in 0.2–3% of all cholecystectomies done for presumed benign disease. Only 30% of patients with gallbladder cancer are suspected of harboring a malignancy preoperatively, and such patients have a good prognosis after surgery (Kanthan et al. 2015). The increase in the number of laparoscopic cholecystectomies currently being performed is associated with an increase in the identification of incidental gallbladder cancer.

Adenocarcinomas are the most common gallbladder cancer (80%), and the fundus is the commonest site. Others are sarcoma, lymphoma, and carcinoid. There is no reliable tumor marker in the diagnosis of gallbladder cancer. The only two markers, carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9, are most often elevated in advanced stages, have low specificity, and are useless for early diagnosis (Srivastava et al. 2013). Genetics of GB cancer shows that the common genetic alterations are in the oncogenes,

63

Biliary Neoplasms

tumor suppressor genes, microsatellite instability, methylation of gene promoter areas, p53 mutation, and K-ras point mutations (Hundal and Shaffer 2014). The Oxford hepatobiliary 2015 consensus statement recommendations included high-quality cross-sectional imaging with CT or MRI and selective use of PET scan to clarify features of concerns before resection. Gallbladder cancer staging is done by the American Joint Committee on Cancer (AJCC) TNM system which is based on tumor size, lymph node involvement, and metastasis. The SEER database uses staging as localized (within the gallbladder), regional (spread outside to the gallbladder to nearby structures), and distant stage (metastases to other organs). The 5-year survival rate from 2008 to 2014 for localized GBC was 61%, with regional spread was 26%, and in the distant spread was 2%. The alarming incidence of GBC in India has prompted investigators there to re-evaluate the need to consider prophylactic cholecystectomy in selected populations. The long-standing correlation of gallstones and GBC prompted Mohandas et al. to advise prophylactic cholecystectomy in young women from high-risk areas with asymptomatic gallstones based on prospective population-based data (Mohandas and Patil 2006). Although the chapter specifically mentions young women, the observation can be extended to the healthy elderly population with many years of life expectancy. Prophylactic cholecystectomy may not be acceptable in the Western world, where the incidence of GBC is very low in contrast to high prevalence areas. The risk-benefit ratio is dramatic in India, with 1 GBC prevented with 67 cholecystectomies (Mathur 2015). For GBC diagnosed after cholecystectomy, tumors T1b and greater necessitate radical cholecystectomy. Radical cholecystectomy includes staging laparoscopy, hepatic resection, and locoregional lymph node clearance to achieve R0 resection (Cavallaro et al. 2014). Resection of the adjacent liver and lymph nodes is also advised in incidentally identified T2 or T3 disease in a cholecystectomy specimen unless contraindicated by advanced disease or poor performance status

1443

(Aloia et al. 2015). Although in patients with early cancer laparoscopic cholecystectomy has not been shown to have a worse prognosis than open cholecystectomy, it was recommended only in specialized centers (Zhao et al. 2018). Laparoscopic cholecystectomy does not affect survival in incidental GBC. Patients with locally advanced disease (T3 or T4), hepatic-sided T2 tumors, node positivity, or R1 resection may benefit from adjuvant chemotherapy. Chemotherapy increases survival in unresectable disease (Hickman and Contreras 2019). Patients with advanced cancer may benefit from palliative endoscopic or percutaneous procedures to relieve the obstruction. Details of current treatment of gallbladder cancer are available in “Update in GBC management” by Zaidi and Maithel (2018). Chemotherapy with targeted therapeutic agents may be available in the future for treatment of advanced gallbladder cancer with potential target genes at ERBB2 amplification, mutations or amplification of the PI3-kinase family genes, FGFR mutations or fusions, and aberrations of the chromatin modulating genes (Jiao et al. 2013; Javle et al. 2013).

Cholangiocarcinoma Cholangiocarcinoma arises from biliary epithelium in both the intrahepatic and extrahepatic biliary tree (de Groen et al. 1999). It is a rare malignancy but is the second most common hepatic malignancy after hepatocellular carcinoma, and the incidence is rising (Hsing et al. 2006). Risk factors for cholangiocarcinoma are primary sclerosing cholangitis, choledochal cysts, inflammatory bowel disease, cirrhosis, congenital fibrosis, hepatolithiasis, and parasitic infections (Opisthorchis, Clonorchis) (Shin et al. 2010; Edil et al. 2008; Mabrut et al. 2013; Chapman et al. 2012). Parasitic infection of the biliary tract is the commonest risk factor worldwide for cholangiocarcinoma as the highest incidence of cholangiocarcinoma is seen in Southeast Asia (Blechacz 2017). In patients with primary

1444

C. S. Pitchumoni and N. Ravindran

Fig. 4 Classification of cholangiocarcinoma

Table 3 Risk factors for cholangiocarcinoma Risk factors Increasing age Sex Genetics

74% of cases after 65 years Incidence higher in men than women range from 1.2 to 1.5:1 Acquired genetic mutations in some poorer prognosis

Inflammatory bowel disease

Increased in Hispanic and Asian populations 2.8–3.3/100,000 Highest incidence rates in Southeast Asia and China Mortality rates highest in Native Americans, Native Alaskans, and Asians Odds ratio 22.92 Viral hepatitis B and C not clear Thorotrast used until 1960s latency >16 years between exposure and malignancy Risk 30 times higher Seen more in Asians Chronic inflammation and segmental stenosis of bile ducts Strong risk factor for (6–36%) cholangiocarcinoma (CC) Not more than 10% of all cases Risk 1% per year Difficult to define due to complex association

Caroli’s disease

Risk up to 30 times higher

Hepatolithiasis

2–10% of patients develop CC

Parasites

Liver flukes including Opisthorchis viverrini, Opisthorchis/Clonorchis sinensis Attributable risk 27% in men

Ethnicity/race

Cirrhosis Exposure to Thorotrast (radiographic contrast agent) Choledochal cysts Primary sclerosing cholangitis

Tyson and El-Serag (2011) Tyson and El-Serag (2011) Razumilava and Gores (2014) Razumilava and Gores (2014)

Razumilava and Gores (2014) Tyson and El-Serag (2011) Tyson and El-Serag (2011) Tyson and El-Serag (2011)

Tyson and El-Serag (2011) Tyson and El-Serag (2011) Tyson and El-Serag (2011) Tyson and El-Serag (2011)

Data from Tyson and El-Serag (2011) and Blechacz (2017)

sclerosing cholangitis, about 50% of cholangiocarcinoma is diagnosed within 2 years. It is rarely diagnosed before 40 years; mean age at diagnosis is 50 years globally and 65 in Western nations

(Rizvi and Gores 2013). In the USA, incidence rates are 2.1–3.3 per 100,000 population, while rates are as high as 113 per 100,000 population in Southeast Asia.

63

Biliary Neoplasms

It is usually asymptomatic in the early stages but in the late stages may present with jaundice, abdominal pain, abdominal mass, ascites, and hepatomegaly. Malaise and weight loss may be the only features. Jaundice is more likely in perihilar or distal cholangiocarcinoma. Depending on the relationship to second-degree bile duct, they are divided into intrahepatic and extrahepatic; extrahepatic may be perihilar or distal. Proximal to second-degree bile ducts, they are called intrahepatic, and between second-degree bile duct and cystic duct, they are perihilar, and between the cystic duct and ampulla of Vater, it is distal. Perihilar cholangiocarcinoma is further stratified depending on biliary and vascular involvement. Extrahepatic cholangiocarcinomas comprise about 90% of these cancers, and perihilar type is about 50%. Klatskin tumor is another term for hilar cholangiocarcinoma. Mixed hepatocellular cholangiocarcinoma is a distinct subtype. Intrahepatic cholangiocarcinoma usually has non-specific symptoms, while extrahepatic presents with jaundice. CEA and CA 19-9 may be elevated. Most cholangiocarcinomas are adenocarcinomas (Fig. 4 and Table 3). Endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography are usually required for obtaining biopsy or cytology for diagnosis. TNM classification, according to the American Joint Committee on Cancer, is used for staging. The most common method of tumor spread in intrahepatic cholangiocarcinoma is via portal vein invasion, similar to hepatocellular carcinoma. Surgical resection has the best outcome in intrahepatic cholangiocarcinoma if the tumors are potentially resectable, with a 5-year survival range of 22–45% (Endo et al. 2008). Liver transplantation does not appear to be an option in these patients due to poor survival rates based on several multicenter trials (Rosen et al. 2010). Transarterial chemoembolization and radiofrequency ablation are treatment options in inoperable intrahepatic cholangiocarcinoma (Kuhlmann and Blum 2013). Liver transplantation in combination with neoadjuvant chemotherapy has the best outcomes in perihilar cholangiocarcinoma with a 5-year survival rate approaching 68% (Gores et al. 2013). In advanced

1445

Fig. 5 Neuronal invasion by gallbladder cancer

disease single-agent chemotherapy with gemcitabine or combination with cisplatinum is used though evidence is limited (Boimel et al. 2018) (Fig. 5).

Key Points • Most common biliary neoplasms are benign polyps. • Cholesterol polyps are the commonest polyp (95%). • Polyps more than 1 cm require cholecystectomy. • High prevalence of gallbladder cancer in Native Americans and certain geographical areas like Northern India, Eastern Europe, and the Andes. • Gallstones are commonly seen in patients with gallbladder cancer. • Incomplete gallbladder calcification but not complete calcification is associated with gallbladder cancer. • Gallbladder cancer has a poor prognosis unless detected incidentally.

References Albores-Saavedra J, Chable-Montero F, GonzalezRomo MA, Ramirez Jaramillo M, Henson DE. Adenomas of the gallbladder. Morphologic features, expression of gastric and intestinal mucins, and

1446 incidence of high-grade dysplasia/carcinoma in situ and invasive carcinoma. Hum Pathol. 2012;43 (9):1506–13. Aloia TA, Jarufe N, Javle M, Maithel SK, Roa JC, Adsay V, et al. Gallbladder cancer: expert consensus statement. HPB (Oxford). 2015;17(8):681–90. Barreto SG, Dutt A, Sirohi B, Shrikhande SV. Gallbladder cancer: a journey of a thousand steps. Future Oncol. 2018;14(13):1299–306. Batra Y, Pal S, Dutta U, Desai P, Garg PK, Makharia G, et al. Gallbladder cancer in India: a dismal picture. J Gastroenterol Hepatol. 2005;20(2):309–14. Benavides M, Anton A, Gallego J, Gomez MA, JimenezGordo A, La Casta A, et al. Biliary tract cancers: SEOM clinical guidelines. Clin Transl Oncol. 2015;17(12): 982–7. Bhattacharjee P, Nanda D. Prospective observational study on cholelithiasis in patients with carcinoma gall bladder in a tertiary referral hospital of Eastern India. J Cancer Res Ther. 2019;15(1):153–6. Blechacz B. Cholangiocarcinoma: current knowledge and new developments. Gut Liver. 2017;11(1):13–26. Boimel PJ, Binder KR, Hong TS, Feng M, Ben-Josef E. Cholangiocarcinoma and gallbladder cases: an expert panel case-based discussion. Semin Radiat Oncol. 2018;28(4):351–61. Cavallaro A, Piccolo G, Di Vita M, Zanghì A, Cardì F, Di Mattia P, et al. Managing the incidentally detected gallbladder cancer: algorithms and controversies. Int J Surg. 2014;12:S108–19. Caygill CP, Hill MJ, Braddick M, Sharp JC. Cancer mortality in chronic typhoid and paratyphoid carriers. Lancet. 1994;343(8889):83–4. Chan SY, Poon RT, Lo CM, Ng KK, Fan ST. Management of carcinoma of the gallbladder: a single-institution experience in 16 years. J Surg Oncol. 2008;97(2):156–64. Chapman MH, Webster GJ, Bannoo S, Johnson GJ, Wittmann J, Pereira SP. Cholangiocarcinoma and dominant strictures in patients with primary sclerosing cholangitis: a 25-year single-centre experience. Eur J Gastroenterol Hepatol. 2012;24(9):1051–8. Chen A, Huminer D. The role of estrogen receptors in the development of gallstones and gallbladder cancer. Med Hypotheses. 1991;36(3):259–60. Christensen AH, Ishak KG. Benign tumors and pseudotumors of the gallbladder. Report of 180 cases. Arch Pathol. 1970;90(5):423–32. de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM. Biliary tract cancers. N Engl J Med. 1999;341(18):1368–78. DesJardins H, Duy L, Scheirey C, Schnelldorfer T. Porcelain gallbladder: is observation a safe option in select populations? J Am Coll Surg. 2018;226(6): 1064–9. Dhir V, Mohandas KM. Epidemiology of digestive tract cancers in India IV. Gall bladder and pancreas. Indian J Gastroenterol. 1999;18(1):24–8. Diehl AK. Gallstone size and the risk of gallbladder cancer. JAMA. 1983;250(17):2323–6.

C. S. Pitchumoni and N. Ravindran Edil BH, Cameron JL, Reddy S, Lum Y, Lipsett PA, Nathan H, et al. Choledochal cyst disease in children and adults: a 30-year single-institution experience. J Am Coll Surg. 2008;206(5):1000–5; discussion 5–8. Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D, et al. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg. 2008;248(1): 84–96. Gallahan WC, Conway JD. Diagnosis and management of gallbladder polyps. Gastroenterol Clin. 2010;39(2): 359–67. Golse N, Lewin M, Rode A, Sebagh M, Mabrut JY. Gallbladder adenomyomatosis: diagnosis and management. J Visc Surg. 2017;154(5):345–53. Gore RM, Yaghmai V, Newmark GM, Berlin JW, Miller FH. Imaging benign and malignant disease of the gallbladder. Radiol Clin North Am. 2002;40(6): 1307–23, vi. Gores GJ, Darwish Murad S, Heimbach JK, Rosen CB. Liver transplantation for perihilar cholangiocarcinoma. Dig Dis. 2013;31(1):126–9. Heitz L, Kratzer W, Grater T, Schmidberger J. Gallbladder polyps – a follow-up study after 11 years. BMC Gastroenterol. 2019;19(1):42. Hickman L, Contreras C. Gallbladder cancer: diagnosis, surgical management, and adjuvant therapies. Surg Clin North Am. 2019;99(2):337–55. Hsing AW, McGlynn KA, Pfeiffer RM, Welzel TM, O’Brien TR. Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intraand extrahepatic cholangiocarcinoma in the United States. J Natl Cancer Inst. 2006;98(12):873–5. Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome. Clin Epidemiol. 2014;6:99–109. Javle MM, Rashid A, Kar SP, Schalper K, Wang N, Peto M, et al. Identification of unique somatic mutations with functional relevance through genetic characterization of gallbladder cancer (GB ca). J Clin Oncol. 2013; 31(4_Suppl):214. Jiao Y, Pawlik TM, Anders RA, Selaru FM, Streppel MM, Lucas DJ, et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet. 2013; 45(12):1470–3. Kanthan R, Senger JL, Ahmed S, Kanthan SC. Gallbladder cancer in the 21st century. J Oncol. 2015;2015:967472. Kapoor VK, McMichael AJ. Gallbladder cancer: an ‘Indian’ disease. Natl Med J India. 2003;16(4):209–13. Kiran RP, Pokala N, Dudrick SJ. Incidence pattern and survival for gallbladder cancer over three decades – an analysis of 10301 patients. Ann Surg Oncol. 2007;14(2):827–32. Komorowski RA, Tresp MG, Wilson SD. Pancreaticobiliary involvement in familial polyposis coli/Gardner’s syndrome. Dis Colon Rectum. 1986; 29(1):55–8. Koshiol J, Wozniak A, Cook P, Adaniel C, Acevedo J, Azocar L, et al. Salmonella enterica serovar Typhi

63

Biliary Neoplasms

and gallbladder cancer: a case-control study and metaanalysis. Cancer Med. 2016;5(11):3235–310. Kratzer W, Haenle MM, Voegtle A, Mason RA, Akinli AS, Hirschbuehl K, et al. Ultrasonographically detected gallbladder polyps: a reason for concern? A sevenyear follow-up study. BMC Gastroenterol. 2008;8:41. Kuhlmann JB, Blum HE. Locoregional therapy for cholangiocarcinoma. Curr Opin Gastroenterol. 2013; 29(3):324–8. Larsson SC, Wolk A. Obesity and the risk of gallbladder cancer: a meta-analysis. Br J Cancer. 2007;96(9):1457–61. Li Y, Tejirian T, Collins JC. Gallbladder polyps: real or imagined? Am Surg. 2018;84(10):1670–4. Lin WR, Lin DY, Tai DI, Hsieh SY, Lin CY, Sheen IS, et al. Prevalence of and risk factors for gallbladder polyps detected by ultrasonography among healthy Chinese: analysis of 34 669 cases. J Gastroenterol Hepatol. 2008;23(6):965–9. Liu YL, Wu JS, Yang YC, Lu FH, Lee CT, Lin WJ, et al. Gallbladder stones and gallbladder polyps associated with increased risk of colorectal adenoma in men. J Gastroenterol Hepatol. 2018;33(4):800–6. Mabrut JY, Kianmanesh R, Nuzzo G, Castaing D, Boudjema K, Letoublon C, et al. Surgical management of congenital intrahepatic bile duct dilatation, Caroli’s disease and syndrome: long-term results of the French Association of Surgery Multicenter Study. Ann Surg. 2013;258(5):713–21; discussion 21. Malhotra RK, Manoharan N, Shukla NK, Rath GK. Gallbladder cancer incidence in Delhi urban: a 25-year trend analysis. Indian J Cancer. 2017;54(4):673–7. Mariani PJ, Hsue A. Adenomyomatosis of the gallbladder: the good omen comet. J Emerg Med. 2011;40(4):415–8. Mathur AV. Need for prophylactic cholecystectomy in silent gall stones in North India. Indian J Surg Oncol. 2015;6(3):251–5. McCain RS, Diamond A, Jones C, Coleman HG. Current practices and future prospects for the management of gallbladder polyps: a topical review. World J Gastroenterol. 2018;24(26):2844–52. Mellnick VM, Menias CO, Sandrasegaran K, Hara AK, Kielar AZ, Brunt EM, et al. Polypoid lesions of the gallbladder: disease spectrum with pathologic correlation. Radiographics. 2015;35(2):387–99. Mishra PK, Saluja SS, Prithiviraj N, Varshney V, Goel N, Patil N. Predictors of curative resection and long term survival of gallbladder cancer – a retrospective analysis. Am J Surg. 2017;214(2):278–86. Mohandas KM, Patil PS. Cholecystectomy for asymptomatic gallstones can reduce gall bladder cancer mortality in northern Indian women. Indian J Gastroenterol. 2006;25(3):147–51. Moriguchi H, Tazawa J, Hayashi Y, Takenawa H, Nakayama E, Marumo F, et al. Natural history of polypoid lesions in the gall bladder. Gut. 1996; 39(6):860–2. Nabatame N, Shirai Y, Nishimura A, Yokoyama N, Wakai T, Hatakeyama K. High risk of gallbladder carcinoma in elderly patients with segmental

1447 adenomyomatosis of the gallbladder. J Exp Clin Cancer Res. 2004;23(4):593–8. Nagaraja V, Eslick GD. Systematic review with metaanalysis: the relationship between chronic Salmonella typhi carrier status and gall-bladder cancer. Aliment Pharmacol Ther. 2014;39(8):745–50. Nath G, Singh H, Shukla VK. Chronic typhoid carriage and carcinoma of the gallbladder. Eur J Cancer Prev. 1997;6(6):557–9. Ootani T, Shirai Y, Tsukada K, Muto T. Relationship between gallbladder carcinoma and the segmental type of adenomyomatosis of the gallbladder. Cancer. 1992;69(11):2647–52. Owen CC, Bilhartz LE. Gallbladder polyps, cholesterolosis, adenomyomatosis, and acute acalculous cholecystitis. Semin Gastrointest Dis. 2003;14(4): 178–88. Park JK, Yoon YB, Kim YT, Ryu JK, Yoon WJ, Lee SH, et al. Management strategies for gallbladder polyps: is it possible to predict malignant gallbladder polyps? Gut Liver. 2008;2(2):88–94. Parrilla Paricio P, Garcia Olmo D, Pellicer Franco E, Prieto Gonzalez A, Carrasco Gonzalez L, Bermejo Lopez J. Gallbladder cholesterolosis: an aetiological factor in acute pancreatitis of uncertain origin. Br J Surg. 1990;77(7):735–6. Patel S, Roa JC, Tapia O, Dursun N, Bagci P, Basturk O, et al. Hyalinizing cholecystitis and associated carcinomas: clinicopathologic analysis of a distinctive variant of cholecystitis with porcelain-like features and accompanying diagnostically challenging carcinomas. Am J Surg Pathol. 2011;35(8):1104–13. Persley KM. Gallbladder polyps. Curr Treat Options Gastroenterol. 2005;8(2):105–8. Ram MD, Midha D. Adenomyomatosis of the gallbladder. Surgery. 1975;78(2):224–9. Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer. 2006;118(7):1591–602. Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet. 2014;383(9935):2168–79. Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology. 2013; 145(6):1215–29. Rosen CB, Heimbach JK, Gores GJ. Liver transplantation for cholangiocarcinoma. Transpl Int. 2010;23(7):692–7. Sastry AV, Abbadessa B, Wayne MG, Steele JG, Cooperman AM. What is the incidence of biliary carcinoma in choledochal cysts, when do they develop, and how should it affect management? World J Surg. 2015;39(2):487–92. Shin HR, Oh JK, Lim MK, Shin A, Kong HJ, Jung KW, et al. Descriptive epidemiology of cholangiocarcinoma and clonorchiasis in Korea. J Korean Med Sci. 2010; 25(7):1011–6. Shukla VK, Prakash A, Tripathi BD, Reddy DC, Singh S. Biliary heavy metal concentrations in carcinoma of the gall bladder: case-control study. BMJ. 1998; 317(7168):1288–9.

1448 Srivastava K, Srivastava A, Mittal B. Potential biomarkers in gallbladder cancer: present status and future directions. Biomarkers. 2013;18(1):1–9. Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma. Hepatology. 2011;54(1):173–84. Wada K, Tanaka M, Yamaguchi K, Wada K. Carcinoma and polyps of the gallbladder associated with PeutzJeghers syndrome. Dig Dis Sci. 1987;32(8):943–6. Wee A, Teh M, Raju GC. Clinical importance of p53 protein in gall bladder carcinoma and its precursor lesions. J Clin Pathol. 1994;47(5):453–6. Wernberg JA, Lucarelli DD. Gallbladder cancer. Surg Clin North Am. 2014;94(2):343–60. Wiles R, Thoeni RF, Barbu ST, Vashist YK, Rafaelsen SR, Dewhurst C, et al. Management and follow-up of gallbladder polyps: joint guidelines between the European Society of Gastrointestinal and Abdominal Radiology (ESGAR), European Association for Endoscopic

C. S. Pitchumoni and N. Ravindran Surgery and other Interventional Techniques (EAES), International Society of Digestive Surgery – European Federation (EFISDS) and European Society of Gastrointestinal Endoscopy (ESGE). Eur Radiol. 2017;27(9):3856–66. Yamin Z, Xuesong B, Guibin Y, Liwei L, Fei L. Risk factors of gallbladder polyps formation in East Asian population: a meta-analysis and systematic review. Asian J Surg. 2019;43:52. Yang JI, Lee JK, Ahn DG, Park JK, Lee KH, Lee KT, et al. Predictive model for neoplastic potential of gallbladder polyp. J Clin Gastroenterol. 2018;52(3):273–6. Zaidi MY, Maithel SK. Updates on gallbladder cancer management. Curr Oncol Rep. 2018;20(2):21. Zhao X, Li XY, Ji W. Laparoscopic versus open treatment of gallbladder cancer: a systematic review and metaanalysis. J Minim Access Surg. 2018;14(3):185–91.

Acute Pancreatitis

64

C. S. Pitchumoni

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1450 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1451 Older Age Increases the Severity of AP and Mortality (Kara et al. 2018; Forsmark et al. 2016; Ahn et al. 2010) . . . . . . . . . . . . . . . . . . . . . . . . . 1451 Difficulties in Diagnosing AP in the Older Adult . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1453 AP Based on Etiological Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gallstones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alcoholic Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Post ERCP Pancreatitis (PEP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drug-Induced AP (DIP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Idiopathic AP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1454 1455 1457 1457 1457 1458 1459

Physical Examination Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1459 Initial Laboratory Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1460 Severity Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1460 Imaging Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1462

C. S. Pitchumoni (*) Department of Medicine, Robert Wood Johnson School of Medicine, Rutgers University, New Brunswick, NJ, USA Department of Medicine, New York Medical College, Valhalla, NY, USA Division of Gastroenterology, Hepatology and Clinical Nutrition, Saint Peters University Hospital, New Brunswick, NJ, USA e-mail: [email protected] © Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_55

1449

1450

C. S. Pitchumoni General Management of AP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pain Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fluid Administration in Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nutritional Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacological Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Emergent ERCP in AP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgery in Acute Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Complications and Their Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1464 1465 1465 1466 1468 1468 1468 1469 1469

Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1472 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1473

Abstract

Roughly one-third of patients with acute pancreatitis (AP) admitted to hospitals are reported to be over 65 years, and the number is expected to increase along with changes in the demographics. In younger patients, the diagnosis of AP is valid if the patient has a sudden onset of epigastric pain radiating to the back, associated with elevated serum levels of amylase or lipase more than three times of normal levels. In the older adults, the diagnosis may be difficult without an early CT scan of abdomen (considered unnecessary in younger adults) because a number of other abdominal emergencies that require prompt surgery, such as intestinal ischemia, perforated peptic ulcer, appendicitis, volvulus, and abdominal aortic aneurysm, may also be associated with elevations of serum levels of amylase and/or lipase . Older age has been recognized as a marker of severity in all scoring systems of severity, such as Ranson’s criteria, modified Glasgow, Imrie, BISAP, and the APACHE II score. The overall mortality is approximately 1–3% among all AP patients but reaches 20–30% in older adults. The etiological factors, while the same in younger adults, a biliary etiology, drug-induced, and a procedure-related AP and less often an early manifestation of an occult pancreatic cancer are to be emphasized. The Atlanta II classification of AP (2013) clarifies the terms acute pancreatic fluid collection, pseudocyst, sterile, and infected necrotizing and walled-off pancreatic necrosis.

Older patients with CBD stones, ascending cholangitis, and persistent biliary obstruction require prompt endoscopic therapy, which may be life-saving even in advanced age. In the care of older adults, aggressive fluid administration, recommended as early therapy in younger patients, is associated with risk of pulmonary edema. AP in the older adult is to be considered an indication for ICU care. Keywords

Acute pancreatitis · Drug induced pancreatitis · Gallstones · Alcoholism · Hyperlipdemia · Trauma · Cholangitis. Contrast enhanced CT · MRCP · ERCP · Pseudocyst · Pleural effusion · Sterile necrosis · Infected necrosis · Walled off necrosis · Organ system failure · Atlanta criteria · Ranson criteria · BISAP · Criteria · SIRS criteria · Amylase · Lipase · Abdominal ultrasound · Antibiotics · Enteral nutrition · Parenteral nutrition · Intensive care

Introduction Acute pancreatitis (AP) is an acute inflammatory disorder of the pancreas clinically characterized by sudden onset of epigastric pain radiating to the back associated with anorexia, nausea, and vomiting. Other features are low-grade fever, tachycardia, and in severe cases, shortness of breath and features of Systemic Inflammatory Response Syndrome (SIRS). AP is morphologically associated with varying degrees of

64

Acute Pancreatitis

Table 1 Revised ATLANTA definitions of morphological features of acute pancreatitis A. Two morphological types Interstitial edematous (without recognizable tissue necrosis CECT criteria) and necrotizing B. Two peaks of severity. Early and late C. Three degrees of severity Mild: No organ failure, no local complications (e.g., peripancreatic fluid collections, pancreatic necrosis, peripancreatic necrosis), no systemic complications, typically resolves in first week Moderate: Transient organ failure (48 h), local complications. Exacerbation of comorbid disease Severe: Persistent organ failure (>48 h), presence of findings of peripancreatic necrosis Fluid collections Edematous pancreatitis I) Acute peripancreatic fluid collections (APFC). < 4 weeks, fluid only, not or only partially encapsulated. Often regress spontaneously II) Pseudocyst. > 4 weeks, encapsulated, no necrotic material, may disappear without intervention. May cause abdominal pain, compress upon adjacent organs, grow progressively, and/or get infected I infected pseudocyst) Edematous pancreatitis Necrotizing pancreatitis I) Acute Necrotic Collections (ANC): a mixture of fluid and necrotic material, not or only partially encapsulated, 4 weeks of onset. May get infected Modified from Banks et al. (2013)

pancreatic inflammation from minimal edema to necrosis and fluid collections. The natural history of AP and its complications in the older adult are discussed in this chapter. A clinically based classification system for AP was available since (Atlanta I) 1992 (Bradley 1993). The Atlanta classification was revised in 2012 and provided clear definitions to classify AP using easily identifiable clinical and radiologic criteria (Table 1). Also, greater emphasis was stressed on organ failure and severity was graded as mild, moderately severe, and severe acute pancreatitis. The two terms phlegmon and pancreatic abscess were deleted from the terminologies (Banks et al. 2013).

1451

Epidemiology Independent of the growing number of older adults, the incidence of AP and in particular severe AP (SAP) is increasing. Worldwide, the incidence of AP widely varies between 4.5 and 73.4 per hundred thousand population and is increasing (Peery et al. 2015; Yadav and Lowenfels 2006; Tenner et al. 2013; Crockett et al. 2018; Krishna et al. 2017; Gullo et al. 2002; Whitcomb 2006). Three major factors, the prevalence of obesity, the genetic predisposition for gallstones, and prevalence of alcoholism in the community significantly affect the etiology, epidemiology, and severity of AP (Yadav and Lowenfels 2006). The spectrum of severity varies from a brief self-limited course to a fulminant disease associated with multiple organ dysfunction syndrome (MODS) and death. In the United States, AP is the leading cause of hospitalization for any gastrointestinal disorder with >275,000 admissions per year, and the rate is increasing. The annual cost of care is an aggregate cost of >$2.6 billion per year (Krishna et al. 2017; Whitcomb 2006; Tinto et al. 2002). The number of patients with AP admitted and readmitted to hospitals has also increased irrespective of age (Noel et al. 2016; Otsuki et al. 2013; Martin and Ulrich 1999). Roughly, one-third of patients admitted to US hospitals are reported to be >65 years, and the number is expected to increase along with changes in the demographics (Martin and Ulrich 1999; Yadav and Lowenfels 2006; Carvalho et al. 2018; Gullo et al. 2002; Gloor et al. 2002; Peery et al. 2015; Fagenholz et al. 2007). Routine evaluation of serum pancreatic enzymes and imaging studies, including ultrasound and or CT scans of the abdomen, certainly contribute to the increase in the number of cases diagnosed.

Older Age Increases the Severity of AP and Mortality (Kara et al. 2018; Forsmark et al. 2016; Ahn et al. 2010) Older age has been recognized as a marker of severity in most severity scoring systems such as Ranson criteria, modified Glasgow, Imrie, BISAP, and the

1452

APACHE II score (Wu et al. 2008). The overall mortality is approximately 1–3% among all AP patients but reaches 20–30% in older adults (Kesselman and Holt 1991; Xin et al. 2008; Gardner et al. 2008; van Dijk et al. 2017; Losurdo et al. 2016; Somasekar et al. 2011). Many older patients, even with moderately severe and SAP, require Intensive care unit (ICU) management given the presence of comorbid conditions. The risk of increased systemic inflammatory response syndrome (SIRS), local complications, and sepsis needs early monitoring and special attention (Frossard et al. 2008). In managing AP in the older adult, the three major steps are (1) establish the diagnosis of AP excluding other causes of acute abdomen, (2) assess the severity of AP initially and through the clinical course, (3) establish the etiology for AP by biochemical and imaging studies, and (4) in biliary AP where emergency therapy is available, initiate appropriate and prompt management strategies including early therapeutic endoscopic interventions. AP is morphologically defined as interstitial, edematous, and necrotizing pancreatitis (Figs. 1 and 2). In very mild cases, the pancreas may appear normal with no morphological changes even in contrast-enhanced CT scans (CECT). Necrotizing pancreatitis occurs in 5–10% of patients. The extent of necrosis may vary and involve the pancreatic parenchyma, the peripancreatic tissue, or both. AP has two peaks of severity, an early peak occurring within a week of onset and a second peak after the second week. Organ system dysfunctions and mortality occur in both peaks, in the first peak with no morphological changes visible in imaging studies and in the second peak with evidence of pancreatic necrosis with or without infection. In the early peak of severity, death may occur even before the patient seeks medical attention (McKay et al. 1999) with no cause identifiable except in an autopsy examination. The diagnosis of AP requires two out of the three items in the following diagnostic criteria. (1) A history of abdominal pain is consistent with AP (epigastric, sudden in onset, radiating to back), (2) serum level of amylase or lipase >3 times the upper limit of normal, and (3) the characteristic

C. S. Pitchumoni

Fig. 1 Flat plate abdomen. Acute pancreatitis. The findings are not specific for acute pancreatitis. The dilatation of transverse colon and stomach indicate ileus. Once popular colon cut-off sign is as a result of gaseous distension of proximal colon associated with narrowing of the spleen, originally described in plain X-ray of abdomen has also been demonstrated in computed tomography of abdomen. A “sentinel loop” is a dilated segment of small intestine that indicates localized ileus from nearby inflammation

imaging findings in CT, MRI, or abdominal ultrasound. Serum levels of amylase and lipase are required only for diagnosing AP but not useful for assessment of severity. An initial abdominal plain x-ray may not be diagnostic (Fig. 1). On the other hand, an initial abdominal ultrasound is mandatory in all patients to identify the presence of gallstones, the size of the common bile duct, CBD stones, and other findings. Abdominal ultrasound is often not useful in imaging the pancreas since abdominal fat and gas in the intestine obscure the findings. According to guidelines in the younger population, an initial CT scan of the abdomen is not recommended to diagnose AP except in circumstances when other diagnostic considerations exist. Routine CT abdomen is considered overuse of the resources. However, in the older adult, the indications for a CT scan with or without IV contrast on admission are invariably indicated given the many other critical abdominal emergencies in the differential diagnosis, inadequate history, and many comorbid conditions confusing the picture. It is important to recognize that a number of conditions

64

Acute Pancreatitis

1453

Table 2 Conditions associated with elevation of serum amylase and/or lipase in the older adult With abdominal pain Pancreatic causes Acute pancreatitis Chronic pancreatitis (acute exacerbation) Trauma Abdominal surgery Intervention (ERCP) Nonpancreatic abdominal causes Mesenteric infarction Intestinal obstruction Appendicitis Systemic disorders (abdominal pain due to a nonpancreatic cause) Diabetic ketoacidosis

Without abdominal pain Malignancies of Lung Ovary Pancreas Colon Thymus Bone marrow Breast Tongue Esophagus Stomach

Small bowel Liver Other causes Renal failure Liver failure Shock ARDS Postburn Cardiac surgery Pneumonia Benign hyperlipasemia/ Hypermylasemia

other than AP cause elevation of amylase and lipase (see Table 2); in particular, a few other ICU-related disorders may also cause incidental elevations of pancreatic enzymes. In the latter category are diabetic ketoacidosis, liver disease, renal failure, severe burns, head injury/stroke, abdominal trauma (blunt or penetrating), abdominal surgery, shock, pulmonary disease (ARDS, lung cancer, pulmonary embolism, perforated peptic ulcer, posttransplant (cardiac, liver, renal, bone marrow)), ruptured abdominal aortic aneurysm, and postcardiac surgery (Muniraj and Dang 2015). There are three grades of severity of AP: mild, moderately severe (MSAP), and severe acute pancreatitis (SAP). Mild AP is defined as AP with no organ failure and no systemic complications. MSAP is associated with organ failure, but it

resolves within 48 h (transient organ failure). In MSAP, local or systemic complications may be present but without persistent organ failure. In SAP, there is persistent single organ failure (>48 h) or multiple organ failure. SAP is associated with high morbidity and mortality as a result of pancreatic and extra-pancreatic necrosis, subsequent infection, and MODS. SAP accounts for around 20% of AP patients and is associated with a high mortality rate (Johnson and Abu-Hilal 2004; Mofidi et al. 2006).

Difficulties in Diagnosing AP in the Older Adult Acute abdominal pain, a frequent presentation of elderly patients to any emergency department, poses a significant challenge for various reasons (Lyon and Clark 2006). The initial diagnosis of the acute abdomen made in the emergency department often needs to be revised based on changes in subsequent clinical assessments, imaging studies, and laboratory results (Laurell et al. 2006; Lyon and Clark 2006). The diagnosis of AP may be missed in some cases (underdiagnosis) due to lack of classic history, or over-diagnosed because of a large number of nonpancreatic causes for serum pancreatic enzymes elevation (see Table 2) (Yegneswaran and Pitchumoni 2010). The classic teaching is that evaluation of abdominal pain necessarily starts with a good history. However, in many older adults, in particular in the oldest old (>85 years), severe cognitive impairment may make it impossible. The patient may be disoriented, demented, depressed, or aphasic, and a complete history from the patient may be difficult. The health care provider or a proxy may be the source of history, which may not be accurate. A delay in recognition of abdominal pain is not unusual. Often the older patient’s symptoms initially get ignored until the disease advances to a critical situation. In the absence of an accurate history, AP may be confused with several disorders that need emergency surgery. The differential diagnosis of sudden onset abdominal pain with or without elevation of serum pancreatic enzymes in the older adult is broad. A surgical diagnosis such as acute

1454

appendicitis, cholecystitis, intestinal ischemia, intestinal obstruction, volvulus, diverticulitis, or perforated peptic ulcer (related to increased use of NSAIDs for many chronic painful conditions) is more often in the picture compared to that in the younger adult. On the other hand, older adults often complain of vague abdominal pain of musculoskeletal origin when the diagnosis of AP is considered and serum pancreatic enzymes are appropriately evaluated. Mild to moderate elevations of pancreatic enzymes even twofold to threefold occur in many instances with any inflammatory process (Table 2). Persons with Type 2 diabetes have an increased incidence of AP (Girman et al. 2010). It has been noted that many patients with diabetes and with acidosis of any etiology including diabetic ketoacidosis (DKA) have elevated levels of serum amylase and lipase (Steinberg 2011). A few elderly patients with AP may present with organ failure of unknown origin, hyperglycemia, and hypothermia. There may be a total absence of abdominal pain in the setting of even SAP (Gullo et al. 1994; Gloor et al. 2002) or if the patient is already on therapy with NSAIDs or another narcotic analgesic. Although small in number, it is reported that some patients may be brought to the emergency department in a state of shock, respiratory difficulties, or evidence of multiple organ system dysfunctions. AP is a multisystem disease (see Table 3) and one or more organ system dysfunction may be the presenting feature (Coelho et al. 2019; Szakács et al. 2018). Early identification with interventions is crucial for AP irrespective of age. There is evidence that after the initial 48–72 h, the progression of the disease may be fully established, leading to multisystem organ failure. The diagnosis of AP should be included in older patients with unexplained organ system dysfunction because of the urgent need for effective treatment options to prevent disease progression. Despite the availability of multiple scoring systems and their use in the emergency departments, more than 15–20% of patients with AP will develop SAP and according to one study up to 40% of this subgroup will die as a result (Sarri et al. 2019). Physical examination findings are also often unimpressive or misleading. Many findings of concomitant disorders

C. S. Pitchumoni Table 3 Complications of acute pancreatitis (AP) Systemic complications Pulmonary Early arterial hypoxia Atelectasis, pneumonia, pleural effusion, and mediastinal abscess Acute respiratory distress syndrome Cardiac: shock, pericardial effusion, EKG changes, arrhythmias, SIRS Hematologic: disseminated intravascular coagulation, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome Gastrointestinal: gastrointestinal bleeding (portal-splenic vein thrombosis, colonic infarction) Renal: azotemia, oliguria Metabolic: hyperkalemia, hypocalcemia, hypophosphatemia, hyperglycemia, hypertriglyceridemia, acidosis, elevation of free fatty acids, hypoalbuminemia Central nervous system: psychosis, pancreatic encephalopathy, Purtscher-like retinopathy Peripheral: fat necrosis (skin and bones), arthritis Rhabdomyolysis Pancreatic/peripancreatic complications Acute fluid collection Necrosis, sterile and infected, walled off pancreatic necrosis (WOPN) Pseudocyst Infected pseudocyst Local extrapancreatic complications Involvement of contiguous organs (intraperitoneal hemorrhage, gastrointestinal bleeding, thrombosis of spleen vein, bowel infarction) Obstructive jaundice Colonic involvement (necrosis, stricture) Abdominal compartment syndrome

divert the path to the correct diagnosis. It is also likely that older people may have had previous abdominal surgical procedures complicating the history and physical findings (Sandblom et al. 2008).

AP Based on Etiological Factors The etiological factors for AP are tabulated (Tables 4 and 5). While the etiological factors are the same as in the young, the frequency of

64

Acute Pancreatitis

Table 4 Etiologic factors for acute pancreatitis (AP) in the older adult Common Gallstones Alcohol Drugs Hypertriglyceridemia Rare Hypercalcemia Obstruction of the ampulla of Vater, pancreatic adenocarcinoma, IPMN Post-ERCP Genetic Pancreas divism Trauma to abdomen Viral (CMV, EBV, Mumps, Coxsackie B) Parasitic (Toxoplasma, Cryptosporidium, Ascaris, Clonorchis sinensis, Fasciola hepatica) Bacterial (Legionella) Shock/ischemia/reperfusion injury (ICU pancreatitis) Vasculitis Duodenal diverticula Choledochocele Metastasis from primary tumor (lung, breast) Abdominal and cardiac Surgery Organophosphate poisoning Idiopathic Organ transplantation Scorpion bite (in Trinidad)

Table 5 Obscure causes for acute pancreatitis (AP) Microlithiasis Ampullary tumors Mucinous tumors of the pancreas (IPMN) Undiagnosed chronic pancreatitis (early stages) Anomalies of the pancreatic duct Hereditary pancreatitis (initial episodes) Sphincter of Oddi dysfunction Choledochocele (type III choledochal cyst) Annular pancreas Anomalous pancreato-biliary junction Duodenal diverticulum Autoimmune Even after completion of all tests, 15% of AP cases, an etiology is not identifiable

cases due to different factors varies. In general, the etiology of AP does not influence the course.

1455

Gallstones Similar to the younger age groups, gallstoneinduced AP is the most frequent. The prevalence of gallstones increases as age advances and is over 25–30% in those aged >50. At least half of all cases of AP are due to the passage of small stones, usually 5 mm or less in diameter (Fogel and Sherman 2014). Common bile duct (CBD) stones are seen more often in older adults than in the general populations. Overall, 5% of patients presenting with cholecystitis have coexisting CBD stones in contrast to 10–20% of the elderly (Siegel and Kasmin 1997). Nationwide increases in the incidence of gallstones and obesity (a well-known risk for gallstones and a marker of severe AP) are expected to increase the incidence and severity of AP. There is a greater incidence of complications of AP, CBD stones, ascending cholangitis, portal vein thrombosis, a higher need for therapeutic procedures in the management of complications, and higher susceptibility to infections (Roulin et al. 2018). Given the frequency of CBD stones and the possibility of ascending cholangitis more often, there is an indication for MRCP, EUS, and therapeutic ERCP (Trust et al. 2011; Roulin et al. 2018). The pathogenesis of biliary pancreatitis is not completely understood. In 1901, Eugene Opie postulated that impairment of the pancreatic outflow due to obstruction of the pancreatic duct causes pancreatitis. Gallstones (and sludge) small enough to pass through the biliary tract, rather than the ones that remain asymptomatically in the gallbladder, confer risk for AP. The mechanisms of biliary pancreatitis are many and include a reflux of bile into the pancreatic duct – either through a common channel created by an impacted gallstone or through an incompetent sphincter, changes in intra-acinar cell calcium signaling, or injury to acinar cells by bile acids (Markus and Lerch 2016). Once a patient has developed AP, it is likely to recur if the gallbladder, the source of migrating bile duct stones, is not removed or their impaction at the duodenal papilla is not prevented (Markus and Lerch 2016). AP due to bile duct stones may rarely occur even years

1456

after cholecystectomy and one should not exclude a biliary cause because of previous cholecystectomy (Gloor et al. 2003). The initial diagnosis of a biliary etiology for AP is made by the combination of history, physical examination findings, serum biochemical studies, and transabdominal ultrasound (stones in the gallbladder and main bile duct). Charcot’s triad (jaundice associated with biliary colic, fever, and chills), indicates acute cholangitis. However, currently, a diagnosis of CBD stone or ascending cholangitis need not wait for Charcot’s triad to develop. The diagnosis of AP of biliary etiology is essentially by imaging studies but is complemented by the evaluation of liver chemistry. The elevated liver enzymes alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) in the setting of AP suggest a biliary etiology (Tenner et al. 1994). The AST/ALT levels may be markedly elevated to thousands in acute biliary obstruction mimicking acute hepatitis. However, normal serum levels do not totally exclude a biliary etiology (Dholakia et al. 2004). Years ago, ERCP was a primary diagnostic tool in suspected biliary pancreatitis, but currently, there is little role for diagnostic ERCP. The availability of endoscopic ultrasound (EUS) of the biliary system and MRCP has changed the diagnostic algorithm (see ASGE guidelines). In addition to CBD stones, EUS identifies microlithiasis, pancreaticobiliary neoplasms, pancreas divisum, and often the most frequent occult causes for AP, sometimes classified as Idiopathic AP. Once an initial etiology of biliary AP is established, the broad principles of management of biliary pancreatitis involve:

C. S. Pitchumoni

3.

4.

5.

6. 1. The treatment of mild biliary AP is conservative, followed by cholecystectomy in the same admission if there is no contraindication. Early cholecystectomy in the setting of gallstone pancreatitis (i.e., during the index admission) reduces the incidence of repeat biliary-related events, including pancreatitis, cholecystitis, and biliary colic (Hwang et al. 2013; Garber et al. 2018). 2. There is no indication for urgent ERCP in patients with mild pancreatitis without

cholangitis (Kapetanos 2010). If cholecystectomy is contraindicated in patients because of comorbidities, ERCP and sphincterotomy should be considered before discharge. ERCP is not indicated in predicted severe biliary pancreatitis without cholangitis (Working Group IAP/APA Acute Pancreatitis Guidelines 2013). Endoscopic therapy is indicated when there is evidence of CBD obstruction. A strong indication for early therapeutic intervention is when patients are suspected with CBD stones and with one of the following: ascending cholangitis (fever, jaundice, sepsis), persistent biliary obstruction (serum conjugated bilirubin of >5 mg/dL), and clinical deterioration (worsening pain, increasing white cell count, and worsening vital signs) (Kapetanos 2010; Takada et al. 2013). Endoscopic therapy may be palliative or in some cases curative even in advanced age. One can safely perform ERCP procedures for patients aged 85 years or older (Sugiyama and Atomi 2000; Obana et al. 2010). Before performing ERCP, MRCP and/or EUS are useful in the diagnosis of biliary obstruction. MRCP is a noninvasive procedure for the detection of CBD stone, with 85–92% sensitivity and 93–97% specificity (Costi et al. 2014). However, it is not recommended in an unstable patient who cannot be monitored in the MRCP chamber (Romagnuolo et al. 2003). Endoscopic ultrasound (EUS) is an excellent modality to detect CBD stones (Garrow et al. 2007). MRCP may not detect small stones lodged near the ampulla. EUS under IV sedation can be followed by ERCP and stone removal if indicated in the same sitting of IV sedation. According to ASGE guideline, the predictor for a CBD stone is very strong when CBD stone is noted on transabdominal ultrasonography (US), the presence of clinical ascending cholangitis or when total serum bilirubin is >4 mg/dL. It is considered strong (dilated CBD > 6 mm on the US with gallbladder in situ and a total bilirubin level of 1.8–4.0 mg/ dL) and moderate (abnormal liver biochemical test other than bilirubin, age more than 55 years, and clinical findings of biliary pancreatitis) (Maple et al. 2010; Kuzu et al. 2017;

64

Acute Pancreatitis

Forsmark et al. 2007). Endoscopic therapy is needed as an emergency. The frequency of ERCP-related complications is almost the same in older as compared to younger individuals except for a lower rate of post-ERCP pancreatitis in the elderly group (Tohda et al. 2016; Greenberg et al. 2016).

1457

effect of cigarette smoking in increasing the risk is well recognized (Yadav et al. 2009; Burns 2000). Older smokers are less likely than younger smokers to attempt quitting (Masamune et al. 2013).

Post ERCP Pancreatitis (PEP) Alcoholic Pancreatitis Alcoholic pancreatitis is generally a disease of the younger generation more than in the elderly based on drinking habits. However, one cannot ignore alcoholism in the older adult with new-onset AP. Although descriptions vary, it is generally accepted that drinking >80 g of alcohol a day in men and lesser amounts in women for 5–10 years or more is a prerequisite for developing alcoholic AP. Alcoholism in the older population is a “silent epidemic” ignored by all (Barry and Blow 2016). The National Institute of Alcohol Abuse and Alcoholism found that about 40 % of adults ages 65 and older drink alcohol (Gunzerath et al. 2004; Rigler 2000; Hall et al. 2005). About 10–15% start drinking in older age as a result of the loss of a spouse, loneliness, a feeling of abandonment, depression, and many other factors. The sensitivity of MCV or GGT in detecting alcohol misuse is higher in older than in younger populations (Caputo et al. 2012). Older adults are more vulnerable to the physiological effects of alcohol than younger adults (Gargiulo et al. 2013). The risk of alcohol-associated disorders is higher since it is processed differently. Reduced activity of gastric and liver alcohol dehydrogenase (ADH) leads to the elevation of blood alcohol level by 20–50% (Lieber 2005). Comorbid conditions and a decrease in lean body mass result in a decrease in the aqueous volume of cells, which in turn increases the effective concentration of alcohol in the body (Ferreira and Weems 2008; Gargiulo et al. 2013). It is likely although not proven that the risk of alcohol-associated disorders is higher as reported in a Japanese study showing that a high consumption of alcohol over a short period as may happen in the older adult could be an independent risk factor for AP. The synergistic

Diagnostic ERCP has decreased substantially, but ERCP for therapeutic indications has increased irrespective of age. Older age is not a contraindication for ERCP and ERCP as a palliative care in biliary pancreatitis may be needed often in the older adult. Perhaps the indications for ERCP are more in the older adult. Choledocholithiasis, biliary and pancreatic cancer, and the postoperative management of adverse events following biliary surgery are all more prevalent in the old age (Day et al. 2014; Lukens et al. 2010). Since endoscopic treatment of pancreaticobiliary disorders is a preferred alternative to surgery in the frail elderly, more procedures are performed. PEP is a complication in up to 10% of cases requiring the procedure and carries significant morbidity and mortality (Sheiybani et al. 2018). AP is a reported complication in 35/1000 ERCPs, but the range varies widely from 16–157/1000 (Day et al. 2014). A prior history of PEP, female sex, normal CBD size, and normal bilirubin are factors that increase the risk. A systematic review in 2015 revealed that rectal NSAIDs significantly reduce the risk. Diclofenac is more effective than indomethacin (Sajid et al. 2015). A risk assessment for PEP is necessary before ERCP and prophylactic measure to prevent PEP are highly recommended.

Pancreatic Cancer Pancreatic cancer is increasing in incidence in Western countries. AP, although is only a rare manifestation of pancreatic cancer, clinicians fail to recognize the association. Other overwhelming confounding factors such as the use of medications, history of alcohol use, or a coexistent incidental gallstone evade the diagnosis. The association of AP with pancreatic cancer is well

1458

documented, with a 20-fold increase in the risk of pancreatic cancer within the first 2 years after diagnosis of AP (Kirkegård et al. 2018). Patients admitted with AP in one study had an increased risk of pancreatic cancer compared with age- and sex-matched comparison subjects from the general (Kirkegård et al. 2018). Although relatively small when pancreatic cancer is diagnosed early, there is a survival benefit in cases presenting with AP (>25%) than with other causes (20%) (Mujica et al. 2000). Thus it is important to exclude pancreatic cancer in an elderly patient with AP (Mujica et al. 2000; Kimura et al. 2015; Köhler and Lankisch 1987; Morales-Oyarvide et al. 2015; Rigler 2000). Endoscopic ultrasound evaluation of the pancreas in AP a few weeks after the acute episode is to be recommended.

Drug-Induced AP (DIP) The topic of DIP is riddled with many doubts, and the cause and effect of the association are rarely established. However, DIP is a real entity and cannot be dismissed. One should be vigilant to the possibility along with consideration of other causes such as biliary disease, alcoholism, hyperlipidemia, and pancreatic cancer. According to WHO, 525 different drugs can induce AP as an adverse reaction, but a recent publication listed only 31 drugs to be associated with an established definite causality (Nitsche et al. 2010). Many individual case reports of DIP are probably incidental findings (Balani and Grendell 2008; Trivedi and Pitchumoni 2005; Tenner 2014; Nitsche et al. 2010). The confounding issues are many. The elderly population is at higher risk for AP for a variety of reasons such as increased incidence of gallstones and hypertriglyceridemia. The incidence of AP in people with type 2 diabetes is higher than in those without diabetes. Although a definite cause and effect cannot be established, the following medications are frequently cited as to cause AP (Table 6). Many of these drugs are often used by older people. A few medications frequently used by older adults for the age-related diseases are emphasized below. Furosemide-induced AP is often mentioned, but its

C. S. Pitchumoni

incidence must be extremely low considering the high frequency of its use. Use of incretin-based drugs ((DPP-4 inhibitors [sitagliptin, vildagliptin, and saxagliptin] or GLP-1 analogs [exenatide, liraglutide]) alone or in combination with other anti-diabetic drugs are reported to cause AP. Some of these observations have overlooked the facts that there is an increased incidence of AP in diabetics unrelated to medications (Tenner 2014). Modest elevations of serum amylase levels in diabetics in particular with DKA is not unusual. Analysis of data from 14,611 patients with type 2 diabetes from 25 clinical trials in the sitagliptin database provided no compelling evidence of an increased risk of pancreatitis or pancreatic cancer (Lyon and Clark 2006). FDA concludes that “assertions concerning a causal relationship between incretin drugs are inconsistent with the scientific literature” and does not support exenatide-induced AP (Tenner 2014). AP-induced by statins has been reported from hours to years after initiation of treatment. Druginduced AP by HMG-CoA reductase inhibitors (statins) is a class effect. The exact incidence is likely to be extremely low. ACE inhibitors (benazepril, captopril, enalapril, lisinopril, quinapril, and ramipril) extensively used by older adults are also associated with drug-induced AP (Laurell et al. 2006). AP is commonly associated with both HIV and the use of HAART in HIV-positive patients. Many chemotherapeutic agents and hormonal agents can cause AP. There are several case reports of AP associated with medications used in the management of inflammatory bowel diseases (5-aminosalicylic acid (5-ASA), immunomodulators, 6-mercaptopurine, and azathioprinez) (Pitchumoni et al. 2010). The association of AP induced by azathioprine is strong. Other drugs suspected are antibiotics (tetracyclines, macrolides, metronidazole, ampicillin, amoxicillin, and amphotericin), cimetidine, clozapine, corticosteroids, methyldopa, metronidazole, salicylates, and zalcitabine, acetaminophen, cyclosporine, cytarabine, erythromycin and roxithromycin, ketoprofen, metolazone, and octreotide. Opiates are used extensively for pain control, including in patients with AP, although AP is a rare adverse effect of opiates.

64

Acute Pancreatitis

Table 6 Drug-induced pancreatitis in the older adult (Egan et al. 2014; Kaurich 2008) Medications implicated in acute pancreatitis in the elderly Cardiovascular agents Antihypertensives ACE-I (Benzapril, captopril, enalapril, forinopril, lisinopril, moexipril, quinapril, ramipril, transolapril) Diuretics (thiazide diuretics, loop diuretics, ethacrynic acid, furosemide) Calcium channel blockers Cholesterol-lowering agents HMG-CoA reductase inhibitors (fluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin) Fibrates (genfibrozil, fenofibrate) Anti-platelets/thrombolytics ASA, alteplase, anagrelide, dipyridamole, reteplase, streptokinase Anti-arrhythmics Smiodarone, mexiletine Antibacterials Tetracyclines (doxycycline, demeclocycline, minocycline) Macrolides (azithromycin, clarithromycin) Quinolones (clatrofloxacin, ciprofloxacin, levofloxacin, norfloxacin, trovafloxacin) Others (atovaquone, metronidazole, secnidazole, ertapenem, nitrofurantoin, trimethoprim/ sulfamethoxazole, quinpristin/dalfopristin) TNF-a inhibitors Etanercept, infliximab Anti-inflammatory agents NSAIDS (diclofenac, ibuprofen, ketorolac, meloxicam, sulindac, mefenamic acid, nabumetone, naproxen, indomethacin, piroxicam COX-II inhibitors (celecoxib, rofecoxib) Acetaminophen Hypoglycemic agents Incretin mimetics (exenatide, liraglutide) Glitazones (troglitazone, rosiglitazone, pioglitazone) GI agents PPIs (omeprazole, pantroprazole, rabeprazole) Antacids (cimetidine, ranitidine) IBD medications Aminosalicylates (balsalazide, mesalamine, olsalazine, sulfasalazine) Others (azathioprine, mercaptopurine) Hormones Steroids (cortisone, dexamethasone, fludrocortisone, methylprednisolone, prednisone) Others (somatropin, octretide) (continued)

1459 Table 6 (continued) Antineoplastic drugs L-asparaginase, 6-mercaptopurine, vincristine, vinblastine) Immunemodulators Cyclosporine, glatiramer, interferon b-1B, interferon g-1B, mycophenolate, sirolimus, tacrolimus, thalidomide, PegInterferon a-2B Modified from Trivedi and Pitchumoni (2005)

Idiopathic AP Idiopathic AP accounts for 20–40% of patients influenced by the diligence with which one would look for an etiological factor. Idiopathic AP by definition is AP with no identifiable etiological factor after a thorough evaluation with biochemical (including the exclusion of hypercalcemia, hyperlipidemia) and imaging studies (including MRI, CT scan abdomen with pancreatic protocol, exclusion of pancreas divisum and neoplasms). Genetic predisposition to pancreatitis is a topic of importance, but it is less likely in the elderly. Mutations of the trypsinogen PRSS1gene, SPINK1, and CFTR gene (cystic fibrosis) are known to have a high risk of developing pancreatitis. There is a possibility that many cases of idiopathic AP cases are erroneously attributed to one or more medications that the older adult is taking. Although obesity in itself is not a cause for AP, it is an association with gallstones and a risk for severe AP.

Physical Examination Findings There is no specific or diagnostic finding that would strongly suggest AP but epigastric tenderness is a prominent sign that may not be reliably elicited if the patient is demented or not capable of verbalizing. Cholecystitis, perforated peptic ulcer, intestinal ischemia, and a few other conditions are also associated with epigastric tenderness. The finding of hypoactive bowel sounds is unreliable. Cullen and Grey- Turner signs (periumbilical and flank echymoses) are text book signs of curiosity, extremely rare, and are seldom useful in the diagnosis. When present in a patient with proven AP,

1460

the signs indicate severity. Many older persons may be on anticoagulants with a higher tendency for easy echymosis unrelated to AP.

Initial Laboratory Studies The initial tests are a complete blood count, serum electrolytes, liver tests, and other tests that evaluate the severity as discussed below. Serum amylase levels rapidly increase first but decrease rapidly. This gradual decrease in serum amylase may delay early treatment in patients with a long interval between the onset of symptoms and admission to the hospital, often the case in elderly patients. The sensitivity of serum lipase ranges from 85% to 100%, and it is more specific than amylase and useful in patients who present after several days. The critically ill patient in an intensive care unit and patients with DKA may have false elevations of serum pancreatic enzymes (Muniraj and Dang 2015). C-reactive protein (CRP) is an acute phase reactant that usually rises after 36 h of pancreatic inflammation and peaks at 48 h. When distinguishing between mild and severe disease, CRP was shown to be the most useful biomarker if serum levels are greater than 150 mg/dl; CRP is especially useful in the elderly in whom the initial diagnosis can be a great challenge.

Severity Assessment AP may be severe in nearly 20% of all cases of pancreatitis, but a larger percentage of patients in the older age group is logically expected to suffer a serious course. Severe AP causes significant morbidity and increased mortality due to numerous local and systemic complications, an intense inflammatory response that may progress to multiorgan failure and or pancreatic necrosis. In the geriatric population, AP is reported to be associated with a more severe course than the nongeriatric population with a longer duration of hospital stay (Kara et al. 2018) and a higher incidence of organ failure and mortality (Gardner et al. 2008). Age > 70 years is noted as an

C. S. Pitchumoni

independent risk factor for mortality in patients with SAP (Gardner et al. 2008; Carvalho et al. 2018). Not all studies agree; there is a considerable conflict about the effect of older age and outcomes in AP (Fan et al. 1988; Kim et al. 2012; Schütte and Malfertheiner 2008). One large study concluded that despite multiple comorbidities and higher Charlson index in the elderly at admission, old age solely did not affect mortality or severity of acute biliary pancreatitis (Roulin et al. 2018). Since comorbidity is a common feature of old age, it is irrelevant to state that AP in the older adult is intrinsically not more serious, if not for the presence of concomitant diseases with advanced age. The need to predict the severity of AP is because, in the first 24–48 h of the onset of symptoms, aggressive treatment may benefit the patient. A delay in transferring the patient to ICU is associated with poor prognosis. Unfortunately, on day one of AP, it may be difficult to differentiate a mild case of AP from a severe case with an increase in mortality (Brivet et al. 1999). Hence the predictors of severity of AP are important (Tables 7, 8, and 9). There are single markers of severity (Table 7) and multiple scoring systems. There is not one sure prognostic factor for mortality in patients with AP and only an association between several factors can lead to an accurate mortality prediction (Popa et al. 2016). Judgment based on findings, clinical as well as laboratory, Table 7 Single markers of severity and comments Obesity: BMI >30 is a poor prognostic marker Ecchymosis (Cullen and Grey Turner signs); both signs are very rare Admission hemoconcentration >44%: (lack of hemoconcentration denotes milder pancreatitis) Failure to correct hemoconcentration to 2 mg/dL on admission and failure to decline below 2 mg/dL with adequate fluid administration is a marker of volume depletion Fasting blood glucose >125 mg/dL (in nondiabetics) C-reactive protein >150 mg/L at 48 h after admission Fall in serum calcium, albumin CT scan of abdomen: not necessary in most, but is a good marker when used appropriately

64

Acute Pancreatitis

Table 8 Scoring system for Bedside Index of Severity in Acute Pancreatitis (BISAP) Score one point for each of the following criteria: Blood urea nitrogen level > 8.9 mmol/L Impaired mental status Systemic inflammatory response syndrome is present Age > 60 years Pleural effusion on radiography A score of more than three indicates an increased risk of death Wu et al. (2008)

Table 9 Systemic inflammatory response syndrome (SIRS) SIRS criteria Temperature > 38 or < 36  C Respiratory rate >20 breaths/minute or PaCO2 < 32 mmHg Pulse >90 beats/minute White blood cell count 10% immature bands Note: SIRS is defined as the presence of two or more SIRS criteria

should be the basis of an assessment of severity. Older age, comorbid conditions, multiorgan dysfunction syndrome, the extent of pancreatic necrosis, infection, and sepsis are the major determinants of mortality in AP (Buter et al. 2002; Khanna et al. 2013; Otsuki et al. 2013). The severity prediction systems include, importantly, frequent clinical assessment, early and repeated biochemical markers, and a scoring system. Multiple scoring systems are available, and early assessment of severity using one or more of the above is necessary to triage the patient to a medical floor or the ICU. A recent multivariate analysis revealed that patients suffering from severe comorbidities commonly noted in older patients were about 4.5 times more likely to have a fatal episode of AP and about two times more likely to develop severe AP than those having no comorbidities. In the same study, the authors noted that aging and comorbidities influenced the development of local and systemic complications in a completely different manner. Charlson Comorbidity Index (CCI) covering preexisting chronic conditions is to be included in the

1461

prognostic assessment (Szakács et al. 2018; Quero et al. 2019; Carvalho et al. 2018). The single markers of severity. 1. Obesity (BMI) (Khatua et al. 2017). Obesity is a risk factor for the development of local and systemic complications in AP, and also increases the mortality of this disease. 2. Hemoconcentration on admission is a reflection of fluid loss and hypovolemia that leads to microcirculatory compromise and a potential cause of pancreatic necrosis. Hemoconcentration with a hematocrit >44% on admission and failure to correct within 48 h are markers of severity. A normal or low hematocrit at admission and during the first 24 h has a negative predictive value in that it is generally associated with a milder clinical course. Overall, initial hematocrit evaluation is a simple and useful predictor of severe pancreatitis (Gan and Romagnuolo 2004). 3. Blood urea nitrogen. BUN, as a single marker of severity in AP is easy to perform and inexpensive. 4. Creatinine. Increased serum creatinine in the first 48 h of admission is strongly associated with the development of pancreatic necrosis. 5. Blood sugar level. An elevated blood sugar in a nondiabetic and hypoglycemia indicate severity. 6. C-reactive protein. As an acute phase, reactant CRP levels in serum help to predict severity. Levels of CRP >150 mg/L at 48 h denotes SAP (Lin et al. 2017; Wu et al. 2009). C reactive protein assay is a simple and inexpensive method (Neoptolemos et al. 2000). Elevated levels, however, are not specific to AP since many other causes of inflammation such as cholangitis and pneumonia also raise the levels. 7. Hypocalcemia occurs in severe AP the pathophysiology of the finding is not clear. The fall is mostly in the unionized form and hence tetany is a rare finding. 8. Hypoalbuminemia a day after admission indicates severity attributed to various causes including extravasation of protein rich

1462

exudates in the retroperitoneal space, calcium trapping in the peripancreatic tissues (soap formation) and muscles. The role of calcitonin and other hormones release is speculated. 9. Pleural effusion. Often considered a marker of pancreatitis in the past, is indeed a sign of severity. 10. Plain X-ray abdomen in severe AP shows ileus but is not a reliable sign of severity (see Fig. 1). Many other less-often used single markers are trypsinogen activation peptide, carboxypeptidase B activation peptide, procalcitonin, interleukins polymorphonuclear elastase, and coagulation parameters. Serum levels of IL-6 and procalcitonin have the highest sensitivity for prediction of severity (Mofidi et al. 2009). Modalities of assessment of the severity of AP are Ranson and Glasgow Criteria, but both require 48 h for accurate assessment of mortality and cannot be used beyond 48 h after admission to the hospital (Mounzer et al. 2012; Harshit Kumar and Singh Griwan 2018). The APACHE II scoring system takes into account 12 variables which include, (Bradley 1993) body temperature (Banks et al. 2013), mean arterial pressure (mm Hg) (Peery et al. 2015), Heart rate (HR) (Yadav and Lowenfels 2006), respiratory rate (R.R/mt) (Tenner et al. 2013), Oxygenation (mm Hg) (Crockett et al. 2018), pH (Krishna et al. 2017), Na (mmol/l) (Gullo et al. 2002), K (mmol/l) (Whitcomb 2006), creatinine (mg/100 ml) (Tinto et al. 2002), hematocrit (Noel et al. 2016), total leucocyte count, and the (Otsuki et al. 2013) Glasgow coma score. The scoring system can be used on admission as well as to reassess the severity and disease progression. By adding obesity to the scoring system, APACHEO was introduced to include the added prognostic marker. APACHE II has not been developed specifically for AP but has been proven to be an early and reliable tool. APACHE II measures the physiological response to injury and inflammation-driven stress designed to predict prolonged intensive care unit treatment and mortality and is not specific for AP. Other limitations of the APACHE II system are the requirement for multiple parameters. Older age is given a high negative score to start with. Age over 65 to 74 is given 5 points and over 75 carries 6 points.

C. S. Pitchumoni

Bedside index of severity in acute pancreatitis (BISAP) is a newer scoring system that needs to be carefully interpreted in the elderly with AP (see Table 8 for BISAP score (Wu et al. 2008)). In a recent study a BISAP score at a cut-off of >3 had a moderate sensitivity and a high specificity for predicting mortality and severe AP. In comparison, at a cut-off of 20 mmHg (with or without an abdominal perfusion pressure < 60 mmHg) with organ failure (Kirkpatrick et al. 2013; Marcos-Neira et al. 2017). ACS is probably secondary to either the severity of AP and or overhydration. In ACS, the increased pressure in a confined anatomical space adversely affects circulation and threatens the perfusion of tissues therein. A similar complication is IAH, characterized by repeated pathological elevation of intraabdominal pressure increase of 12 mm Hg or more. IAP and ACS imply severity and predict high mortality. The incidence of IAP and ACS is quite variable and probably not determined by age. IAH leads to a reduction of chest wall compliance

C. S. Pitchumoni

and hypoperfusion of the gastrointestinal tract contributing to the pathogenesis of organ dysfunction (Radenkovic et al. 2016). The reduction of peripheral blood CD4+ T lymphocytes is associated with ACS in SAP and may act as a potential predictor of ACS in SAP (Liu et al. 2015). The frequency of ACS in SAP may be rising due to more aggressive fluid resuscitation that is recommended in the management of AP. Therefore a delicate balance exists between adequate hydration and aggressive overhydration precipitating ACS. The diagnosis of ACS requires a high index of clinical suspicion combined with an increased IAP, measured by urinary bladder pressure (UBP) measurement. First line therapy is a conservative treatment to decrease IAP and to restore organ dysfunction. All patients with bladder pressure of >20 mmHg benefit from decompression methods, abdominal percutaneous decompression drainage, or decompressive laparotomy. Many older adults with moderately severe and severe AP require ICU care. A well-staffed ICU provides a capacity for proper respiratory and cardiovascular care and life support that is typically unavailable elsewhere in the hospital. Patients with organ system dysfunction need ICU care irrespective of age. There are no rigid criteria for ICU admission. In general, not specifically for AP, patients aged 85 years and older are less likely to be admitted into the ICU compared to those between 65 and 84 years. This attitude will not help the sick AP patient who primarily requires adequate hydration and supportive care.

Key Points • Acute pancreatitis (AP) is an acute inflammatory disorder of the pancreas clinically characterized by sudden onset of epigastric pain radiating to the back associated with anorexia, nausea, and vomiting. • The Atlanta II classification in 2012 provided clear definitions to classify AP using easily identifiable clinical and radiologic criteria.

64

Acute Pancreatitis

• AP morphologically is defined as interstitial edematous and necrotizing pancreatitis. • Two peaks of severity (early and late) and three degrees of severity (mild, moderately severe, and severe) are recognized. The two terms: phlegmon and pancreatic abscess have been deleted from the terminologies. The new terms include necrotizing pancreatitis (sterile or infected, walled off necrosis (WON)) and infected pseudocyst. • Complications include organ system dysfunction early or late in the course. • Older age increases the severity of AP and mortality. • In managing AP in the older adult, the three major steps are: (1) establish the diagnosis of AP excluding other causes of acute abdomen in the older adult, (2) assess the severity of AP initially and in an ongoing manner, and (3) establish the etiology for AP by biochemical and imaging studies. • In biliary AP where emergency therapy is available, initiate appropriate and prompt management strategies including early therapeutic endoscopic interventions. • The diagnosis of AP in the older adult can be missed in some cases (underdiagnosis) due to lack of classic history or overdiagnosed because of a large number of nonpancreatic causes for serum pancreatic enzymes elevation. • Biliary diseases and alcoholism are the most frequent etiological factors. • According to WHO, 525 different drugs can induce AP as an adverse reaction. • Older patients suffering from severe comorbidities are about 4.5 times more likely to have a fatal episode of AP and about two times more likely to develop severe AP than those having no comorbidities. • The increased prevalence of dementia and communication disorders adds a new dimension of challenges in pain control in the elderly. • Traditional practices of placing patients nil per os (NPO) or on a clear liquid diet (CLD) for prolonged periods delay adequate nutritional support and often is without any scientific basis. • Biliary pancreatitis with evidence of CBD obstruction needs therapeutic ERCP. Even in advanced age, ERCP is an effective and safe

1473

procedure when indicated and performed by experienced endoscopists. • Necrotizing pancreatitis, sterile or even infected, does not need emergency surgery. Infected pancreatic necrosis needs early drainage and delayed surgery.

References Abou Rached A, Basile M, El Masri H. Gastric leaks post sleeve gastrectomy: review of its prevention and management. World J Gastroenterol [Internet]. 2014 [cited 2019 Jun 21];20(38):13904–10. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/25320526 AGS Panel on Persistent Pain in Older Persons. The management of persistent pain in older persons. J Am Geriatr Soc [Internet]. 2002 [cited 2018 Dec 24];50 (6 Suppl):S205–24. Available from: http://www.ncbi. nlm.nih.gov/pubmed/12067390 Ahmed A, Gibreel W, Sarr MG. Recognition and importance of new definitions of peripancreatic fluid collections in managing patients with acute pancreatitis. Dig Surg [Internet]. 2016 [cited 2018 Dec 24];33 (4):259–66. Available from: https://www.karger.com/ Article/FullText/445005 Ahn JR, Lee SH, Kim JE, Cha BH, Hwang J-H, Ryu JK, et al. The etiology, severity, and clinical outcome of acute pancreatitis in the elderly. HPB [Internet]. 2010;12:305. Available from: http://www.embase.com/ search/results?subaction=viewrecord&from=export& id=L70458889%5Cn. https://doi.org/10.1111/j.14772574.2010.00165.x. http://sfx.library.uu.nl/utrecht? sid=EMBASE&issn=1365182X&id=doi:10.1111% 2Fj.1477-2574.2010.00165.x&atitle=The+etio Balani AR, Grendell JH. Drug-induced pancreatitis. Drug Saf [Internet]. 2008 [cited 2018 Dec 24];31(10):823–37. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 18759507 Balthazar EJ. Acute pancreatitis: assessment of severity with clinical and CT evaluation. Radiology [Internet]. 2002 [cited 2018 Dec 24];223(3):603–13. Available from: http://pubs.rsna.org/doi/10.1148/radiol.2233010680 Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, et al. Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by international consensus. Gut [Internet]. 2013 [cited 2018 Dec 24];62(1):102–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23100216 Barrie J, Jamdar S, Smith N, McPherson SJ, Siriwardena AK, O’Reilly DA. Mis-use of antibiotics in acute pancreatitis: insights from the United Kingdom’s national confidential enquiry into patient outcome and death (NCEPOD) survey of acute pancreatitis. Pancreatology [Internet]. 2018 [cited 2019 Jun 22];18(7):721–6. Available from: https://www.sciencedirect.com/science/arti cle/abs/pii/S142439031830591X?via%3Dihub

1474 Barry KL, Blow FC. Drinking over the lifespan: focus on older adults. Alcohol Res [Internet]. 2016 [cited 2018 Dec 24];38(1):115–20. Available from: http://www. ncbi.nlm.nih.gov/pubmed/27159818 Basurto Ona X, Rigau Comas D, Urrútia G. Opioids for acute pancreatitis pain. Cochrane Database Syst Rev [Internet]. 2013 [cited 2019 Jun 21];(7). Available from: http://doi. wiley.com/10.1002/14651858.CD009179.pub2 Besselink MGH. The “step-up approach” to infected necrotizing pancreatitis: delay, drain, debride. Dig Liver Dis [Internet]. 2011 [cited 2018 Dec 24];43(6):421–2. Available from: https://linkinghub.elsevier.com/ retrieve/pii/S1590865811001253 Bradley EL. A clinically based classification system for acute pancreatitis. Arch Surg [Internet]. 1993 [cited 2019 Jun 21];128(5):586. Available from: http:// archsurg.jamanetwork.com/article.aspx?doi=10.1001/ archsurg.1993.01420170122019 Brivet FG, Emilie D, Galanaud P. Pro- and antiinflammatory cytokines during acute severe pancreatitis: an early and sustained response, although unpredictable of death. Parisian Study Group on Acute Pancreatitis. Crit Care Med [Internet]. 1999 [cited 2018 Dec 24];27(4):749–55. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10321665 Burns DM. Cigarette smoking among the elderly: disease consequences and the benefits of cessation. Am J Health Promot [Internet]. 2000 [cited 2018 Dec 24];14(6):357–61. Available from: http://journals. sagepub.com/doi/10.4278/0890-1171-14.6.357 Buter A, Imrie CW, Carter CR, Evans S, McKay CJ. Dynamic nature of early organ dysfunction determines outcome in acute pancreatitis. Br J Surg [Internet]. 2002 [cited 2019 Jun 21];89(3):298–302. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/11872053 Buxbaum J, Quezada M, Chong B, Gupta N, Yu CY, Lane C, et al. The pancreatitis activity scoring system predicts clinical outcomes in acute pancreatitis: findings from a prospective cohort study. Am J Gastroenterol [Internet]. 2018 [cited 2018 Dec 24];113(5):755–64. Available from: http://www.ncbi. nlm.nih.gov/pubmed/29545634 Buyukasik K, Toros AB, Bektas H, Ari A, Deniz MM. Diagnostic and therapeutic value of ERCP in acute cholangitis. ISRN Gastroenterol [Internet]. 2013 [cited 2019 Jun 22];2013:191729. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23997958 Caputo F, Vignoli T, Leggio L, Addolorato G, Zoli G, Bernardi M. Alcohol use disorders in the elderly: a brief overview from epidemiology to treatment options. Exp Gerontol [Internet]. 2012 [cited 2018 Dec 24];47(6):411–6. Available from: https://linkinghub.elsevier.com/retrieve/pii/ S0531556512000745 Carvalho JR, Fernandes SR, Santos P, Moura CM, Antunes T, Velosa J. Acute pancreatitis in the elderly: a cause for increased concern? Eur J Gastroenterol Hepatol. 2018;30(3):337–41. Cavalieri TA. Pain management in the elderly. J Am Osteopath Assoc [Internet]. 2002 [cited 2018 Dec 24];102(9):481–5.

C. S. Pitchumoni Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 12361180 Chau DL, Walker V, Pai L, Cho LM. Opiates and elderly: use and side effects. Clin Interv Aging [Internet]. 2008 [cited 2018 Dec 24];3(2):273–8. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/18686750 Clark JD. Chronic pain prevalence and analgesic prescribing in a general medical population. J Pain Symptom Manage [Internet]. 2002 [cited 2018 Dec 24];23(2):131–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 11844633 Coelho AMM, Machado MCC, Sampietre SN, da Silva FP, Cunha JEM, D’Albuquerque LAC. Local and systemic effects of aging on acute pancreatitis. Pancreatology [Internet]. 2019 [cited 2019 Jun 22]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31204259 Costi R, Gnocchi A, Di Mario F, Sarli L. Diagnosis and management of choledocholithiasis in the golden age of imaging, endoscopy and laparoscopy. World J Gastroenterol [Internet]. 2014 [cited 2018 Dec 24];20(37):13382–401. Available from: http://www. wjgnet.com/1007-9327/full/v20/i37/13382.htm Crockett SD, Wani S, Gardner TB, Falck-Ytter Y, Barkun AN, American Gastroenterological Association Institute Clinical Guidelines Committee S, et al. American gastroenterological association institute guideline on initial management of acute pancreatitis. Gastroenterology [Internet]. 2018 [cited 2018 Dec 24];154(4):1096–101. Available from: https://linkinghub.elsevier.com/retrieve/ pii/S0016508518300763 Day LW, Lin L, Somsouk M. Adverse events in older patients undergoing ERCP: a systematic review and meta-analysis. Endosc Int open [Internet]. 2014 [cited 2018 Dec 24];2(1):E28–36. Available from: http://www. thieme-connect.de/DOI/DOI?10.1055/s-0034-1365281 De-Madaria E, Herrera-Marante I, González-Camacho V, Bonjoch L, Quesada-Vázquez N, Almenta-Saavedra I, et al. Fluid resuscitation with lactated Ringer’s solution vs normal saline in acute pancreatitis: a triple-blind, randomized, controlled trial. United Eur Gastroenterol J [Internet]. 2018 [cited 2018 Dec 24];6(1):63–72. Available from: http://journals.sagepub.com/doi/10. 1177/2050640617707864 Dholakia K, Pitchumoni CS, Agarwal N. How often are liver function tests normal in acute biliary pancreatitis? J Clin Gastroenterol [Internet]. 2004 [cited 2018 Dec 24];38(1):81–3. Available from: http://www.ncbi.nlm. nih.gov/pubmed/14679333 Donald G, Donahue T, Reber HA, Hines OJ. The evolving management of infected pancreatic necrosis. Am Surg [Internet]. 2012 [cited 2018 Dec 24];78(10):1151–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23025961 Eckerwall GE, Tingstedt BBA, Bergenzaun PE, Andersson RG. Immediate oral feeding in patients with mild acute pancreatitis is safe and may accelerate recovery–a randomized clinical study. Clin Nutr [Internet]. 2007 [cited 2018 Dec 24];26(6):758–63. Available from: http://linkinghub. elsevier.com/retrieve/pii/S0261561407000714 Egan AG, Blind E, Dunder K, de Graeff PA, Hummer BT, Bourcier T, et al. Pancreatic safety of incretin-based

64

Acute Pancreatitis

drugs–FDA and EMA assessment. N Engl J Med [Internet]. 2014 [cited 2018 Dec 24];370(9):794–7. Available from: http://www.nejm.org/doi/10.1056/ NEJMp1314078 Fagenholz PJ, Del Castillo CF, Harris NS, Pelletier AJ, Camargo CA. Increasing United States hospital admissions for acute pancreatitis, 1988–2003. Ann Epidemiology. 2007;17(7):491–7 Fan ST, Choi TK, Lai CS, Wong J. Influence of age on the mortality from acute pancreatitis. Br J Surg [Internet]. 1988 [cited 2018 Dec 24];75(5):463–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3390679 Feng P, He C, Liao G, Chen Y. Early enteral nutrition versus delayed enteral nutrition in acute pancreatitis. Medicine (Baltimore) [Internet]. 2017 [cited 2018 Dec 24];96(46):e8648. Available from: http://www.ncbi. nlm.nih.gov/pubmed/29145291 Ferreira MP, Weems MKS. Alcohol consumption by aging adults in the United States: health benefits and detriments. J Am Diet Assoc [Internet]. 2008 [cited 2018 Dec 24];108 (10):1668–76. Available from: http://linkinghub.elsevier. com/retrieve/pii/S0002822308014089 Fogel EL, Sherman S. ERCP for gallstone pancreatitis. N Engl J Med. 2014;370(2):150–7 Forsmark CE, Baillie J, AGA Institute Clinical Practice and Economics Committee, AGA Institute Governing Board. AGA Institute technical review on acute pancreatitis. Gastroenterol [Internet]. 2007 [cited 2019 Jun 22];132(5):2022–44. Available from: http://www.ncbi. nlm.nih.gov/pubmed/17484894 Forsmark CE, Swaroop Vege S, Wilcox CM. Acute pancreatitis. N Engl J Med [Internet]. 2016;375(20):197 2–81. Available from: http://www.nejm.org/doi/10. 1056/NEJMra1505202 Franklin GA, McClave SA, Hurt RT, Lowen CC, Stout AE, Stogner LL, et al. Physician-delivered malnutrition: why do patients receive nothing by mouth or a clear liquid diet in a university hospital setting? JPEN J Parenter Enteral Nutr [Internet]. 2011 [cited 2018 Dec 24];35(3):337–42. Available from: http://doi.wiley. com/10.1177/0148607110374060 Freeman ML, Werner J, van Santvoort HC, Baron TH, Besselink MG, Windsor JA, et al. Interventions for necrotizing pancreatitis: summary of a multidisciplinary consensus conference. Pancreas [Internet]. 2012 [cited 2018 Dec 24];41(8):1176–94. Available from: http://con tent.wkhealth.com/linkback/openurl?sid=WKPTLP: landingpage&an=00006676-201211000-00004 Frossard J-L, Steer ML, Pastor CM. Acute pancreatitis. Lancet (London, England) [Internet]. 2008 [cited 2018 Dec 24];371(9607):143–52. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18191686 Gan SI, Romagnuolo J. Admission hematocrit: a simple, useful and early predictor of severe pancreatitis. Dig Dis Sci [Internet]. 2004 [cited 2018 Dec 24];49 (11–12):1946–52. Available from: http://www.ncbi. nlm.nih.gov/pubmed/15628731 Gao W, Yang HX, Ma CE. The value of BISAP score for predicting mortality and severity in acute pancreatitis: a systematic review and meta-analysis. PLoS One

1475 [Internet]. 2015 [cited 2019 Jun 21];10(6). Available from: https://journals.plos.org/plosone/article/file?id=10. 1371/journal.pone.0130412&type=printable Garber A, Frakes C, Arora Z, Chahal P. Mechanisms and management of acute pancreatitis. Gastroenterol Res Pract [Internet]. 2018 [cited 2018 Dec 24];2018. Available from: https://www.hindawi.com/journals/grp/ 2018/6218798/ Gardner TB, Vege SS, Chari ST, Pearson RK, Clain JE, Topazian MD, et al. The effect of age on hospital outcomes in severe acute pancreatitis. Pancreatol [Internet]. 2008;8(3):265–70. Available from: http://ovidsp. ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D= med5&NEWS=N&AN=18497539 Gardner TB, Vege SS, Chari ST, Petersen BT, Topazian MD, Clain JE, et al. Faster rate of initial fluid resuscitation in severe acute pancreatitis diminishes in-hospital mortality. Pancreatol [Internet]. 2009 [cited 2018 Dec 24];9 (6):770–6. Available from: https://linkinghub.elsevier. com/retrieve/pii/S1424390309801154 Gargiulo G, Testa G, Cacciatore F, Mazzella F, Galizia G, Della-Morte D, et al. Moderate alcohol consumption predicts long-term mortality in elderly subjects with chronic heart failure. J Nutr Health Aging [Internet]. 2013 [cited 2019 Jun 22];17(5):480–5. Available from: http://link.springer.com/10.1007/s12603-012-0430-4 Garrow D, Miller S, Sinha D, Conway J, Hoffman BJ, Hawes RH, et al. Endoscopic ultrasound: a meta-analysis of test performance in suspected biliary obstruction. Clin Gastroenterol Hepatol [Internet]. 2007 [cited 2018 Dec 24];5(5):616–23. Available from: http://linkinghub. elsevier.com/retrieve/pii/S1542356507002212 Gianotti L, Meier R, Lobo DN, Bassi C, Dejong CHC, Ockenga J, et al. ESPEN guidelines on parenteral nutrition: pancreas. Clin Nutr [Internet]. 2009 [cited 2018 Dec 24];28(4):428–35. Available from: https://linkinghub. elsevier.com/retrieve/pii/S026156140900082X Giner M, Laviano A, Meguid MM, Gleason JR. In 1995 a correlation between malnutrition and poor outcome in critically ill patients still exists. Nutrition [Internet]. 1996 [cited 2018 Dec 24];12(1):23–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8838832 Girman CJ, Kou TD, Cai B, Alexander CM, O’Neill EA, Williams-Herman DE, et al. Patients with type 2 diabetes mellitus have higher risk for acute pancreatitis compared with those without diabetes. Diabetes Obes Metab [Internet]. 2010 [cited 2018 Dec 24];12(9):766–71. Available from: http://doi.wiley.com/10.1111/j.1463-1326.2010. 01231.x Gloor B, Ahmed Z, Uhl W, Buchler MW. Pancreatic disease in the elderly. Best Pract Res Clin Gastroenterol. 2002;16(1):159–70. Gloor B, Stahel PF, Müller CA, Worni M, Büchler MW, Uhl W. Incidence and management of biliary pancreatitis in cholecystectomized patients. Results of a 7-year study. J Gastrointest Surg [Internet]. 2003 [cited 2018 Dec 24];7(3):372–7. Available from: http://www.ncbi. nlm.nih.gov/pubmed/12654562 Gou S, Yang Z, Liu T, Wu H, Wang C. Use of probiotics in the treatment of severe acute pancreatitis: a systematic

1476 review and meta-analysis of randomized controlled trials. Crit Care [Internet]. 2014 [cited 2018 Dec 24];18(2): R57. Available from: http://ccforum.biomedcentral. com/articles/10.1186/cc13809 Greenberg JA, Hsu J, Bawazeer M, Marshall J, Friedrich JO, Nathens A, et al. Clinical practice guideline: management of acute pancreatitis. Can J Surg. 2016;59:128–40. Gullo L, Sipahi HM, Pezzilli R. Pancreatitis in the elderly. J Clin Gastroenterol. 1994;19(1):64–8. Gullo L, Migliori M, Oláh A, Farkas G, Levy P, Arvanitakis C, et al. Acute pancreatitis in five European countries: etiology and mortality. Pancreas [Internet]. 2002 [cited 2018 Dec 24];24(3):223–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11893928 Gunzerath L, Faden V, Zakhari S, Warren K. National Institute on Alcohol Abuse and Alcoholism report on moderate drinking. Alcohol Clin Exp Res [Internet]. 2004 [cited 2018 Dec 24];28(6):829–47. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15201626 Gupta R, Patel K, Calder PC, Yaqoob P, Primrose JN, Johnson CD. A randomised clinical trial to assess the effect of total enteral and total parenteral nutritional support on metabolic, inflammatory and oxidative markers in patients with predicted severe acute pancreatitis (APACHE II > or =6). Pancreatol [Internet]. 2003 [cited 2018 Dec 24];3(5):406–13. Available from: http://linkinghub.elsevier.com/retrieve/pii/ S1424390303800352 Hall KE, Proctor DD, Fisher L, Rose S. American gastroenterological association future trends committee report: effects of aging of the population on gastroenterology practice, education, and research. Gastroenterol [Internet]. 2005 [cited 2018 Dec 24];129(4):1305–38. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 16230084 Harshit Kumar A, Singh Griwan M. A comparison of APACHE II, BISAP, Ranson’s score and modified CTSI in predicting the severity of acute pancreatitis based on the 2012 revised Atlanta Classification. Gastroenterol Rep [Internet]. 2018 [cited 2019 Jun 21];6(2):127–31. Available from: https://academic. oup.com/gastro/article/6/2/127/4055926 Hwang SS, Li BH, Haigh PI. Gallstone pancreatitis without cholecystectomy. JAMA Surg [Internet]. 2013 [cited 2018 Dec 24];148(9):867–72. Available from: http://archsurg.jamanetwork.com/article.aspx?doi=10. 1001/jamasurg.2013.3033 Iida T, Kaneto H, Wagatsuma K, Sasaki H, Naganawa Y, Nakagaki S, et al. Efficacy and safety of endoscopic procedures for common bile duct stones in patients aged 85 years or older: a retrospective study. PLoS One [Internet]. 2018 [cited 2019 Jun 22];13(1): e0190665. Available from: http://www.ncbi.nlm.nih. gov/pubmed/29298346 Iqbal U, Anwar H, Scribani M. Ringer’s lactate versus normal saline in acute pancreatitis: a systematic review and meta-analysis. J Dig Dis [Internet]. 2018 [cited 2018 Dec 24];19(6):335–41. Available from: http:// doi.wiley.com/10.1111/1751-2980.12606

C. S. Pitchumoni Jacobson BC, Vander Vliet MB, Hughes MD, Maurer R, McManus K, Banks PA. A prospective, randomized trial of clear liquids versus low-fat solid diet as the initial meal in mild acute pancreatitis. Clin Gastroenterol Hepatol [Internet]. 2007 [cited 2018 Dec 24];5(8):946–51; quiz 886. Available from: http://linkinghub.elsevier.com/ retrieve/pii/S1542356507004533 Johnson CD, Abu-Hilal M. Persistent organ failure during the first week as a marker of fatal outcome in acute pancreatitis. Gut. 2004; Jones AE, Trzeciak S, Kline JA. The sequential organ failure assessment score for predicting outcome in patients with severe sepsis and evidence of hypoperfusion at the time of emergency department presentation. Crit Care Med [Internet]. 2009 [cited 2018 Dec 24];37(5):1649–54. Available from: https://insights. ovid.com/crossref?an=00003246-200905000-00015 Kapetanos DJ. ERCP in acute biliary pancreatitis. World J Gastrointest Endosc [Internet]. 2010 [cited 2018 Dec 24];2(1):25–8. Available from: http://www.wjgnet. com/1948-5190/full/v2/i1/25.htm Kara B, Olmez S, Yalcın MS, Tas A, Ozturk NA, Sarıtaş B. Update on the effect of age on acute pancreatitis morbidity: a retrospective, single-center study. Prz Gastroenterol [Internet]. 2018 [cited 2018 Dec 24];13(3):223–7. Available from: https://www.termedia. pl/doi/10.5114/pg.2018.75677 Kaurich T. Drug-induced acute pancreatitis. Proc (Bayl Univ Med Cent) [Internet]. 2008 [cited 2018 Dec 24];21(1):77–81. Available from: http://www.ncbi. nlm.nih.gov/pubmed/18209761 Kesselman MS, Holt PR. Acute pancreatitis in the elderly. J Am Geriatr Soc [Internet]. 1991 [cited 2018 Dec 24];39(10):1043. Available from: http://doi.wiley. com/10.1111/j.1532-5415.1991.tb04055.x Khanna AK, Meher S, Prakash S, Tiwary SK, Singh U, Srivastava A, et al. Comparison of Ranson, Glasgow, MOSS, SIRS, BISAP, APACHE-II, CTSI Scores, IL-6, CRP, and Procalcitonin in Predicting Severity, Organ Failure, Pancreatic Necrosis, and Mortality in Acute Pancreatitis. HPB Surg [Internet]. 2013 [cited 2019 Jun 21];2013:367581. Available from: http://www. ncbi.nlm.nih.gov/pubmed/24204087 Khatua B, El-Kurdi B, Singh VP. Obesity and pancreatitis. Curr Opin Gastroenterol [Internet]. 2017 [cited 2018 Dec 24];33(5):374–382. Available from: http://insights. ovid.com/crossref?an=00001574-201709000-00010 Kim JE, Hwang JH, Lee SH, Cha BH, Park YS, Kim JW, et al. The clinical outcome of elderly patients with acute pancreatitis is not different in spite of the different etiologies and severity. Arch Gerontol Geriatr. 2012;54(1):256–60. Kimura Y, Kikuyama M, Kodama Y. Acute pancreatitis as a possible indicator of pancreatic cancer: the importance of mass detection. Intern Med [Internet]. 2015 [cited 2018 Dec 24];54(17):2109–14. Available from: https:// www.jstage.jst.go.jp/article/internalmedicine/54/17/54_ 54.4068/_article Kirkegård J, Cronin-Fenton D, Heide-Jørgensen U, Mortensen FV. Acute pancreatitis and pancreatic cancer

64

Acute Pancreatitis

risk: a nationwide matched-cohort study in Denmark. Gastroenterol [Internet]. 2018 [cited 2018 Dec 24];154(6):1729–36. Available from: https://linkinghub. elsevier.com/retrieve/pii/S0016508518302002 Kirkpatrick AW, Roberts DJ, De Waele J, Jaeschke R, Malbrain MLNG, De Keulenaer B, et al. Intra-abdominal hypertension and the abdominal compartment syndrome: updated consensus definitions and clinical practice guidelines from the world society of the abdominal compartment syndrome. Intensive Care Med [Internet]. 2013 [cited 2018 Dec 24];39(7):1190–206. Available from: http://link.springer.com/10.1007/s00134-013-2906-z Köhler H, Lankisch PG. Acute pancreatitis and hyperamylasaemia in pancreatic carcinoma. Pancreas [Internet]. 1987 [cited 2018 Dec 24];2(1):117–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2437571 Koutroumpakis E, Slivka A, Furlan A, Dasyam AK, Dudekula A, Greer JB, et al. Management and outcomes of acute pancreatitis patients over the last decade: a US tertiary-center experience. Pancreatol [Internet]. 2017 [cited 2018 Dec 24];17(1):32–40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28341116 Krishna SG, Kamboj AK, Hart PA, Hinton A, Conwell DL. The changing epidemiology of acute pancreatitis hospitalizations. Pancreas [Internet]. 2017 [cited 2018 Dec 24];46(4):482–8. Available from: http://www. ncbi.nlm.nih.gov/pubmed/28196021 Kuip EJM, Zandvliet ML, Koolen SLW, Mathijssen RHJ, van der Rijt CCD. A review of factors explaining variability in fentanyl pharmacokinetics; focus on implications for cancer patients. Br J Clin Pharmacol [Internet]. 2017 [cited 2018 Dec 24];83(2):294–313. Available from: http://doi.wiley.com/10.1111/bcp.13129 Kuzu UB, Ödemiş B, Dişibeyaz S, Parlak E, Öztaş E, Saygılı F, et al. Management of suspected common bile duct stone: diagnostic yield of current guidelines. HPB [Internet]. 2017 [cited 2019 Jun 22];19(2):126–32. Available from: https://www.sciencedirect.com/science/ article/pii/S1365182X16319724 Laurell H, Hansson L-E, Gunnarsson U. Acute abdominal pain among elderly patients. Gerontology [Internet]. 2006 [cited 2018 Dec 24];52(6):339–44. Available from: https://www.karger.com/Article/FullText/94982 Lee F, Cundiff D. Meperidine vs morphine in pancreatitis and cholecystitis. Arch Intern Med [Internet]. 1998 [cited 2018 Dec 24];158(21):2399. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9827794 Lieber CS. Metabolism of alcohol. Clin Liver Dis [Internet]. 2005 [cited 2018 Dec 24];9(1):1–35. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15763227 Lin S, Hong W, Basharat Z, Wang Q, Pan J, Zhou M. Blood urea nitrogen as a predictor of severe acute pancreatitis based on the revised Atlanta criteria: timing of measurement and cutoff points. Can J Gastroenterol Hepatol [Internet]. 2017 [cited 2019 Jun 21];2017:9592831. Available from: http://www.ncbi. nlm.nih.gov/pubmed/28487848 Linnebur SA, O’Connell MB, Wessell AM, McCord AD, Kennedy DH, DeMaagd G, et al. Pharmacy practice,

1477 research, education, and advocacy for older adults. Pharmacother [Internet]. 2005 [cited 2019 Jun 21];25 (10):1396–430. Available from: http://doi.wiley.com/ 10.1592/phco.2005.25.10.1396 Liu Y, Wang L, Cai Z, Zhao P, Peng C, Zhao L, et al. The decrease of peripheral blood CD4+ T cells indicates abdominal compartment syndrome in severe acute pancreatitis. Strnad P, editor. PLoS One [Internet]. 2015 [cited 2018 Dec 24];10(8):e0135768. Available from: https://dx.plos.org/10.1371/journal.pone.0135768 Losurdo G, Iannone A, Principi M, Barone M, Ranaldo N, Ierardi E, et al. Acute pancreatitis in elderly patients: a retrospective evaluation at hospital admission. Eur J Intern Med [Internet]. 2016 [cited 2018 Dec 24];30:88–93. Available from: https://linkinghub. elsevier.com/retrieve/pii/S0953620516000121 Lukens FJ, Howell DA, Upender S, Sheth SG, Jafri S-MR. ERCP in the very elderly: outcomes among patients older than eighty. Dig Dis Sci [Internet]. 2010 [cited 2018 Dec 24];55(3):847–51. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/19337836 Lyon C, Clark DC. Diagnosis of acute abdominal pain in older patients. Am Fam Physician [Internet]. 2006 [cited 2018 Dec 24];74(9):1537–44. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17111893 Maple JT, Ben-Menachem T, Anderson MA, Appalaneni V, Banerjee S, Cash BD, et al. The role of endoscopy in the evaluation of suspected choledocholithiasis. Gastrointest Endosc [Internet]. 2010 [cited 2018 Dec 24];71(1):1–9. Available from: http://www. ncbi.nlm.nih.gov/pubmed/20105473 Marcos-Neira P, Zubia-Olaskoaga F, López-Cuenca S, Bordejé-Laguna L, Epidemiology of acute pancreatitis in intensive care medicine study group. Relationship between intra-abdominal hypertension, outcome and the revised Atlanta and determinant-based classifications in acute pancreatitis. BJS Open [Internet]. 2017 [cited 2018 Dec 24];1(6):175–81. Available from: http://doi.wiley.com/10.1002/bjs5.29 Markus M, Lerch AA. Gallstone-related pathogenesis of acute pancreatitis. Pancreapedia Exocrine Pancreas Knowl Base [Internet]. 2016 [cited 2018 Dec 24]; Available from: https://www.pancreapedia.org/reviews/gall stone-related-pathogenesis-of-acute-pancreatitis Martin SP, Ulrich CD. Pancreatic disease in the elderly. Clin Geriatr Med [Internet]. 1999;15(3):579–605. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10393743 Masamune A, Kume K, Shimosegawa T. Sex and age differences in alcoholic pancreatitis in Japan: a multicenter nationwide survey. Pancreas [Internet]. 2013 [cited 2018 Dec 24];42(4):578–83. Available from: http://insights. ovid.com/crossref?an=00006676-201305000-00003 Mayer J, Rau B, Gansauge F, Beger HG. Inflammatory mediators in human acute pancreatitis: clinical and pathophysiological implications. Gut [Internet]. 2000 [cited 2018 Dec 24];47(4):546–52. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10986216 McKay CJ, Evans S, Sinclair M, Carter CR, Imrie CW. High early mortality rate from acute pancreatitis

1478 in Scotland, 1984–1995. Br J Surg [Internet]. 1999 [cited 2018 Dec 24];86(10):1302–5. Available from: http://www.blackwell-synergy.com/links/doi/10.1046/ j.1365-2168.1999.01246.x Meier R, Ockenga J, Pertkiewicz M, Pap A, Milinic N, Macfie J, et al. ESPEN guidelines on enteral nutrition: pancreas. Clin Nutr [Internet]. 2006 [cited 2018 Dec 24];25(2):275–84. Available from: http://linkinghub. elsevier.com/retrieve/pii/S0261561406000392 Mofidi R, Duff MD, Wigmore SJ, Madhavan KK, Garden OJ, Parks RW. Association between early systemic inflammatory response, severity of multiorgan dysfunction and death in acute pancreatitis. Br J Surg [Internet]. 2006 [cited 2019 Jun 21];93(6):738–44. Available from: http://doi.wiley.com/10.1002/bjs.5290 Mofidi R, Suttie SA, Patil P V, Ogston S, Parks RW. The value of procalcitonin at predicting the severity of acute pancreatitis and development of infected pancreatic necrosis: systematic review. Surgery [Internet]. 2009 [cited 2018 Dec 24];146(1):72–81. Available from: https://linkinghub. elsevier.com/retrieve/pii/S0039606009001561 Moggia E, Koti R, Belgaumkar AP, Fazio F, Pereira SP, Davidson BR, et al. Pharmacological interventions for acute pancreatitis. Cochrane database Syst Rev [Internet]. 2017 [cited 2019 Jun 22];4(4):CD011384. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28431202 Moraes JMM, Felga GEG, Chebli LA, Franco MB, Gomes CA, Gaburri PD, et al. A full solid diet as the initial meal in mild acute pancreatitis is safe and result in a shorter length of hospitalization: results from a prospective, randomized, controlled, double-blind clinical trial. J Clin Gastroenterol [Internet]. 2010 [cited 2018 Dec 24]; 44(7):517–22. Available from: http://content.wkhealth. com/linkback/openurl?sid=WKPTLP:landingpage& an=00004836-900000000-99447 Morales-Oyarvide V, Mino-Kenudson M, Ferrone CR, Gonzalez-Gonzalez LA, Warshaw AL, Lillemoe KD, et al. Acute pancreatitis in intraductal papillary mucinous neoplasms: a common predictor of malignant intestinal subtype. Surgery [Internet]. 2015 [cited 2018 Dec 24];158(5):1219–25. Available from: https://linkinghub. elsevier.com/retrieve/pii/S003960601500358X Mounzer R, Langmead CJ, Wu BU, Evans AC, Bishehsari F, Muddana V, et al. Comparison of existing clinical scoring systems to predict persistent organ failure in patients with acute pancreatitis. Gastroenterol [Internet]. 2012 [cited 2019 Jun 21];142(7):1476–82. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 22425589 Mourad MM, Evans R, Kalidindi V, Navaratnam R, Dvorkin L, Bramhall SR. Prophylactic antibiotics in acute pancreatitis: endless debate. Ann R Coll Surg Engl [Internet]. 2017 [cited 2018 Dec 24];99(2):107–12. Available from: http://publishing.rcseng.ac.uk/doi/10.1308/ rcsann.2016.0355 Mowbray NG, Ben-Ismaeil B, Hammoda M, Shingler G, Al-Sarireh B. The microbiology of infected pancreatic necrosis. Hepatobiliary Pancreat Dis Int [Internet]. 2018 [cited 2018 Dec 24];17(5):456–60. Available from: https:// linkinghub.elsevier.com/retrieve/pii/S1499387218301887

C. S. Pitchumoni Mujica VR, Barkin JS, Go VL. Acute pancreatitis secondary to pancreatic carcinoma. Study Group Participants. Pancreas [Internet]. 2000 [cited 2018 Dec 24];21(4):329–32. Available from: http://www.ncbi. nlm.nih.gov/pubmed/11075985 Muniraj T, Dang S, Pitchumoni CS. PANCREATITIS OR NOT?–Elevated lipase and amylase in ICU patients. J Crit Care [Internet]. 2015 [cited 2018 Dec 24];30(6):1370–5. Available from: https://linkinghub. elsevier.com/retrieve/pii/S0883944115004554 Navadgi S, Pandanaboyana S, Windsor JA. Surgery for acute pancreatitis. Indian J Surg [Internet]. 2015 [cited 2019 Jun 22];77(5):446–52. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/26722210 Neoptolemos JP, Kemppainen EA, Mayer JM, Fitzpatrick JM, Raraty MG, Slavin J, et al. Early prediction of severity in acute pancreatitis by urinary trypsinogen activation peptide: a multicentre study. Lancet (London, England) [Internet]. 2000 [cited 2018 Dec 24];355(9219):1955–60. Available from: http://www. ncbi.nlm.nih.gov/pubmed/10859041 Nitsche CJ, Jamieson N, Lerch MM, Mayerle J V. Drug induced pancreatitis. Best Pract Res Clin Gastroenterol [Internet]. 2010 [cited 2018 Dec 24];24(2):143–55. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 20227028 Noel P, Patel K, Durgampudi C, Trivedi RN, de Oliveira C, Crowell MD, et al. Peripancreatic fat necrosis worsens acute pancreatitis independent of pancreatic necrosis via unsaturated fatty acids increased in human pancreatic necrosis collections. Gut [Internet]. 2016 [cited 2018 Aug 29];65(1):100–11. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/25500204 Obana T, Fujita N, Noda Y, Kobayashi G, Ito K, Horaguchi J, et al. Efficacy and safety of therapeutic ERCP for the elderly with choledocholithiasis: comparison with younger patients. Intern Med [Internet]. 2010 [cited 2018 Dec 24];49(18):1935–41. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20847495 Otsuki M, Takeda K, Matsuno S, Kihara Y, Koizumi M, Hirota M, et al. Criteria for the diagnosis and severity stratification of acute pancreatitis. World J Gastroenterol [Internet]. 2013 [cited 2018 Dec 24];19 (35):5798–805. Available from: http://www.wjgnet. com/1007-9327/full/v19/i35/5798.htm Pan L-L, Li J, Shamoon M, Bhatia M, Sun J. Recent advances on nutrition in treatment of acute pancreatitis. Front Immunol [Internet]. 2017 [cited 2018 Dec 24];8:762. Available from: http://journal.frontiersin. org/article/10.3389/fimmu.2017.00762/full Payor A, Jois P, Wilson J, Kedar R, Nallamshetty L, Grubb S, et al. Efficacy of noncontrast computed tomography of the abdomen and pelvis for evaluating nontraumatic acute abdominal pain in the emergency department. J Emerg Med [Internet]. 2015 [cited 2018 Dec 24];49 (6):886–92. Available from: https://linkinghub.elsevier. com/retrieve/pii/S0736467915006848 Peery AF, Crockett SD, Barritt AS, Dellon ES, Eluri S, Gangarosa LM, et al. Burden of gastrointestinal, liver, and pancreatic diseases in the United States.

64

Acute Pancreatitis

Gastroenterology [Internet]. 2015 [cited 2018 Dec 24];149(7):1731–41.e3. Available from: http://www. ncbi.nlm.nih.gov/pubmed/26327134 Pergolizzi J, Böger RH, Budd K, Dahan A, Erdine S, Hans G, et al. Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone). Pain Pract [Internet]. 2008 [cited 2018 Dec 24];8(4):287–313. Available from: http://doi.wiley.com/10.1111/j.1533-2500. 2008.00204.x Pezzilli R, Zerbi A, Campra D, Capurso G, Golfieri R, Arcidiacono PG, et al. Consensus guidelines on severe acute pancreatitis. Dig Liver Dis. 2015;47(7):532–43. Pitchumoni CS, Rubin A, Das K. Pancreatitis in inflammatory bowel diseases. J Clin Gastroenterol [Internet]. 2010 [cited 2018 Dec 24];44(4):246–53. Available from: https://insights.ovid.com/crossref?an=00004836201004000-00009 Popa CC, Badiu DC, Rusu OC, Grigorean VT, Neagu SI, Strugaru CR. Mortality prognostic factors in acute pancreatitis. J Med Life. 2016;9(4):413–8. Preiser J-C, van Zanten ARH, Berger MM, Biolo G, Casaer MP, Doig GS, et al. Metabolic and nutritional support of critically ill patients: consensus and controversies. Crit Care [Internet]. 2015 [cited 2019 Jun 21];19(1):35. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 25886997 Puli SR, Graumlich JF, Pamulaparthy SR, Kalva N. Endoscopic transmural necrosectomy for walledoff pancreatic necrosis: a systematic review and metaanalysis. Can J Gastroenterol Hepatol [Internet]. 2014 [cited 2018 Dec 24];28(1):50–3. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/24212912 Quero G, Covino M, Fiorillo C, Rosa F, Menghi R, Simeoni B, et al. Acute pancreatitis in elderly patients: a single-center retrospective evaluation of clinical outcomes. Scand J Gastroenterol [Internet]. 2019 [cited 2019 Jun 21];54(4):492–8. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/30905212 Radenkovic D V., Johnson CD, Milic N, Gregoric P, Ivancevic N, Bezmarevic M, et al. Interventional treatment of abdominal compartment syndrome during severe acute pancreatitis: current status and historical perspective. Gastroenterol Res Pract [Internet]. 2016 [cited 2019 Jun 22];2016:5251806. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/26839539 Rasslan R, Novo FdaCF, Bitran A, Utiyama EM, Rasslan S. Management of infected pancreatic necrosis: state of the art. Rev Col Bras Cir [Internet]. 2017 [cited 2018 Dec 24];44(5):521–9. Available from: http://www. scielo.br/scielo.php?script=sci_arttext&pid=S010069912017000500521&lng=en&tlng=en Reuken PA, Albig H, Rödel J, Hocke M, Will U, Stallmach A, et al. Fungal infections in patients with infected pancreatic necrosis and pseudocysts: risk factors and outcome. Pancreas [Internet]. 2018 [cited 2019

1479 Jun 22];47(1):92–8. Available from: http://www.ncbi. nlm.nih.gov/pubmed/29215543 Rigler SK. Alcoholism in the elderly. Am Fam Physician [Internet]. 2000 [cited 2018 Dec 24];61(6):1710–6, 1883–4, 1887–8 passim. Available from: http://www. ncbi.nlm.nih.gov/pubmed/10750878 Romagnuolo J, Bardou M, Rahme E, Joseph L, Reinhold C, Barkun AN. Magnetic resonance cholangiopancreatography: a meta-analysis of test performance in suspected biliary disease. Ann Intern Med [Internet]. 2003 [cited 2018 Dec 24];139(7):547–57. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/14530225 Roulin D, Girardet R, Duran R, Hajdu S, Denys A, Halkic N, et al. Outcome of elderly patients after acute biliary pancreatitis. Biosci Trends. 2018;12(1):54–9. Sajid MS, Khawaja AH, Sayegh M, Singh KK, Philipose Z. Systematic review and meta-analysis on the prophylactic role of non-steroidal anti-inflammatory drugs to prevent post-endoscopic retrograde cholangiopancreatography pancreatitis. World J Gastrointest Endosc [Internet]. 2015 [cited 2018 Dec 24];7(19):1341–9. Available from: http://www.wjgnet.com/1948-5190/ full/v7/i19/1341.htm Sandblom G, Bergman T, Rasmussen I. Acute pancreatitis in patients 70 years of age or older [Internet]. Clinical Medicine: Geriatrics. 2008 [cited 2019 Jun 22]. Available from: https://pdfs.semanticscholar.org/9c19/ d72a25247e8e1f2906673203f126e636e841.pdf Sansom LT, Duggleby L. Intravenous fluid prescribing: improving prescribing practices and documentation in line with NICE CG174 guidance. BMJ Qual Improv reports [Internet]. 2014 [cited 2019 Jun 21];3(1). Available from: http://www.ncbi.nlm.nih.gov/pubmed/26734287 Sarri G, Guo Y, Iheanacho I, Puelles J. Moderately severe and severe acute pancreatitis: a systematic review of the outcomes in the USA and European Union-5. BMJ open Gastroenterol [Internet]. 2019 [cited 2019 Jun 22];6(1):e000248. Available from: http://www.ncbi. nlm.nih.gov/pubmed/30899535 Sathiaraj E, Murthy S, Mansard MJ, Rao G V, Mahukar S, Reddy DN. Clinical trial: oral feeding with a soft diet compared with clear liquid diet as initial meal in mild acute pancreatitis. Aliment Pharmacol Ther [Internet]. 2008 [cited 2018 Dec 24];28(6):777–81. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19145732 Schorn S, Ceyhan GO, Tieftrunk E, Friess H, Demir IE. Pain management in acute pancreatitis. 2015 [cited 2019 Jun 21]; Available from: https://www. pancreapedia.org/sites/default/files/DOI V2. Pain management in acute pancreatitis 5–22-15_0.pdf. Schütte K, Malfertheiner P. Markers for predicting severity and progression of acute pancreatitis. Best Pract Res Clin Gastroenterol [Internet]. 2008 [cited 2018 Dec 24];22(1):75–90. Available from: http://linkinghub. elsevier.com/retrieve/pii/S1521691807001199 Sheiybani G, Brydon P, Toolan M, Linehan J, Farrant M, Colleypriest B. Does rectal diclofenac reduce postERCP pancreatitis? A district general hospital experience. Frontline Gastroenterol [Internet]. 2018 [cited 2018 Dec 24];9(1):73–7. Available from:

1480 http://fg.bmj.com/lookup/doi/10.1136/flgastro-2017100832 Siegel JH, Kasmin FE. Biliary tract diseases in the elderly: management and outcomes. Gut [Internet]. 1997 [cited 2018 Dec 24];41(4):433–5. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/9391238 Singh VK, Wu BU, Bollen TL, Repas K, Maurer R, Mortele KJ, et al. Early systemic inflammatory response syndrome is associated with severe acute pancreatitis. Clin Gastroenterol Hepatol [Internet]. 2009 [cited 2018 Dec 24];7(11):1247–51. Available from: https://linkinghub. elsevier.com/retrieve/pii/S1542356509007745 Somasekar K, Foulkes R, Morris-Stiff G, Hassn A. Acute pancreatitis in the elderly - can we perform better? Surgeon. 2011;9(6):305–8. Spanier BWM, Bruno MJ, Mathus-Vliegen EMH. Enteral nutrition and acute pancreatitis: a review. Gastroenterol Res Pract [Internet]. 2011 [cited 2019 Jun 22];2011. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 20811543 Steinberg WM. Comment: acute pancreatitis associated with liraglutide. Ann Pharmacother [Internet]. 2011 [cited 2018 Dec 24];45(9):1169. Available from: http://journals.sagepub.com/doi/10.1345/aph.1P714a Sugiyama M, Atomi Y. Endoscopic sphincterotomy for bile duct stones in patients 90 years of age and older. Gastrointest Endosc [Internet]. 2000 [cited 2018 Dec 24];52(2):187–91. Available from: http://www.ncbi. nlm.nih.gov/pubmed/10922089 Szakács Z, Gede N, Pécsi D, Izbéki F, Papp M, Kovács G, et al. Aging and comorbidities in acute pancreatitis II.: a cohort-analysis of 1203 prospectively collected cases. Front Physiol [Internet]. 2018 [cited 2019 Jun 21];9:1776. Available from: http://www.ncbi.nlm.nih. gov/pubmed/31001148 Takada T, Strasberg SM, Solomkin JS, Pitt HA, Gomi H, Yoshida M, et al. TG13: updated Tokyo guidelines for the management of acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci [Internet]. 2013 [cited 2018 Dec 24];20(1):1–7. Available from: http://www. ncbi.nlm.nih.gov/pubmed/23307006 Tenner S. Drug induced acute pancreatitis: does it exist? World J Gastroenterol [Internet]. 2014 [cited 2019 Jun 21];20(44):16529–34. Available from: http://www. ncbi.nlm.nih.gov/pubmed/25469020 Tenner S, Dubner H, Steinberg W. Predicting gallstone pancreatitis with laboratory parameters: a metaanalysis. Am J Gastroenterol [Internet]. 1994 [cited 2018 Dec 24];89(10):1863–6. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/7942684 Tenner S, Baillie J, DeWitt J, Vege SS, American College of Gastroenterology. American college of gastroenterology guideline: management of acute pancreatitis. Am J Gastroenterol [Internet]. 2013 [cited 2018 Sep 5]; 108(9):1400–15. Available from: http://www.ncbi.nlm. nih.gov/pubmed/23896955 Teoh AYB, Ho LKY, Dhir VK, Jin ZD, Kida M, Seo DW, et al. A multi-institutional survey on the practice of endoscopic ultrasound (EUS) guided pseudocyst

C. S. Pitchumoni drainage in the Asian EUS group. Endosc Int open [Internet]. 2015 [cited 2018 Dec 24];3(2):E130–3. Available from: http://www.thieme-connect.de/DOI/ DOI?10.1055/s-0034-1390890 Teoh AYB, Dhir V, Kida M, Yasuda I, Dong Jin Z, Wan Seo D, et al. Consensus guidelines on the optimal management in interventional EUS procedures: results from the Asian EUS group RAND/UCLA expert panel. Gut [Internet]. 2018 [cited 2019 Jun 22];67:1209–28. Available from: http://gut.bmj.com/ Thoeni RF. The revised atlanta classification of acute pancreatitis: its importance for the radiologist and its effect on treatment. Radiology [Internet]. 2012;262(3):751–64. Available from: http://pubs.rsna.org/doi/10.1148/radiol. 11110947 Tinto A, Lloyd DAJ, Kang J-Y, Majeed A, Ellis C, Williamson RCN, et al. Acute and chronic pancreatitis – diseases on the rise: a study of hospital admissions in England 1989/90–1999/2000. Aliment Pharmacol Ther [Internet]. 2002 [cited 2018 Dec 24];16(12):2097–105. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 12452943 Tohda G, Ohtani M, Dochin M. Efficacy and safety of emergency endoscopic retrograde cholangiopancreatography for acute cholangitis in the elderly. World J Gastroenterol [Internet]. 2016 [cited 2018 Dec 24];22(37):8382–8. Available from: http://www.wjgnet.com/1007-9327/full/ v22/i37/8382.htm Trikudanathan G, Navaneethan U, Vege SS. Current controversies in fluid resuscitation in acute pancreatitis: a systematic review. Pancreas [Internet]. 2012 [cited 2018 Dec 24];41(6):827–34. Available from: http://con tent.wkhealth.com/linkback/openurl?sid=WKPTLP: landingpage&an=00006676-201208000-00001 Trivedi CD, Pitchumoni CS. Drug-induced pancreatitis: an update. J Clin Gastroenterol [Internet]. 2005 [cited 2018 Dec 24];39(8):709–16. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/16082282 Trust MD, Sheffield KM, Boyd CA, Benarroch-Gampel J, Zhang D, Townsend CM, et al. Gallstone pancreatitis in older patients: are we operating enough? Surgery [Internet]. 2011 [cited 2018 Dec 24];150(3):515–25. Available from: https://linkinghub.elsevier.com/ retrieve/pii/S0039606011004284 van Dijk SM, Hallensleben NDL, van Santvoort HC, Fockens P, van Goor H, Bruno MJ, et al. Acute pancreatitis: recent advances through randomised trials. Gut [Internet]. 2017 [cited 2018 May 16];66(11):2024–32. Available from: http://gut.bmj.com/lookup/doi/10. 1136/gutjnl-2016-313595 Varadarajulu S, Bang JY, Sutton BS, Trevino JM, Christein JD, Wilcox CM. Equal efficacy of endoscopic and surgical cystogastrostomy for pancreatic pseudocyst drainage in a randomized trial. Gastroenterol [Internet]. 2013 [cited 2018 Dec 24];145(3):583–90.e1. Available from: https://linkinghub.elsevier.com/retrieve/pii/S001650851 3008445 Veal FC, Peterson GM. Pain in the frail or elderly patient: does tapentadol have a role? Drugs Aging [Internet].

64

Acute Pancreatitis

2015 [cited 2018 Dec 24];32(6):419–26. Available from: http://link.springer.com/10.1007/s40266-0150268-7 Wallace JI. Malnutrition and enteral/parenteral alimentation. In: Hazzard W, Blass J, Ettinger WJ, Halter J, Ouslander J, editors. Principles of geriatric medicine and gerontology. 4th ed. New York: McGraw-Hill; 1999. p. 1455–69. Whitcomb DC. Clinical practice. Acute pancreatitis. N Engl J Med [Internet]. 2006;354(20):2142–50. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16707751 Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guidelines for the management of acute pancreatitis Working Group IAP/APA Acute Pancreatitis Guidelines. Pancreat. 2013;13: e1–15. Wu BU, Johannes RS, Sun X, Tabak Y, Conwell DL, Banks PA. The early prediction of mortality in acute pancreatitis: a large population-based study. Gut [Internet]. 2008 [cited 2018 Dec 24];57(12):1698–703. Available from: http://gut.bmj.com/cgi/doi/10.1136/ gut.2008.152702 Wu BU, Johannes RS, Sun X, Conwell DL, Banks PA. Early changes in blood urea nitrogen predict mortality in acute pancreatitis. Gastroenterology [Internet]. 2009 [cited 2019 Jun 21];137(1):129–35. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19344722 Wu BU, Hwang JQ, Gardner TH, Repas K, Delee R, Yu S, et al. Lactated ringer’s solution reduces systemic inflammation compared with saline in patients with acute pancreatitis. Clin Gastroenterol Hepatol [Internet]. 2011 [cited 2018 Dec 24];9(8):710–7.e1. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21645639 Xin M-J, Chen H, Luo B, Sun J-B. Severe acute pancreatitis in the elderly: etiology and clinical characteristics. World J Gastroenterol [Internet]. 2008;14(16):2517–21. Available from: http://www.pubmedcentral.nih.gov/articlerender. fcgi?artid=2708362&tool=pmcentrez&rendertype= abstract Yadav D, Lowenfels AB. Trends in the epidemiology of the first attack of acute pancreatitis. Pancreas [Internet]. 2006 [cited 2018 Dec 24];33(4):323–30. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17079934

1481 Yadav D, Hawes RH, Brand RE, Anderson MA, Money ME, Banks PA, et al. Alcohol consumption, cigarette smoking, and the risk of recurrent acute and chronic pancreatitis. Arch Intern Med [Internet]. 2009 [cited 2018 Dec 24];169(11):1035–45. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19506173 Yegneswaran B, Pitchumoni CS. When should serum amylase and lipase levels be repeated in a patient with acute pancreatitis?|Cleveland Clinic Journal of Medicine. Cleve Clin J Med [Internet]. 2010;77(4):230–1. Available from: https://www.mdedge.com/ccjm/article/95282/gastroenter ology/when-should-serum-amylase-and-lipase-levels-berepeated-patient Yegneswaran B, Kostis JB, Pitchumoni CS. Cardiovascular manifestations of acute pancreatitis. J Crit Care [Internet]. 2011 [cited 2019 Jun 22];26(2):225.e11–225.e18. Available from: https://www.sciencedirect.com/science/ article/abs/pii/S0883944110002959?via%3Dihub Yıldırım AE, Öztürk ZA, Konduk BT, Balkan A, Edizer B, Gulsen MT, et al. The safety and efficacy of ERCP in octogenarians: a comparison of two geriatric age cohorts. Acta Gastroenterol Belg [Internet]. 2017 [cited 2018 Dec 24];80(2):263–70. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29560692 Yip HC, Teoh AYB. Endoscopic management of peripancreatic fluid collections. Gut Liver [Internet]. 2017 [cited 2018 Dec 24];11(5):604–11. Available from: http://www.gutnliver.org/journal/view.html?doi=10. 5009/gnl16178 Zhao G, Zhang J-G, Wu H-S, Tao J, Qin Q, Deng S-C, et al. Effects of different resuscitation fluid on severe acute pancreatitis. World J Gastroenterol [Internet]. 2013 [cited 2018 Dec 24];19(13):2044–52. Available from: http://www.wjgnet.com/1007-9327/full/v19/i13/2044. htm Zou X-P, Chen M, Wei W, Cao J, Chen L, Tian M. Effects of enteral immunonutrition on the maintenance of gut barrier function and immune function in pigs with severe acute pancreatitis. JPEN J Parenter Enteral Nutr [Internet]. 2010 [cited 2018 Dec 24];34(5):554–66. Available from: http://doi.wiley.com/10.1177/0148607110362691

Chronic Pancreatitis

65

Sonmoon Mohapatra, Gaurav Aggarwal, and Suresh T. Chari

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1484 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1484 Effects of Aging on the Pancreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Functional Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathological Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Morphological Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1485 1485 1485 1486

Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Idiopathic Chronic Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Obstructive Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alcoholic Chronic Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tobacco . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recurrent Acute Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1486 1486 1486 1486 1487 1487 1487

Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1487 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1488 Tests of Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1488 Tests of Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1490

Conflicts of Interest/Disclosures: None S. Mohapatra (*) Division of Gastroenterology and Hepatology, Saint Peter’s University Hospital – Rutgers Robert Wood Johnson School of Medicine, New Brunswick, NJ, USA G. Aggarwal GA Bellevue Medical Center, Bellevue, WA, USA Division of Epidemiology, Mayo Clinic, Rochester, MN, USA S. T. Chari Department of Gastroenterology, Hepatology and Nutrition, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA e-mail: [email protected] © Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_56

1483

1484

S. Mohapatra et al. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abdominal Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Steatorrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nutritional Deficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1492 1492 1494 1494 1494

Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1495 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1495

Abstract

Chronic pancreatitis refers to progressive chronic inflammation and fibrosis along with impaired exocrine and endocrine pancreatic function, eventually leading to endocrine and exocrine failure. In the USA, pancreatitis is not an uncommon diagnosis in an ambulatory care setting in subjects over 65 years of age. While alcohol is the most common cause of chronic pancreatitis in the general population, most cases of chronic pancreatitis in the older adult are idiopathic. Other causes in the geriatric population include those related to obstruction (e.g., ampullary malignancy or pancreatic cancer). Most older adults with idiopathic chronic pancreatitis do not have pain and instead present with exocrine and endocrine insufficiency. No single test is adequately sensitive for the diagnosis of chronic pancreatitis. The diagnosis is based on clinical presentation with stool testing and radiologic imaging. Exocrine function testing and endoscopic evaluation for diagnosis are typically used when the imaging is inconclusive. Therapy targets the prevention of ongoing damage to the pancreas, alleviation of symptoms, and treating complications. Exclusion of malignancy, pancreatic enzyme replacement, and treatment of diabetes along with the cessation of tobacco and alcohol use are mainstays of therapy. Surgical and endoscopic interventions are reserved for those who do not respond to conservative therapy and for complications. Keywords

Chronic pancreatitis · Alcoholic pancreatitis · Pancreatic pseudocyst · Amylase · Lipase · Autoimmune pancreatitis · Pancreatic cancer ·

Steatorrhea · Diabetes · Smoking · Exocrine insufficiency · Amylase · Lipase · Elastase · Fecal fat · Endoscopic ultrasound · Steroids · Chronic abdominal pain · ERCP · Pseudoaneurysm · Gastric varices · Splenic vein thrombosis · Pancreatic fistula · Pancreatic ascites

Introduction Chronic pancreatitis is characterized by progressive chronic inflammation and fibrosis of the pancreas resulting in impaired exocrine and endocrine function (Aggarwal and Chari 2012). In true acute pancreatitis, there is restitution of the gland to structural and functional normalcy after an acute attack, characterized by acute abdominal pain, elevated serum amylase/lipase, and morphological changes on imaging. In chronic pancreatitis, patients often experience attacks of clinically acute pancreatitis, but in contrast to true acute pancreatitis, there is progressive structural and functional damage to the pancreas despite clinical recovery from the attacks. Despite the differences in the two entities, a subset of patients with (recurrent) acute pancreatitis will progress to chronic pancreatitis (Dimagno and Dimagno 2010).

Epidemiology The incidence rate of clinical chronic pancreatitis has increased significantly from 2.94/100,000 during 1977–1986 to 4.35/100,000 person years during 1997–2006 (P < 0.05) because of an increase in the incidence of alcoholic chronic pancreatitis. (Yadav et al. 2011) In the USA,

65

Chronic Pancreatitis

pancreatitis was listed among the top three principal diagnoses with a 291,915 annual number of admissions in 2014 (Peery et al. 2019). Although the peak age for diagnosis of alcohol-related chronic pancreatitis is the 45–54 age group, the age of diagnosing nonalcoholic chronic pancreatitis is most common in the 65–74 age group (Yadav et al. 2011). A survey in Japan revealed the prevalence of chronic pancreatitis in men between 65 and 69 years of age to be 115 per 100,000 population and in women aged 75– 79 years to be 39.6 per 100,000 population (Lin et al. 2000). A prospective survey in France yielded a crude prevalence rate of 26 per 100,000 population and estimated that about 20% of chronic pancreatitis cases occurred in the over 65 year age group (Levy et al. 2006). The most common causes of death in chronic pancreatitis include malignancies (23%) and cardiovascular causes (21%). (Yadav et al. 2011).

1485

>80 years (Bulow et al. 2014). An age-related decrease in the secretory flow of pancreatic juice in the main pancreatic duct has been demonstrated noninvasively by cine-dynamic MRCP using spatially selective inversion recovery pulse (Torigoe et al. 2014). A decrease in fecal elastase-1 (level 60 years with no history of gastrointestinal disease, gastrointestinal surgery, or diabetes mellitus (Herzig et al. 2011). In contrast, another study on fecal elastase-1 has shown no functional impairment in those over 90 years old (Gullo et al. 2009). Regardless, even if there was some age-related decline (10–30%), this would not be clinically relevant since >90% of the pancreas has to be damaged to cause clinically evident exocrine insufficiency (Dimagno et al. 1973).

Pathological Changes

Effects of Aging on the Pancreas The effect of aging on the pancreas has been well described (Ross and Forsmark 2001). They involve not only pancreatic parenchyma but also functional, pathological, and ductal changes as described below.

Functional Changes Studies of changes on exocrine pancreatic function with aging yield conflicting data. Early studies showed a 10–30% reduction in the volume, bicarbonate, and lipase in pancreatic juice in the older adults (Ross and Forsmark 2001). In contrast, there was no difference in secretinstimulated pancreatic secretion between 25 older subjects and 30 young controls (Gullo et al. 1983). These contradictory data may be due to differences in methodology and inadvertent inclusion of patients with asymptomatic pancreatic disease. In a population-based German study of nearly 1000 healthy individuals with normal serum lipase and amylase, there was a significant 30% reduction in secretin-stimulated output in those

In contrast to the effects of age on function, marked changes in pancreatic structure occur with aging. Autopsy series reveal duct proliferation, lobular degeneration, and fatty infiltration (Pitchumoni et al. 1984; Shimizu et al. 1989; Ross and Forsmark 2001). Severe pancreatic steatosis was demonstrated in 15% of those 60to 69-year-olds compared to no severe pancreatic steatosis in subjects below 40 years (Olsen 1978). There is a marginal decline in volume densities of islets and loss of both β- and non-β-cells with aging (Matsuda 2018). Mild focal or segmental ductal ectasia of the main or branched pancreatic ducts can also be seen. Main pancreatic ductal dilation greater than 4 mm in diameter has been reported in 16% of patients at autopsy (Stamm 1984). Pancreatic lithiasis ranges from being absent in those 90 years (Nagai and Ohtsubo 1984). Pancreatic lithiasis was found in the peripheral ducts upstream from sites of squamous metaplasia, in asymptomatic persons, not associated with alcoholism or hypercalcemia (Nagai and Ohtsubo 1984). Extensive parenchymal atrophy and fibrosis were also seen in areas upstream from the stones.

1486

S. Mohapatra et al.

Morphological Changes

Risk Factors

A significant negative correlation was reported between age and pancreatic size based on ultrasound (US) in 1000 males and females aged between 18 and 65 years (Niederau et al. 1983). In a large CT-based study on the pancreatic volume in humans from birth to age 100 years, the reported volumes of the pancreas increased linearly with age during childhood and adolescence, reached a plateau at age 20–60 years, and declined thereafter (Saisho et al. 2007). Postmortem pancreatography performed by physicians trained in Endoscopic Retrograde Cholangio-Pancreatography (ERCP) found ductal changes similar to those seen in chronic pancreatitis in 81% of older adults (Schmitz-Moormann et al. 1985; Gloor et al. 2002). However, histopathology in the same cases confirmed the findings to be age-related and not due to chronic pancreatitis (Schmitz-Moormann et al. 1985). Compared to subjects 90 years old increased significantly from 3.3 to 5.3 mm 2.3 to 3.7 mm, and 1.6 to 2.6 mm in the head, body, and tail of the pancreas, respectively (Hastier et al. 1998). The suggested ERCP criteria for diagnosing of chronic pancreatitis in older adults are summarized in Table 1 (Jones et al. 1989; Gloor et al. 2002). Age-related pancreatic changes are also seen on endoscopic ultrasonography (EUS). In a prospective study of 120 patients without pancreatic disease, 39% of patients >60 years had at least one EUS abnormality of chronic pancreatitis (Rajan et al. 2005). In this study, the presence of >3 EUS abnormalities, ductal or parenchymal stones, ductal narrowing, or dilation were more likely to represent disease than age-related changes (Rajan et al. 2005). Thus, caution should be exercised when interpreting ERCP and EUS findings in the geriatric patient.

Idiopathic Chronic Pancreatitis

Table 1 ERCP criteria for diagnosis of chronic pancreatitis in the elderly. (Adapted from Jones et al. 1989, Gloor et al. 2002) Ductal obstruction and stricture Gross irregularity of the main pancreatic duct Presence of large cavities (>5 mm) (due to pre-stenotic ductal dilation)

Most of the cases of chronic pancreatitis identified in the older subjects are due to “late-onset” idiopathic disease, described initially as “senile” chronic pancreatitis by Amman et al. and characterized by the age of onset of 56 years, absence of pain, and early development of structural (diffuse calcifications) and functional (exocrine and endocrine) abnormalities (Ammann and Sulser 1976; Layer et al. 1994). This is in contrast to “early-onset” idiopathic disease with a mean age of onset of 20 years, presence of pain, and long delay to the development of pancreatic abnormalities (Ammann et al. 1987; Layer et al. 1994).

Obstructive Pancreatitis Obstruction of the main pancreatic duct (e.g., by an ampullary malignancy or cancer in the pancreatic head) can be an important cause in the elderly patient with new-onset chronic pancreatitis (Gloor et al. 2002; Cavallini and Frulloni 2009). This form of chronic pancreatitis differs from other varieties in the absence of calcifications and higher prevalence of a dilated pancreatic duct (Cavallini and Frulloni 2009).

Alcoholic Chronic Pancreatitis In the general population, alcohol is the most common cause of chronic pancreatitis, accounting for 70–80% cases; however in patients with onset of pancreatitis after the age of 65, alcohol is an exceedingly uncommon cause (Yang et al. 2008). The risk increases with increasing dose (>4 drinks/day) and duration (>10 years) of alcohol consumption (Yadav et al. 2007). While alcohol appears to play an essential role in the development of chronic pancreatitis, only 5–15% of alcoholics develop the disease, suggesting a role for cofactors such as genetics, tobacco, etc. (Yadav et al. 2007).

65

Chronic Pancreatitis

Tobacco While smoking is an independent risk factor for chronic pancreatitis, the damage to the pancreas is often compounded by ongoing alcohol use (Andriulli et al. 2010). After adjusting for alcohol use, the pooled risk estimate for chronic pancreatitis was 2.5 (95% CI 1.3–4.6) for current smokers when compared with never smokers (Andriulli et al. 2010). Also, the association between smoking and chronic pancreatitis was dose dependent, with a pooled risk estimate of 3.3 (95% CI 1.4–7.9) for people smoking one or more packs per day, compared with 2.4 (95% CI 0.9–6.6) for those smoking less than one pack per day and 1.4 (95% CI 1.1–1.9) for former smokers (Andriulli et al. 2010). The detrimental effects of smoking seem synergistic with alcohol use in patients with chronic pancreatitis (Yadav et al. 2009).

Recurrent Acute Pancreatitis Approximately one out of every five patients with acute alcoholic pancreatitis will progress to chronic pancreatitis (Yadav 2011).

1487

infiltration of the pancreas by IgG4-positive plasma cells and typically affects older men. Over 80% of patients with type 1 AIP are males, with >80% over age 50 (Sah et al. 2010). Type 1 disease is also associated with a higher relapse rate as well as extra-pancreatic involvement. In contrast, type 2 or idiopathic duct-centric pancreatitis is characterized by a granulocytic epithelial lesion (GEL) with minimal IgG4-positive cells and affects younger patients (affecting males and females equally). This entity is discussed in detail in a separate chapter. • Tropical pancreatitis: Although the life expectancy of patients with tropical pancreatitis has considerably improved, it is not yet a geriatric problem. The entity is common in southern India, and is characterized by onset at young age, severe malnutrition, diabetes mellitus, and pancreatic calculi. In summary, the etiology of chronic pancreatitis may be attributed to a complex interplay of environmental and genetic factors. The former include alcohol, tobacco, and occupational chemicals (volatile hydrocarbons) (Braganza et al. 2011) while the genetic factors include mutations in trypsin-controlling or cystic fibrosis genes (Whitcomb 2004).

Other Causes • Hereditary pancreatitis: Hereditary pancreatitis is an uncommon cause of chronic pancreatitis and is rare in the older adults (Rebours et al. 2009). While mutations in the cationic trypsinogen gene (PRSS1) are most commonly associated with chronic pancreatitis, mutated cystic fibrosis gene (CFTR) and trypsin inhibitor (SPINK1) genes are being increasingly identified in patients with idiopathic chronic pancreatitis (Etemad and Whitcomb 2001; Bishop et al. 2005). • Autoimmune pancreatitis: Autoimmune pancreatitis (AIP) is a rare autoimmune disorder that is subclassified into two types, based on distinct pathological and clinical profiles (Sah et al. 2010). Type 1 or lymphoplasmacytic sclerosing pancreatitis is characterized by

Clinical Presentation Abdominal pain, an uncommon symptom in lateonset idiopathic chronic pancreatitis, is often a major complaint in alcoholic chronic pancreatitis (Layer et al. 1994; Gloor et al. 2002). The typical pain is epigastric, post-prandial, radiates to the back, and is relieved by sitting up or leaning forward. However, the severity and character of pain are highly variable in chronic pancreatitis, with some patients having severe daily pain (continuous pattern) while others have fleeting discomfort (intermittent pattern). The continuous and intermittent pain patterns do not seem to be the result of distinctly different pathophysiological entities (Kempeneers et al. 2020). The subjectively reported character of the pain often does not

1488

correlate with morphologic changes or disease duration, indicating a complex mechanism of pain in chronic pancreatitis (Wilcox et al. 2015; Kempeneers et al. 2020). Earlier theories focused on a mechanical cause of pain related to pancreatic ductal or parenchymal hypertension (White and Bourde 1970). An inflammatory mass in the head of the pancreas is reported in nearly one-third of patients with chronic pain (Frey and Reber 2005; Roch et al. 2014). Other factors such as activation of intrapancreatic nociceptors, hypertrophy, and inflammation of intrapancreatic nerves and abnormal pain processing in the central nervous system have been suggested (Drewes et al. 2008). The pancreatic nociceptive afferent injury over time leads to peripheral sensitization, central sensitization, or both, characterized by neuronal hyperresponsiveness, which results in a continuous state of pain independent of peripheral nociceptive input (Olesen et al. 2010). The persistence of pain despite complete removal of the noxious stimulus (e.g., total pancreatectomy) supports this central sensitization hypothesis. Pancreatic exocrine insufficiency is often the presenting symptom in patients with late-onset idiopathic chronic pancreatitis (Layer et al. 1994). While protein and carbohydrate malabsorption might occur in advanced pancreatic insufficiency, they are generally less pronounced than fat malabsorption due to compensatory secretions from intact salivary amylase and brush border peptidases in most patients. Most patients with exocrine insufficiency present with greasy, foul-smelling stools (steatorrhea). Patients might also present with weight loss, malnutrition, fat-soluble vitamin deficiencies (Vitamin A, D, E, and K), and vitamin B12 deficiency (due to noncleavage of R-factor from vitamin B12, dependent on pancreatic function). Malnutrition is common in patients with chronic pancreatitis. Anorexia secondary to abdominal pain, pancreatic enzyme insufficiency, alcohol abuse, and diabetes mellitus may contribute to malnutrition in chronic pancreatitis. Endocrine pancreatic insufficiency (type 3c diabetes, also known as pancreatogenic diabetes) eventually develops in most patients due to progressive beta-cell loss (American Diabetes 2013). The

S. Mohapatra et al.

patients with type 3c diabetes are at a higher risk of hypoglycemia because of concomitant loss of counter-regulatory hormones such as glucagon and pancreatic polypeptide (Hart et al. 2016). The risk of developing type 3c diabetes increases with increasing age, duration of disease, surgical intervention (especially distal pancreatectomy), smoking, and the presence of pancreatic calcifications. Patients with chronic pancreatitis are at significantly higher risk (relative risk 13.3, 95% CI 6.1– 28.9) of pancreatic adenocarcinoma, although this risk is greatest for early-onset disease and in patients with hereditary and tropical pancreatitis (Raimondi et al. 2010). Some other common complications in patients with long-standing chronic pancreatitis include pseudocysts, common bile duct stricture; duodenal stenosis; pleural effusion; splenic vein thrombosis with the formation of gastric varices; portal vein thrombosis; pseudoaneurysm affecting the splenic, hepatic, gastroduodenal, and pancreaticoduodenal arteries; and pancreatic ascites.

Diagnosis No single diagnostic test is adequately sensitive or specific for chronic pancreatitis in all patients. Age-related structural changes in the older adult may make the diagnosis even more difficult. A suggested diagnostic algorithm for chronic pancreatitis is outlined in Fig. 1.

Tests of Function • Amylase and lipase levels: Amylase and lipase levels are generally normal and are not useful in the diagnosis of chronic pancreatitis. • Stool fat quantitation: A 72-hour fecal fat quantitation is useful in patients with steatorrhea. Patients with pancreatic insufficiency typically excrete >10–14 grams of fat. Since exocrine pancreatic insufficiency develops only when 2 upper limit of normal or definitive other organ involvement and supportive features of AIP: less than twofold elevation of IgG4, clinical/radiologic, evidence of other organ involvement (radiologic evidence of hilar/intrahepatic biliary strictures, renal involvement, retroperitoneal fibrosis, parotid/lacrimal gland enlargement, positive IgG4 immunostaining in other organs, inflammatory bowel disease, and compatible histology) as listed in box B. LPSP lymphoplasmacytic sclerosing pancreatitis, IDCP idiopathic duct centric pancreatitis, GEL granulocyte epithelial lesion, AIP autoimmune pancreatitis, hpf high-power field (Adapted with permission from Nagpal et al. 2018)

addition to heterogeneously diminished enhancement during the early phase and delayed enhancement during the late phase of contrast enhancement (Sahani et al. 2004; Yang et al. 2006). Pancreatic imaging findings in AIP are shown in Fig. 3. Positron emission tomography (PET) scans are not required for diagnosis. If a PET scan ends up getting performed due to suspected underlying pancreatic cancer, it may show diffuse or focal fluorine-18 fluorodeoxyglucose (FDG) uptake in the inflamed areas of the pancreas, which resolves with steroid treatment. Therefore, a single PET scan may not allow for a distinction to be made between pancreatic cancer and AIP (Nakamoto et al. 2000).

MRCP and endoscopic retrograde cholangiopancreatography (ERCP) may reveal diffuse narrowing of the pancreatic duct with long (greater than one-third of the pancreatic duct) or multifocal strictures, with lack of upstream dilatation and side branches originating from a strictured segment (Sugumar et al. 2011). However, it should be noted that ERCP alone is not a reliable modality to diagnose AIP. ERCP is also not reliably able to distinguish IAC, which is the most common extrapancreatic manifestation of AIP, from primary sclerosing cholangitis or cholangiocarcinoma (Kalaitzakis et al. 2011).

1504

S. Nagpal

Fig. 2 Characteristic features of LPSP and IDCP. Histological features of LPSP (a–e) and IDCP (f). (a) Low power and (b) high power view of lymphoplasmacytic infiltration surrounding the duct, (c) storiform fibrosis,

(d) obliterative phlebitis, (e) IgG4 infiltration (>10/hpf) and (f) GEL (granulocyte epithelial lesion) showing neutrophilic infiltration with duct epithelial destruction (Adapted with permission from Nagpal et al. 2018)

Fig. 3 Pancreatic imaging findings of AIP. (a) Diffuse enlargement of the pancreas with peripheral rim-like hypoenhancement; (b) diffuse enlargement without peripheral

hypoenhancement; and (c) mass-like presentation (Adapted with permission from Nagpal et al. 2018)

Serology

specificity to 99% (Ghazale et al. 2007). A diagnosis of LPSP can be made even when the levels of IgG4 are elevated less than twofold. As demonstrated in Fig. 1, this requires the presence of other features as well (such as other certain imaging features, other organ involvement, histologic features that meet some but not all criteria for diagnosis, etc.). Elevation in serum IgG4 levels is not specific to LPSP and up to 10% of patients with pancreatic cancer may have elevated serum IgG4 values, out of which 1% may even have elevation >2 the upper limit of normal (Ghazale et al. 2007).

The serologic criteria required for diagnosis involve measurement of IgG4 levels. Elevated levels of IgG4 (>2 the upper limit of normal) are a “Level 1” criterion for the diagnosis of LPSP according to our diagnostic algorithm and are seen in about two-third of patients with LPSP (Chari et al. 2006; Shimosegawa et al. 2011). Using a higher threshold of IgG4 levels (i.e., >2 the normal IgG4) leads to a lower sensitivity in differentiating LPSP from pancreatic cancer but increases the

66

Autoimmune Pancreatitis

Other Organ Involvement Other organs are involved in individuals with LPSP. Extrapancreatic involvement is most commonly seen in the biliary system (IAC), but can also be seen in other areas of the body such as eyes (orbital pseudolymphoma), salivary glands, lungs and mediastinum (interstitial lung disease and mediastinal fibrosis), kidneys and retroperitoneum, and even prostate gland. Examples of extrapancreatic involvement are shown in Fig. 4.

Response to Therapy Even though the risk of relapse in patients with LPSP is high, whenever a recurrence occurs, each episode is highly responsive to treatment (e.g., with steroids). In fact, response to treatment for the initial and subsequent episodes is one of the diagnostic criteria within the HiSORt criteria for diagnosis of AIP. An example of response to treatment is shown in Fig. 5.

Other Criteria for Diagnosis Various criteria for diagnosis of AIP have been proposed from societies and institutions around the world. These include the Japanese Pancreatic Society, HISORt, Korean, Asian, Mannheim, and Italian criteria (Chari et al. 2009; Kamisawa et al. 2008; Kwon et al. 2007; Okazaki et al. 2006; Pearson et al. 2003; Schneider and Lohr 2009; Shimosegawa et al. 2011). After a review of these criteria, the ICDC (International Consensus Diagnostic Criteria) were developed. However, in their current form, ICDC suggests the use of endoscopic retrograde pancreatography (ERP) for ductal imaging, which is not routinely performed to diagnose AIP in the West (Shimosegawa et al. 2011), and may also be associated with a higher risk of complications than noninvasive imaging. As noninvasive imaging modalities such as computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) are more commonly used in the West for diagnosing AIP, we suggest using

1505

those for pancreatic ductal imaging as reasonable alternatives to ERP when using the ICDC criteria in the Western setting.

Other Laboratory Findings Patients with LPSP most commonly present with a cholestatic pattern of liver enzyme elevation, i.e., elevated alkaline phosphatase and/or bilirubin levels. Other antibodies that have been reported to be associated with autoimmune pancreatitis but are not a part of the diagnostic criteria include antibodies to carbonic anhydrase, Lactoferrin, antimitochondrial antibodies (AMA), antismooth muscle antibodies (ASMA), and antithyroglobulin (Kino-Ohsaki et al. 1996; Kim et al. 2004; Yoshida et al. 1995; Deshpande et al. 2005; Uchida et al. 2000). Antibodies against a peptide homologous to an amino acid sequence of plasminogen-binding protein (PBP) of Helicobacter pylori was reported to be positive in patients with AIP but was also found to be positive in 5% patients with pancreatic cancer (Frulloni et al. 2009). A more recent study identified antibodies to laminin 511-E8, a truncated laminin 511, an extracellular matrix protein in patients with AIP (Shiokawa et al. 2018).

Treatment and Long-Term Outcomes While steroids have been traditionally considered the mainstay of initial treatment, there is also emerging evidence on the use of other immunomodulators and Rituximab. Most patients with LPSP have remarkable initial improvement with the use of Prednisone, both biochemically (based on liver biochemistries) as well as on imaging. A high dose of prednisone at 40 mg/day for 4 weeks is recommended, although some have suggested that a lower dose (20 mg/day) may be used (Buijs et al. 2014). After 4 weeks, response can be assessed with clinical evaluation, radiology, and serology (IgG4 levels) (Ghazale et al. 2008). If there is clinical, serologic, and radiologic improvement at 4 weeks, the dose of prednisone can start to be tapered by 5 mg/week. A lower dose (30 mg/day) can be the initial dose for

1506

S. Nagpal

Fig. 4 Other organ involvement in LPSP. (a) Cholangiogram revealing extensive biliary stricturing from IgG4associated cholangitis; (b) orbital pseudolymphoma; (c) submandibular gland involvement; (d) interstitial lung

disease; (e) mediastinal involvement, and (f) retroperitoneal involvement (Adapted with permission from Nagpal et al. 2018)

patients with diabetes. A thorough evaluation for underlying malignancy is recommended in all cases. Only in a very select group of patients a therapeutic trial of steroids may be undertaken for 2 weeks with reassessment at the end of the trial period after ensuring there is no malignancy (Moon et al. 2008). Recent data suggests that Rituximab can also be used for as an induction agent for remission as a first-line agent if steroids are absolutely contraindicated (Hart et al. 2013b). Rituximab may also be considered as first-line treatment for patients at a high risk of relapse, such as those with proximal biliary involvement, younger age, and high alkaline phosphatase levels at initial presentation (Majumder et al. 2018). There is no data from randomized clinical trials for patients with AIP assessing or comparing the efficacy of steroids or other therapies for the induction of remission in these patients. There is a high likelihood of relapses in patients with LPSP, despite the brisk response to steroids

seen upon initial treatment. Relapses can be seen in up to 60% of patients and can happen even during the steroid taper and in many cases within the first 3 years of treatment (Hart et al. 2013a; Zamboni et al. 2004; Kamisawa et al. 2009; Huggett et al. 2014; Ryu et al. 2008). In a previous study from Mayo Clinic, Rochester, relapse rates of 25%, 44%, and 59% were seen at 1, 2, and 3 years, respectively (Sah et al. 2010). Relapses are managed with another course of steroids or Rituximab. As the likelihood of relapsing disease is very high in patients with LPSP, it is advised that consideration be given to an immunosuppressive regimen for maintenance early in the course of the treatment. In fact, immunosuppression can be considered at the first episode of LPSP as the likelihood of relapse is high. Recent studies have identified patients at a high risk of relapsing disease (those with intrahepatic and suprapancreatic portion of the common bile duct, those with diffuse pancreatic enlargement, younger age, higher IgG4-responder index

66

Autoimmune Pancreatitis

Fig. 5 Response to therapy in patients with AIP. Images (a) and (b) show a computed tomography (CT) scan of a patient with LPSP and images (c) and (d) show the

(IgG4-RI) score after induction therapy, and elevated serum alkaline phosphatase levels either at baseline or after RTX induction) (Majumder et al. 2018). These patients may especially be considered for immunosuppression at the first episode of LPSP. While in the West steroids are not given for prolonged periods and alternative immunosuppressive agents such as azathioprine and mycophenolate are preferred, studies from Japan suggest the use of a prolonged taper followed by a low dose of steroids (2.5–10 mg/day) for 1–3 years and sometimes even indefinitely (Kamisawa et al. 2010). We recommend azathioprine (2 mg/kg daily) or mycophenolate mofetil (750 mg twice daily) also appear to be effective in maintaining remission and allow for a steroid-free regimen to be used for these patients (REF). Alternatively, Rituximab is an agent that can be used to maintain remission (Hart et al. 2013b).

1507

cholangiogram of a patient with IgG4-associated cholangitis (IAC) demonstrating response to treatment (Adapted with permission from Nagpal et al. 2018)

Idiopathic Duct-Centric Pancreatitis (IDCP) Clinical Presentation Demographic characteristics of the typical patient with IDCP are different from those with LPSP. IDCP is not commonly seen among the geriatric population and mostly afflicts a younger age group, with a mean age at presentation usually between 40 and 50 years. Additionally, IDCP has no predilection towards a particular sex and affects males and females equally. Patients with IDCP tend to present mostly with recurrent acute pancreatitis (up to 50% of these patients present with that history). It should be mentioned here that IgG4 is very commonly checked in patients with

1508

acute pancreatitis in hospitals around the world, but since IgG4 levels can be falsely elevated during an episode of acute pancreatitis and are not good markers of IDCP (which can present with acute pancreatitis), checking IgG4 levels for acute pancreatitis is not advised. Other presentations of IDCP may include painless obstructive jaundice, pancreatic ductal stricture, or a focal pancreatic mass. As opposed to LPSP, IDCP is a disease of the pancreas alone and extrapancreatic involvement is characteristically absent. However, it can be associated with independent autoimmune processes elsewhere in the body, most characteristically concurrent IBD (predominantly ulcerative colitis) as compared to LPSP (Sah et al. 2010). In fact, a diagnosis of IBD is a supportive diagnostic criterion in a patient suspected to have IDCP (Shimosegawa et al. 2011).

S. Nagpal

Similar to LPSP, an EUS-guided trucut biopsy is important as it can provide a better yield of tissue as compared to fine needle aspiration (Levy et al. 2011).

Imaging and Endoscopy Endoscopic findings from ERCP and imaging findings on CT and MRCP can be similar to IDCP in patients with IDCP.

Treatment

There is no specific laboratory-based test for IDCP, therefore its diagnosis can be challenging. Therefore, histopathology remains the cornerstone of diagnosis. Other laboratory tests may reveal a cholestatic pattern of liver enzyme elevation as seen in LPSP as well. As opposed to LPSP, only about 25% of patients with IDCP have elevated IgG4 levels which is why IgG4 levels are not good markers for IDCP (Kamisawa et al. 2011).

IDCP is treated similar to a first episode of LPSP using steroids. Any symptoms and inflammation associated with IDCP respond rapidly to corticosteroid therapy. We recommend starting prednisone at an initial dose of 40 mg/day for 4 weeks followed by reassessment using clinical evaluation, radiology, and measurement of liver biochemistries. Once response is documented, the dose of steroids can begin to be tapered at 5 mg/ week for the next 8 weeks. The likelihood of relapses is much lower in IDCP than LPSP ( 2 elevation of IgG4 levels Association with inflammatory bowel disease Imaging

LPSP

IDCP

Decade 7

Decade 5

3:1 ~2/3rd

1:1 ~1/4th

Weak

Strong (10– 20%)

Similar imaging features in both

Histology Lymphoplasmacytic infiltration Periductal inflammation Storiform fibrosis Obliterative phlebitis Granulocyte epithelial lesion (GEL) IgG4 staining Treatment Response to steroids Relapse

Yes

Yes

Yes

Yes

Prominent Characteristic

Less prominent Rare

Absent

Characteristic

Abundant; >10/hpf

Rare; 10 bowel movements per day, with considerable urgency (70%) and episodes of nocturnal diarrhea (50%) and stool incontinence (40%) (Pardi 2017; Munch and Langner 2015). Despite the frequent bowel movements, electrolyte abnormalities and major fluid loss, serious dehydration is uncommon (Boland and Nguyen 2017). Abdominal pain and weight loss are often present in as many as half the patients (Boland and Nguyen 2017). Severe pain is seen occasionally with active disease and in general tends to be mild. The occurrence of significant abdominal pain with relatively milder diarrhea can often be confused for irritable bowel syndrome (IBS). In one study, more than half the patients with microscopic colitis fulfilled Rome II criteria for IBS (Madisch et al. 2005). Some patients may also report symptoms of generalized fatigue and nausea (Pardi 2017). Patients with microscopic colitis often report significant impairment in quality of life comparable to patients with IBD (Munch et al. 2012). As per one study, the major determinant of impairment in QoL is stool consistency and not stool frequency, and active disease can be defined as three or more stools per day or one or more watery stools/day and can be used to guide treatment decisions (Munch et al. 2012). The disease tends to run a chronic, relapsing course and as many as 59–93% patients with LC may go into spontaneous remission with future recurrence (Pardi et al. 2007). Some drug treatment studies showed response rates as high as 48% in placebo arms, although they subsequently have a high relapse rate (Pardi et al. 2007). There is no conclusive evidence that LC and CC are part of a continuing disease spectrum despite some initial reports suggesting that. Given the high

75

Non-IBD and Noninfectious Colitis

1695

Initial evaluation should focus on thorough history and examination with emphasis on severity of diarrhea and associated symptoms as well as risk factors for microscopic colitis. Routine labs along with stool tests to rule out parasite infections should be performed, especially in individuals with risk factors such as history of travel to endemic areas. Inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) and fecal calprotectin as

well as autoimmune serologies such as antinuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA), anti-saccharomyces cerevisiae antibody (ASCA) have not been shown to be clinically relevant in establishing or ruling out diagnosis (Pardi et al. 2007). Fecal calprotectin and lactoferrin are typically not elevated in the setting of microscopic colitis and unlike inflammatory bowel diseases do not help with diagnosis or monitoring response to treatment (Pardi et al. 2007). Celiac serologies should be checked in patients with persistent diarrhea not responding to treatment or significant weight loss to rule out concomitant celiac disease (Pardi et al. 2007; Boland and Nguyen 2017). The mainstay of diagnosis is colonoscopy with colonic biopsies. The colonic mucosa is usually normal appearing but may show mild edema and nonspecific erythema (Pardi et al. 2007). Ulceration of the colonic mucosa as well as mucosal tears are usually rare although may be seen in cases with heavy NSAID use. Biopsies should be taken from both right and left colon as there is some data to suggest higher distribution of histologic findings on the right colon resulting in missed diagnosis with sigmoidoscopy only (Pardi et al. 2007). The essential histologic finding in CC is a thickened subepithelial collagen layer (SCL)

Fig. 1 Pathology of collagenous colitis. (a) Thickened subepithelial collagen on a background of otherwise normal colonic mucosa. Inset shows thickened subepithelial

collagen with entrapped capillaries and inflammatory cells. (b) Trichrome stain highlights patchy thickening of subepithelial collagen band

prevalence of CD in MC, it should be ruled out in patients with symptoms refractory to treatment as well as those with significant weight loss (Munch et al. 2012). MC is not associated with a higher risk of colon cancer and is less likely to have adenomatous polyps (Chan et al. 1999). Complications including colonic perforation are seen in rare cases (Munch et al. 2012). There are no clear studies or societal guidelines that help define disease severity based on symptoms and histologic findings. As such, severity is often based on physician and patient assessment determined by frequency of bowel movements and impairment in quality of life (Munch et al. 2012).

Diagnosis

1696

of 10 μm (normal 20 lymphocytes per 100 surface epithelial cells (normal 80 years, higher number of severe comorbidities, and malnutrition were associated with death independently from impaired ECOG-PS and other geriatric prognostic scores (Toya et al. 2019). Presence and severity of

1860

M. K. Mallath

Table 13 Prognostic factors for survival in gastric adenocarcinoma TNM classification T – Primary tumor TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria, high-grade dysplasia T1 Tumor invades lamina propria, muscularis mucosae, or submucosa T1a Tumor invades lamina propria or muscularis mucosae T1b Tumor invades submucosa T2 Tumor invades muscularis propria T3 Tumor invades subserosa T4 Tumor perforates serosa (visceral peritoneum) or invades adjacent structuresa–c T4a Tumo perforates serosa T4b Tumor invades adjacent structuresa,b N – Regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasized N1 Metastasis in 1 to 2 regional lymph nodes N2 Metastasis in 3 to 6 regional lymph nodes N3 Metastasis in 7 or more regional lymph nodes N3a Metastasis in 7 to 15 regional lymph nodes N3b Metastasis in 16 or more regional lymph nodes M – Distant etastasise M0 No distant metastasis M1 Distant metastasis a

The adjacent structures of the stomach are the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum b Intramural extension to the duodenum or esophagus is classified by the depth of greatest invasion in any of these sites including stomach c Tumor that extends into gastro-colic or gastro-hepatic ligaments or into greater or lesser omentum, without perforation of visceral peritoneum, is T3 d Histological examination of a regional lymphadenectomy specimen will ordinarily include 16 or more lymph nodes. If the lymph nodes are negative, but the number ordinarily examined is not met, classify as pN0 e Distant metastasis includes peritoneal seeding, positive peritoneal cytology, and omental tumor not part of continuous extension

associated comorbidity in elderly patients (e.g., severe CVD or COPD or CKD or liver disease) can hinder curative surgery of localized and curable cancers. A recent umbrella review showed that the MDT approach is the best way to deliver the complex care needed by cancer patients; however, it is a challenge that requires organizational and cultural changes and must be led by competent health managers who can improve teamwork within their organizations (Specchia et al. 2020). The MDT discussion is best held after the pathological diagnosis is made and clinical staging procedures, evaluation of the comorbidities, and preanesthetic fitness are complete. The MDT treatment plans should be discussed with the

patient and their caregivers explaining the benefits, the risks, alternatives, the costs, and expected short- and long-term results. This will serve well to arrive at a truly shared decision (Specchia et al. 2020). In general, curative intent is considered when there are no metastatic deposits. Because of the low therapeutic ratio, excess risk-taking in elderly patients with oligometastasis including in the peritoneum is to be avoided. Elderly patients in many countries are not financially well of and have adequate medical insurance and great risk of financial toxicity as well of dropping out of treatments. They also tend to suffer from loss of autonomy. Hence the treating team must involve the patient early in the shared decision-making in the

83

Gastric Cancer

1861

Table 14 TNM stage grouping Clinical stage grouping Stage I T1, T2 N0 M0

Stage III T3, T4a N1, N2, N3 M0

Stage IIA T1,2 N1,2,3 M0 Stage IIB T3, T4a N0 M0

Stage IVA T4b Any N M0 Stage IVB Any T Any N M1

Pathological stage grouping (prefix “y” added if neoadjuvant therapy is used) Stage 0 Stage IIIA Tis N0 M0 T2 N3a M0 Stage IA T3 N2 M0 T1 N0 M0 T4a N1, N2 M0 Stage IB T4b N0 M0 T1 N1 M0 Stage IIIB T2 N0 M0 T1, T2 N3b M0 T3, T4a N3a M0 T4b N1, N2 M0 Stage IIIC T3, T4a N3b M0 T4b N3a, N3b M0 Stage IIA Stage IV Any T Any N M1 T1 N2 M0 T2 N1 M0 T3 N0 M0 Stage IIB T1 N3a M0 T2 N2 M0 T3 N1 M0 T4a N0 M0

Table 15 Prognostic factors for survival in gastric adenocarcinoma Prognostic factors Essential Additional

New and promising

Tumor factors T, N, M stage and HER-2 status Tumor site Cardia or distal stomach Vessel infiltration Molecular profile

Host factors Age

Environmental factors Residual disease R0 R1 R2 Extent of lymph-node resection

Race: Asian versus nonAsian

Table 16 Shows stage grouping and corresponding 5-year survival rates (%) according to the 8th edition AJCC T, N, and M categories TNM pT1 pT2 pT3 pT4a pT4b

pN0 (0) IA (90.6%) IB (85.9%) IIA (66.3%) IIB (55.3%) IIIA (55.2%)

M1 Data from Cao et al. (2019)

pN1 (1–2) IB (75.4%) IIA (77.4%) IIB (53.0%) IIIA (48.6%) IIIB (48.4%)

pN2 (3–6) IIA (74.4%) IIB (48.5%) IIIA (41.1%) IIIA (35.5%) IIIB (23.3%)

pN3a (7–15) IIB (66.8%) IIIA (43.4%) IIIB (28.6%) IIIB (21.1%) IIIC (14.2%)

pN3b (>15) IIIB (37.5%) IIIB (50.8%) IIIC (11.9%) IIIC (9.4%) IIIC (2.8%)

M1

IV (9.2%)

1862

best interests of the patients rather than leaving the treatment decisions to the family members. Because of the stage in life the decision to “do not resuscitate” should also be taken in advance (Cheng et al. 2008). Surgery is the definitive curative treatment of most gastric cancers. The role of adjuvant therapy in very old patients over 80 years is presently under evaluation (Mizutani et al. 2018) Rarely, surgery is justified in an old patient with metastatic gastric cancer outside a clinical trial. Palliative surgery to relieve obstruction or bleeding in the presence of metastasis should be performed judicially. The randomized REGATA trial revealed that palliative surgery has limited role in management of metastatic gastric cancer (Fujitani et al. 2016). There has been lot of progress in anesthesia and postoperative care, and elderly patients with coexisting diseases can be subjected to major gastric surgery with reasonable safety. The goals of radical surgery are to have a wide resection of the tumor along with its lymph nodes and to reconstruct an appropriate passage for food and gastric juices (Tan 2019). Advances in modern imaging has reduced the likelihood of missing a tiny metastasis before surgery. Laparoscopic surgery has benefits in the elderly (Honda et al. 2019). Surgery has little role after the cancer has recurred. Resection of oligometastasis in the liver or lung is experimental. The use of postoperative surgical adjuvant therapy is determined by the final pathology findings and the severity of comorbid illness. Adjuvant therapies do cause serious life-threatening complications in the elderly and must be used with extreme caution in patients severely debilitated by radical surgery.

Surgical Treatment Early gastric cancer is limited to the mucosa or submucosa (p T1) irrespective of the lymph nodal status. The final diagnosis of EGC is possible only after an EMR or ESD. Japanese and Korean researchers based on their large gastric cancer screening experience have established inclusion and exclusion criteria which increase the efficacy and safety of these procedures. Early gastric

M. K. Mallath

cancers that are not amenable to EMR or ESD are usually treated with minimally invasive surgery with laparoscopy. Imaging may need in patients suspected with EGC to look for lymphnode metastases in some patients with deep penetrating EGC or when the mucosal tumor diameter is more than 3 cm. There are no randomized trials comparing endoscopic and surgical resection of early gastric cancer. Traditionally, surgical resection offers 5-year recurrence-free survival up to 80–90% with most of the elderly patients dying from other causes (Sano et al. 1993; Guadagni et al. 1997). In general, the postoperative mortality is lower and long-term recurrence free survival higher in east Asians countries compared to Europe or North America indicating that total experience of the team is an important determinant of short-term and long-term outcomes (Sano et al. 1993; Tanabe et al. 2017; Guadagni et al. 1997). One of the cardinal principles of endoscopic resection is that it should not be attempted in EGC when the likelihood of lymph-node metastasis. In patients with mucosal EGC (T1a), endoscopic resection is sufficient as metastasis to the lymph node is extremely low. When the final pathology of an EMR or ESD reveals submucosal carcinoma (T1b) extension, surgical resection with systematic lymphadenectomy is advised for 20% of such patients would have lymph node metastasis. Like open surgery endoscopic resection of EGC should be done by experts as a complete En-bloc resection and complete pathological assessment of the margins (Fuccio et al. 2018). In an audit of 1000 patients from Korea, the rates of En bloc resection and complete En bloc resection were 95.3% and 87.7% and the rates of delayed bleeding, significant bleeding, perforation, and surgery related to complication were 15.6%, 0.6%, 1.2%, and 0.2%, respectively (Chung et al. 2009). ESD is an extremely important technique in the elderly patients who can be spared of a major surgery provided sufficient training and quality assurance are maintained. The experience with ESD for early gastric cancer is increasing worldwide and the procedure appears to be a safe and effective technique when performed by experienced Endoscopists also in Western setting (Petruzziello et al. 2018).

83

Gastric Cancer

Elderly patients with EGC not suited for ESD and more advanced gastric cancer needs to undergo surgery by transabdominal or minimal invasive approach (Hu et al. 2016; Wei et al. 2018). Minimally invasive surgery is better for elderly patients as this approach is associated with reduce postoperative stress and often results in quicker recovery. In order to reduce the postoperative complications and achieve maximum textbook outcomes, all gastric cancer surgery in the elderly should be performed at large volume centers by experienced surgical team. Irrespective of the surgical approach to the resection must follow the well-established principles of surgical oncology. The extent of gastrectomy is determined by clinical stage, location, and histological type of gastric cancer with complete resection of the gastric primary with adequate tumor-free surgical margins (4 cm or more) with adequate lymphadenectomy (D2) (Mocellin et al. 2015). Total gastrectomy is usually performed for diffuse cancers (linitis plastica) with signet-ring cells or tumors located in the upper third of the stomach. Subtotal gastrectomy is usually done for gastric cancers located in the lower two-thirds of the stomach. Patients with carcinoma of the GEJ/cardia-Siewert type II or III are best managed by total gastrectomy. Extended trans hiatal esophageal resection is needed for type I involving the esophagus. Thoracoabdominal approach is not recommended because the morbidity and mortality are much more without any survival advantage and not usually recommended. Most experts recommend a D2 lymph node resection (peri-gastric lymph nodes along with lymph nodes along with celiac axis and its branches) provided sufficient expertise is available with the surgical team with acceptable postoperative morbidity and mortality. The minimal nodal harvest should include 16 nodes. Splenectomy and station 10 nodal resection are to be avoided as they are associated with increased morbidity and mortality (Mocellin et al. 2015). New approaches to spleen preserving station 10 nodal resection are being developed (Sano et al. 2017b; Toriumi and Terashima 2020). The D2 lymphadenectomy has been shown to improve recurrence free and overall survival. As for the distal anastomosis, a Roux-en-Y type of jejunal

1863

anastomosis is recommended as bile reflux is a major problem after gastrectomy. Minimally invasive surgery appears to be superior to open approach even in patients receiving neoadjuvant therapy (Li et al. 2019b). Laparoscopic approach appears to provide higher textbook outcomes after advanced gastric cancer surgery (Priego et al. 2019). Cytoreductive surgery with hyperthermia intraperitoneal chemotherapy (CRS-HIPEC) has been extensively evaluated in patients with gastric cancer with peritoneal carcinomatosis from gastric cancer (Ji et al. 2017). A systematic review has reported that CRS-HIPEC can improve shortterm survival (Liu et al. 2019). Minimally invasive surgery through laparoscopy is a widely accepted method for evaluation and resection of gastric cancer (Fig. 26).

Locoregional Cancer Large proportion of gastric cancer diagnosed after the onset of symptoms have invaded through the gastric wall or have metastasized to regional lymph nodes. The 5-year survival of these patients is usually below 30% and often around 20% in elderly (Chen et al. 2016). In an audit of 7762 patients with gastric cancer in the SEER database and treated from 2007 to 2011, the Kaplan-Meier plots showed that patients older than 76 years had the worst 5-year CSS of 56.0% rate in all the subgroups. Age, tumor size, primary site, histological type, and Tumor Node Metastasis stage were identified as significant risk factors for poor survival (all P < 0.001, log-rank test) (Chen et al. 2016). Neoadjuvant therapy has been evaluated shown to improve complete surgical resection (R0) rates as well as improve recurrence free survival and overall survival (Reddavid et al. 2018; Russo et al. 2017; Kano et al. 2019). Therefore, perioperative chemotherapy has become the standard of care in America, Europe and South Asia. This approach was not popular in the Easter Asian countries, but is now being evaluated (Russo et al. 2017; Kano et al. 2019). Japanese and Korean and other East Asian countries treating large number of gastric patients prefer to

1864

M. K. Mallath

a 120 ECF/ECX Group

FLOT Group

100

Percentage

80 60 40 20 0 Tumor was R-0 Resecon Had serious Completed Completed pre Underwent surgery resected achieved adverse events preoperave and postchemotherapy operave chemotherapy Clinical variables of trial subjects (%)

b 80 ECF/ECX Group

FLOT Group

70

Percentage

60 50 40 30 20 10 0 Final T stage ypT1

Final N-Stage Overall survival at Overall survival at Overall survival at ypN0 2 years 3 years 5 years Clinical variables of trial subjects (%)

Fig. 26 Summary of the results of the AIO FLOT-4 randomized trial showing the outcomes. Panel A above shows the clinical findings and panel B below shows the

tumor regression rates and survival rates in the two arms. (Data from Al-Bartan et al. 2019)

undertake surgery and then offer postoperative adjuvant chemotherapy (Russo et al. 2017). The advantages of preoperative chemotherapy include the making more tumors amenable to R0 resection

by shrinking them and sterilizing microscopic metastasis (Kano et al. 2019; Terashima et al. 2019; Tomasello et al. 2017). Three pivotal randomized trials have used combination

83

Gastric Cancer

1865

Table 17 Neoadjuvant and adjuvant chemotherapy and chemoradiotherapy in locally advanced gastric carcinoma Trial Control arm Peri-operative neoadjuvant trials MAGIC Surgery FFCD Surgery FLOT ECF/ECX Post-operative adjuvant trials INT0016 Surgery (Few D2) ARTIST 6 XP ACTS-GC Surgery CLASSIC Surgery

Test arm

Control-RFS

Test-RFS

Control-OS

Test-OS

ECF FU Cisplatin FLOT

NA 19.0 NA

NA 34.0 NA

23.0 24.0 35.0

36.3 38.0 50.0

LV + 5FU + RT 2XP + CRT + 2XP S1 CapeOx

31 74.2 53.1 59

48 78.2 65.4 74

41 NA 61.1 78

50 NA 71.7 83

OS median overall survival in months, FLOT 5FU leucovorin oxaliplatin docetaxel,RT radiotherapy, XP capecitabine cisplatin, ECF Epirubicin, cisplatin 5FU, RFS median relapse free survival in months, CRT chemoradiotherapy

chemotherapy before and after surgery to achieve significant improvement in survival as summarized in the Table 17 (Ychou et al. 2011; Cunningham et al. 2006; Al-Batran et al. 2019). The drawback with this approach is that a small percentage of patient have resistant tumors which progress on treatment and make it inoperable and clinical deterioration with progression of cancer cachexia due to which they become unfit for surgery and further treatment. One of the advantages of postoperative chemotherapy is that the final histopathology results will help to risk stratify the patients and offer postoperative chemotherapy to those at real high risk of recurrence. In elderly patients with gastric cancer, one needs to individualize the treatment and offer postoperative adjuvant chemotherapy when possible. Preoperative neoadjuvant therapy can be given to carefully selected patients who are likely to end up with a R1 or R2 resection upfront and are likely to remain fit for surgery at the end of preoperative chemotherapy. In everyday practice, we avoid perioperative neoadjuvant therapy in our old patients with advanced gastric cancer who have multiple comorbidity, who are sarcopenic or cachectic, who have bleeding or obstructing tumors, who have poor performance status (ECOG 2 and 3) and those who are unlikely to comply with the long drawn neoadjuvant chemotherapy protocol (Fig. 27). There no good evidence to pick the best of the three approaches in elderly patients with gastric cancer; use neoadjuvant approach; adjuvant approach; no surgical adjuvant (Joharatnam-

Fig. 27 Computed tomographic scan of a patient with locally advanced gastric carcinoma before and after chemotherapy. Panel above shows thickening of the distal gastric wall and large perigastric lymph nodes which have regressed after chemotherapy as shown in the lower panel

Hogan et al. 2020). Upfront surgery followed by no chemotherapy or postoperative adjuvant chemotherapy is an option that is more frequently used in elderly patients (Schendel et al. 2020). As

1866

M. K. Mallath

Table 18 Treatment summary based on clinical stage for gastric cancers Clinical stage Early gastric cancer

Localized cancer, curable intent Locally advanced curable cancer Metastatic gastric cancer

Recurrent gastric cancer

First option ESD* or EMR for small lesions or Upfront minimally invasive surgery Appropriate follow-up surgical therapy and chemotherapy based on histopathology H. pylori eradication to prevent recurrence of cancer Radical surgery [D2, R0] followed by adjuvant chemotherapy if high risk Neoadjuvant chemotherapy followed by radical surgery [D2, R0] followed by adjuvant chemotherapy Palliative chemotherapy with or without targeted therapy or immunotherapy Palliative stenting of obstructing tumors at gastric inlet and gastric outlet Palliative surgical by pass Palliative chemotherapy or immunotherapy

Remarks To follow the guidelines If the pathology of EMR or ESD is high risk a surgery may be needed to evaluate lymph nodes Ablative treatments used in very sick patients

Localized non-early gastric cancer s and those with obstruction or bleeding should be treated by this pathway Neoadjuvant therapy is useful to achieve an R0 status as well as for shortening the operating time

Up to three different lines of treatment are available. Monotherapy is best for those with frailty Palliative surgery has little use Up to three different lines of treatment are available

Adequate supportive care for pain relief, nutritional support and other symptomatic therapy should be provided to all patients with all stages of cancer

mentioned above, this approach does not delay the primary treatment and final histopathology-based adjuvant therapy can be offered to the elderly patients after they have recovered from the surgery. The completeness of surgical resection (R0) and lymph nodal resection (D2) are prime importance with this approach. Most elderly patients are unable to tolerate adjuvant chemoradiotherapy (Macdonald et al. 2001). However, many are able to tolerate postoperative adjuvant therapy. The CLASSIC trial and the trial have been the major sources of evidence for postoperative adjuvant therapy (Noh et al. 2014). Postoperative radiotherapy was a major modality for two decades but lost its appeal in recent times after the results of the ARTIST I and II trials and the CRITICS trial failed to improve survival (Park et al. 2015, 2019; Slagter et al. 2020). The ARTIST-II trial showed that a S1 plus oxaliplatin was superior to S-1 alone and the DFS at 3-years were 65%, 78%, and 73% in S1, SOX, and SOXRT arms, respectively. In the ARTIST-1 study, a subgroup of patients having lymph-node metastasis had longer survival with chemoradiation and the absolute DFS benefit at 3years was 4%. Given the toxicity of postoperative

CRT, it should be used with extreme caution in older patients (Macdonald et al. 2001). The FLOT4 study like the Asian studies show large benefits from an adjuvant chemotherapy after D2 resection and is emerged as the standard of care in many parts of the world (Al-Batran et al. 2019). However, many elderly patients are unable to tolerate postoperative adjuvant therapy (Slagter et al. 2020). Preoperative CRT like the one used in the CROSS protocol is useful in patients with GEJ cancers (Shapiro et al. 2015). The evidence to support the routine use of preoperative CRT in gastric cancer is lacking (Table 18).

Metastasic or Recurrent Gastric Cancer The global long-term survival of all gastric cancer patients low (Bray et al. 2018). In countries where gastric cancer screening is practiced, over half of all patients are diagnosed in stage I or II and are likely to die of other causes. In rest of the world where screening is not practiced, large proportion of patients are diagnosed with metastasis or in stage III where local and distant recurrence is common after the initial treatments. Over all,

83

Gastric Cancer

prognosis of gastric cancer patients with metastasis is poor, with median survival ranging from 4 to 6 months with best supportive care and may go up to 10 to 14 months when treated with multiple lines of cytotoxic chemotherapy (Choi et al. 2020b; Dijksterhuis et al. 2020). The results of a Japanese group revealed that patients with better performance status, a small number of metastatic sites and macroscopically non-scirrhous type tumors are independent favorable factors for survival (Yoshida et al. 2004). There were a few 5year survivors with unresectable gastric cancers, most of whom had only abdominal lymph node metastases and received gastrectomy before or after chemotherapy. Randomized pivotal trials have demonstrated that palliative chemotherapy is effective in improving the quality of life as well as all pivotal trials testing palliative chemotherapy have selected younger patients with good performance status and adequate organ function. The small number of elderly patients included in these trials have benefited. The subgroup analysis of older patients does suggest that they are more likely to face problems during chemotherapy (Casaretto et al. 2006). There is no data on toxicity or benefits in sicker patients or those with multiple comorbidities or those above 80 years age. They are all likely to experience more toxicity, more drop outs, and inferior survivals.

Palliative Chemotherapy Chemotherapy plays an important role in the management of patients with gastric cancers in three settings: neoadjuvant (before surgery to shrink the tumor and limit micro metastasis), adjuvant (after surgery to reduce recurrence), and palliative (to arrest the progression of metastasis) therapy. On the whole, the role chemotherapy in elderly patients with gastric cancers is evolving and currently used on a case to case basis. Current pragmatic practice in elderly patients is to offer chemotherapy to those who are functionally fit, have limited comorbidities, have good family and social support, and are willing to take chemotherapy for many months are offered chemotherapy. Standard adjuvant chemotherapy given within

1867

8 weeks after surgical resection of stomach to prevent recurrence and improve long-term survival are associated with considerable morbidity in older patients. Disruptions in the administration and discontinuation is not uncommon. Less doseintense regimens and metronomic regimens need to be developed for elderly patients (He et al. 2012). Chemotherapy also plays a very important role in palliation of advanced gastric cancers. In a nationwide population-based audit in South Korea, 229 of the 1871 new patients diagnosed with metastatic gastric cancer in 2010 went on to receive third-line chemotherapy (Choi et al. 2018). Prior to third-line chemotherapy, more than 90% of patients received fluoropyrimidine and platinum, and 43.7% and 40.6% received taxanes and irinotecan, respectively. The third line chemotherapy regimens contained taxanes (docetaxel or paclitaxel), irinotecan, or oxaliplatin. The median overall survival (OS) of all patients receiving third-line chemotherapy was 4.4 months. The median time from the start date of first-line chemotherapy to the start date of third-line chemotherapy was 9.5 months. There was no difference in OS based on sequencing of the drugs. Ten percent of patients in this audit were over 70 years and the median survival of the elderly receiving third line therapies was similar to the younger patients, suggesting that fit elderly patients should not be denied several lines of palliative chemotherapy. The role of palliative chemotherapy in improving survival and quality of life of patients with gastric cancer has been established beyond any doubt in multiple randomized trials (Wagner et al. 2017). The toxicity profile of the combinations does vary and may be a limiting factor in their routine use in the management of advanced gastric cancer in elderly patients. Most chemotherapy protocols use combinations of cytotoxic drugs which includes; fluoropyrimidines (fluorouracil, capecitabine, S-1 and Tegafur), platinum’s (cisplatin and oxaliplatin), taxanes (paclitaxel, docetaxel), and the topoisomerase inhibitor irinotecan. Epirubicin an anthracycline drug used extensively in yesteryears is nowadays rarely used (Van Cutsem et al. 2016). The overall tumor response rates are generally low, and usually in

1868

M. K. Mallath

the range of 20–40%. Complete tumor response and long-tern tumor control are rare. Various pivotal trials that were positive in metastatic gastric cancer are summarized in the Table 19. The fluorouracil, doxorubicin, and mitomycin (FAM) protocol was the first standard regimen in 1980s. Later other doublet and triplet regimens were developed and the FAM regimen and doxorubicin or mitomycin is rarely used nowadays. Oral derivative of 5FU such as capecitabine, S-1 and Uracil are active in patients with gastric cancer and are especially suited for elderly patients as monotherapy. The doublet oxaliplatin plus capecitabine is the most popular first-line therapy in north America and Europe while S-1 plus Cisplatin or Oxaliplatin is the most popular first line therapy in east Asia. Platinum use is often associated with development of debilitating neuropathy particularly in older patients. Patients who progress on first-line therapy can be offered second-line treatment if they remain in good physical condition with good organ function. Most second-line chemotherapies offer 2 or 3 months of progressionfree survival although the overall survival is considerably higher among East Asian patients. It is not established if sequencing of the treatments or molecular characteristics are responsible for the differences. Combination chemotherapies are superior to monotherapy for tumor response rates and

survival. A Cochrane meta-analysis reported that the median survival of 8.3 months was achieved with combination chemotherapy in comparison to 6·7 months with monotherapy (Wagner et al. 2017). The toxicity is higher with triplet combination therapy and is probably best avoided in elderly patients. Monotherapy is very useful in management of elderly patients who are often unable to tolerate the toxicity of combination chemotherapy. As stated previously, all most all the successful clinical trials done in patients with metastatic gastric cancer had patients who were younger and fitter than the average elderly patient seen in the clinic. Targeted therapy and immunotherapy with or without chemotherapy have been evaluated and found to improve the survival in a subgroup of patients expressing a predictive biomarker. Various targeted therapies that have been successful in other cancer sites have been tried in patients with gastric cancer. These drugs have been tested in palliative, adjuvant, and neoadjuvant settings. Human epidermal receptor 2 (HER2) is amplified in up to 20% of patients with gastric cancer. The ToGA trial confirmed the benefit of adding trastuzumab (monoclonal antibody against HER2) to standard chemotherapy in patients having HER2-amplified gastric and GEJ cancer (Bang et al. 2010). The overall survival was 11.1 months in the standard arm (cisplatin +

Table 19 Pivotal first line palliative chemotherapy for advanced gastric cancer Trial V325 trial EU and USA JCOG9912 Japanese trial SPIRITS trial Japan FLAGS trial EU and USA REAL-2 Trial Europe

ML17032 Trial Korea ToGA Global in

Trial comparisons Compared cisplatin ¼ 5FU with cisplatin +5FU ¼ docetaxel Compared 5FU with S1 with Irinotecan with cisplatin. Compared S1 with S1 + cisplatin Cisplatin +5FU versus Cisplatin + S1 Four arm factorial design Epirubicin + cisplatin +5FU Epirubicin + cisplatin +capecitabine Epirubicin + oxaliplatin +5FU; Epirubicin + oxaliplatin +capecitabine Cisplatin ¼ 5FU versus Cisplatin + capecitabine. Cisplatin + capecitabine versus Cisplatin + capecitabine + Trastuzumab in HER2 enriched patients

Outcomes Had some improvement in ORR, PFS, and OS Had modest improvement in ORR, PFS, and OS in S1 and triplet arm Had modest improvement in ORR, PFS, and OS in doublet arm Had modest improvement in PFS, and OS in cisplatin + S1 arm Best survival was achieved in the EOX triplet and evolved to be the most popular first line regimen. Best ORR, PFS and OS in CisCape arm. Best ORR, PFS and OS in the triplet combination

83

Gastric Cancer

capecitabine or 5-FU) and 13.8 months in the arm that got trastuzumab + chemotherapy. Furthermore, patients with high HER2 overexpression got median survival of 16.0 months and this combination is currently recommended as first-line therapy for the subgroup of patients with HER2 overamplified. There were many attempts to demonstrate the benefits of other targeting agents like Bevacizumab, other EGFR, etc. without success. Lapatinib, a tyrosine-kinase inhibitor and TDM-1 targeting HER2 also failed to improve survival. Ramucirumab an antibody that targets VEGFR-2 was demonstrated to be successful in increasing survival in second-line settings; however. The net benefit is small (Khan and Shah 2019). Several other biological targeted agents are under investigation. The long-term survival of elderly patients advanced or metastatic gastric cancer is poor after using current treatments including combination chemotherapy and biological agents. Immune checkpoint blocking antibodies like programmed cell death-1 (PD-1) and its ligand (PD-L1) have been found to be useful in first and later-line treatment of gastric cancers (Katz et al. 2020). The outcomes are better in tumors expressing PD-L1, mismatch repair high and other predictive biomarkers. Immunotherapy as monotherapy or when combined with chemotherapy appears promising in a subgroup of patients with advanced gastric cancer. More outcomes-based research is needed for the routine use of immunotherapy in gastric cancer. Biomarkers such as TILs density and PD-L1 expression predict better survival in gastric cancer. Anti-PD-1 treatment seems effective in gastric cancer patients who have received two lines of chemotherapy. Randomized trials are underway to confirm (or not) the role of immunotherapy in advanced gastric cancer, especially in initial-line therapy. The PD-L1 expression, MSI phenotype, EBV status are able to predict response and needs to be validated by prospective studies. Immunotherapy outcomes according to molecular classification need more studies (Katz et al. 2020).

Radiation Therapy Radiation therapy have undergone tremendous improvements with regards to the machines,

1869

planning systems, beam delivery, and dosing schedules and has reduced the short-term and long-term toxicity associated with radiotherapy. Radiation therapy has been used with surgery and or chemotherapy in curative settings and in palliative settings (Shapiro et al. 2015; Izuishi and Mori 2016). Gastric cancers are relatively radio-resistant at doses that would be safe and tolerated by elderly patients. Postoperative chemoradiotherapy which was the first major breakthrough in adjuvant therapy for gastric cancer is not well tolerated by elderly patients (Macdonald et al. 2001). Chemoradiotherapy used as preoperative neoadjuvant therapy of locally advanced adenocarcinoma of the GEJ has been highly effective and emerged as a standard (Shapiro et al. 2015). Radiation is very useful in palliation of obstructing cancer, bleeding cancer, and in palliation of painful bone metastasis (Izuishi and Mori 2016).

Follow-Up Periodic follow-up is required to identify and treat problems arising from surgery, radiotherapy, or chemotherapy as well as for detecting recurrences early so that they are treatable. There are no randomized studies to offer high-quality evidence. In general, most guidelines recommend that patients may be followed up at 4–6 months interval for the first 2 years and then at 6–12 months intervals for 3 more years after a curative surgery. The true benefit of periodic follow-up of elderly patients is not known. The purpose of follow-up includes management of weight loss and cachexia, micronutrient deficiencies, recurrence of cancer and development of a second cancer in the gastric stump. In addition to taking history, physical examinations may be performed at every visit. Following radical surgery, nutritional problems are very common. Micronutrient deficiency such as vitamin B-12 and iron as well as macronutrient deficiency with weight loss are common and must be looked into at each follow up. Depending on the nature of the treatment, proper dietary and nutritional advice should be given to all patients. Complete evaluation for recurrence at each follow-up is unlikely to have major impact on the long-term outcome of gastric cancer in elderly

1870

M. K. Mallath

patients, although some metastatic and recurrent primary cancers are treatable. A proper gastroscopic assessment is recommended once in 5 years (Han et al. 2020).

Palliation of Advanced Cancer Many elderly patients with gastric cancer present with very advanced stage or have severe comorbid ailments which results in the exclusion of aggressive cancer treatments (Hofheinz et al. 2016; Chmelo et al. 2020; NICE). In such patients less invasive endoscopic procedures help to palliate symptoms such as dysphagia, and vomiting. Expandable metallic stents have helped to relieve obstruction in different parts including the gastroesophageal junction and gastric outlet obstruction, without the need for bypass surgery (Hamada et al. 2017). Enteral nutrition support can be provided by oral supplements by mouth or after endoscopic placement of feeding tubes (Shastri et al. 2008). Home-based physiotherapy is important throughout a gastric patients clinical course up to final palliation (Chmelo et al. 2020). Elderly patients often have sarcopenia and regular exercise and physiotherapy helps to maintain the muscle mass, performance status, and quality of life during treatments as well as off treatments for exercise slows down the development of

cachexia. Pain can be major and distressing complaint in patients with advanced cancer. Adequate pain control can be achieved with analgesics using the step ladder approach using drugs with increasing analgesic effects including the liberal use of morphine. The NICE guidelines on palliative care offers valuable information (NICE). Some may need specialized pain clinic and palliation care referral. The use of narcotic analgesics often results in constipation, which is troublesome in elderly patients. Continuous counselling and adequate psychological support are important in improving the quality of life of patients with advanced cancer (Table 20).

Financial Toxicity and Cost Effectiveness Elderly patients are financially challenged. Gastric cancer is one of the deadliest and costliest malignancies to treat. Modern cancer therapies are well known to cause financial toxicities which reached catastrophic proportions in many. Financial toxicity directly impacts the continuity of care, dignity, quality of life, and survival intervals. Although studies on financial toxicity in elderly gastric cancer patients is lacking, studies on gastrointestinal cancer patients in general reveal that over a third of all patients suffer serious financial toxicity and old age is an independent

Table 20 Palliation and symptom management in patients with advanced gastric cancer Symptoms Pain Anorexia and early satiety Nausea, vomiting and regurgitation Weakness

Anemia

Ascites Sleep and depression.

Remarks Requires graded approach to pain. Narcotics are often needed at end of life Major complaint of a patient throughout the course of illness. Sometimes this symptom persists after the cancer has been effectively treated Occurs mostly due to mechanical obstruction or neuromuscular dysfunction causing gastroparesis. Sometime this improves after correcting electrolytes such as hypokalemia and hypomagnesemia Mostly due to sarcopenia and cancer cachexia. There is limited intervention available to reverse this. Often improves when cancer is adequately treated. Small percent of the weakness may be due to reduced food intake that is partly reversable Anemia is usually present from the beginning and is usually caused by iron deficiency due to GI bleeding or Vitamin B12 deficiency due to atrophic gastritis or gastrectomy. Anemia can also be due to chemotherapy. Erythropoietin analogues should be used with cautions as these patients are prone for VTE Most often due to peritoneal involvement. Sometimes it may be related to chronic liver disease due to several reasons Sad thoughts, depression and insomnia are common in gastric cancer patients. Rarely patient could have suicidal thoughts when the symptoms are severe and poorly controlled

83

Gastric Cancer

risk factor for the same (Rapp et al. 2019; LaRocca et al. 2020). Patients could benefit from preemptive education and counselling interventions as part of their routine cancer care (LaRocca et al. 2020). A population-based cohort study of patients undergoing noncurative treatments for gastric cancer using administrative datasets has shown that care by high-volume providers is associated with superior survival and lower healthcare costs (Hallet et al. 2020). Compliance with evidence-based treatment guidelines is also associated with improved outcomes (Thiels et al. 2020). Therefore in order to increase the survival and value for money treating patients through highvolume integrated care networks that are likely to comply with national guidelines (see below), may be an important way of improving the quality of gastric cancer care delivery and its cost-effectiveness within the community.

Conclusions Gastric cancer is a leading cause of cancer mortality in elderly populations. High degree of suspicion is needed to avoid delays in diagnosing gastric cancer in elderly as early symptoms are absent or nonspecific. When diagnosed early as EGC, local therapy such as ESD can be performed. Radical surgical resection that is needed by majority of patients could be restricted in the elderly due to severe or multiple comorbidities. Appropriate and optimal treatment an elderly patient with gastric cancer is guided by four essential factors: the exact site and extent of the cancer (e.g., GEJ and proximal stomach, pylorus, etc.); the histopathologic type of cancer (e.g., poorly differentiated adenocarcinoma, Her 2-neu + ve adenocarcinoma); the anatomical stage of the cancer (T3N2M0); and the overall physical and mental fitness of the elderly patient to withstand prolonged multimodality treatments. They are best evaluated and managed by a multidisciplinary team. Elderly patients are at higher risk for developing serious adverse events during surgery, radiotherapy, and chemotherapy and interruptions for recovery is not uncommon. However, their survival is similar to the younger ones, when they are able to get the

1871

right treatments. The autonomy of elderly patients and their personal wishes must be respected while treatment decisions are made. The outcomes are best when managed by evidence-based guidelines in high volume centers.

Key Points • Gastric cancer is a leading cause of health-care costs and cancer-related mortality in all parts of the world. • Over 90% of all gastric cancer are mucosal adenocarcinomas. • Gastric carcinoma is a common and highly lethal disease globally. • Gastric carcinoma is primarily a disease of elderly populations. • Gastric carcinoma is a preventable cancer by preventing and eradicating Helicobacter pylori infection and by diet and life style modifications. • Gastric carcinoma screening is recommended in population with very high incidence of this cancer. • Most gastric carcinoma are advanced and less amenable for cure once symptoms arise. • Endoscopic methods are used in the prevention, diagnosis, staging, and palliation of gastric carcinoma. • Planning the management of a patient with gastric cancer is best done by a multidisciplinary team. • Radical surgery with adequate lymph nodal resection (D2) and clear margins (R/0) are necessary for cure. • Neoadjuvant chemotherapy increases the curative resection rates, and adjuvant chemotherapy improves survival after curative resection. • Up to three lines of palliative chemotherapy is now approved for improving survival and quality of life of patients with very advanced gastric carcinoma. • Malnutrition and pain are important determinants of quality of life and survival. • Managing elderly patients with gastric cancer is challenging due to their comorbidities, frailty, and lack of financial and personal support.

1872

References Abad MRA, Inoue H, Ikeda H, et al. Utilizing fourthgeneration endocytoscopy and the ‘enlarged nuclear sign’ for in vivo diagnosis of early gastric cancer. Endosc Int Open. 2019;7(8):E1002–7. https://doi.org/ 10.1055/a-0957-2866. Abrahao-Machado LF, Scapulatempo-Neto C. HER2 testing in gastric cancer: an update. World J Gastroenterol. 2016;22(19):4619–25. https://doi.org/10.3748/wjg. v22.i19.4619. Al-Batran SE, Homann N, Pauligk C, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019;393(10184):1948–57. https://doi.org/10.1016/S0140-6736(18)32557-1. Ali R, Barnes I, Cairns BJ, et al. Incidence of gastrointestinal cancers by ethnic group in England, 2001–2007. Gut. 2013;62(12):1692–703. https://doi.org/10.1136/ gutjnl-2012-303000. An L, Gaowa S, Cheng H, Hou M. Long-term outcomes comparison of endoscopic resection with gastrectomy for treatment of early gastric cancer: a systematic review and meta-analysis. Front Oncol. 2019;9:725. https://doi.org/10.3389/fonc.2019.00725. Published 2019 Aug 7. Aragonés N, Pollán M, Rodero I, López-Abente G. Gastric cancer in the European Union (1968–1992): mortality trends and cohort effect. Ann Epidemiol. 1997;7:294– 303. Arnold M, Park JY, Camargo MC, Lunet N, Forman D, Soerjomataram I. Is gastric cancer becoming a rare disease? A global assessment of predicted incidence trends to 2035. Gut. 2020;69(5):823–9. https://doi. org/10.1136/gutjnl-2019-320234. Ashktorab H, Kupfer SS, Brim H, Carethers JM. Racial disparity in gastrointestinal cancer risk. Gastroenterology. 2017;153(4):910–23. https://doi.org/10.1053/j. gastro.2017.08.018. Balakrishnan M, George R, Sharma A, Graham DY. Changing trends in stomach cancer throughout the world. Curr Gastroenterol Rep. 2017;19(8):36. https:// doi.org/10.1007/s11894-017-0575-8. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–97. https://doi.org/ 10.1016/S0140-6736(10)61121-X. [Published correction appears in Lancet. 2010;376(9749):1302]. Bang CS, Park JM, Baik GH, et al. Therapeutic outcomes of endoscopic resection of early gastric cancer with undifferentiated-type histology: a Korean ESD registry database analysis. Clin Endosc. 2017;50(6):569–77. https://doi.org/10.5946/ce.2017.017.

M. K. Mallath Banks M, Graham D, Jansen M, et al. British Society of Gastroenterology guidelines on the diagnosis and management of patients at risk of gastric adenocarcinoma. Gut. 2019;68(9):1545–75. https://doi.org/10.1136/ gutjnl-2018-318126. Bergquist JR, Leiting JL, Habermann EB, Cleary SP, Kendrick ML, Smoot RL, Nagorney DM, Truty MJ, Grotz TE. Early-onset gastric cancer is a distinct disease with worrisome trends and oncogenic features. Surgery. 2019;166(4):547. https://doi.org/10.1016/j. surg.2019.04.036. Bonequi P, Meneses-González F, Correa P, Rabkin CS, Camargo MC. Risk factors for gastric cancer in Latin America: a meta-analysis. Cancer Causes Control. 2013;24(2):217–31. https://doi.org/10.1007/s10552012-0110-z. Borggreve AS, Goense L, Brenkman HJF, et al. Imaging strategies in the management of gastric cancer: current role and future potential of MRI. Br J Radiol. 2019;92 (1097):20181044. https://doi.org/10.1259/bjr. 20181044. Boyd J, Langman M, Doll R. The epidemiology of gastrointestinal cancer with special reference to causation. Gut. 1964;5(2):196–200. https://doi.org/10.1136/gut. 5.2.196. PMID: 14159414; PMCID: PMC1552188. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68 (6):394–424. https://doi.org/10.3322/caac.21492. PMID:30207593. Caillet P, Liuu E, Raynaud Simon A, et al. Association between cachexia, chemotherapy and outcomes in older cancer patients: a systematic review. Clin Nutr. 2017;36(6):1473–82. https://doi.org/10.1016/j.clnu. 2016.12.003. Camargo MC, Anderson WF, King JB, et al. Divergent trends for gastric cancer incidence by anatomical subsite in US adults. Gut. 2011;60(12):1644–9. https://doi. org/10.1136/gut.2010.236737. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202–9. https://doi.org/10. 1038/nature13480. Cao LL, Lu J, Li P, et al. Evaluation of the eighth edition of the american joint committee on cancer TNM staging system for gastric cancer: an analysis of 7371 patients in the SEER database. Gastroenterol Res Pract. 2019;2019:6294382. https://doi.org/10.1155/2019/ 6294382. Published 2019 Apr 14. Carter KJ, Schaffer HA, Ritchie WP Jr. Early gastric cancer. Ann Surg. 1984;199(5):604–9. https://doi.org/10. 1097/00000658-198405000-00016. Casaretto L, Sousa PL, Mari JJ. Chemotherapy versus support cancer treatment in advanced gastric cancer: a metaanalysis. Braz J Med Biol Res. 2006;39(4):431–40. https://doi.org/10.1590/s0100-879x2006000400002. Chen J, Chen J, Xu Y, et al. Impact of age on the prognosis of operable gastric cancer patients: an analysis based on

83

Gastric Cancer

seer database. Medicine (Baltimore). 2016;95(24): e3944. https://doi.org/10.1097/MD.000000000000 3944. [Published correction appears in Medicine (Baltimore). 2016;95(31):e5074; published correction appears in Medicine (Baltimore). 2016;95(34):e21ed]. Cheng SY, Hu WY, Liu WJ, Yao CA, Chen CY, Chiu TY. Good death study of elderly patients with terminal cancer in Taiwan. Palliat Med. 2008;22(5):626–32. https://doi.org/10.1177/0269216307087142. Chmelo J, Phillips AW, Greystoke A, et al. A feasibility study to investigate the utility of a home-based exercise intervention during and after neo-adjuvant chemotherapy for oesophago-gastric cancer-the ChemoFit study protocol. Pilot Feasibility Stud. 2020;6:50. https://doi.org/10. 1186/s40814-020-00597-y. Published 2020 Apr 23. Choi YJ, Kim N. Gastric cancer and family history. Korean J Intern Med. 2016;31:1042–53. Choi IS, Choi M, Lee JH, et al. Treatment patterns and outcomes in patients with metastatic gastric cancer receiving third-line chemotherapy: A populationbased outcomes study. PLoS One. 2018;13(6): e0198544. Published 2018 Jun 7. https://doi.org/10. 1371/journal.pone.0198544. Choi YI, Chung JW, Kim KO, et al. Concordance rate between clinicians and watson for oncology among patients with advanced gastric cancer: early, realworld experience in Korea. Can J Gastroenterol Hepatol. 2019;2019:8072928. https://doi.org/10.1155/ 2019/8072928. Published 2019 Feb 3. Choi S, Jang J, Heo YJ, et al. CDH1 mutations in gastric cancers are not associated with family history. Pathol Res Pract. 2020a;216(5):152941. https://doi.org/10. 1016/j.prp.2020.152941. Choi JH, Choi YW, Kang SY, et al. Combination versus single-agent as palliative chemotherapy for gastric cancer. BMC Cancer. 2020b;20(1):167. https://doi.org/10. 1186/s12885-020-6666-1. Published 2020 Mar 2. Chung IK, Lee JH, Lee SH, et al. Therapeutic outcomes in 1000 cases of endoscopic submucosal dissection for early gastric neoplasms: Korean ESD Study Group multicenter study. Gastrointest Endosc. 2009;69(7):1228–35. https:// doi.org/10.1016/j.gie.2008.09.027. Cimerman M, Repse S, Jelenc F, Omejc M, Bitenc M, Lamovec J. Comparison of Lauren’s, Ming’s and WHO histological classifications of gastric cancer as a prognostic factor for operated patients. Int Surg. 1994;79(1):27–32. Coker OO, Dai Z, Nie Y, et al. Mucosal microbiome dysbiosis in gastric carcinogenesis. Gut. 2018;67 (6):1024–32. https://doi.org/10.1136/gutjnl-2017314281. Colquhoun A, Arnold M, Ferlay J, Goodman KJ, Forman D, Soerjomataram I. Global patterns of cardia and non-cardia gastric cancer incidence in 2012. Gut. 2015;64(12):1881– 8. https://doi.org/10.1136/gutjnl-2014-308915. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process – first American Cancer Society award lecture on cancer epidemiology and prevention. Cancer Res. 1992;52(24):6735–40.

1873 Correa P. The biological model of gastric carcinogenesis. IARC Sci Publ. 2004;157:301–10. Correa P, Piazuelo MB. The gastric precancerous cascade. J Dig Dis. 2012;13(1):2–9. https://doi.org/10.1111/j. 1751-2980.2011.00550.x. PMID: 22188910; PMCID: PMC3404600. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11–20. https://doi. org/10.1056/NEJMoa055531. D’Elia L, Rossi G, Ippolito R, Cappuccio FP, Strazzullo P. Habitual salt intake and risk of gastric cancer: a metaanalysis of prospective studies. Clin Nutr. 2012;31 (4):489–98. https://doi.org/10.1016/j.clnu.2012.01. 003. Di L, Wu H, Zhu R, et al. Multi-disciplinary team for early gastric cancer diagnosis improves the detection rate of early gastric cancer. BMC Gastroenterol. 2017;17 (1):147. https://doi.org/10.1186/s12876-017-0711-9. Published 2017 Dec 6. Dijksterhuis WPM, Verhoeven RHA, Slingerland M, et al. Heterogeneity of first-line palliative systemic treatment in synchronous metastatic esophagogastric cancer patients: a real-world evidence study. Int J Cancer. 2020;146(7):1889–901. https://doi.org/10.1002/ijc. 32580. Dixon MF. Gastrointestinal epithelial neoplasia: Vienna revisited. Gut. 2002;51(1):130–1. https://doi.org/10. 1136/gut.51.1.130. Dobrilla G, Benvenuti S, Amplatz S, Zancanella L. Chronic gastritis, intestinal metaplasia, dysplasia and Helicobacter pylori in gastric cancer: putting the pieces together. Ital J Gastroenterol. 1994;26(9):449–58. Dong D, Tang L, Li ZY, et al. Development and validation of an individualized nomogram to identify occult peritoneal metastasis in patients with advanced gastric cancer. Ann Oncol. 2019;30(3):431–8. https://doi.org/10. 1093/annonc/mdz001. Dorant E, van den Brandt PA, Goldbohm RA, Sturmans F. Consumption of onions and a reduced risk of stomach carcinoma. Gastroenterology. 1996;110(1):12–20. https://doi.org/10.1053/gast.1996.v110.pm8536847. Du CZ, Li J, Cai Y, Sun YS, Xue WC, Gu J. Effect of multidisciplinary team treatment on outcomes of patients with gastrointestinal malignancy. World J Gastroenterol. 2011;17(15):2013–8. https://doi.org/10. 3748/wjg.v17.i15.2013. El-Omar EM, Carrington M, Chow WH, et al. Interleukin1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000;404:398–402. European Network of Cancer Registries. Stomach cancer (SC) fact sheet. 2017. https://www.encr.eu/sites/ default/files/factsheets/ENCR_Factsheet_Stomach_ 2017.pdf Faguet GB. A brief history of cancer: age-old milestones underlying our current knowledge database. Int J Cancer. 2015;136:2022–36.

1874 Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, Znaor A, Soerjomataram I, Bray F. Global cancer observatory: cancer today. Lyon: International Agency for Research on Cancer; 2018a. Available from: https:// gco.iarc.fr/today. Accessed 26 May 2020. Ferlay J, Colombet M, Bray F. Cancer incidence in five continents, CI5plus: IARC Cancer Base No. 9 [Internet]. Lyon: International Agency for Research on Cancer; 2018b. Available from: http://ci5.iarc.fr Ferro A, Peleteiro B, Malvezzi M, et al. Worldwide trends in gastric cancer mortality (1980–2011), with predictions to 2015, and incidence by subtype. Eur J Cancer. 2014;50(7):1330–44. https://doi.org/10.1016/j.ejca. 2014.01.029. Findlay JM, Antonowicz S, Segaran A, et al. Routinely staging gastric cancer with18F-FDG PET-CT detects additional metastases and predicts early recurrence and death after surgery. Eur Radiol. 2019;29(5):2490– 8. https://doi.org/10.1007/s00330-018-5904-2. Fox JG, Beck P, Dangler CA, et al. Concurrent enteric helminth infection modulates inflammation and gastric immune responses and reduces helicobacter-induced gastric atrophy. Nat Med. 2000;6(5):536–42. https:// doi.org/10.1038/75015. Fuccio L, Bhandari P, Maselli R, et al. Ten quality indicators for endoscopic submucosal dissection: what should be monitored and reported to improve quality. Ann Transl Med. 2018;6(13):262. https://doi.org/10.21037/ atm.2018.05.42. Fuentes HE, Oramas DM, Paz LH, Wang Y, Andrade XA, Tafur AJ. Venous thromboembolism is an independent predictor of mortality among patients with gastric cancer. J Gastrointest Cancer. 2018;49(4):415–21. https:// doi.org/10.1007/s12029-017-9981-2. Fujitani K, Yang HK, Mizusawa J, et al. Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomised controlled trial. Lancet Oncol. 2016;17(3):309–18. https://doi.org/10. 1016/S1470-2045(15)00553-7. Ge S, Xia X, Ding C, et al. A proteomic landscape of diffuse-type gastric cancer. Nat Commun. 2018;9 (1):1012. https://doi.org/10.1038/s41467-018-031212. Published 2018 Mar 8. [Published correction appears in Nat Commun. 2018;9(1):1850]. Ghoshal UC, Chaturvedi R, Correa P. The enigma of Helicobacter pylori infection and gastric cancer. Indian J Gastroenterol. Author manuscript; available in PMC 2011 Nov 16. Published in final edited form as: Indian J Gastroenterol. 2010;29(3):95–100. Published online 2010 Jun 29. https://doi.org/10.1007/s12664-0100024-1. PMCID: PMC3217495. Gomez SL, Noone AM, Lichtensztajn DY, et al. Cancer incidence trends among Asian American populations in the United States, 1990–2008. J Natl Cancer Inst. 2013;105(15):1096–110. https://doi.org/10.1093/jnci/ djt157. González CA, Pera G, Agudo A, et al. Fruit and vegetable intake and the risk of stomach and oesophagus

M. K. Mallath adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST). Int J Cancer. 2006;118(10):2559–66. https://doi.org/ 10.1002/ijc.21678. Gotoda T, Kusano C, Nonaka M, et al. Non-anesthesiologist administrated propofol (NAAP) during endoscopic submucosal dissection for elderly patients with early gastric cancer. Gastric Cancer. 2014;17(4):686–91. https://doi.org/10.1007/s10120-013-0336-9. Graham DY, Lu H, Yamaoka Y. African, Asian or Indian enigma, the East Asian Helicobacter pylori: facts or medical myths. J Dig Dis. Author manuscript; available in PMC 2010 Mar 28. Published in final edited form as: J Dig Dis. 2009;10(2):77–84. https://doi.org/10.1111/j. 1751-2980.2009.00368.x. PMCID: PMC2846403. Guadagni S, Catarci M, Kinoshitá T, Valenti M, De Bernardinis G, Carboni M. Causes of death and recurrence after surgery for early gastric cancer. World J Surg. 1997;21(4):434–9. https://doi.org/10.1007/ pl00012266. Hallet J, Look Hong NJ, Zuk V, et al. Economic impacts of care by high-volume providers for non-curative esophagogastric cancer: a population-based analysis. Gastric Cancer. 2020;23(3):373–81. https://doi.org/10. 1007/s10120-019-01031-w. Hamada T, Hakuta R, Takahara N, et al. Covered versus uncovered metal stents for malignant gastric outlet obstruction: systematic review and meta-analysis. Dig Endosc. 2017;29(3):259–71. https://doi.org/10.1111/ den.12786. Han F, Wang X, Wang X, Luo Y, Li W. Meta-analysis of the association of CYP1A1 polymorphisms with gastric cancer susceptibility and interaction with tobacco smoking. Mol Biol Rep. 2012;39(8):8335–44. https:// doi.org/10.1007/s11033-012-1683-z. Han ES, Seo HS, Kim JH, Lee HH. Surveillance endoscopy guidelines for postgastrectomy patients based on risk of developing remnant gastric cancer. Ann Surg Oncol. 2020. https://doi.org/10.1245/s10434-020-08517-3. [Published online ahead of print, 2020 May 5]. Haron NH, Mohamad Hanif EA, Abdul Manaf MR, et al. Microsatellite instability and altered expressions of MLH1 and MSH2 in gastric cancer. Asian Pac J Cancer Prev. 2019;20(2):509–17. https://doi.org/10.31557/ APJCP.2019.20.2.509. Published 2019 Feb 26. He S, Shen J, Hong L, Niu L, Niu D. Capecitabine “metronomic” chemotherapy for palliative treatment of elderly patients with advanced gastric cancer after fluoropyrimidine-based chemotherapy. Med Oncol. 2012;29(1):100–6. https://doi.org/10.1007/s12032010-9791-x. Hirayama T. Epidemiology of cancer of the stomach with special reference to its recent decrease in Japan. Cancer Res. 1975;35(11 Pt. 2):3460–3. Hofheinz R, Clouth J, Borchardt-Wagner J, et al. Patient preferences for palliative treatment of locally advanced or metastatic gastric cancer and adenocarcinoma of the gastroesophageal junction: a choice-based conjoint analysis study from Germany. BMC Cancer. 2016;16

83

Gastric Cancer

(1):937. https://doi.org/10.1186/s12885-016-2975-9. Published 2016 Dec 6. Holcombe C. Helicobacter pylori: the African enigma. Gut. 1992;33(4):429–31. https://doi.org/10.1136/gut. 33.4.429. Holster IL, Aarts MJ, Tjwa ET, Lemmens VE, Kuipers EJ. Trend breaks in incidence of non-cardia gastric cancer in the Netherlands. Cancer Epidemiol. 2014;38(1):9– 15. https://doi.org/10.1016/j.canep.2013.11.001. Honda M, Kumamaru H, Etoh T, et al. Surgical risk and benefits of laparoscopic surgery for elderly patients with gastric cancer: a multicenter prospective cohort study. Gastric Cancer. 2019;22(4):845–52. https://doi. org/10.1007/s10120-018-0898-7. Hu Y, Huang C, Sun Y, et al. Morbidity and mortality of laparoscopic versus open D2 distal gastrectomy for advanced gastric cancer: a randomized controlled trial. J Clin Oncol. 2016;34(12):1350–7. https://doi. org/10.1200/JCO.2015.63.7215. Huang Q, Sun Q, Fan XS, Zhou D, Zou XP. Recent advances in proximal gastric carcinoma. J Dig Dis. 2016;17(7):421–32. https://doi.org/10.1111/17512980.12355. In H, Solsky I, Palis B, Langdon-Embry M, Ajani J, Sano T. Validation of the 8th edition of the AJCC TNM staging system for gastric cancer using the national cancer database. Ann Surg Oncol. 2017;24(12):3683– 91. https://doi.org/10.1245/s10434-017-6078-x. Itoi T, Baron TH, Khashab MA, et al. Technical review of endoscopic ultrasonography-guided gastroenterostomy in 2017. Dig Endosc. 2017;29(4):495–502. https://doi. org/10.1111/den.12794. Izuishi K, Mori H. Recent strategies for treating stage IV gastric cancer: roles of palliative gastrectomy, chemotherapy, and radiotherapy. J Gastrointestin Liver Dis. 2016;25(1):87–94. https://doi.org/10.15403/jgld.2014. 1121.251.rv2. Jacob CE, Gama-Rodrigues J, Bresciani CJ, et al. Trends in tumor location in gastric carcinoma over a 28-year period. Hepato-Gastroenterology. 2007;54(76):1297– 301. Jamel S, Markar SR, Malietzis G, Acharya A, Athanasiou T, Hanna GB. Prognostic significance of peritoneal lavage cytology in staging gastric cancer: systematic review and meta-analysis. Gastric Cancer. 2018;21 (1):10–8. https://doi.org/10.1007/s10120-017-0749-y. Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011;14(2):101–12. https://doi.org/10.1007/ s10120-01. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2018 (5th edition). Gastric Cancer. 2020;https://doi.org/10.1007/s10120-020-01042-y. [Published online ahead of print, 2020 Feb 14]. Ji ZH, Peng KW, Yu Y, et al. Current status and future prospects of clinical trials on CRS + HIPEC for gastric cancer peritoneal metastases. Int J Hyperth. 2017;33 (5):562–70. https://doi.org/10.1080/02656736.2017. 1283065.

1875 Joharatnam-Hogan N, Shiu KK, Khan K. Challenges in the treatment of gastric cancer in the older patient. Cancer Treat Rev. 2020;85:101980. https://doi.org/10.1016/j. ctrv.2020.101980. Kano M, Hayano K, Hayashi H, et al. Survival benefit of neoadjuvant chemotherapy with S-1 plus docetaxel for locally advanced gastric cancer: a propensity scorematched analysis. Ann Surg Oncol. 2019;26(6):1805– 13. https://doi.org/10.1245/s10434-019-07299-7. Katz H, Biglow L, Alsharedi M. Immune checkpoint inhibitors in locally advanced, unresectable, and metastatic upper gastrointestinal malignancies. J Gastrointest Cancer. 2020;51(2):611–9. https://doi.org/10.1007/ s12029-019-00243-8. Kawashima S. Early gastric cancer in Japan. Scand J Gastroenterol. 1966;1(4):248–52. Khan U, Shah MA. Ramucirumab for the treatment of gastric or gastro-esophageal junction cancer. Expert Opin Biol Ther. 2019;19(11):1135–41. https://doi.org/ 10.1080/14712598.2019.1656715. Kobayashi T, Kikuchi S, Lin Y, et al. Trends in the incidence of gastric cancer in Japan and their associations with Helicobacter pylori infection and gastric mucosal atrophy. Gastric Cancer. 2004;7(4):233–9. https://doi. org/10.1007/s10120-004-0297-0. LaRocca CJ, Li A, Lafaro K, et al. The impact of financial toxicity in gastrointestinal cancer patients. Surgery. 2020;S0039-6060(20)30072-6. https://doi.org/10. 1016/j.surg.2020.02.006. [Published online ahead of print, 2020 Mar 17]. Lauren P. The two histological main types of gastric carcinoma; diffuse and so called intestinal type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand. 1965;64:31–49. https://doi.org/10. 1111/apm.1965.64.1.31. Lee MH, Choi D, Park MJ, Lee MW. Gastric cancer: imaging and staging with MDCT based on the 7th AJCC guidelines. Abdom Imaging. 2012;37(4):531–40. https://doi.org/10.1007/s00261-011-9780-3. Lee JS, Kim YS, Kim EY, Jin W. Prognostic significance of CT-determined sarcopenia in patients with advanced gastric cancer. PLoS One. 2018;13(8):e0202700. https://doi.org/10.1371/journal.pone.0202700. Published 2018 Aug 20. Li J. Gastric cancer in young adults: a different clinical entity from carcinogenesis to prognosis. Gastroenterol Res Pract. 2020;2020:9512707. https://doi.org/10. 1155/2020/9512707. Published 2020 Mar 2. Li Y, Tan B, Fan L, et al. Clinicopathologic characteristics of elderly with gastric cancer, and the risk factors of postoperative complications. J Investig Surg. 2017;30(6):394– 400. https://doi.org/10.1080/08941939.2016.1265617. Li WY, Han Y, Xu HM, et al. Smoking status and subsequent gastric cancer risk in men compared with women: a meta-analysis of prospective observational studies. BMC Cancer. 2019a;19(1):377. https://doi.org/10. 1186/s12885-019-5601-9. Published 2019 Apr 24. Li Z, Shan F, Ying X, et al. Assessment of laparoscopic distal gastrectomy after neoadjuvant chemotherapy for

1876 locally advanced gastric cancer: a randomized clinical trial. JAMA Surg. 2019b;154(12):1093–101. https:// doi.org/10.1001/jamasurg.2019.3473. Liu YW, Du Y, Chen BA. Effect of hyperthermic intraperitoneal chemotherapy for gastric cancer patients: a meta-analysis of the randomized controlled trials. J Int Med Res. 2019;47(12):5926–36. https://doi.org/10. 1177/0300060519882545. Liu Q, Ding L, Qiu X, Meng F. Updated evaluation of endoscopic submucosal dissection versus surgery for early gastric cancer: a systematic review and metaanalysis. Int J Surg. 2020;73:28–41. https://doi.org/ 10.1016/j.ijsu.2019.11.027. Lu Z, Lu M, Zhang X, et al. Advanced or metastatic gastric cancer in elderly patients: clinicopathological, prognostic factors and treatments. Clin Transl Oncol. 2013;15(5):376–83. https://doi.org/10.1007/s12094012-0938-4. Lu J, Zheng ZF, Xie JW, et al. Is the 8th edition of the AJCC TNM staging system sufficiently reasonable for all patients with noncardia gastric cancer? A 12,549patient international database study. Ann Surg Oncol. 2018;25(7):2002–11. https://doi.org/10.1245/s10434018-6447-0. Lunet N, Barros H. Helicobacter pylori infection and gastric cancer: facing the enigmas. Int J Cancer. 2003;106 (6):953–60. https://doi.org/10.1002/ijc.11306. Luo G, Zhang Y, Guo P, Wang L, Huang Y, Li K. Global patterns and trends in stomach cancer incidence: age, period and birth cohort analysis. Int J Cancer. 2017;141 (7):1333–44. https://doi.org/10.1002/ijc.30835. Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001;345:725–30. https://doi.org/10. 1056/NEJMoa010187. Maixner F, Krause-Kyora B, Turaev D, et al. The 5300year-old Helicobacter pylori genome of the Iceman. Science. 2016;351(6269):162–5. https://doi.org/10. 1126/science.aad2545. Maixner F, Thorell K, Granehäll L, Linz B, Moodley Y, Rattei T, Engstrand L, Zink A. Helicobacter pylori in ancient human remains. World J Gastroenterol. 2019;25 (42):6289–98. https://doi.org/10.3748/wjg.v25.i42. 6289. PMID: 31754290; PMCID: PMC6861846. Marano L, D’Ignazio A, Cammillini F, et al. Comparison between 7th and 8th edition of AJCC TNM staging system for gastric cancer: old problems and new perspectives. Transl Gastroenterol Hepatol. 2019;4:22. https://doi.org/10.21037/tgh.2019.03.09. Published 2019 Apr 3. Mason MK. Surface carcinoma of the stomach. Gut. 1965;6 (2):185–93. https://doi.org/10.1136/gut.6.2.185. Miao ZF, Xu H, Xu YY, et al. Diabetes mellitus and the risk of gastric cancer: a meta-analysis of cohort studies. Oncotarget. 2017;8(27):44881–92. https://doi.org/10. 18632/oncotarget.16487.

M. K. Mallath Mizutani T, Yamaguchi K, Mizusawa J, et al. A phase III trial to confirm modified S-1 adjuvant chemotherapy for pathological stage II/III vulnerable elderly gastric cancer patients who underwent gastric resection (JCOG1507, BIRDIE). Jpn J Clin Oncol. 2018;48 (12):1101–4. https://doi.org/10.1093/jjco/hyy152. Moayyedi P, Talley NJ, Fennerty MB, Vakil N. Can the clinical history distinguish between organic and functional dyspepsia? JAMA. 2006;295(13):1566–76. https://doi.org/10.1001/jama.295.13.1566. Mocellin S, Pasquali S. Diagnostic accuracy of endoscopic ultrasonography (EUS) for the preoperative locoregional staging of primary gastric cancer. Cochrane Database Syst Rev. 2015, 2015;(2): CD009944. https://doi.org/10.1002/14651858. CD009944.pub2. Published 2015 Feb 6. Mocellin S, McCulloch P, Kazi H, Gama-Rodrigues JJ, Yuan Y, Nitti D. Extent of lymph node dissection for adenocarcinoma of the stomach. Cochrane Database Syst Rev. 2015;(8):CD001964. https://doi.org/10. 1002/14651858.CD001964.pub4. Published 2015 Aug 12. Morishima T, Matsumoto Y, Koeda N, et al. Impact of comorbidities on survival in gastric, colorectal, and lung cancer patients. J Epidemiol. 2019;29(3):110–5. https://doi.org/10.2188/jea.JE20170241. Muñoz N, Connelly R. Time trends of intestinal and diffuse types of gastric cancer in the United States. Int J Cancer. 1971;8(1):158–64. https://doi.org/10.1002/ijc. 2910080119. Nagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, Washington KM, Carneiro F, Cree IA, for the WHO Classification of Tumours Editorial Board. WHO classification of tumours, digestive system tumours, vol. 1. 5th ed. Lyon: International Agency for Research on Cancer, World Health Organization. 2019;pp 59–110. Nelen SD, Verhoeven RHA, Lemmens VEPP, de Wilt JHW, Bosscha K. Increasing survival gap between young and elderly gastric cancer patients. Gastric Cancer. 2017;20(6):919–28. https://doi.org/10.1007/ s10120-017-0708-7. NICE. Palliative management for people with oesophageal and gastric cancer. http://pathways.nice.org.uk/path ways/oesophageal-and-gastric-cancer. NICE Pathway last updated: 27 May 2020. Noh SH, Park SR, Yang HK, et al. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15 (12):1389–96. https://doi.org/10.1016/S1470-2045 (14)70473-5. O’Sullivan B, Brierley JD, D’Cruz AK, Fey MF, Pollock R, Vermorken JB, Huang SH, editors. UICC manual of clinical oncology. 9th ed. Chichester: Wiley; 2015. © 2015 UICC. Oliveira C, Pinheiro H, Figueiredo J, Seruca R, Carneiro F. Familial gastric cancer: genetic susceptibility, pathology, and implications for management. Lancet Oncol.

83

Gastric Cancer

2015;16(2):e60–70. https://doi.org/10.1016/S14702045(14)71016-2. Oue N, Sentani K, Sakamoto N, Uraoka N, Yasui W. Molecular carcinogenesis of gastric cancer: Lauren classification, mucin phenotype expression, and cancer stem cells. Int J Clin Oncol. 2019;24(7):771–8. https:// doi.org/10.1007/s10147-019-01443-9. Park SH, Sohn TS, Lee J, et al. Phase III trial to compare adjuvant chemotherapy with capecitabine and cisplatin versus concurrent chemoradiotherapy in gastric cancer: final report of the adjuvant chemoradiotherapy in stomach tumors trial, including survival and subset analyses. J Clin Oncol. 2015;33(28):3130–6. https://doi.org/10. 1200/JCO.2014.58.3930. Park SH, Zang DY, Han B, Ji JH, Kim TG, Oh SY, Hwang IG, Kim JH, Shin D, Lim DH, Kim KM, An JY, Choi M-G, Lee J-H, Sohn TS, Bae J-M, Kim S, Kim S, Lee J, Kang WK. ARTIST 2: interim results of a phase III trial involving adjuvant chemotherapy and/or chemoradiotherapy after D2-gastrectomy in stage II/ III gastric cancer (GC). J Clin Oncol. 2019;37 (15_suppl):4001–4001. Petrovchich I, Ford JM. Genetic predisposition to gastric cancer. Semin Oncol. 2016;43(5):554–9. https://doi. org/10.1053/j.seminoncol.2016.08.006. Petruzziello L, Campanale M, Spada C, Ricci R, Hassan C, Gullo G, Costamagna G. Endoscopic submucosal dissection of gastric superficial neoplastic lesions: a single Western center experience. United European Gastroenterol J. 2018;6(2):203–12. https://doi.org/10. 1177/2050640617722901. Epub 2017 Jul 25. PMID: 29511550; PMCID: PMC5833229 Pimenta-Melo AR, Monteiro-Soares M, Libânio D, DinisRibeiro M. Missing rate for gastric cancer during upper gastrointestinal endoscopy: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol. 2016;28 (9):1041–9. https://doi.org/10.1097/MEG. 0000000000000657. Pimentel-Nunes P, Libânio D, Marcos-Pinto R, et al. Management of epithelial precancerous conditions and lesions in the stomach (MAPS II): European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG), European Society of Pathology (ESP), and Sociedade Portuguesa de Endoscopia Digestiva (SPED) guideline update 2019. Endoscopy. 2019;51(4):365–88. https:// doi.org/10.1055/a-0859-1883. Poorolajal J, Moradi L, Mohammadi Y, Cheraghi Z, Gohari-Ensaf F. Risk factors for stomach cancer: a systematic review and meta-analysis. Epidemiol Health. 2020;42:e2020004. https://doi.org/10.4178/ epih.e2020004. Priego P, Cuadrado M, Ballestero A, Galindo J, Lobo E. Comparison of laparoscopic versus open gastrectomy for treatment of gastric cancer: analysis of a textbook outcome. J Laparoendosc Adv Surg Tech A. 2019;29 (4):458–64. https://doi.org/10.1089/lap.2018.0489. Rao DN, Ganesh B, Dinshaw KA, Mohandas KM. A casecontrol study of stomach cancer in Mumbai, India. Int J

1877 Cancer. 2002;99(5):727–31. https://doi.org/10.1002/ ijc.10339. Rapp J, Tuminello S, Alpert N, Flores RM, Taioli E. Disparities in surgery for early-stage cancer: the impact of refusal. Cancer Causes Control. 2019;30(12):1389– 97. https://doi.org/10.1007/s10552-019-01240-9. Reddavid R, Sofia S, Chiaro P, et al. Neoadjuvant chemotherapy for gastric cancer. Is it a must or a fake? World J Gastroenterol. 2018;24(2):274–89. https://doi.org/10. 3748/wjg.v24.i2.274. Rugge M, Correa P, Di Mario F, et al. OLGA staging for gastritis: a tutorial. Dig Liver Dis. 2008;40(8):650–8. https://doi.org/10.1016/j.dld.2008.02.030. Russo A, Li P, Strong VE. Differences in the multimodal treatment of gastric cancer: east versus west. J Surg Oncol. 2017;115:603–14. Saif MW, Makrilia N, Zalonis A, Merikas M, Syrigos K. Gastric cancer in the elderly: an overview. Eur J Surg Oncol. 2010;36(8):709–17. https://doi.org/10.1016/j. ejso.2010.05.023. Sano T, Sasako M, Kinoshita T, Maruyama K. Recurrence of early gastric cancer. Follow-up of 1475 patients and review of the Japanese literature. Cancer. 1993;72 (11):3174–8. https://doi.org/10.1002/1097-0142 (19931201)72:113.0. co;2-h. Sano T, Coit DG, Kim HH, et al. Proposal of a new stage grouping of gastric cancer for TNM classification: International Gastric Cancer Association staging project. Gastric Cancer. 2017a;20(2):217–25. https://doi. org/10.1007/s10120-016-0601-9. Sano T, Sasako M, Mizusawa J, et al. Randomized controlled trial to evaluate splenectomy in total gastrectomy for proximal gastric carcinoma. Ann Surg. 2017b;265(2):277–83. https://doi.org/10.1097/SLA. 0000000000001814. Schendel J, Jost E, Mah M, et al. Gastric cancer management in elderly patients: a population-based study of treatment patterns and outcomes in gastric cancer patients  75 years from Alberta, Canada. Am J Surg 2020;S0002-9610(20)30148-3. https://doi.org/10. 1016/j.amjsurg.2020.03.006. [Published online ahead of print, 2020 Mar 19]. Schmidt HM, Ha DM, Taylor EF, et al. Variation in human genetic polymorphisms, their association with Helicobacter pylori acquisition and gastric cancer in a multi-ethnic country. J Gastroenterol Hepatol. 2011;26 (12):1725–32. https://doi.org/10.1111/j.1440-1746. 2011.06799.x. Shahidi N, Bourke MJ. ESD, not EMR, should be the firstline therapy for early gastric neoplasia. Gut. 2019;gutjnl2019-319646. https://doi.org/10.1136/gutjnl-2019319646. [Published online ahead of print, 2019 Sep 3]. Shapiro J, van Lanschot JJB, Hulshof MCCM, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 2015;16(9):1090–8. https://doi. org/10.1016/S1470-2045(15)00040-6.

1878 Shastri YM, Shirodkar M, Mallath MK. Endoscopic feeding tube placement in patients with cancer: a prospective clinical audit of 2055 procedures in 1866 patients. Aliment Pharmacol Ther. 2008;27(8):649–58. https:// doi.org/10.1111/j.1365-2036.2008.03621.x. Shen Y, Hao Q, Zhou J, Dong B. The impact of frailty and sarcopenia on postoperative outcomes in older patients undergoing gastrectomy surgery: a systematic review and meta-analysis. BMC Geriatr. 2017;17(1):188. https://doi.org/10.1186/s12877-017-0569-2. Published 2017 Aug 21. Sheth T, Nair C, Nargundkar M, Anand S, Yusuf S. Cardiovascular and cancer mortality among Canadians of European, south Asian and Chinese origin from 1979 to 1993: an analysis of 1.2 million deaths. CMAJ. 1999;161(2):132–8. [Published correction appears in CMAJ 1999;161(5):489]. Shimazu T, Wakai K, Tamakoshi A, et al. Association of vegetable and fruit intake with gastric cancer risk among Japanese: a pooled analysis of four cohort studies. Ann Oncol. 2014;25(6):1228–33. https://doi.org/ 10.1093/annonc/mdu115. Siewert JR, Stein HJ. Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg. 1998;85 (11):1457–9. https://doi.org/10.1046/j.1365-2168. 1998.00940.x. Sinagra E, Luppino I, Messina M, et al. Endoscopic approach to early gastric cancer in older adults. J Geriatr Oncol. 2020;S1879-4068(20)30208-3. https:// doi.org/10.1016/j.jgo.2020.05.005. [Published online ahead of print, 2020 May 26]. Slagter AE, Tudela B, van Amelsfoort RM, et al. Older versus younger adults with gastric cancer receiving perioperative treatment: results from the CRITICS trial. Eur J Cancer. 2020;130:146–54. https://doi.org/ 10.1016/j.ejca.2020.02.008. Solsky I, Rapkin B, Wong K, Friedmann P, Muscarella P, In H. Gastric cancer diagnosis after presentation to the ED: the independent association of presenting location and outcomes. Am J Surg. 2018;216(2):286–92. https://doi.org/10.1016/j.amjsurg.2017.10.030. Specchia ML, Frisicale EM, Carini E, Di Pilla A, Cappa D, Barbara A, Ricciardi W, Damiani G. The impact of tumor board on cancer care: evidence from an umbrella review. BMC Health Serv Res. 2020;20(1):73. https:// doi.org/10.1186/s12913-020-4930-3.PMID: 32005232; PMCID: PMC6995197. Strong VE, Gholami S, Shah MA, et al. Total gastrectomy for hereditary diffuse gastric cancer at a single center: postsurgical outcomes in 41 patients. Ann Surg. 2017;266(6):1006–12. https://doi.org/10.1097/SLA. 0000000000002030. Suh YS, Yang HK. Screening and early detection of gastric cancer: east versus west. Surg Clin North Am. 2015;95 (5):1053–66. https://doi.org/10.1016/j.suc.2015.05.012. Tahara E. Genetic pathways of two types of gastric cancer. IARC Sci Publ. 2004;157:327–49. Takahashi-Kanemitsu A, Knight CT, Hatakeyama M. Molecular anatomy and pathogenic actions of

M. K. Mallath Helicobacter pylori CagA that underpin gastric carcinogenesis. Cell Mol Immunol. 2020;17(1):50–63. https://doi.org/10.1038/s41423-019-0339-5. Tan Z. Recent advances in the surgical treatment of advanced gastric cancer: a review. Med Sci Monit. 2019;25:3537–41. https://doi.org/10.12659/MSM. 916475. Published 2019 May 13. Tanabe S, Hirabayashi S, Oda I, et al. Gastric cancer treated by endoscopic submucosal dissection or endoscopic mucosal resection in Japan from 2004 through 2006: JGCA nationwide registry conducted in 2013. Gastric Cancer. 2017;20(5):834–42. https://doi.org/10.1007/ s10120-017-0699-4. Tanaka S, Kashida H, Saito Y, et al. JGES guidelines for colorectal endoscopic submucosal dissection/endoscopic mucosal resection. Dig Endosc. 2015;27 (4):417–34. https://doi.org/10.1111/den.12456. Tang GH, Hart R, Sholzberg M, Brezden-Masley C. Iron deficiency anemia in gastric cancer: a Canadian retrospective review. Eur J Gastroenterol Hepatol. 2018;30 (12):1497–501. https://doi.org/10.1097/MEG. 0000000000001251. Tavakoli A, Monavari SH, Solaymani Mohammadi F, Kiani SJ, Armat S, Farahmand M. Association between Epstein-Barr virus infection and gastric cancer: a systematic review and meta-analysis. BMC Cancer. 2020;20(1):493. https://doi.org/10.1186/s12885-02007013-x. Published 2020 Jun 1. Tedaldi G, Pirini F, Tebaldi M, et al. Multigene panel testing increases the number of loci associated with gastric cancer predisposition. Cancers (Basel). 2019;11(9):1340. https://doi.org/10.3390/cancers11091340. Published 2019 Sep 11. Temel JS, Greer JA, El-Jawahri A, et al. Effects of early integrated palliative care in patients with lung and GI cancer: a randomized clinical trial. J Clin Oncol. 2017;35(8):834–41. https://doi.org/10.1200/JCO. 2016.70.5046. Terashima M, Iwasaki Y, Mizusawa J, et al. Randomized phase III trial of gastrectomy with or without neoadjuvant S-1 plus cisplatin for type 4 or large type 3 gastric cancer, the short-term safety and surgical results: Japan Clinical Oncology Group Study (JCOG0501). Gastric Cancer. 2019;22(5):1044–52. https://doi.org/10.1007/s10120-019-00941-z. The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon: November 30 to December 1, 2002. Gastrointest Endosc. 2003;58 (6 Suppl):S3–43. https://doi.org/10.1016/s0016-5107 (03)02159-x. Thiels CA, Hanson KT, Habermann EB, Boughey JC, Grotz TE. Integrated cancer networks improve compliance with national guidelines and outcomes for resectable gastric cancer. Cancer. 2020;126(6):1283–94. https://doi.org/10.1002/cncr.32660. Tomasello G, Petrelli F, Ghidini M, et al. Tumor regression grade and survival after neoadjuvant treatment in gastro-esophageal cancer: a meta-analysis of 17 published studies. Eur J Surg Oncol. 2017;43

83

Gastric Cancer

(9):1607–16. https://doi.org/10.1016/j.ejso.2017.03. 001. Toriumi T, Terashima M. Disadvantages of complete no. 10 lymph node dissection in gastric cancer and the possibility of spleen-preserving dissection: review. J Gastric Cancer. 2020;20(1):1–18. https://doi.org/10. 5230/jgc.2020.20.e8. Toya Y, Endo M, Nakamura S, et al. Long-term outcomes and prognostic factors with non-curative endoscopic submucosal dissection for gastric cancer in elderly patients aged  75 years. Gastric Cancer. 2019;22 (4):838–44. https://doi.org/10.1007/s10120-01800913-9. Tsuda M, Asaka M, Kato M, et al. Effect on Helicobacter pylori eradication therapy against gastric cancer in Japan. Helicobacter. 2017;22(5):e12415. https://doi. org/10.1111/hel.12415. Ushimaru Y, Fujiwara Y, Shishido Y, et al. Condition mimicking peritoneal metastasis associated with preoperative staging laparoscopy in advanced gastric cancer. Asian J Endosc Surg. 2019;12(4):457–60. https://doi. org/10.1111/ases.12678. Vahid F, Davoodi SH. Nutritional factors involved in the etiology of gastric cancer: a systematic review. Nutr Cancer. 2020:1–15. https://doi.org/10.1080/01635581. 2020.1756353. [Published online ahead of print, 2020 Apr 27]. Van Cutsem E, Sagaert X, Topal B, Haustermans K, Prenen H. Gastric cancer. Lancet. 2016;388(10060):2654–64. https://doi.org/10.1016/S0140-6736(16)30354-3. van der Kaaij RT, Koemans WJ, van Putten M, et al. A population-based study on intestinal and diffuse type adenocarcinoma of the oesophagus and stomach in the Netherlands between 1989 and 2015. Eur J Cancer. 2020;130:23–31. https://doi.org/10.1016/j.ejca.2020. 02.017. Veitch AM, Uedo N, Yao K, East JE. Optimizing early upper gastrointestinal cancer detection at endoscopy. Nat Rev Gastroenterol Hepatol. 2015;12(11):660–7. https://doi.org/10.1038/nrgastro.2015.128. Voutilainen ME, Juhola MT. Evaluation of the diagnostic accuracy of gastroscopy to detect gastric tumours: clinicopathological features and prognosis of patients with gastric cancer missed on endoscopy. Eur J Gastroenterol Hepatol. 2005;17(12):1345–9. https:// doi.org/10.1097/00042737-200512000-00013. Wadhwa R, Song S, Lee J-S, Yao Y, Wei Q, Ajani JA. Gastric cancer: molecular and clinical dimensions. Nat Rev Clin Oncol. Author manuscript; available in PMC 2014 May 1. Published in final edited form as: Nat Rev Clin Oncol. 2013; 10(11): 643–655. https://doi.org/10. 1038/nrclinonc.2013.170. Published online 2013 Sep 24. Wagner AD, Syn NL, Moehler M, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. 2017;8(8):CD004064. https://doi.org/10.1002/ 14651858.CD004064.pub4. Published 2017 Aug 29. Wang Z, Graham DY, Khan A, et al. Incidence of gastric cancer in the USA during 1999 to 2013: a 50-state

1879 analysis. Int J Epidemiol. 2018;47(3):966–75. https:// doi.org/10.1093/ije/dyy055. Wang Q, Liu G, Hu C. Molecular classification of gastric adenocarcinoma. Gastroenterology Res. 2019;12 (6):275–82. https://doi.org/10.14740/gr1187. Wei Y, Yu D, Li Y, Fan C, Li G. Laparoscopic versus open gastrectomy for advanced gastric cancer: a meta-analysis based on high-quality retrospective studies and clinical randomized trials. Clin Res Hepatol Gastroenterol. 2018;42(6):577–90. https://doi.org/10. 1016/j.clinre.2018.04.005. Whary MT, Muthupalani S, Ge Z, et al. Helminth coinfection in Helicobacter pylori infected INS-GAS mice attenuates gastric premalignant lesions of epithelial dysplasia and glandular atrophy and preserves colonization resistance of the stomach to lower bowel microbiota. Microbes Infect. 2014;16(4):345–55. https://doi.org/10.1016/j.micinf.2014.01.005. Yaghoobi M, McNabb-Baltar J, Bijarchi R, Hunt RH. What is the quantitative risk of gastric cancer in the first-degree relatives of patients? A meta-analysis. World J Gastroenterol. 2017;23:2435–42. Yan S, Gan Y, Song X, Chen Y, Liao N, Chen S, Lv C. Association between refrigerator use and the risk of gastric cancer: a systematic review and meta-analysis of observational studies. PLoS One. 2018;13(8): e0203120. https://doi.org/10.1371/journal.pone. 0203120. PMID: 30161245; PMCID: PMC6117033. Yang P, Zhou Y, Chen B, et al. Overweight, obesity and gastric cancer risk: results from a meta-analysis of cohort studies. Eur J Cancer. 2009;45(16):2867–73. https://doi.org/10.1016/j.ejca.2009.04.019. Yang Z, Zhou X, Ma B, Xing Y, Jiang X, Wang Z. Predictive value of preoperative sarcopenia in patients with gastric cancer: a meta-analysis and systematic review. J Gastrointest Surg. 2018;22(11):1890–902. https://doi. org/10.1007/s11605-018-3856-0. Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011;29(13):1715–21. https://doi.org/10.1200/JCO. 2010.33.0597. Yokoyama A, Inoue H, Minami H, et al. Novel narrowband imaging magnifying endoscopic classification for early gastric cancer. Dig Liver Dis. 2010;42(10):704–8. https://doi.org/10.1016/j.dld.2010.03.0131-0041-5. Yoshida M, Ohtsu A, Boku N, et al. Long-term survival and prognostic factors in patients with metastatic gastric cancers treated with chemotherapy in the Japan Clinical Oncology Group (JCOG) study. Jpn J Clin Oncol. 2004;34(11):654–9. https://doi.org/10.1093/ jjco/hyh120. Yuan G, Chen Y, He S. Family history of gastric cancer and Helicobacter pylori treatment. N Engl J Med. 2020;382 (22):2171. https://doi.org/10.1056/NEJMc2003542. Zhang Q, Wang F, Chen ZY, et al. Comparison of the diagnostic efficacy of white light endoscopy and magnifying endoscopy with narrow band imaging for early

1880 gastric cancer: a meta-analysis. Gastric Cancer. 2016;19(2):543–52. https://doi.org/10.1007/s10120015-0500-5.

List of National and Global Guidelines on Gastric Cancer Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2018 (5th edition). Gastric Cancer. 2020; https://doi.org/10.1007/s10120-020-01042-y. [Published online ahead of print, 2020 Feb 14]. Muro K, Van Cutsem E, Narita Y, et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic gastric cancer: a JSMO-ESMO initiative endorsed by CSCO, KSMO,

M. K. Mallath MOS, SSO and TOS. Ann Oncol. 2019;30(1):19–33. https://doi.org/10.1093/annonc/mdy502. National Cancer Institute. Gastric Cancer Treatment (PDQ ®)–Health Professional Version. https://www. cancer.gov/types/stomach/hp/stomach-treatment-pdq National Institute for Health and care Excellence. Oesophago-gastric cancer: assessment and management in adults. NICE guideline [NG83]. Published date: 24 January 2018. https://www.nice.org.uk/guid ance/ng83 NCCN Clinical practice guidelines in oncology (NCCN Guidelines) Gastric cancer Version 2.2020. Gastric Cancer. https://www.nccn.org/ Smyth EC, Verheij M, Allum W, et al. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(Suppl 5): v38–49. https://doi.org/10.1093/annonc/mdw350.

Gastric Tumors (Other than Adenocarcinoma)

84

C. S. Pitchumoni, Abhijeet Chaubal, and Gopal Desai

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1882 Histological Types and Their Clinical Associations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hyperplastic Polyps (HPs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fundic Gland Polyps (FGPs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gastric Adenomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1882 1883 1884 1884

Gastric Malignant Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GIST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gastric Neuroendocrine Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gastric Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Primary Gastric Lymphoma (PGL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MALT Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Primary Gastric Hodgkin’s Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Squamous Cell Carcinoma of the Stomach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1885 1885 1889 1893 1894 1896 1897 1898

Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1898 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1898

Abstract

C. S. Pitchumoni (*) Department of Medicine, Robert Wood Johnson School of Medicine, Rutgers University, New Brunswick, NJ, USA Department of Medicine, New York Medical College, Valhalla, NY, USA Division of Gastroenterology, Hepatology and Clinical Nutrition, Saint Peters University Hospital, New Brunswick, NJ, USA e-mail: [email protected] A. Chaubal Department of Anatomic Pathology, Saint Peters University Hospital, New Brunswick, NJ, USA e-mail: [email protected]

In addition to adenocarcinoma, the stomach carries the risk for many benign and some malignant tumors. There is an increase in the prevalence of these tumors as age advances. The benign tumors of importance are the neoplastic epithelial adenomas, fundic gland polyps, and the hyperplastic polyps. The malignant tumors are primary gastric lymphoma, GISTs, the neuro-endocrine carcinoids tumors, and rarely others. The majority (70–90%) of gastric epithelial polyps are incidental findings and by histology fundic gland polyps (FGPs) or hyperplastic polyps. The mean age of diagnosis is between

© Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_117

1881

1882

the ages of 65 and 75 years. Gastric adenomas (GA) may be tubular, villous, or tubulovillous, arise in the background of gastric mucosal atrophy and intestinal metaplasia, and are premalignant. A gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. GIST tumors grow from interstitial cells of Cajal (ICCs) and can be malignant or benign. GIST tumors are treated by surgery and in selected cases with the chemotherapeutic agent Imatinib. Carcinoid tumors may occur with or without hypergastrinemia. Type 1 carcinoid tumors associated with atrophic gastritis and type 2 with gastrin producing tumors arise in association with hypergastrinemia. In contrast, the more malignant type, type 3, is not associated with high gastrin levels. Primary non-Hodgkin’s lymphoma (NHL) is a relatively uncommon gastric neoplasm, accounting for about 5% of gastric malignancies. The two major histological subtypes are marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) and diffuse large B-cell lymphoma (DLBCL). Keywords

Gastric polyps · Adenoma · Hyperplastic · Fundic gland · Mixed · Gastrointestinal stromal tumor (GIST) · MALT lymphoma · Gastrin · Atrophic gastritis · ZE syndrome · PPI · Leiomyoma · Inflammatory fibroid polyp · Fibroma and fibromyoma · Lipoma · Ectopic pancreas · Neurogenic and vascular tumors · Neuroendocrine tumors (carcinoids) · KIT and PDGFRA mutations · 5-Fluorouracil or cyclophosphamide · Doxorubicin mono drug · Dacarbazine · Temozolomide · Oxaliplatin · Capecitabine · Leucovorin ·

G. Desai Department of Radiation Oncology, Saint Peters University Hospital, New Brunswick, NJ, USA e-mail: [email protected]

C. S. Pitchumoni et al.

Endoscopic full-thickness resection (EFTR) · Endoscopic submucosal dissection · Targeted medication · Imatinib

Introduction Gastric polyps are mostly incidental findings in upper endoscopy, appearing as luminal lesions projecting above the plane of the gastric mucosal surface. There are neoplastic and nonneoplastic gastric polyps (see Table 1). In routine esophagigastro-duodenoscopy (EGD), polyps are detected incidentally in 1–6% of procedures. Solely by endoscopic appearance, the histologic type cannot be reliably distinguished without biopsy (Carmack et al. 2009; Cao et al. 2012; Evans et al. 2015; Markowski et al. 2016; Argüello Viúdez et al. 2017; Castro et al. 2017; Velázquez-Dohorn et al. 2018). The non-neoplastic polyps are mostly hyperplastic, and rarely, inflammatory fibroid polyp, xanthoma/xanthelasma, hamartomatous polyp of the Peutz-Jeghers Type (Park and Lauwers 2008). The neoplastic polyps are fundic gland polyps and adenomas. Gastric neuroendocrine polyps are mainly carcinoids. The goal of this chapter is to discuss the frequently discovered gastric tumors, benign as well as malignant; the most frequent tumor, adenocarcinoma of the stomach, is discussed in another chapter in this text.

Histological Types and Their Clinical Associations The majority (70–90%) of gastric epithelial polyps by histology are fundic gland polyps (FGPs) or hyperplastic polyps. In a significant endoscopic study of 78,909 of a total 121,564 patients, the overall prevalence of gastric polyps was 6.35%; 77% were fundic gland polyps, 17% hyperplastic polyps/polypoid foveolar hyperplasia, 0.69% adenomas, and 0.1% inflammatory fibroid polyps. Malignant neoplasms were slightly over 2%. The presence of adenomas was rarely associated with synchronous adenocarcinomas (Carmack et al. 2009). See Tables 1 and 2 for a list of common benign polyps in the

84

Gastric Tumors (Other than Adenocarcinoma)

1883

Table 1 Common benign polyps (epithelial) Hyperplastic polyps More in the antrum Sessile or pedunculated Smooth or superficial erosion Background mucosa: inflammation, atrophic/chronic Fundic gland polyps More in fundus and body 80%) Sessile/flat velvety, lobulated surface Background mucosa: chronic atrophic gastritis Source: Castro et al. (2017)

Fig. 1 Gastric polyps endoscopic appearance. Endoscopic appearance is not enough to make a diagnosis of the type; a biopsy is necessary. A pedunculated adenoma

Table 2 Non-mucosal intramural polyps A gastrointestinal stromal tumor (GIST) Leiomyoma (true smooth muscle tumors are rare) Inflammatory fibroid polyp Fibroma and fibromyoma Lipoma Ectopic pancreas Neurogenic and vascular tumors Neuroendocrine tumors (carcinoids)

stomach. The polyps may have varying degrees of malignant potential (Tables 1 and 2).

Hyperplastic Polyps (HPs) Gastric hyperplastic polyps result from excessive proliferation of foveolar cells accompanied by increased exfoliation (Markowski et al. 2016). HPs are endoscopically indistinguishable from other polyps with lower or higher malignant potentials (Markowski et al. 2016). HPs occur throughout the stomach, solitary or numerous, most measure less than 1 cm. HPs are more common in older adults (mean age, 65.5–75 years with a slightly higher predisposition in H. pylori gastritis (Nam et al. 2016). The natural history of HPs is variable. The polyps occur in association with chronic atrophic

Fig. 2 Multiple antral polyps. Gastric hyperplastic polyps can be single or multiple

gastritis and intestinal metaplasia (see Figs. 1 and 2). Although mostly asymptomatic, hyperplastic polyps may present with occult gastrointestinal (GI) bleeding with anticoagulant therapy. The reported Incidence of malignant transformation ranges from 1.5% to 2.1% of gastric hyperplastic polyps (Han et al. 2009). Synchronous gastric

1884

carcinoma elsewhere in the stomach is a possibility, and careful endoscopic assessment of the entire surrounding mucosa is essential (Hattori 1985). HPs being generally benign, often require no intervention. However, a size of greater than 1 cm is a risk factor for malignant potential and should undergo endoscopic removal. Given the ease with which gastric polypectomies can be performed, some national guidelines do not want to take any chance and recommend polypectomy of all gastric hyperplastic polyps greater than 0.5–1 cm (Han et al. 2009).

C. S. Pitchumoni et al.

The association with H. pylori is controversial. H. pylori infection probably induces fundic gland atrophy (Goddard et al. 2010). Long-term PPI use is an association with sporadic FGPs. A pooled analysis of 12 studies demonstrated that PPI users are more than twice as likely to develop fundic gland polyps as non-PPI users (Martin et al. 2016). Patients who have been on long-term PPI therapy (defined as
5 years) have four-times higher prevalence for development of fundic gland polyps, and withdrawal of PPI therapy is shown to cause a reduction in FGPs (Abraham et al. 2000; Islam et al. 2013; Evans et al. 2015; Tran-Duy et al. 2016; Velázquez-Dohorn et al. 2018).

Fundic Gland Polyps (FGPs) FGPs represent polyps about 16–51% of all gastric epithelial polyps (Fig. 3). They are usually multiple, small, transparent, and sessile, often located in the gastric fundus and body (Castro et al. 2017). FGPs develop from hyperplasia of the fundic glands as well as shortened foveolae. They occur in a background of the otherwise normal gastric mucosa. Once considered rare and insignificant, for reasons not clear, the prevalence of incidental FGPs has become the dominant type currently (Abraham et al. 2000). FGPs are usually not associated with an increased risk of cancer except in patients with familial adenomatous polyposis syndrome (FAP). However, it is essential to note that FGPs occur in 12.5–84% of patients with FAP.

Fig. 3 A hyperplastic polyp

Gastric Adenomas Adenomatous polyps polyps are more common in advanced age. While FGP, hyperplastic and mixed polyps are more frequent in chronic gastritis, adenomatous polyps are more common (60%) in intestinal metaplasia (P < 0.001) (Elhanafi et al. 2015; Argüello Viúdez et al. 2017). Gastric adenomas demonstrate neoplastic progression to infiltrating adenocarcinoma and indicate a higher risk of adenocarcinoma elsewhere in the stomach. Gastric adenomas represent 6–10% of all gastric polyps in Western populations. Often solitary, gastric adenomas are frequently found in the antrum as flat or sessile elevations rather than as pedunculated polyps and ranges in size from a few millimeters to centimeters (Chandrasekhara and Ginsberg 2011). Similar to colonic polyps, the gastric adenoma may be tubular, villous, or tubulovillous. A second classification is based on phenotype, and the two types are intestinal type or gastric type (pyloric gland, foveolar and fundic gland adenomas). There is no proven association for gastric adenoma with H. pylori infection. Polyps greater than 2 cm in size or with villous histology have a higher risk of neoplasia (28–40%) (Islam et al. 2013). Since endoscopic biopsy may occasionally miss the tumor site, it is advisable to remove any polyp of
1 cm. Recurrence is rare about 2.6% after complete endoscopic excision. Endoscopic

84

Gastric Tumors (Other than Adenocarcinoma)

1885

Table 3 Gastric polyps. Recommendations At initial EGD polyps, a biopsy of all polyps is needed, and symptomatic polyps should be removed Multiple biopsies of the intervening non-polypoid gastric mucosa is essential Hyperplastic gastric polyps are strongly associated with H. pylori infection. If Helicobacter pylori are positive, it should be eradicated with triple therapy Following initial EGD and biopsies of polyps, a second endoscopy may be needed for the complete removal of all gastric polyps with dysplastic foci All gastric adenomatous polyps should be removed when safe to do so Gastroscopy should be repeated at 1 year following complete polypectomy for high-risk polyps Gastric adenomas infrequently are manifestations of FAP (in the younger population), more in Asians Source: Goddard et al. (2010) and Islam et al. (2013)

submucosal resection is a better and effective procedure to reduce recurrence. The risk of bleeding and perforation exists. A follow-up endoscopy is recommended 1 year after polyp resection, and surveillance endoscopy every 3–5 years. Gastric adenoma and gastric cancer are recognized as an extra-colonic manifestation of FAP; a rare autosomal dominantly inherited condition due to a germline mutation in the APC gene. Gastric cancer is not a prominent extra-colonic feature of FAP in the Western world. The risk in patients with FAP is higher in Asian countries and in Asian populations compared to the Western world (Walton et al. 2017). Table 3 summarizes the recommendations in managing gastric polyps (Goddard et al. 2010).

Fig. 4 High power Atrophic gastritis. Gastric mucosa with chronic inflammation, glandular atrophy, and intestinal metaplasia

Gastric Malignant Tumors Among the malignant tumors of the stomach, adenocarcinoma is discussed at length in another chapter. The more prevalent tumors are gastrointestinal stromal tumors (GISTs), primary gastric lymphoma (PGL), neuroendocrine tumors (NETs), mainly carcinoids, and primary squamous cell carcinoma are presented here.

GIST Introduction Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract (Figs. 4, 5, and 6). The term GIST is relatively new, has replaced the terms of the past, such as leiomyomas, leiomyosarcomas, and

Fig. 5 Low power Atrophic gastritis. Gastric mucosa with chronic inflammation, glandular atrophy, and intestinal metaplasia

leiomyoblastomas because of their histological similarity to smooth muscle neoplasms. Most studies demonstrate an increased risk with increasing age, with age-related Incidence

1886

reported over 30 per million per year for those >70 years of age (Søreide et al. 2016) (Figs. 7, 8, and 9). SEER data suggests the incidence is about eight cases per million per year, which is in line with several European studies (Søreide et al. 2016). Approximately 10–30% of GISTs have a malignant clinical course (Akahoshi et al. 2018). The term GIST was first used in 1983 by Mazur and Clark to characterize gastrointestinal

Fig. 6 Fundic gland polyp. Gastric polyp lined by cystically dilated glands lined by chief cells, parietal cells, and mucinous foveolar cells

Fig. 7 GIST tumor along the lesser curvature of the stomach measuring 29  30  35 mm seen on MRI of the abdomen with contrast

C. S. Pitchumoni et al.

nonepithelial neoplasms. Subsequently, in 1998, Hirota and colleagues demonstrated mutations of the KIT proto-oncogene in the vast majority of GISTs. Much knowledge has been gained. Now we know that GISTs are primarily caused by oncogenic mutations in the tyrosine kinase receptor KIT and/or platelet-derived growth factor receptor-α (PDGFR-α). Mutations in PDGFRA are involved in the development of 2–15% of the GIST tumors (Hirota et al. 1998; Miettinen et al. 2002). GIST has been viewed as a rare, enigmatic, and unpredictable tumor capable of aggressive behavior (Nilsson et al. 2005). Epidemiology. The prevalence of GISTs is variable, autopsy studies showing a higher number. In a series of consecutive autopsies performed in Germany, where small GISTs (1–10 mm) were grossly detectable in 22.5% of the autopsies, older than 50 years (Agaimy et al. 2007). The abovenoted prevalence does not include the so-called mini GISTs. Subclinical microscopic (50% of autopsy studies in >50 age group Equal in men and women Affects all groups equally No predisposing factors have been described Esophagus 5% Stomach 50–70% Small intestine 25–40% (ileum > jejunum > duodenum) Colon 10%

et al. 2010). GIST of the stomach is considered to be a potentially malignant tumor. GISTs are not classified as either benign or malignant. Still, they are stratified by their clinical risk of malignancy: very low, low, intermediate, or high (Joensuu 2008; Akahoshi et al. 2018). The pathogenesis of GISTs is attributed to genes controlling tyrosine kinase expression undergoing mutation leading to neoplastic growth involving cells from the lineage of the interstitial cells of Cajal (Blay et al. 2005; Joensuu 2006). SEER (Surveillance, Epidemiology, and End Results) data from the National Cancer Institute in the mid-1990s indicated that sarcomas account for 2.2% of gastric cancer (Tran et al. 2005; Søreide et al. 2016). See Table 4 for the epidemiology of GIST. The total number of GIST cases diagnosed each year in the United States range from about 4000 to about 6000. Asymptomatic GISTs of low malignancy potential may be more common than diagnosed in older adults (Joensuu 2006). Many recent developments in driver mutations (Mutations that provide a selective growth advantage, and thus promote cancer development, others are termed passenger mutations) in the KIT or PDGFRA (platelet-derived growth factor receptor alpha) gene have to lead to molecularly targeted therapy based on molecular mechanisms of tumor cell proliferation.

1888

There are three main histological patterns of GISTs: spindle cell type (70%), epithelioid cell type (20%), and mixed type (10%) (Nishida et al. 2016). GIST can be associated with other neoplastic syndromes such as the Von Recklinghausen’s disease (Neurofibromatosis 1 (NF1), a genetic disorder characterized by the development of multiple neurofibromas and Café au lait pigmentation), the Carney triad (gastric GIST, lung chondroma, and paraganglioma), and Familial GIST. For malignant GISTs, the lymphatic spread is infrequent, and these lesions most commonly spread hematogenously (most commonly to the liver) or to the peritoneum. Severity varies from benign asymptomatic incidental neoplasms to aggressive sarcomas (20–35%). Clinical Manifestations. Nearly 15–30% of patients with GISTs are asymptomatic. Of the symptomatic GIST tumors, most present with nonspecific symptoms of abdominal pain, distension, and discomfort due to a tumor-induced mass effect. Chronic anemia, weakness, melena, and hematemesis are other manifestations. Diagnosis. There is no definitive history or physical examination findings that will suggest a GIST tumor. The initial diagnosis is mostly incidental detection by an imaging study or upper endoscopy to evaluate a patient with abdominal symptoms, GI bleeding, or anemia. The diagnosis is by imaging studies, endoscopy, EUS, biopsy, and resection. Immunohistochemical analysis including assessment of KIT, CD34, and discovered on gastrointestinal stromal tumor 1 DOG1, a recently described protein expressed in GISTs irrespective of mutation status. The endoscopic mucosal biopsy is often inconclusive because of the submucosal location (Nishida et al. 2016; Akahoshi et al. 2018; Wu et al. 2019). A contrast-enhanced CT scan is the imaging modality of choice for patients with suspected abdominal mass or biopsy-proven GIST. Other imaging studies, such as magnetic resonance imaging (MRI) and fluorine-18fluorodeoxyglucose (FDG) positron emission tomography (PET), are acceptable. EUS findings show a hypoechoic solid mass. The possible high-risk features for malignancy are the size of >2 cm, irregular borders,

C. S. Pitchumoni et al.

heterogeneous echo patterns, anechoic spaces, echogenic foci, and growth during follow-up (Akahoshi et al. 2018). The EUS based, “jumbo” or “bite-on-bite” biopsy for immunohistochemical analysis is required for a definite diagnosis before surgery or chemotherapy. In addition to standard histology, immunohistochemistry is needed. KIT (CD117) immunohistochemistry is a reliable diagnostic tool. Approximately 95% of GISTs stain positive for KIT.

Management Options A team approach of surgical and medical oncologists, pathologists, gastroenterologists, and radiologists is required to provide optimal treatment for GIST patients. Clinical guidelines from different professional societies are summarized here (Demetri et al. 2004; Joensuu et al. 2013; Rossi et al. 2013; Nishida et al. 2016; Derbel et al. 2017). The principles of treatment of stomach GISTs are (1) surgical resection, intending to achieve R0 resection (R0 corresponds to resection for cure or complete remission) in GISTs without metastasis and (2) administration of tyrosine kinase inhibitors such as Imatinib for the unresectable, metastatic, or recurrent GISTs (ESMO/European Sarcoma Network Working Group 2014; Akahoshi et al. 2018). Endoscopic techniques for removal of small GIST tumors are available in tertiary care centers. The outcome for GIST has dramatically improved since the approval by the FDA of imatinib mesylate in 2002. Imatinib is a kinase inhibitor marketed as Gleevec (USA) or Glivec (Europe/Australia). For unresectable and metastatic disease, the panelists of the Consensus meeting recommend immediate treatment with Imatinib. The evidence from a randomized phase III, a placebo-controlled, multicenter trial showed that 400 mg of imatinib mesylate/day for 1 year significantly improved recurrence-free survival. Many societies recommend Imatinib as the standard treatment for metastatic, recurrent, or unresectable GIST 9 (DeMatteo et al. 2009; Joensuu et al. 2012). According to ESMO, Imatinib is the standard treatment for locally advanced inoperable and metastatic disease and patients previously treated with adjuvant imatinib who did not relapse while receiving it (Casali et al. 2018).

84

Gastric Tumors (Other than Adenocarcinoma)

Gastric Neuroendocrine Tumors Introduction Neuroendocrine tumors arise from enterochromaffin-like cells (ECL) . Neuroendocrine cells in the brain and gut have a common embryological origin; they are widely distributed in various sites and organ systems. These cells produce peptide hormones and the ability to synthesize amines from specific precursors, which gave rise to the concept known as Amine Precursor Uptake and Decarboxylation, and were referred to as APUD cells until recently. And the tumors that arose from these cells were classified as APUDomas, currently referred to as neuroendocrine tumors (Hanson 2001). ECL cells are a specialized type of neuroendocrine cell in the gastric mucosa, most prevalent in the acid-secreting regions of the stomach, underlying the epithelium. The ECL cells play a significant role in the regulation of acid secretion. The intake of food stimulates the G cells of the antrum. The hormone gastrin is secreted, stimulating the ECL cells. The ECL cells produce histamine, a paracrine stimulant to promote the secretion of hydrochloric acid (HCL) by the parietal cells and peptides such as chromogranins. “Gastric

Fig. 10 Gastric carcinoid sometimes present as polypoid lesions and are very hard to see on a CT scan unless there are of a large size. However, there are seen on double contrast barium studies

1889

carcinoids” formally named “gastric neuroendocrine neoplasms” or tumors (gNETS) are neoplasms derived from the enterochromaffin-like cells (ECL cells) of the gastric mucosa. The term “karzinoide” was coined in 1907. The original term carcinoid tumor was discarded in the most recent (2010) World Health Organization classification of tumors in favor of neuroendocrine tumor (Nikou and Angelopoulos 2012; Rindi et al. 2018) (Figs. 10, 11, 12, and 13). The GC is grouped as type I (related to autoimmune gastritis) and type II (related to gastrinoma) and types III gastric carcinoids, the non–gastrin-related lesions that are highly malignant (Table 5). Epidemiology. Carcinoids are increasingly recognized at endoscopy, accounting for 0.6–2% of all gastric polyps (Castro et al. 2017). Carcinoid tumors Carcinoids are relatively uncommon neoplasms, occurring in 1.9/100,000 persons annually worldwide. Gastric neuroendocrine tumors comprised less than 2% of gastric polypoid lesions (Solcia et al. 2010). We prefer to use the term GCs because of its popularity among clinicians. Gastric carcinoids (GC) are slowgrowing tumors of the neuroendocrine system. The Incidence of gastric carcinoids may have increased over the last 50 years. Most carcinoids

1890

C. S. Pitchumoni et al.

Fig. 11 High grade carcinoid of the antrum of the stomach seen on CT scan of the abdomen

Fig. 12 Gastric carcinoids neuroendocrine tumor. Welldifferentiated tumor with uniform small bland tumor cells growing in a glandular and insular pattern

are currently diagnosed at an earlier stage, and the prognosis has dramatically improved (Modlin et al. 2004). In Canada, the incidence is noted to increase from 2 per million in 1964 to 22 per million in 2002. It is a speculation that the advent and increasing use of proton pump inhibitors is a major contributory factor to that increased Incidence (Maroun et al. 2006; Yao et al. 2008). Many other reports observe the same trend (Kaltsas et al. 2004, 2014; Grozinsky-Glasberg et al. 2018).

Clinical Features. There are three subtypes of GCs, each one with a distinct pathophysiologic mechanism, clinical outcomes, and different management options (Nikou and Angelopoulos 2012). Type 1 and 2 are associated with hypergastrinemia. Type 3 is not related to high gastrin levels (Grozinsky-Glasberg et al. 2018) (see Table 1). Type 1–3 are ECL cell carcinoids, and type 4 other endocrine cell tumors, e.g., serotonin, gastrin, adrenocorticotrophic hormone (ACTH) secreting tumors. Types 3 and 4 are solitary, larger, and highly malignant (Borch et al. 2005). In type 1, the most frequent one there is hypergastrinemia secondary to atrophy of parietal cells, decrease in gastric acid and intrinsic factor production, and secondary hypergastrinemia because of preserved antral mucosa. Approximately 70– 80% of the total GCs are associated with autoimmune chronic atrophic gastritis, including pernicious anemia, parietal cell atrophy results in achlorhydria, and intrinsic factor deficiency. Only a minority of patients with autoimmune chronic atrophic gastritis, achlorhydria, and hypergastrinemia develop gastric carcinoid tumors. Perhaps other factors, in addition to gastrin, are required for tumor development (Nikou and Angelopoulos 2012). The normal physiologic

84

Gastric Tumors (Other than Adenocarcinoma)

1891

Fig. 13 (a, b) Gastric carcinoids neuroendocrine tumor. Well-differentiated tumor with uniform small bland tumor cells growing in a glandular and insular pattern. Positive Chromogranin immuno-stain

Table 5 Classification and features of gastric carcinoids (gNETs) Features Epidemiology

Type 1 gNET 50–70 years 70–85%

Association

Pernicious anemia, atrophic gastritis of fundus persistent achlorhydria, G cells in the gastric antrum undergo hyperplasia and secrete more gastrin resulting in hypergastrinemia

Laboratory Serum gastrin Gastric acid Endoscopic findings Size and number Location of carcinoids Tendency for Mets Prognosis

High Decreased Atrophic mucosa 6), recurrent several lesions (>1 cm), and atypical pathology (Ki-67 >2%) are indications for resection. Type 1 carcinoid has a benign clinical course. The best operation for type I gNETs is controversial. Antrectomy to remove the gastrin-producing G cells is used in patients with multifocal (>6 lesions, 3–4 lesions >1 cm, or 1 lesion >2 cm), invasive, or recurrent disease (Dias et al. 2017). Antrectomy induces the regression of the tumors in a majority of patients with ECL hyperplastic

1893

lesions. Long-acting somatostatin analogs (SSAs) inhibit gastrin secretion from G cells and have a direct effect on the ECL cells (Gladdy et al. 2009; Grozinsky-Glasberg et al. 2018). In type II gNETs localizing and resecting the gastrinoma is the recommendation. Endoscopic resection is enough for gastric lesions unless there is an indication for poor prognosis (Dias et al. 2017). Type 3 lesions should be managed aggressively with total or subtotal gastrectomy (depending on location) associated with lymphadenectomy. Systemic therapy with cytotoxic chemotherapy (streptozocin combined with 5-fluorouracil or cyclophosphamide, doxorubicin mono drug or with 5-fluorouracil, dacarbazine or temozolomide, oxaliplatin with capecitabine or 5-fluorouracil with leucovorin) or molecular targeted agents (bevacizumab, sorafenib, sunitinib, pazopanib, and everolimus) (Dias et al. 2017) are available. Other options are arterial embolization or radio ablation.

Gastric Lymphoma Introduction The most common extranodal site of nonHodgkins lymphoma (NHL) in the stomach, representing between 30% and 40% of all extranodal lymphomas, a relatively uncommon gastric neoplasm (Al-Akwaa et al. 2004; Wang et al. 2016; Juárez-Salcedo et al. 2018; Miranda-Filho et al. 2019). Primary gastric NHL accounts for about 5% of gastric malignancies. Diffuse large B-cell lymphoma and MALT lymphoma account for approximately 60% and 40% of all gastric lymphomas, respectively (Ferrucci and Zucca 2007). The two major histological subtypes of primary gastric lymphoma (PGL) are marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) and diffuse large B-cell lymphoma (DLBCL); both are from B lymphocytes in origin (Park and Koo 2014). PGL is a disease of older adults; the median age of onset is 60–65 years; males are two to three times more affected than females (Table 6). The other two rare types are follicular and mantle cell lymphomas. While MALT lymphomas are low-grade lesions,

1894

DLBCL gastric lymphomas are high-grade lesions (Figs. 14, 15, 16, 17, and 18).

Primary Gastric Lymphoma (PGL) The stomach is the most frequent site for extranodal lymphoma (ENL). Epidemiology. PGL is a rare tumor, with an incidence of 4–20% of NHL and approximately 5% of primary gastric neoplasms. PGL represents only 5% of gastric neoplasms (Juárez-Salcedo et al. 2018). PGL is mostly a disease of the older adult, two to three times more in men than women. Histopathologically, Table 6 Predisposing factors that increase the risk for NHL Older age Obesity Immunosuppression Radiation exposure Autoimmune disorders Infection with a human T-cell lymphotropic virus (HTLV-1) Epstein-Barr virus (EBV) Human herpesvirus 8 (HHV-8) Helicobacter pylori (in particular the MALT-type)

Fig. 14 Thickening of gastric folds along the greater curvature of the stomach consistent with MALT lymphoma seen on a CT of the abdomen

C. S. Pitchumoni et al.

nearly 90% are of the B cell type, including MALT lymphoma. Less than 2% are mantle lymphoma, follicular lymphoma, and T-cell lymphoma. Several speculations and observations of interest are made in light of the etiological association between H. pylori and gastric MALT lymphoma and DLBCL. With efforts in diagnosing and eradicating H. pylori in the last four decades and considerable overall improvements in the public health factors contributing to H. pylori infection in any society, the incidences of gastric MALT lymphoma and DLBCL are logically expected to decrease (Chang et al. 2019). Many European and US studies show a decrease. Based on data from the 18 US Surveillance, Epidemiology, and End Results, Khalil and colleagues reported that the Incidence of gastric marginal zone lymphoma has decreased (Khalil et al. 2014). Clinical Features. The symptoms are usually non-specific. Weight loss, nausea, vomiting, abdominal fullness, and indigestion at onset may resemble the picture of peptic ulcer disease, chronic pancreatitis, pancreatic cancer, or IBS. Less frequent symptoms include those of gastric obstruction and perforation, weakness, night sweats, jaundice and dysphagia (Juárez-Salcedo et al. 2018).

84

Gastric Tumors (Other than Adenocarcinoma)

Fig. 15 Low power Gastric MALToma. Gastric mucosa with infiltrate of heterogeneous B-cells including marginal zone (centrocyte-like) cells, monocytoid cells, small lymphocytes, and plasmacytoid cells

Fig. 16 High power Gastric MALToma. Gastric mucosa with infiltrate of heterogeneous B-cells including marginal zone (centrocyte-like) cells, monocytoid cells, small lymphocytes, and plasmacytoid cells

Fig. 17 Gastric large cell lymphoma endoscopic picture

1895

Upper gastrointestinal bleeding manifests in 20% of cases. The physical examination is inconclusive. Rarely, fever, hepatomegaly, splenomegaly, and lymphadenopathy are features. In some cases, physical examination findings include epigastric tenderness, adenopathy, and palpable epigastric masses (Muller et al. 1995). Pathogenesis. H. pylori, a class 1 carcinogen, according to WHO, plays a role in the pathology of DLBCL gastric lymphomas in addition to gastric carcinomas. The chronic inflammation of gastric mucosa by H. pylori infection induces lymphomagenesis (Ishikura et al. 2019). An international workgroup has renewed the classification of PGL; a modified Lugano staging has now been accepted as the standard in patients with PGL. The Lugano staging classification is the lymphoma staging system that is most commonly used in clinical practice currently (Cheson et al. 2014; Juárez-Salcedo et al. 2018). Diagnosis. A clinical diagnosis is not easy because of nonspecific symptoms. Esophagogastroduodenoscopy (EGD) and target biopsies are primary methods for diagnosis. The endoscopic findings are nonspecific and include mucosal edema, friability, patchy redness, irregular patchy gray or whitish granularity, contact bleeding, superficial irregular erosions, and ulcerations. Initial biopsies may miss the diagnosis, and repeat endoscopy and biopsies may be needed (Stolte 1992). In addition to histological examination, immunohistochemical and genotyping studies are useful. EUS examination, following EGD, is necessary to assess the extent and the depth of lymphomatous infiltration, the presence of perigastric lymph nodes, staging the disease and planning therapy. EUS differentiates lymphomas from carcinomas in the early stages. The abdominal sonographic examination has limited value. Sonographic identification of gastrointestinal involvement as well as enlarged abdominal lymph nodes aid in lymphoma staging. The findings in CT scan of the abdomen are gastric wall thickening or mass lesions seen in 85% of cases. CT findings may also help to differentiate lymphoma from adenocarcinoma and in the detection of lymphadenopathy (Table 7). MRI shows

1896

C. S. Pitchumoni et al.

Fig. 18 (a–c) Large cell lymphoma

Table 7 Staging of primary gastrointestinal (GI) lymphoma Stage I II

IIE IV

Extent of lymphoma Confined to the GI tract (single primary or multiple noncontiguous lesions) Extending into the abdomen from primary GI site II1 ¼ local nodal involvement, II2 ¼ distant nodal involvement Penetration of serosa to involve adjacent organ or tissues. Specify site of involvement Disseminated extranodal involvement or concomitant supradiaphragmatic nodal involvement

Source: Rohatiner et al. (1994)

the same findings as CT. Many advanced radiological studies such as 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in primary gastric lymphoma

(PGL) are being evaluated (Ren et al. 2020). The Lugano international conference classification] or the modified Ann Arbor staging system (Ruskoné-Fourmestraux et al. 2011; Cheson et al. 2014) are the two staging systems.

MALT Lymphoma The normal gastric mucosa contains very few lymphocytes in the lamina propria. However, following an inflammatory process by H. pylori, lymphatic follicles develop (in 27.4% and 100%) in gastric mucosa, configuring the so-called MALT (Isaacson 2005). Epidemiology. The development of MALT in gastric mucosa may be a sign of H. pylori infection. It is unclear why the very high prevalence of

84

Gastric Tumors (Other than Adenocarcinoma)

H. pylori in the world MALT lymphoma is a rare disease. Virulent factors of H. pylori seem to play a marginal role in the pathogenesis of gastric lymphoma. Genetic factors, a familial background of NHL, and other environmental influences are additional factors postulated (Parsonnet et al. 1994; Violeta Filip et al. 2018). Approximately, 10% of gastric MALT lymphomas occur independently of H. pylori infection (Asano et al. 2015). Pathology. Histologically MALT lymphoma is characterized by a dense lymphoid infiltration that invades and destroys gastric glands and results in the so-called lymphoepithelial lesion pathognomonic for lymphoma. Although MALT lymphoma is a low-grade lesion, it can transform into a high-grade lymphoma (Zullo et al. 2014; Thieblemont and Zucca 2017). The disease has a multifocal location in the stomach and the rest of the GI tract explaining the high rate of relapse after surgical excision. MALT lymphoma remains localized for a prolonged period within the tissue of origin, but the involvement of regional lymph nodes may occur. Localized MALT lymphoma is often multifocal within the stomach, and it may not reflect a disseminated disease (Thieblemont and Zucca 2017). Clinical presentation may vary from mild symptoms such as nausea, vomiting, dyspepsia, and epigastric pain to massive hemorrhage, chronic gastric bleeding with iron-deficiency anemia, pyloric stenosis, and weight loss. In rare cases, fever or night sweats can be present (typical manifestation of B-cell lymphoma). Massive infiltration of the gastric wall may lead to perforation. Gastric MALT lymphoma can involve any part of the stomach. The antrum is affected more often. Diagnosis. The diagnosis is by endoscopy and multiple biopsies. The endoscopic ultrasound (EUS) helps assess the depth of invasion into the different layers of the gastric wall, the regional lymph nodes involvement, and is predictive of remission following therapy. Management. According to the new MALT lymphoma prognostic index (MALT-IPI) published in 2017 (Thieblemont 2005), age >70 years, elevated LDH, and Ann Arbor stage III or IV are the most important adverse prognostic factors, with poor outcomes.

1897

H. pylori eradication can cure gastric MALT lymphoma and very rarely even DLBCL but not adenocarcinoma (Kuo et al. 2012; Shen et al. 2013; Zullo et al. 2014). H. pylori eradication is the first-line of therapy for early-stage (I–II1 according to the modified Ann Arbor classification), low-grade, MALT lymphoma; that is when the neoplasia is confined in the stomach or perigastric lymph nodes (Zullo et al. 2014). A highdose dual or 7–14 days triple therapies cured H. pylori infection in 91% of cases. Increasing antibiotic resistance in the communities is a concern, and more effective first-line regimens – such as sequential or concomitant therapy is suggested, also used in gastric lymphoma patients (Zullo et al. 2010; de Francesco et al. 2012). H. pylori is a risk factor for both gastric adenocarcinoma and lymphoma (MALT lymphoma and DLBCL). However, the guidelines for the treatment of patients with gastric MALT lymphoma beyond H. pyloric eradication or with the extensive disease is not uniform. Radiotherapy, chemotherapy with oral alkylating agents (either cyclophosphamide or chlorambucil) or purine nucleoside analogs (fludarabine, cladribine), rituximab or a combination of rituximab plus chlorambucil. Aggressive anthracycline-containing chemotherapy is an option; details are beyond the scope of this chapter (Colucci et al. 1992).

Primary Gastric Hodgkin’s Lymphoma Primary Hodgkin’s lymphoma of the GI tract is a clinical curiosity, the incidence being 150), low-volume ascites,

tumor in body of the pancreas, tumor size >3 cm, borderline resectable tumor, and common bile duct lymphadenopathy. Staging laparoscopy is shown to reduce the nontherapeutic laparotomy rate and identifies patients for neoadjuvant protocols.

Management The diagnostic and therapeutic approach to a patient with PC (Orth et al. 2019) is described in Fig. 3. A discussion of each element follows.

1910

S. T. Chari et al.

Diagnosis

Imaging

Tumor Markers

Contrast-enhanced multi-detector computed tomography with an arterial and a venous phase remains the cornerstone for diagnosis and staging of PC. The sensitivity of the “pancreas protocol CT” for diagnosis is approximately 85% (Costache et al. 2017). PC typically appears as a hypoattenuating mass in the pancreas (Fig. 2). In patients with biliary obstruction, the “double duct sign” with a dilated pancreatic and common bile duct may be seen (Fig. 2). CT is almost 100% sensitive in predicting unresectability. The criteria for resectability of PC are listed in Table 2. Alternative imaging modalities including ultrasound, magnetic resonance cholangiopancreatography (MRCP), and PET scan are of limited utility in the absence of a contraindication to a pancreas protocol CT scan. PET scan is utilized for assessing response to chemotherapy and to differentiate tumor recurrence from postoperative changes following resection.

Although several tumor markers are elevated in PC, CA19-9 is the only one with clinical utility as an adjunct in diagnosis (Goonetilleke and Siriwardena 2007) (Fig. 4). Its utility in prognosis and following response to therapy is controversial. Several studies approve estimating serum CA19-9 as a complementary test but does not recommended the test for diagnosing early PC (Ge et al. 2017). The sensitivity and specificity of CA19-9 varies with the threshold value used. A systematic review of literature on using CA19-9 in the diagnosis of PC yielded a median sensitivity of 79% (70–90%) and a median specificity of 82% (68– 91%) (Goonetilleke and Siriwardena 2007). Furthermore, the sensitivity of CA19-9 in detecting early-stage PC is lower than advanced disease. The test has other pitfalls. Patients with jaundice (even due to benign biliary tract obstruction), renal failure, autoimmune disease, and hypothyroidism may have elevated CA19-9 levels resulting in false-positive results (Pavai and Yap 2003). Further, 5–10% of the population does not express Lewis antigens, accounting for falsenegative results in this group (Wu et al. 2013). Fig. 4 Pancreas protocol CT scan showing a hypoattenuating mass (black arrow) in the pancreatic head, a dilated pancreatic duct (white arrow), and a dilated bile duct (gray arrow). (Reproduced from prior edition: Aggarwal and Chari 2012)

Endoscopic Ultrasound (EUS) EUS is the most accurate test for diagnosis and detection of vascular involvement from PC (higher sensitivity and specificity than CT)

85

Pancreatic Cancer

1911

(Bhutani et al. 2016). In addition, EUS has the advantage of the ability to perform fine needle aspiration (FNA) of the tumor for cytology. Improved technology in EUS has made it possible to obtain high-resolution images of the pancreas, including contrast-enhanced EUS (CE-EUS), EUS elastography, and EUS-guided fine needle aspiration (EUS-FNA). EUS plays an important role in the clinical evaluation of even small cancers, the differential diagnosis of pancreatic solid or cystic lesions, and the staging of PCs (Kitano et al. 2019). The sensitivities and specificities of EUS-FNA are high in the range of 85–92% and 96–98% as per recent meta-analysis (Hewitt et al. 2012; Banafea et al. 2016). The relative disadvantages with EUS are its operator dependence, cost, and the inability to detect distant metastases.

Table 3 Criteria for resectability of PC (all three must be absent for the cancer to be considered resectable)

Treatment

Chemotherapy and Radiotherapy

Curative treatment of PC is surgical resection which is combined with neoadjuvant or adjuvant chemotherapy and radiation therapy. Only approximately 20% of patients with pancreatic adenocarcinoma irrespective of age are diagnosed at a resectable stage. This is primarily attributable to the advanced stage at diagnosis and the poor performance status of the individuals at diagnosis. Although PC has a poor prognosis in any age group, in the older adults, age-related comorbid conditions and other factors influence the outcome.

This aspect of management is multimodal and clearly underutilized in the elderly (Parmar et al. 2014). Studies show that only 11% of older patients with locoregional disease received chemotherapy. In addition, over half of older patients with potentially treatable PC did not receive any treatment at all. While traditionally, surgical resection followed by adjuvant chemotherapy was the standard approach to management at most centers, today chemoradiation prior to surgery (neoadjuvant therapy) is increasingly gaining acceptance as the best approach to treatment of PC. However, majority of patients have metastatic or advanced disease and cannot avail this option. In those presenting with poor performance, no treatment may be tolerated. In those with advanced disease and good performance status, systemic chemotherapy is the first line of treatment. This encompasses nucleoside analogues, including gemcitabine and capecitabine, or pyrimidine analogue, 5 fluorouracil (5-FU) (Werner et al. 2013). Multi-agent combination of folinic acid, 5-FU, irinotecan, and oxaliplatin (FOLFIRINOX) has been reported to nearly double median survival as compared to gemcitabine (Conroy et al. 2011). Although these regimens come with high

Surgery Surgical resection is the only potentially curative treatment for PC. Unfortunately, only 15–20% of patients are suitable candidates for surgery (Higuera et al. 2016; Nakamura et al. 2017). In the United States, surgery is underutilized for the treatment of PC especially for patients over 65 years. The standard surgical procedure is a pancreaticoduodenectomy or Whipple procedure. Other procedures performed include distal pancreatectomy, total pancreatectomy, and pylorus-preserving pancreaticoduodenectomy. The traditional criteria for resectability are

1. Distant metastasis (e.g., liver, peritoneum, others) 2. Arterial involvement (celiac axis, superior mesenteric artery, hepatic artery, or aorta) 3. Occlusion of the portal vein or superior mesenteric vein Information from Callery et al. (2009)

described in Table 3. With advances in surgical techniques, the overall mortality rates for the procedure are less than 3% in centers with experience (Khorana et al. 2016). In individuals 65–69 years of age, the overall post-procedure mortality is 7% and rises to 11.5% in the octogenarian population. The surgical results may become more favorable in the future.

1912

toxicities that prevent their use in older patients, recent studies show improved survival in elderly patients with chemotherapy (Xie et al. 2020). Stereotactic body radiation therapy is a recent advancement in therapy for unresectable PC patients. It is well tolerated and provides excellent local control in the elderly age group. Interestingly, it is not associated with acute or late grade 3 toxicities and provides effective symptoms relief especially abdominal and back pain (Venkatesulu et al. 2018). Currently, the role of immunotherapy is being evaluated with vaccines, antibody targets, immune checkpoint inhibitors, CAR-T cells, and adoptive T-cell transfer (Amin et al. 2020).

S. T. Chari et al.

Venous thrombosis is a well-established complication of PC and almost fourfold higher than other malignancies. It warrants the use of low molecular weight heparin as prophylaxis but is contraindicated in thrombocytopenia (200 pmol/L establish the diagnosis (Grant 2005) • Hypokalemia is a feature due to insulinrelated cellular shifts (Wolf et al. 2015) • Laparoscopic enucleation is the procedure of choice • Diazoxide is highly effective and should be considered for all patients not cured by surgery, or unsuitable for surgical treatment (Gill et al. 1997) • Blind distal pancreatectomy for occult insulinoma should not be performed (Hirshberg et al. 2002)

Characteristics of Gastrinoma

• Second most common GI tract NET after insulinoma • Long delay before presentation/diagnosis (mean delay around 5 years) (Roy et al. 2000; Gibril and Jensen 2004) • 50–60% tumors are malignant at the time of diagnosis • 90% gastrinomas are seen in “gastrinoma triangle” (see Fig. 3) • 25% of gastrinomas are associated with MEN-1 syndrome (Yang and Chu 2015) • Prominent gastric body folds noted on endoscopy may be a clue for diagnosis (Roy et al. 2000) • Chronic PPI use may cause hypergastrinemia similar to that of ZES (Gibril and Jensen 2004; Jensen et al. 2006)

1937

• Fasting gastrin >1000 pg/mL (increased tenfold) and fasting gastric pH
2.0 favors ZES (Roy et al. 2000) • Duodenotomy is an essential part of surgical treatment (Akerstrom and Hellman 2007)

Characteristics of Nonfunctioning Tumors

• >60% are malignant at the time of diagnosis • Aggressive surgical approach warranted even in presence of metastasis (Akerstrom and Hellman 2007; Fendrich et al. 2009)

WHO Clinico-pathologic Classification of Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) A recent standard World Health Organization classification and grading system has been proposed for GEP-NETs. The new system facilitates the comparison and evaluation of clinical, pathologic, and prognostic features and the results of treatment in GEP- NETs from different studies. The WHO classification is based on histopathologic criteria (size, invasion, number of mitoses, Ki67 index, etc.) irrespective of the site of origin and is used to predict a tumor’s biological behavior (benign, malignant) with high probability (Kloppel et al. 2004) (Table 2). Tumors are classified as “well differentiated with benign” or “uncertain” behavior G1, “well differentiated with low-grade malignant” G2, or “poorly differentiated with high-grade malignant behavior” G3. Only the well-differentiated NETs (G1) are classified as carcinoid tumors. Neuroendocrine carcinoma (NEC) refers to all poorly differentiated G3 NETs. Well-differentiated NETs show a solid, trabecular, gyriform, or glandular pattern, with

1938

fairly uniform nuclei, salt-and-pepper chromatin, and finely granular cytoplasm. Poorly differentiated NECs resemble small cell carcinoma or large cell neuroendocrine carcinoma of the lung. The optimal criteria to separate low-grade (G1) from intermediate-grade well-differentiated (G2) tumors are yet to be defined. Poorly differentiated neuroendocrine carcinomas (G3) are often associated with a rapid clinical course, while well-differentiated NETs of the digestive system generally have a much better prognosis. However, welldifferentiated tumors are not a homogeneous group, and there is a spectrum of aggressiveness (Kloppel et al. 2004) (Fig. 2).

T. Muniraj and H. R. Aslanian

Fig. 2 Neuroendocrine tumor in head of pancreas. (Adapted with permission from O’Grady and Conlon 2008)

Staging The American Joint Committee on Cancer (AJCC) and European Neuroendocrine Tumor Society (ENETS) and several other organizations such as the Union for International Cancer Control (UICC) (Liszka et al. 2011; Rindi et al. 2006) have proposed staging systems for pancreatic neuroendocrine tumors using TNM (tumor status-nodal status-metastatic status) notation (Edge and Compton 2010). The ENETS system includes the tumor diameter in the assessment of T stage, and the AJCC system includes factors which determine tumor resectability. Both systems have been validated and are similar in defining stage IV disease. The WHO classification is complemented by GEP-NET specific TNM staging which improves prognostic and treatment stratification (Schott et al. 2011). Ito et al. from Harvard Medical School showed that the WHO classification with TNM staging is very useful for prognostic stratification among patients with PNETs (Ito et al. 2010). The modified ENETS-TNM system predicts survival based on the stage of the disease. The 5year survival is almost 100% for stage I disease (tumors 4 cm but still restricted to the pancreas), 65% for stage III disease (tumors invading adjacent structures or with positive lymph nodes), and 35% for stage IV (metastatic) disease (Scarpa et al. 2010).

90%

10%

Fig. 3 Gastrinoma triangle – Junction of the pancreatic body and neck, the junction of the 2nd and 3rd portion of the duodenum and the junction of the cystic duct and common bile duct. (Adapted with permission from O’Grady and Conlon 2008)

The overall average 5-year survival rate for patients with pancreatic neuroendocrine tumors is 42%, ranging from 15% to 61% (American Cancer Society 2012). One population-based study found the average life expectancy after diagnosis of metastatic pancreatic neuroendocrine tumor to be 23 months (Yao et al. 2007) (Table 3). The prognostic significance of both TNM stage and WHO classification in luminal GI tract and PNETs is validated by several studies (Strosberg et al. 2009; Strosberg et al. 2011a; Pape et al. 2008). In one series of 425 patients with a PNET, using WHO classification, the 5-year

87

Pancreatic Neuroendocrine Tumors

1939

Table 2 WHO classification of neuroendocrine tumors 2010: Histological grading (Bosman et al. 2010) No. of Proliferation index % Histological type Mitoses (Ki-67) Necrosis 1. Well differentiated NET Grade 1 (G1) (Carcinoid) 2/10 hpf 20/10 hpf >20 Present cell type) 4. Mixed adeno-neuroendocrine carcinoma (MANEC) – Recognized as both adeno- and neuroendocrine carcinoma. Each component exceeds at least 30% of all the neoplastic cells 5. Hyperplastic and pre-neoplastic lesions – MANECs with 2 cm tumor limited to the pancreas T3 Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery T4 Tumor involves the celiac axis or the superior mesenteric artery Regional lymph nodes (N) Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis Distant metastasis (M) M0 No distant metastasis M1 Distant metastasis Anatomic stage/prognostic groups Stage 0 Tis N0 M0 Stage IA T1 N0 M0 Stage IB T2 N0 M0 Stage IIA T3 N0 M0 Stage IIB T1 N1 M0 T2 N1 M0 T3 N1 M0 Stage III T4 Any N M0 Stage IV Any T Any N M1

survival rates for low-, intermediate-, and highgrade tumors were 75%, 62%, and 7%, respectively (Strosberg et al. 2011a). Using the AJCC TNM classification, 5-year overall survival rates for stage I, II, III, and IV tumors were 92%, 84%, 81%, and 57%, respectively. The SEER program database also uses a “localized,” “regional,” and “distant” system to stage disease, but both WHO and AJCC classification systems reflect the widespread recognition that NETs should be staged

using TNM criteria (Bosman et al. 2010; Klimstra et al. 2010).

Prognostic Factors in PNETs Patients with PNETs other than insulinomas and carcinoids have a poorer prognosis. The presence of liver metastases is the single most important prognostic factor for PNETs. The size of the

1940

primary tumor is particularly important in development of liver metastases. Other significant prognostic factors for the development of metastasis include lymph node involvement, depth of invasion, rapidity of growth, various histologic features (see Table 4), presence of necrosis, elevated serum alkaline phosphatase levels, older age and advancedstages in WHO, and TNM classification systems. With PNETs, a worse prognosis is associated with female sex, absence of MEN1, higher levels of tumor markers including gastrin and chromogranin A, and certain molecular features as listed in Table 4 (Jameson et al. 2012).

Tumor Markers Tumor markers have been found to be useful for diagnosis/prognosis, especially with nonfunctional PNETs. Plasma chromogranin A (increased in 88–100%) is the most widely used. Other markers include plasma neuron-specific enolase (increased in 83–100%), pancreatic polypeptide (PP), pancreastatin, and α or β subunits of human chorionic gonadotropin (increased in

T. Muniraj and H. R. Aslanian

25–40%) (de Herder 2007). Chromogranin A has an overall diagnostic sensitivity of less than 50% in patients with localized/early disease; however, sensitivity increases to 60–100% in patients with metastatic disease. Chromogranin A levels reflect tumor burden, and it has been used to assess for recurrence and changes in tumor size (de Herder 2007; Campana et al. 2007; Zatelli et al. 2007).

Molecular Pathogenesis The molecular pathogenesis of PNETs differs from many non-endocrine tumors (Corleto et al. 2002; Duerr and Chung 2007). Genetic alterations important in their pathogenesis include the MEN 1 gene, p16/MTS1 tumor-suppressor gene, DPC 4/ Smad 4 gene; amplification of the HER-2/neu protooncogene; and alterations in transcription factors [Hoxc6 (GI carcinoids)], growth factors, and their receptor expression; several of these molecular alterations have been shown to correlate with tumor aggressiveness and may have prognostic significance (Corleto et al. 2002; Duerr and Chung 2007).

Table 4 Prognostic factors in PNETs Presence of liver or lymph node metastases Depth of invasion Rapid rate of tumor growth Elevated serum alkaline phosphatase levels Primary tumor site and size Various histologic features – vascular or perineural invasion, vessel density, necrosis, tumor differentiation High growth indices (high Ki–67 index, PCNA expression) or mitotic counts Presence of cytokeratin 19 High CD10 metalloproteinase expression (in series with all grades of NETs) Flow cytometric features (i.e., aneuploidy) High VEGF expression (in low-grade or well-differentiated NETs only) WHO, TNM, and grading classification Presence of a pancreatic NET rather than GI NET Older age Ha-ras oncogene or p53 overexpression Female gender MEN 1 syndrome absent Presence of nonfunctional tumor (some studies, not all) Molecular findings [increased HER2/neu expression chr 1q, 3p, 3q, or 6q LOH, EGF receptor overexpression, gains in chr 7q, 17q, 17p, 20q; alterations in the VHL gene)

87

Pancreatic Neuroendocrine Tumors

Diagnosis and Imaging: Tumor Localization Overview Evaluation of a PNET requires biopsy and staging of the tumor. Cross-sectional imaging studies such as multiphasic computerized tomography (CT) scan or magnetic resonance imaging (MRI) with a focus on the abdomen play an important role. Somatostatin-receptor scintigraphy is recommended in most guidelines especially if metastatic disease is suspected. In patients who present with a PNET hormonal syndrome without evidence of disease on routine imaging, endoscopic ultrasonography, or less commonly, arterial stimulation with venous sampling may be useful.

Computed Tomography Helical multiphasic contrast-enhanced CT is recommended for initial evaluation of PNETs. The sensitivity of this approach is >80% (Legmann et al. 1998). The sensitivity is decreased in tumors smaller than 2 cm. Symptomatic but nonfunctioning tumors, VIPomas and glucagonomas are usually >3 cm at the time of diagnosis. The sensitivity of contrastenhanced CT for these tumors approaches 100%, and it is considered the imaging study of choice (King et al. 1994; Wang et al. 2010) A dual phase image in both arterial and portal phases is used to detect pancreatic neoplasms and also to show peripancreatic vascular anatomy. Following a bolus of non-ionic contrast, thin slice images are obtained at 45 and 70 s for arterial and portal phases, respectively (Brizi et al. 2001). An oral contrast agent such as water allows optimum visualization of the duodenum, improving the detection of duodenal gastrinomas (Fidler and Johnson 2001; Van Hoe et al. 1995).

1941

images and high signal intensity on T2-weighted images. MRI is a reasonable alternative to CT, as lesions can be visualized without contrast in T1- and T2-weighted sequences, reducing the variability sometimes seen with CT imaging. In a study of 64 patients with metastatic NETs, multiphasic MRI detected more hepatic lesions than either contrast-enhanced CT or somatostatin receptor scintigraphy (Dromain et al. 2005). As a result of this greater sensitivity for liver metastases, some physicians prefer MRI over CT for assessing the status of the liver. The size of the lesion impacts the sensitivity of MRI as with other imaging modalities. In one series, tumors less than 1 cm were not detected by MRI with gadolinium, and 50% of tumors between 1 and 2 cm were not identified (Boukhman et al. 1999). Continuous improvement in cross-sectional imaging resolution and technology, however, has been seen every few years.

Endoscopic Ultrasonography (EUS) Endoscopic ultrasonography provides high-resolution imaging of the pancreas, and it can detect lesions as small as 2–3 mm in diameter (Fig. 4). Studies of EUS for detecting PNETs suggest high sensitivity for tumor detection. In a report of 37 patients with PNET, who had negative imaging workup with transabdominal ultrasonography and

Magnetic Resonance Imaging On MRI, pancreatic NETs are typically characterized by low signal intensity on T1-weighted

Fig. 4 Endoscopic ultrasound showing PNET. (Adapted with permission from O’Grady and Conlon 2008)

1942

CT scan, EUS detected the tumor with high sensitivity (82%) and specificity (95%) (Rosch et al. 1992). EUS has also proven to be a useful tool for identifying PNETs such as gastrinomas that arise in the duodenal wall and have a high frequency of metastases to peripancreatic lymph nodes (Cadiot et al. 1996). Duodenal gastrinomas are notoriously difficult to localize by CT. EUS-guided fine-needle aspiration can often provide a histologic diagnosis of PNET (Chatzipantelis et al. 2008). EUS is limited by the requirement of a highly skilled endoscopist (Mertz and Gautam 2004). EUS has an increasingly important role in patients with MEN1 (Langer et al. 2004; Wamsteker et al. 2003; Hellman et al. 2005). EUS is able to detect PNETs in MEN1 patients, especially in the size range from 0.4 to 1.1 cm, not detected on cross-sectional imaging or Octreoscan, 55–100% of asymptomatic patients had nonfunctional PNETs identified by EUS. Hence it has been proposed that serial EUS studies could be used to monitor growth and determine when intervention should be considered (Langer et al. 2004; Wamsteker et al. 2003).

Somatostatin-Receptor Scintigraphy (Octreoscan) Many pancreatic NETs express high levels of somatostatin receptors (especially subtype 2) and can therefore be imaged with a radiolabeled form of the somatostatin analog (111In-DTPA-D-Phel 1) octreotide. Somatostatin receptor scintigraphy (SRS) has proven particularly effective for visualizing gastrinomas (100%), glucagonomas, and nonfunctioning pancreatic tumors (Lamberts et al. 1990; Modlin et al. 1995). Insulinomas (62%) and poorly differentiated neuroendocrine tumors express low somatostatin receptor levels and are less likely to be detected on SRS (Krenning et al. 1993). SRS has the additional advantage of whole body scanning, which allows detection of metastases outside of the abdominal region; hence it has become an obligatory molecular imaging method in the management of patients when metastatic

T. Muniraj and H. R. Aslanian

disease is suspected (Miederer et al. 2010). In addition to anatomical information, SRS offers functional information on levels of somatostatin receptor expression which can help in the selection of appropriate candidates with advanced disease for somatostatin-based therapies. SRS, however, does not provide information on tumor size or surgical resectability. The accuracy of SRS has improved with the addition of single photon emission computed tomography (SPECT) to planar imaging, as SPECT permits more accurate differentiation between areas of pathologic and physiologic uptake in the abdomen (Schillaci et al. 1999; Krausz et al. 2003). SPECT scan uses labeling of PET isotopes including fluorine-18 (T1/2 ¼ 110 min) or gallium-68 (T1/2 ¼ 68 min) to somatostatin analogs (Schottelius et al. 2004).

Laser Confocal Endomicroscopy with Fluorescein-Labeled Somatostatin Analogs Although EUS-guided FNA (EUS-FNA) is very useful in diagnosing PNETs, limitations include sampling error, nondiagnostic cytology, and limited on-site cytological evaluation (Konda et al. 2011). Laser confocal microscopy is a novel technology that has been recently introduced into clinical diagnostics. A submillimeter needle-based confocal laser endomicroscopy (nCLE) probe that provides real-time imaging at the microscopic level through the EUS-FNA needle has recently been developed (Konda et al. 2011). This allows histological diagnosis of the pancreas or duodenal wall lesions at the cellular and subcellular levels in vivo and provides instantaneous histopathology during ongoing upper (and lower) endoscopy and EUS-FNA (Konda et al. 2011). In animal studies, somatostatin receptors (SSTRs) were used as targets for in vivo realtime molecular imaging using a miniaturized laser confocal microscopy system (Goetz and Kiesslich 2010; Fottner et al. 2010). For selective visualization of SSTR, a novel contrast agent for laser confocal microscopy has been specifically

87

Pancreatic Neuroendocrine Tumors

1943

developed by conjugating 5-carboxyfluorescein to octreotate (OcF). This fluorescein-labeled somatostatin analog has been demonstrated to specifically bind to SSTR and exert a functional antiproliferative effect on SSTR-positive tumor cells on mice models. After systemic application, it allows specific dynamic in vivo imaging of SSTR-positive neuroendocrine tumor cells as correlated with ex vivo immunohistochemistry. Confocal mini-microscopy may play an important role in evaluating the morphological, functional, and molecular characteristics of areas accessible to EUS-FNA, possibly facilitating screening for and early diagnosis of SSTR-positive neoplasia. These agents are not approved for human use yet, and further human studies and development of nontoxic contrast agents are required.

Intraoperative Localization Techniques

Arterial Stimulation Venous Sampling

Management

For cases in which radiographically occult, hormonally functional tumors elude detection by conventional imaging modalities, invasive approaches may be necessary to localize tumors to a particular region of the pancreas for treatment planning (e.g., tail, body/neck, head/uncinate). Transhepatic portal venous sampling (THPVS) is a technically demanding technique in which small peripancreatic veins are accessed and tested for levels of hormones such as insulin. A more recent innovation, arterial stimulation with hepatic venous sampling (ASVS), involves selective injection of a stimulating secretagogue (secretin for gastrinomas and calcium gluconate for insulinomas) into arteries supplying the pancreas with subsequent sampling of the hepatic venous effluent (Thom et al. 1992; Doppman et al. 1991). Intra-arterial calcium is a potent stimulator of insulin production from islet beta cells, and a twofold increase in the hormone level would confirm the diagnosis of insulinoma (Doppman et al. 1995). While techniques such as THPVS and ASVS are valuable for patients with radiographically occult hormonally functioning tumors, the need for them has diminished due to the continuously improving sensitivity of CT, MRI, and EUS.

The management of PNETs is based on a number of factors including the severity of symptoms, tumor differentiation, and staging. The aim of therapy is curative; however, the lack of symptoms particularly in nonfunctioning PNETs often leads to delayed diagnosis and advanced disease that may require a palliative approach (Dabizzi et al. 2010).

Laparoscopic intraoperative ultrasonography allows high-resolution examination of the pancreas. When combined with palpation of the organ with the ultrasound probe, the sensitivity for tumor detection ranges from 83% to 100% (Frucht et al. 1990; Huai et al. 1998). Laparoscopic intraoperative transillumination has equivalent efficacy (sensitivity of 83%) for the localization of duodenal wall gastrinomas (Frucht et al. 1990). These techniques are used as adjuncts to intraoperative palpation in patients who have a suspected hormone-secreting pancreatic NET that cannot be identified or localized preoperatively.

Surgical Management of PNET Curative surgical resection is the cornerstone of treatment for PNETs in the absence of metastasis or significant comorbidities (Plockinger et al. 2004; Modlin et al. 2008; Norton et al. 2006). Patients with completely resected tumors generally have a good prognosis (Fendrich et al. 2009). The specific surgical approach employed depends largely on tumor size and location. PNETs more often arise in the pancreatic tail where they can be resected with distal pancreatectomy. Whipple resections are performed for tumors in the pancreatic head (Halperin and Kulke 2012). A retrospective study of 728 patients with PNETs found that surgery was recommended in 425 cases. Of these, 310 underwent resection.

1944

There was a significant survival benefit in the patients with localized, regional, and metastatic disease who underwent resection (average overall survival 114 months vs. 35 months) when compared with those who did not undergo resection) (Hill et al. 2009).

T. Muniraj and H. R. Aslanian

aggressive surgical approach. These patients often benefit from a radical approach which could include duodeno-pancreatic resection, distal pancreatectomy, lymph node dissection, excision of any liver metastasis, and vascular reconstruction if necessary (Hellman et al. 2000; Norton et al. 2003).

Sporadic PNET PNET Associated with MEN1 Benign sporadic functioning PNETs such as insulinomas are usually treated with enucleation, when 1 cm in the pancreatic head (Jensen et al. 2008; Goudet et al. 2010). Insulinomas associated with MEN1 are mostly located in the body or tail of the pancreas. Distal pancreatectomy is most often indicated; however the risk of developing glucose intolerance and diabetes may favor parenchymal preserving approaches like enucleation or central pancreatectomy when possible (Sakurai et al. 2007; Kouvaraki et al. 2006). Gastrinomas in MEN1 are usually located in the duodenum and rarely in the pancreas, and therefore curative resection usually requires a pancreaticoduodenectomy or partial duodenal resection or pancreas preserving total duodenectomy (Imamura et al. 2005).

87

Pancreatic Neuroendocrine Tumors

Treatment of Hepatic Metastases Surgical Management In contrast to patients with pancreatic adenocarcinoma, hepatic resection has been shown to improve outcomes in patients with metastatic pancreatic PNET. Hepatic resection is generally favored in patients with limited hepatic disease. It should not be attempted unless at least 90% of the lesions can be safely removed. In a study of 170 patients, hepatic resection improved symptoms in over 90% of cases (Kulke et al. 2010; Touzios et al. 2005; Chamberlain et al. 2000; Sarmiento and Que 2003). Reported survival rates for this approach have been greater than 60% at 5 years, which is double that of patients with untreated liver metastases (Touzios et al. 2005; Chamberlain et al. 2000).

Liver Transplantation Liver transplantation (LT) can be considered in patients who are symptomatic and have failed other treatment options, with well-differentiated tumors and no evidence of extrahepatic disease where standard surgery is not feasible. A review of 85 patients undergoing LT for metastatic endocrine tumors revealed a 5-year survival rate of 45%. In this study a primary PNET was found to be a negative prognostic factor. LT is not recommended in patients with a primary PNET or in cases with extensive liver involvement (Le Treut et al. 2008; Gregoire and Le Treut 2010).

1945

overall performance status are the suitable candidates for this procedure. Most metastasis from PNETs are hypervascular, and this characteristic can be exploited to target metastasis in the liver. Embolization of the hepatic artery can be achieved by infusion of gel foam powder (bland embolization) or by using cytotoxic drugs like doxorubicin, cisplatin, streptozocin, or drug-eluting beads (chemoembolization). Radioactive isotopes (e.g., yttrium-90) can also be used, and this is called radioembolization. Sufficient data does not exist to support the use of any one of these approaches over another. Response to treatment is determined by reduction in hormone secretion or radiographic evidence of reduction in tumor size. Response rates with all three procedures generally exceed 50% (Halperin and Kulke 2012; Minter and Simeone 2012; Toumpanakis et al. 2007).

Radiofrequency Ablation and Cryoablation RFA and cryoablation can be used alone or along with surgical resection for the treatment of hepatic metastasis. Both these approaches appear to confer a morbidity benefit when compared with surgical resection and hepatic arterial embolization. Ablative techniques are most beneficial in patients with less than ten lesions, each lesion being less than 4 cm in size. It is particularly useful to target small tumors deep in the hepatic parenchyma following resection of larger tumors. While RFA is important in the multimodality approach to the management of hepatic metastasis in PNETs, more data is required to establish a clear mortality benefit (Kulke et al. 2010; Minter and Simeone 2012).

Hepatic Artery Embolization Hepatic artery embolization can be considered for palliation in patients who are not candidates for surgical resection of hepatic metastasis. Patients who have not undergone pancreaticoduodenectomy, but having a patent portal vein, and having metastasis limited to the liver without significant hepatic insufficiency and with a good

Role of Neoadjuvant Therapy Cytotoxic drugs have an important role to play in the treatment of poorly differentiated and rapidly growing PNETs. A randomized trial comparing the combination of streptozocin with doxorubicin versus streptozocin with fluorouracil demonstrated a

1946

mortality benefit as well as radiological and biochemical regression of 69%. The use of streptozotocin-based regimens is however limited by their toxicity and cumbersome administration schedule. Oral temozolomide may be a better tolerated alternative with comparable efficacy (Moertel et al. 1992; Strosberg et al. 2011b).

Newer Advances The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trials planning meeting and formulated key recommendations in management of PNETs and to formulate priorities for future NET studies (see Table 5). As many patients have longer survival, progression-free survival (PFS) is recommended as a feasible and relevant primary end point for clinical studies.

VEGF Pathway Inhibitors Tissue from malignant PNETs has shown extensive expression of platelet-derived growth factor, stem cell factor receptor, and vascular endothelial growth factor (VEGF) which promotes angiogenesis in these tumors. Three tyrosine kinase inhibitors have shown activity against VEGF receptors – pazpanib, sorafenib, and sunintinib. Recently a multinational, randomized, double-blind, placebo-controlled trial demonstrated the efficacy of sunitinib in the treatment of advanced pancreatic neuroendocrine tumors. In this study 171 patients were randomly assigned to receive best

T. Muniraj and H. R. Aslanian

supportive care along with either 37.5 mg per day of sunitinib or placebo. Median progression-free survival in the sunitinib group was 11.4 months compared with 5.5 months in the placebo group. The study was discontinued early because of more serious adverse events and deaths in the placebo group (25%) compared with the group receiving sunitinib (10%). Another study reported that use of sunitinib did not affect quality of life and could be safely combined with somatostatin analogs for the treatment of PNET’s (Raymond et al. 2011).

mTor Inhibitors The mammalian target of rapamycin (mTor) regulates tumor cell growth, proliferation, and apoptosis. Everolimus, an inhibitor of mTor, has been shown to significantly prolong progression-free survival in patients with advanced PNETs. In a study involving 410 patients with advanced, low-grade, or intermediate-grade PNETs with radiologic progression within the last 12 months, who were randomly assigned to receive either everolimus or placebo, progression-free survival at 18 months was found to be 34% with everolimus compared with 9% with placebo (Yao et al. 2011) (Table 6).

Peptide Receptor Radionucleotide Therapy (PRRT) The majority of PNETs express somatostatin receptors. Somatostatin analogs are used for symptom control in patients with hormone

Table 5 Key recommendations from the NET clinical trials planning meeting (Kulke et al. 2011) Carcinoid tumors and pancreatic NETs should be examined separately in clinical trials Overall survival is not a practical end point for most advanced NET studies. Progression-free survival is recommended as the primary end point for phase III studies Adjuvant therapy is not currently indicated in patients with completely resected NETs Cross-sectional anatomic imaging of the abdomen should be performed with either multiphasic CT or MRI Sunitinib and other tyrosine kinase inhibitors targeting VEGFR are active in patients with advanced pancreatic NETs Everolimus is active in patients with advanced pancreatic NETs In contrast to carcinoid tumors, there is now substantial evidence that pancreatic NETs are sensitive to alkylating agents Randomized phase III studies comparing peptide receptor radiotherapy to standard systemic therapy are warranted

87

Pancreatic Neuroendocrine Tumors

1947

Table 6 Progression-free survival with newer based on studies Agent Target receptor VEGF pathway inhibitors Sunitinib VEGF1-3; PDGFR; C-KIT; RET; CSF-1R Sunitinib VEGF1-3; PDGFR; KIT; RET; CSF1R Sorafenib VGFR; PDGFR; Braf Pazopanib VEGFR1-3; PDGF, C-KIT Mammalian target of rapamycin (mTOR) inhibitors Everolimus mTOR Everolimus mTOR Temsirolimus mTOR Somatostatin analogs Lu-DOTASomatostatin receptors tate

hypersecretion associated with PNETs. PRRT is a newer treatment option that can be used for tumors that express a high density of somatostatin receptors on somatostatin receptor imaging. These receptors are targets for cytotoxic drugs coupled to somatostatin. Initially octreotide was used, but this has been largely replaced by yttrium-90- or lutetium-177-coupled analogs, which have been shown to be effective for both symptom relief and tumor remission. Adverse effects are typically mild and limited primarily to toxicity to the bone marrow and kidneys (Forrer et al. 2007).

Key Points 1. Neuroendocrine tumors (NETs) are heterogeneous tumors which originate from endocrine glands, such as the pituitary, parathyroid, adrenal, thyroid, and pancreas, and gastrointestinal and respiratory tracts. 2. The incidence of NETs increases with age and most often occurs in the fourth to sixth decades of life. 3. NETs may present with functional or nonfunctional endocrine syndromes. 4. In nonfunctioning NETs, the presentation is related to the mass effect of the tumor with symptoms often being non-specific.

Progression-free survival (months)

Study

11.4

Raymond et al. 2011

10.2

Kulke et al. 2011

11.9 11.7

Hobday et al. 2007 Phan et al. 2010

18 16.7 10.6

Yao et al. 2011 Yao et al. 2010 Duran et al. 2006

40

Kwekkeboom et al. 2008

5. NETs may be familial and have other associated tumors with expression of neuroendocrine markers. 6. Various imaging modalities such as CT and MRI, EUS, and particularly scintigraphy with somatostatin analogs are useful in diagnosis and localization. 7. Curative surgical resection is the cornerstone of treatment for PNETs. 8. Successful treatment of disseminated NETs requires a multimodal approach. 9. Medical management includes somatostatin analogs, alpha-interferon, and radionucleotides. 10. Chemotherapy is reserved for poorly differentiated and progressive tumors.

References Akerstrom G, Hellman P. Surgery on neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab. 2007;21:87–109. American Cancer Society. Pancreatic cancer survival by stage. http://www.cancer.org/Cancer/ PancreaticCancer/DetailedGuide/pancreatic-cancer-sur vival-rates. 2012 Basu B, Sirohi B, Corrie P. Systemic therapy for neuroendocrine tumours of gastroenteropancreatic origin. Endocr Relat Cancer. 2010;17:R75–90. Bosman FT, Carneiro F, Hruban RH, Theise ND. Tumours of the pancreas. Lyon: IARC Press; 2010.

1948 Boukhman MP, et al. Localization of insulinomas. Arch Surg. 1999;134:818–22; discussion 822–813. Boyce M, Thomsen L. Gastric neuroendocrine tumors: prevalence in Europe, USA, and Japan, and rationale for treatment with a gastrin/CCK2 receptor antagonist. Scand J Gastroenterol. 2015;50:550–9. Brizi MG, et al. High resolution spiral computed tomography of the pancreas. Rays. 2001;26:111–5. Cadiot G, et al. Preoperative detection of duodenal gastrinomas and peripancreatic lymph nodes by somatostatin receptor scintigraphy. Groupe D’etude Du Syndrome De Zollinger-Ellison. Gastroenterology. 1996;111:845–54. Campana D, et al. Chromogranin A: is it a useful marker of neuroendocrine tumors? J Clin Oncol. 2007;25:1967–73. Chamberlain RS, et al. Hepatic neuroendocrine metastases: does intervention alter outcomes? J Am Coll Surg. 2000;190:432–45. Chatzipantelis P, et al. Endoscopic ultrasound-guided fineneedle aspiration cytology of pancreatic neuroendocrine tumors: a study of 48 cases. Cancer. 2008;114:255–62. Corleto VD, Delle Fave G, Jensen RT. Molecular insights into gastrointestinal neuroendocrine tumours: importance and recent advances. Dig Liver Dis. 2002;34:668–80. Dabizzi E, Panossian A, Raimondo M. Management of pancreatic neuroendocrine tumors. Minerva Gastroenterol Dietol. 2010;56:467–79. de Herder WW. Biochemistry of neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab. 2007;21:33–41. Doppman JL, et al. Insulinomas: localization with selective intraarterial injection of calcium. Radiology. 1991;178:237–41. Doppman JL, et al. Localization of insulinomas to regions of the pancreas by intra-arterial stimulation with calcium. Ann Intern Med. 1995;123:269–73. Dromain C, et al. Detection of liver metastases from endocrine tumors: a prospective comparison of somatostatin receptor scintigraphy, computed tomography, and magnetic resonance imaging. J Clin Oncol. 2005;23:70–8. Duerr EM, Chung DC. Molecular genetics of neuroendocrine tumors. Best Pract Res Clin Endocrinol Metab. 2007;21:1–14. Duran I, et al. A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer. 2006;95:1148–54. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17:1471–4. Falconi M, et al. Well-differentiated pancreatic nonfunctioning tumors/carcinoma. Neuroendocrinology. 2006;84:196–211. Fendrich V, Waldmann J, Bartsch DK, Langer P. Surgical management of pancreatic endocrine tumors. Nat Rev Clin Oncol. 2009;6:419–28. Fidler JL, Johnson CD. Imaging of neuroendocrine tumors of the pancreas. Int J Gastrointest Cancer. 2001;30:73–85.

T. Muniraj and H. R. Aslanian Fink G, et al. Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature. Chest. 2001;119:1647–51. Forrer F, Valkema R, Kwekkeboom DJ, de Jong M, Krenning EP. Neuroendocrine tumors. Peptide receptor radionuclide therapy. Best Pract Res Clin Endocrinol Metab. 2007;21:111–29. Fottner C, et al. In vivo molecular imaging of somatostatin receptors in pancreatic islet cells and neuroendocrine tumors by miniaturized confocal laser-scanning fluorescence microscopy. Endocrinology. 2010;151:2179–88. Frucht H, et al. Detection of duodenal gastrinomas by operative endoscopic transillumination. A prospective study. Gastroenterology. 1990;99:1622–7. Gibril F, Jensen RT. Zollinger-Ellison syndrome revisited: diagnosis, biologic markers, associated inherited disorders, and acid hypersecretion. Curr Gastroenterol Rep. 2004;6:454–63. Gibril F, Venzon DJ, Ojeaburu JV, Bashir S, Jensen RT. Prospective study of the natural history of gastrinoma in patients with MEN1: definition of an aggressive and a nonaggressive form. J Clin Endocrinol Metab. 2001;86:5282–93. Gill GV, Rauf O, MacFarlane IA. Diazoxide treatment for insulinoma: a national UK survey. Postgrad Med J. 1997;73:640–1. Goetz M, Kiesslich R. Advances of endomicroscopy for gastrointestinal physiology and diseases. Am J Physiol Gastrointest Liver Physiol. 2010;298: G797–806. Goudet P, et al. Risk factors and causes of death in MEN1 disease. A GTE (Groupe d’Etude des Tumeurs Endocrines) cohort study among 758 patients. World J Surg. 2010;34:249–55. Grant CS. Surgical management of malignant islet cell tumors. World J Surg. 1993;17:498–503. Grant CS. Insulinoma. Best Pract Res Clin Gastroenterol. 2005;19:783–98. Gray’s anatomy: the anatomical basis of clinical practice. (ed. DSc, S.S.P.) 1562 (Elsevier, 2015). Gregoire E, Le Treut YP. Liver transplantation for primary or secondary endocrine tumors. Transpl Int. 2010;23:704–11. Halperin DM, Kulke MH. Management of pancreatic neuroendocrine tumors. Gastroenterol Clin N Am. 2012;41:119–31. Hellman P, et al. Surgical strategy for large or malignant endocrine pancreatic tumors. World J Surg. 2000;24:1353–60. Hellman P, Hennings J, Akerstrom G, Skogseid B. Endoscopic ultrasonography for evaluation of pancreatic tumours in multiple endocrine neoplasia type 1. Br J Surg. 2005;92:1508–12. Hill JS, et al. Pancreatic neuroendocrine tumors: the impact of surgical resection on survival. Cancer. 2009;115:741–51. Hirshberg B, et al. Blind distal pancreatectomy for occult insulinoma, an inadvisable procedure. J Am Coll Surg. 2002;194:761–4.

87

Pancreatic Neuroendocrine Tumors

Hobday TJ, Rubin J, Holen K, Picus J, Donehower R, Marschke R, Maples W, Lloyd R, Mahoney M, Erlichman C. MC044h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): a Phase II Consortium (P2C) study. In: 2007 ASCO annual meeting proceedings, vol. 25, p. 4504. J Clin Oncol, 2007. Huai JC, et al. Localization and surgical treatment of pancreatic insulinomas guided by intraoperative ultrasound. Am J Surg. 1998;175:18–21. Imamura M, et al. New pancreas-preserving total duodenectomy technique. World J Surg. 2005;29:203–7. Imamura M, Komoto I, Ota S. Changing treatment strategy for gastrinoma in patients with Zollinger-Ellison syndrome. World J Surg. 2006;30:1–11. Ito H, et al. Surgery and staging of pancreatic neuroendocrine tumors: a 14-year experience. J Gastrointest Surg. 2010;14:891–8. Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. Harrison’s principles of internal medicine. United States of America: The McGraw-Hill Companies; 2012. Jensen RT, et al. Gastrinoma (duodenal and pancreatic). Neuroendocrinology. 2006;84:173–82. Jensen RT, Berna MJ, Bingham DB, Norton JA. Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer. 2008;113:1807–43. Kaltsas GA, Besser GM, Grossman AB. The diagnosis and medical management of advanced neuroendocrine tumors. Endocr Rev. 2004;25:458–511. Kato M, et al. Curative resection of microgastrinomas based on the intraoperative secretin test. World J Surg. 2000;24:1425–30. King CM, Reznek RH, Dacie JE, Wass JA. Imaging islet cell tumours. Clin Radiol. 1994;49:295–303. Klimstra DS. Nonductal neoplasms of the pancreas. Mod Pathol. 2007;20(Suppl 1):S94–112. Klimstra DS, et al. Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process to the development of a minimum pathology data set. Am J Surg Pathol. 2010;34:300–13. Kloppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann N Y Acad Sci. 2004;1014:13–27. Konda VJ, et al. First assessment of needle-based confocal laser endomicroscopy during EUS-FNA procedures of the pancreas (with videos). Gastrointest Endosc. 2011;74:1049–60. Kouvaraki MA, et al. Management of pancreatic endocrine tumors in multiple endocrine neoplasia type 1. World J Surg. 2006;30:643–53. Krausz Y, et al. SPECT/CT hybrid imaging with 111Inpentetreotide in assessment of neuroendocrine tumours. Clin Endocrinol. 2003;59:565–73. Krenning EP, et al. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med. 1993;20:716–31.

1949 Kulke MH, et al. NANETS treatment guidelines: welldifferentiated neuroendocrine tumors of the stomach and pancreas. Pancreas. 2010;39:735–52. Kulke MH, et al. Future directions in the treatment of neuroendocrine tumors: consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting. J Clin Oncol. 2011;29:934–43. Kwekkeboom DJ, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26:2124–30. Lamberts SW, Bakker WH, Reubi JC, Krenning EP. Somatostatin-receptor imaging in the localization of endocrine tumors. N Engl J Med. 1990;323:1246–9. Langer P, et al. Prospective evaluation of imaging procedures for the detection of pancreaticoduodenal endocrine tumors in patients with multiple endocrine neoplasia type 1. World J Surg. 2004;28:1317–22. Lawrence B, et al. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin N Am. 2011;40:1–18. , vii. Le Treut YP, et al. Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report. Am J Transplant. 2008;8:1205–13. Legmann P, et al. Pancreatic tumors: comparison of dualphase helical CT and endoscopic sonography. AJR Am J Roentgenol. 1998;170:1315–22. Liszka L, et al. Discrepancies between two alternative staging systems (European Neuroendocrine Tumor Society 2006 and American Joint Committee on Cancer/Union for International Cancer Control 2010) of neuroendocrine neoplasms of the pancreas. A study of 50 cases. Pathol Res Pract. 2011;207:220–4. Mertz H, Gautam S. The learning curve for EUS-guided FNA of pancreatic cancer. Gastrointest Endosc. 2004;59:33–7. Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology. 2008;135:1469–92. Miederer M, Weber MM, Fottner C. Molecular imaging of gastroenteropancreatic neuroendocrine tumors. Gastroenterol Clin N Am. 2010;39:923–35. Minter RM, Simeone DM. Contemporary management of nonfunctioning pancreatic neuroendocrine tumors. J Gastrointest Surg. 2012;16:435–46. Modlin IM, Cornelius E, Lawton GP. Use of an isotopic somatostatin receptor probe to image gut endocrine tumors. Arch Surg. 1995;130:367–73; discussion 373–364. Modlin IM, et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol. 2008;9:61–72. Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocinfluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992;326:519–23. Muniraj T, Vignesh S, Shetty S, Thiruvengadam S, Aslanian HR. Pancreatic neuroendocrine tumors. Dis Mon. 2013;59:5–19.

1950 Norton JA. Surgery for primary pancreatic neuroendocrine tumors. J Gastrointest Surg. 2006;10:327–31. Norton JA, et al. Morbidity and mortality of aggressive resection in patients with advanced neuroendocrine tumors. Arch Surg. 2003;138:859–66. Norton JA, et al. Surgery increases survival in patients with gastrinoma. Ann Surg. 2006;244:410–9. O’Grady HL, Conlon KC. Pancreatic neuroendocrine tumours. Eur J Surg Oncol. 2008;34:324–32. Oronsky B, Ma PC, Morgensztern D, Carter CA. Nothing but NET: a review of neuroendocrine tumors and carcinomas. Neoplasia (New York, NY). 2017;19:991–1002. Pape UF, et al. Prognostic relevance of a novel TNM classification system for upper gastroenteropancreatic neuroendocrine tumors. Cancer. 2008;113:256–65. Phan AT, Yao JC, Fogelman DR, Hess KR, Ng CS, Bullock SA, Malinowski P, Regan E, Kulke M. A prospective, multi-institutional phase II study of GW786034 (pazopanib) and depot octreotide (sandostatin LAR) in advanced low-grade neuroendocrine carcinoma (LGNEC). In: ASCO annual meeting, vol. 28, p. 4001. J Clin Oncol 2010). Plockinger U, et al. Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS). Neuroendocrinology. 2004;80:394–424. Raymond E, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501–13. Rindi G, et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2006;449:395–401. Rosch T, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J Med. 1992;326:1721–6. Roy PK, et al. Zollinger-Ellison syndrome. Clinical presentation in 261 patients. Medicine (Baltimore). 2000;79:379–411. Saadettin Kilickap HKM. Neuroendocrine tumours diagnosis and management. New York: Springer; 2015. Sakurai A, et al. Long-term follow-up of patients with multiple endocrine neoplasia type 1. Endocr J. 2007;54:295–302. Sarmiento JM, Que FG. Hepatic surgery for metastases from neuroendocrine tumors. Surg Oncol Clin N Am. 2003;12:231–42. Scarpa A, et al. Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients. Mod Pathol. 2010;23:824–33. Schillaci O, Corleto VD, Annibale B, Scopinaro F, Delle Fave G. Single photon emission computed tomography procedure improves accuracy of somatostatin receptor scintigraphy in gastro-entero pancreatic tumours. Ital J Gastroenterol Hepatol. 1999;31(Suppl 2): S186–9.

T. Muniraj and H. R. Aslanian Schott M, et al. Neuroendocrine neoplasms of the gastrointestinal tract. Dtsch Arztebl Int. 2011;108: 305–12. Schottelius M, et al. First (18)F-labeled tracer suitable for routine clinical imaging of sst receptor-expressing tumors using positron emission tomography. Clin Cancer Res. 2004;10:3593–606. Strosberg J, Nasir A, Coppola D, Wick M, Kvols L. Correlation between grade and prognosis in metastatic gastroenteropancreatic neuroendocrine tumors. Hum Pathol. 2009;40:1262–8. Strosberg JR, et al. Prognostic validity of a novel American Joint Committee on Cancer Staging Classification for pancreatic neuroendocrine tumors. J Clin Oncol. 2011a;29:3044–9. Strosberg JR, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011b;117:268–75. Thom AK, et al. Prospective study of the use of intraarterial secretin injection and portal venous sampling to localize duodenal gastrinomas. Surgery. 1992;112:1002–8; discussion 1008–1009. Thomas-Marques L, et al. Prospective endoscopic ultrasonographic evaluation of the frequency of nonfunctioning pancreaticoduodenal endocrine tumors in patients with multiple endocrine neoplasia type 1. Am J Gastroenterol. 2006;101:266–73. Thompson NW, Eckhauser FE. Malignant islet-cell tumors of the pancreas. World J Surg. 1984;8:940–51. Thompson GB, van Heerden JA, Grant CS, Carney JA, Ilstrup DM. Islet cell carcinomas of the pancreas: a twenty-year experience. Surgery. 1988;104:1011–7. Toumpanakis C, Meyer T, Caplin ME. Cytotoxic treatment including embolization/chemoembolization for neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab. 2007;21:131–44. Touzios JG, et al. Neuroendocrine hepatic metastases: does aggressive management improve survival? Ann Surg. 2005;241:776–83; discussion 783–775. Triponez F, et al. Is surgery beneficial for MEN1 patients with small (< or ¼ 2 cm), nonfunctioning pancreaticoduodenal endocrine tumor? An analysis of 65 patients from the GTE. World J Surg. 2006;30:654–62; discussion 663–654. Vagefi PA, et al. Evolving patterns in the detection and outcomes of pancreatic neuroendocrine neoplasms: the Massachusetts General Hospital experience from 1977 to 2005. Arch Surg. 2007;142:347–54. Van Hoe L, Gryspeerdt S, Marchal G, Baert AL, Mertens L. Helical CT for the preoperative localization of islet cell tumors of the pancreas: value of arterial and parenchymal phase images. AJR Am J Roentgenol. 1995;165:1437–9. Wamsteker EJ, Gauger PG, Thompson NW, Scheiman JM. EUS detection of pancreatic endocrine tumors in asymptomatic patients with type 1 multiple endocrine neoplasia. Gastrointest Endosc. 2003;58:531–5.

87

Pancreatic Neuroendocrine Tumors

Wang SC, et al. Identification of unknown primary tumors in patients with neuroendocrine liver metastases. Arch Surg. 2010;145:276–80. Wolf P, et al. Clinical presentation in insulinoma predicts histopathological tumour characteristics. Clin Endocrinol. 2015;83:67–71. Yang RH, Chu YK. Zollinger-Ellison syndrome: revelation of the gastrinoma triangle. Radiol Case Rep. 2015;10:827. Yao JC, et al. Population-based study of islet cell carcinoma. Ann Surg Oncol. 2007;14:3492–500.

1951 Yao JC, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010;28:69–76. Yao JC, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514–23. Zatelli MC, et al. Chromogranin A as a marker of neuroendocrine neoplasia: an Italian Multicenter Study. Endocr Relat Cancer. 2007;14:473–82.

Colorectal Cancer Screening

88

Charles J. Kahi and Douglas K. Rex

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1954 Epidemiologic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1954 CRC Screening (Mis)utilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1955 Screening Modalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1956 Benefits and Harms of Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1956 Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1957 Life Expectancy and Screening Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1958 Tailoring Screening Decisions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1959 Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1960 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1960 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1961

Abstract

Colorectal cancer (CRC) is a major contributor to cancer morbidity and mortality in the United States and disproportionately affects the elderly. In parallel, there is a growing group of older patients who have better life

C. J. Kahi (*) Roudebush VA Medical Center, Indiana University School of Medicine, Indianapolis, IN, USA e-mail: [email protected] D. K. Rex Indiana University School of Medicine, Indianapolis, IN, USA e-mail: [email protected]

expectancy and are high utilizers of CRC screening resources. However, screening in older age groups is not well targeted to individual patients, with evidence of both overutilization and underutilization. While several screening options are available, there are agedependent specifics to colorectal neoplasia and screening test performance which render colonoscopy the most important test to consider. In older patients, the benefits of early detection and prevention of CRC may be offset by higher risk of procedure-related harm and diminished health and life expectancy. Screening for CRC should ideally be targeted to elderly patients with a life expectancy of at least 10 years.

© Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_75

1953

1954

Guidelines recommend individualizing screening in adults aged 76–85 years based on overall health and prior screening history and foregoing screening in those 86 years and older. Keywords

Screening · Colorectal neoplasia · Aged · Colonoscopy · Life expectancy

Introduction Colorectal cancer (CRC) screening in the geriatric population can be complex and controversial, as it must balance tensions between several competing factors. On one hand, the prevalence of colorectal neoplasia, including CRC and precursor polyps, increases with advancing age, making early detection and prevention of CRC worthwhile goals in older age groups. On the other hand, older patients have higher risk of procedure-related harm and diminished health and life expectancy, potentially negating the benefits of CRC prevention. Clinicians and older patients contemplating CRC screening decisions face considerable uncertainty due to a relative paucity of studies informing the best course of action in individual situations. However, recent lines of evidence and guidelines provide frameworks to help decision-making. This chapter will review issues pertaining to CRC screening in older adults, including benefits and harms, effect on patient outcomes, and decision-making by patients and health care providers.

Epidemiologic Considerations CRC is one of the leading causes of cancer-related deaths in the United States (Siegel et al. 2019). In 2019, an estimated 145,600 new cases will be diagnosed, and 51,020 deaths will occur, putting CRC incidence and mortality just behind cancers of the lung, breast, and prostate. Age is arguably the single most important risk factor for the development of CRC and its precursor lesions,

C. J. Kahi and D. K. Rex

adenomas, and sessile serrated lesions (SSL). The probability of developing CRC in males and females increases from 1 in 272 and 1 and 292 from birth to age 49, to 1 in 143 and 1 in 190 at ages 50–59, 1 in 87 and 1 in 123 at ages 60–69, and 1 in 30 and 1 in 33 from age 70 onwards (Siegel et al. 2019). Elderly patients constitute the largest proportion of new CRC diagnoses (Day et al. 2011), and these cancers tend to be located in the right colon and associated with agedependent molecular features such as hypermethylation and microsatellite instability (Miyakura et al. 2001; Cucino et al. 2002). These epidemiologic data have to be placed in the context of the demographic changes observed in the US population over the past century (Fig. 1). In 1900, the population 65 years and older numbered 3.1 million people and constituted 4.1% of the total population; in 2010, these numbers were 40.3 million and 13% (Census briefs 2010). Between 2000 and 2010, the population 65 years old increased at a faster rate (15.1%) than the total US population (9.7%), and in 2030, it is projected that baby-boomers who are 65 and older will outnumber persons under the age of 18. In parallel, overall life expectancy has increased from 70.8 to 79.5 years between 1970 and 2015 (US Census Bureau 2012). The proportion of elderly individuals among all those undergoing CRC screening in the USA is not precisely known; however, available evidence suggests it is substantial, and likely to increase as the US population ages and lives longer. In the aftermath of the approval of Medicare coverage for screening colonoscopy in 2001, an increase in the number of older persons undergoing screening colonoscopy was observed (Harewood and Lieberman 2004). An analysis of nearly 1.4 million colonoscopy reports from the Clinical Outcomes Research Initiative (CORI) database revealed that 13% of patients were  75 years old and 23% were  70 years old. In the older age groups, the most common colonoscopy indication was surveillance of polyps or CRC (about one-third), as opposed to screening in those 50–74 years old (43%) and evaluation of symptoms in individuals younger than 50 years (72%) (Lieberman et al. 2014).

88

Colorectal Cancer Screening

1955

Number (in millions)

Millions

Percentage (of total population)

Percent 14

45 40

12

35 10 30 25

8

20

6

15 4 10 2

5 0

0 1900

1910

1920

1930

1940

1950

Fig. 1 Population 65 years and older by size and percent of total population: 1900 to 2010. (For more information on confidentiality protection, nonsampling error, and

CRC Screening (Mis)utilization The overall trend from the above epidemiological data is that of a growing group of older patients who live longer, have better life expectancy, and are high utilizers of CRC screening resources. However, screening in older age groups is not well targeted to individual patients, with evidence of both overutilization and underutilization. A study (Sheffield et al. 2013) of about 75,000 Texas Medicare beneficiaries 70 years or older who underwent screening colonoscopies found that 23.4% of these were inappropriate, based on patient age or performance too soon after a previous colonoscopy with no neoplasia. The rate of inappropriate screening was about 40% for 76–85 year-olds, and 25% for 86 year-olds, and colonoscopists with rates above the mean were more likely to be surgeons, graduates of US medical schools before 1990, and higher-volume colonoscopists. Another study (Goodwin et al. 2011) of over 24,000 average-risk Medicare enrollees who had a negative colonoscopy (without neoplasia) found that 23.5% underwent

1960

1970

1980

1990

2000

2010

definitions. see www.census.gov/prod/cen2010/doc/sf1. pdf). (Source: U.S. Census Bureau, decennial census of population, 1900 to 2000; 2010 Census Summary File 1)

another examination in less than 7 years without a clear indication, whereas 10 years would have been the recommended interval for most. This was associated with geographic region, male sex, higher comorbidity burden, and colonoscopy by a highvolume endoscopist. Conversely, in a cohort (Cooper et al. 2013) of nearly 13,000 Medicare beneficiaries aged 70 years who underwent colonoscopy with polypectomy, only 45.7% of patients underwent repeat colonoscopy at 5 years. The problem of discordance between clinical practice and guidelines is not new, pertains to all age groups, and is even observed in more tightly scrutinized organized screening programs such as the Veterans Affairs system (Murphy et al. 2016). In the elderly, however, the issue is even more problematic: On an individual level, some patients are exposed to unnecessary procedures with risk of harm, while others are deprived of appropriate screening and interventions. On a systems level, the inappropriate utilization of CRC screening further burdens the health care system and may divert already strained resources from other patient groups who are in need of CRC prevention.

1956

Screening Modalities There are several modalities for CRC screening, including noninvasive fecal tests which are primarily intended to detect early cancer, and structural tests such as colonoscopy, which allow early detection as well as prevention of CRC by resection of precursor precancerous polyps. A detailed discussion of the performance characteristics and relative merits and disadvantages of each CRC screening modality is beyond the scope of this chapter and is found in recent practice guidelines (Knudsen et al. 2016; Rex et al. 2017). However, there are important factors to note. First, colonoscopy constitutes the final common pathway of all other screening options, notably fecal tests which detect occult blood or abnormal DNA; patients with a positive result on one of these “gateway” tests have to be further evaluated with colonoscopy. This concept is fundamental to CRC screening in general and particularly relevant to older patients where screening decisions ultimately have to consider the risk-benefit ratio of colonoscopy, whether as a primary screening modality or as a diagnostic procedure to investigate another positive screening test. In other words, clinicians have to carefully consider the implications of a positive noninvasive test based on the appropriateness of colonoscopy which has to follow: a patient who is too frail to undergo colonoscopy should probably not have undergone the index noninvasive screening test in the first place. Second, there are age-dependent specifics to colorectal neoplasia and screening test performance which have to be taken into account: The serrated colorectal neoplasia pathway contributes about 25% of all CRCs, and precursor sessile serrated lesions (SSL) are relatively more prevalent with advancing age (Rex et al. 2012). SSL tend to be flat and with subtle morphological features, located in the proximal colon, and less vascularized than adenomas of comparable size. These features render SSL more difficult to detect by fecal immunochemical tests (FIT) and computed tomographic colonography (CTC), both of which have relatively low sensitivity for SSL (Kahi 2019). The multitarget stool DNA test has better sensitivity for large SSL than FIT (42% vs.

C. J. Kahi and D. K. Rex

5%) (Imperiale et al. 2014) because it includes markers of hypermethylation, one of the molecular hallmarks of serrated neoplasia. However, this advantage is offset by the fact that the multitarget stool DNA has lower specificity with advancing age and may not be an appropriate option for CRC screening after age 65 due to high rates of falsepositivity (Rex et al. 2017). These observations do not imply that colonoscopy is the only viable screening option in the elderly, but they do show that colonoscopy is even more central to decisions regarding screening than in younger patients, given the changes in colorectal neoplasia and the limitations of other tests in older patients.

Benefits and Harms of Screening While there is ample evidence supporting the ages to start screening and when to conduct subsequent surveillance, stopping CRC screening (or surveillance after previous screening) is relatively less well studied. The elderly are either underrepresented or outright excluded from CRC screening studies. For example, the randomized controlled trials of fecal occult blood testing enrolled some patients aged up to 80 years (Mandel et al. 1993; Kronborg et al. 1996; Hardcastle et al. 1996), and the upper age limit in the National Polyp Study was 88 years (Winawer et al. 1993). However, the small number of older patients precludes generalizations regarding screening outcomes and benefits. Several cross-sectional studies (Arora and Singh 2004; Feingold and Forde 2003; Stevens and Burke 2003; Duncan et al. 2006) have assessed the yield and risks of colonoscopy in the elderly, with consistent findings. There is increased prevalence of CRC and histologically advanced polyps with older age, the yield of colonoscopy is highest in patients with symptoms (particularly rectal bleeding), and complications, while relatively infrequent overall, are more common in older age groups. While these findings are informative and an important part of the geriatric CRC screening debate, they do not provide decisive evidence. Most patients were at higher risk for colonic neoplasia due to the

88

Colorectal Cancer Screening

presence of symptoms or a prior personal history of colonic neoplasia, which hampers applicability to average-risk asymptomatic patients. Most studies were single-center and retrospective and thus at risk of selection bias and incomplete capture of relevant data such as complication rates. Finally, the cross-sectional design precluded assessment of outcomes after screening. In fact, most of these studies concluded that the increased prevalence of colonic neoplasia in the elderly justifies offering screening without a finite timeline or guidelines on when to forego screening. This approach is problematic in two fundamental aspects: patients who die after screening from unrelated comorbidities would have been screened without any benefit. On the other hand, setting the same upper age limit for everyone could risk disqualifying certain older patients who have relatively good health and functional status (Ransohoff and Lang 1993; Miller and Waye 2000, 2002; Koretz 1996). An important factor to consider is that all the risks and burdens traditionally associated with colonoscopy are magnified in older patients. There is a higher rate of unsatisfactory bowel preparation (up to 57%) leading to the need for repeat procedures, procedures may be technically more complex and take longer to complete, and the risk of incomplete and aborted procedures is increased (Arora and Singh 2004; Froehlich et al. 2005; Lukens et al. 2002; Day and Velayos 2014). While polyethylene glycol (PEG) regimens are preferred, they are still not risk-free due to electrolyte and renal function disturbances, and difficulty attaining adequate preparation quality even with good compliance due to slower colonic transit time, decreased understanding of instructions, and functional limitations (Day and Velayos 2014). Procedural-related risks are also increased in older patients. One study assessed complications in 53,220 Medicare beneficiaries age 66–95 years who underwent outpatient colonoscopy. Complications measured included GI bleeding, perforation, and cardiovascular events resulting in a hospitalization or emergency department visit within 30 days (Warren et al. 2009). The overall risk per 1000 procedures was 0.6 for bowel

1957

perforation, 8.7 for postpolypectomy hemorrhage, and 19.4 for cardiovascular events. The risk of adverse events was higher for patients undergoing polypectomy, and for those with a history of stroke, chronic obstructive pulmonary disease, atrial fibrillation, or congestive heart failure (Warren et al. 2009). The systematic review (Lin et al. 2016) which provided evidence for the most recent CRC screening guidance by the US Preventive Services Task Force found that colonoscopy complications rates were 4 in 10,000 for perforation and 8 in 10,000 for major bleeding, and that these rates were increased with age and performance of polypectomy. A recent study (Cha et al. 2016) illustrates the tension between increased neoplasia detection and the harms of colonoscopy as patients get progressively older and frailer. Compared to a group of 75- to 79-year-olds, nonagenarians had higher prevalence of advanced neoplasia (28.4% vs. 6.4%) including CRC (13.5% vs. 0%), but increased requirement for general anesthesia (6.6% vs. 0%), more frequent inadequate bowel preparation rate (29.7% vs. 15.0%) and adverse events (9.2% vs. 0.7%) including severe events (5.3% vs. 0%), and lower successful completion (88.2% vs. 99.3%).

Surveillance The issues to consider when contemplating screening in an older patient are not limited to that one episode of screening. An important consequence is that, given the higher prevalence of colorectal neoplasia with age, many older patients are eventually found to have polyps and undergo polypectomy, thus becoming eligible for surveillance with colonoscopy at specific time intervals. In addition, the natural history of adenomas in older patients may be different than in younger patients, as they have had longer dwell time to accumulate more genetic abnormalities, and progress to CRC faster. One study (Brenner et al. 2007) based on over 800,000 participants in the German screening program reported that the annual transition rates from advanced adenomas to CRC increased strongly with age in both men

1958

and women (from 2.6% at ages 55–59 to 5.6% in 80 year-old women, and 5.1% in 80 year-old men). Projections of 10 year cumulative risk increase from 25.4% at age 55 years to 42.9% at age 80 years in women, and from 25.2% at age 55 years to 39.7% at age 80 years in men. Despite these trends, open-ended surveillance colonoscopy may not be appropriate for a majority of older patients due to progressively unfavorable risk-to-benefit ratio. A study (Tran et al. 2014) of patients undergoing surveillance colonoscopy for history of CRC or adenomatous polyp showed that patients 75 years have low CRC incidence, but high rates of hospitalizations after colonoscopy compared to younger individuals. Age 75 (aOR 1.28) and Charlson score 2 (aOR 2.54) were significantly associated with risk of postprocedure hospitalization.

Life Expectancy and Screening Outcomes The fundamental goal of screening for cancer is to prolong life through prevention or early detection, and CRC is an eminently suitable target for screening, in part due to its long latency. Most CRCs remain asymptomatic for long periods of time, and this is preceded by a lengthy preclinical stage where polyps can take several years to progressively transform into an invasive cancer. It is thus not surprising that there is a delay between a screening event and the survival benefit derived from it. A survival meta-analysis (Lee et al. 2013) of 4 FOBT screening RCTs showed that it took 10.3 years (95% CI 6.0–16.4) before one CRC death was prevented for 1000 patients screened. A similar analysis (Tang et al. 2015) of 4 flexible sigmoidoscopy screening RCTs showed a 9.4 year lag (95% CI 7.6–11.3) before one CRC death was prevented for 1000 patients screened. While direct data are not available for screening colonoscopy, a 10-year lag can be expected given that FOBT and sigmoidoscopy screening have comparable times to benefit and that positive findings on either test should lead to a colonoscopy. An overall conclusion from these analyses is that screening for CRC should ideally be targeted

C. J. Kahi and D. K. Rex

to geriatric patients with a life expectancy of at least 10 years. Patients with more limited life expectancy (due to old age, comorbidity, or both) may not live long enough to reap the benefits of screening. As stated by Walter et al. (2005), screening and surveillance in older patients has to be based on the understanding that “the elderly are a heterogeneous group, and there is no single age threshold beyond which screening will suddenly lose its benefits, or become more harmful, equally for all patients.” A framework developed by the same authors (Walter and Covinsky 2001) based on quantitative estimates of life expectancy, risk of CRC death, and screening outcomes showed substantial variation in the likelihood of benefit for patients of similar ages with varying life expectancies. A model (Ko and Sonnenberg 2005), based on this framework (Walter and Covinsky 2001), examined the risks and benefits of screening in patients aged 70–94 years with varying health status using annual fecal occult blood tests, flexible sigmoidoscopy every 5 years, or colonoscopy every 10 years. The authors found that the benefit of screening varied with chronological age and life expectancy and screening modality. For example, for colonoscopy, the number needed to screen (NNS) to prevent one CRC death was 33 for a 50–54 year old in good health and 133 for an 85–89 year-old. Several studies have addressed how life expectancy impacts screening outcomes in clinical practice (Gross et al. 2006; Kahi et al. 2007; Lin et al. 2006). A cross-sectional study of 1244 asymptomatic individuals in 3 age groups (50–54 years, 75–79 years, and 80 years) who underwent screening colonoscopy (Lin et al. 2006) showed increasing prevalence of neoplasia with age, but significantly lower extension of life expectancy in the group aged 80 years or older (0.13 years) compared to the 50- to 54-year-old group (0.85 years) (Lin et al. 2006). Gross et al. (2006) found that life expectancy after early stage CRC diagnosis was strongly related to age and the burden of chronic illness; patients with higher comorbidity had lower gain in life expectancy associated with early-stage CRC diagnosis than those without chronic conditions (Gross et al. 2006). For example, an 81-year-old man with

88

Colorectal Cancer Screening

stage I CRC and no chronic conditions would be expected to have a life expectancy of 10.3 years, compared to 4.3 years for a similar man with 3 or more chronic conditions. A retrospective cohort study of over 400 Veterans aged 75 years or older who underwent colonoscopy (Kahi et al. 2007) found that mortality was predicted by age (hazard ratio 1.16 for each year increase beyond age 75 years) and Charlson comorbidity score (hazard ratio 8.3 for each point increase), but not by indication for the procedure. The implication of these findings is that comorbidity, and its effect on life expectancy, has to be taken into account in screening decisions, as some elderly may not benefit from prevention, or even detection of early stage and potentially curable CRC. Conversely, screening relatively healthy older patients could still be reasonable in certain situations. A cost-effectiveness analysis (Van Hees et al. 2014) assessed previously unscreened average-risk persons 76- to 90-year-olds CRC screened using one-time FIT, sigmoidoscopy, or colonoscopy. At a threshold of $100,000 per QALY, CRC screening was cost-effective in unscreened elders until ages 86 for colonoscopy, 84 for sigmoidoscopy, and 83 for FIT in the absence of comorbidity. The thresholds were 80, 78, and 77 years, respectively, in the presence of severe comorbidity. The authors concluded that previously unscreened elders should be considered for screening after age 75, including with colonoscopy. These findings are extended by studies quantifying the effect on CRC incidence after colonoscopy. A case-control study of VAMedicare patients aged 75 years reported that colonoscopy was associated with an overall 43% CRC reduction, which was significant for both distal (aOR 0.45, 95% CI: 0.32–0.62) and proximal CRC (aOR 0.65, 95% CI: 0.46–0.92) (Kahi et al. 2014).

Tailoring Screening Decisions While predicted life expectancy should be a main factor driving CRC screening decisions in the elderly, there is significant evidence that this not well applied in clinical practice. A study assessed

1959

the relationship between patient comorbidity and FOBT screening in Veterans and found no consistent significant association between comorbidity and the use of FOBT, except in the sickest 1% of patients (Fisher et al. 2007). Another study assessed the VA and Medicare claims of 27 068 veterans 70 years or older for receipt of a CRC screening test (FOBT, colonoscopy, sigmoidoscopy, barium enema) and found that the rate of screening was only 47% for patients with no comorbidity (5-year mortality, 19%), whereas it was 41% for patients with severe comorbidity (5-year mortality, 55%) (Walter et al. 2009). Surveys describing providers’ approach to CRC screening in older adults provide additional insight. A survey of 183 VA healthcare providers using clinical vignettes that varied by patient age, comorbidity, and past CRC screening history reported that over 20% of respondents would screen a 75 year old with an active malignancy, severe heart failure, or chronic obstructive pulmonary disease (Kahi et al. 2009). Another patient scenario-based survey (Haggstrom et al. 2013) of over 1200 physicians found that 25% of primary care physicians recommended CRC screening for an 80-year-old patient with advanced lung cancer. The reasons for such inappropriate screening are unclear, but are likely multifactorial. In the elderly, screening has to take into account variables beyond chronological age and estimated life expectancy, such as functional status, past screening history, patient preference, system factors such as clinical reminders and quality of care measures, as well as individual physicians’ experience and practice (Kahi et al. 2009). There is evidence that organizational pressures, such as the use of performance measures to increase the rates of screening, can lead to the unintended consequence of increasing the rate of inappropriate screening in elderly patients with limited life expectancy (Hoffman and Walter 2009). Other factors are fear of litigation, reliance on heuristics, and oversimplification of the benefits of CRC screening (Hoffman and Walter 2009). In addition, the discussion to forego screening may be difficult for all involved: Some patients are reluctant to discuss age and life expectancy in the

1960

C. J. Kahi and D. K. Rex

Functional Status

Estimated Benefit from Screening

Screening Harms and Overdiagnosis Individual Risk Factors for Colorectal Neoplasia

Comorbidity

Prior CRC Screening and Surveillance History

Life Expectancy

Chronological Age

CRC Screening

Patient Preference

Fig. 2 Factors involved in CRC screening decisions in the elderly

context of screening (Schoenborn et al. 2017), and physicians report difficulty with discussions about CRC screening in adults aged 75 and older because of complexity and uncertainty around estimates of life expectancy (Lewis et al. 2009).

Guidelines The United States Preventive Services Task Force (USPSTF) has recently updated its recommendations for CRC screening (USPSTF 2017). The guideline recommends CRC screening in adults aged 50–75 years, with an “A” grade. In adults aged 76–85 years, the recommendation was more qualified and given a “C” based on the quality of the available evidence. According to the USPSTF, the decision to screen for CRC in adults aged 76–85 years should be an individual one, taking into account the patient’s overall health and prior screening history. The guideline specifies that screening would be most appropriate for those not previously screened, those healthy enough to undergo treatment if CRC is detected, and those without significantly limited life expectancy. In adults 86 years and older, screening is not

recommended because of competing causes of mortality. While guidelines are an important step forward, their uptake and impact on clinical practice are still uncertain. A recent study assessed over 13,000 patients with normal screening colonoscopies within the New Hampshire Colonoscopy Registry. Recommendations against further screening were 16%, 41%, and 65% among age groups 70–74, 75–79, and 80 and older, respectively. Gastroenterologists twice were more likely to recommend stopping colonoscopy in accordance with guidelines than other non-gastroenterology endoscopists. Analysis of temporal trends showed a significant increase in recommendations against future colonoscopy in all age groups, suggestive of improved uptake and awareness of guidelines.

Conclusion CRC screening in the elderly is a complex process which has to balance several, often competing, factors (Fig. 2). While patients and health care providers face an array of considerations, healthadjusted life expectancy is a major determinant of

88

Colorectal Cancer Screening

the likelihood of benefit from screening and should be a central component of individualized and shared decision-making.

References Arora A, Singh P. Colonoscopy in patients 80 years of age and older is safe, with high success rate and diagnostic yield. Gastrointest Endosc. 2004;60:408–13. Brenner H, Hoffmeister M, Stegmaier C, Brenner G, Altenhofen L, Haug U. Risk of progression of advanced adenomas to colorectal cancer by age and sex: estimates based on 840,149 screening colonoscopies. Gut. 2007;56:1585–9. Cha JM, Kozarek RA, La Selva D, Gluck M, Ross A, Chiorean M, Koch J, Lin OS. Risks and benefits of colonoscopy in patients 90 years or older, compared with younger patients. Clin Gastroenterol Hepatol. 2016;14:80–6 e1. Cooper GS, Kou TD, Barnholtz Sloan JS, Koroukian SM, Schluchter MD. Use of colonoscopy for polyp surveillance in medicare beneficiaries. Cancer. 2013;119: 1800–7. Cucino C, Buchner AM, Sonnenberg A. Continued rightward shift of colorectal cancer. Dis Colon Rectum. 2002;45:1035–40. Day LW, Velayos F. Colorectal cancer and the elderly. Clin Geriatr Med. 2014;30:117–31. Day LW, Walter LC, Velayos F. Colorectal cancer screening and surveillance in the elderly patient. Am J Gastroenterol. 2011;106:1197–206; quiz 1207 Duncan JE, Sweeney WB, Trudel JL, Madoff RD, Mellgren AF. Colonoscopy in the elderly: low risk, low yield in asymptomatic patients. Dis Colon Rectum. 2006;49:646–51. Feingold DL, Forde KA. Colorectal cancer surveillance after age 65 years. Am J Surg. 2003;185:297–300. USPSTF Final Recommendation Statement: Colorectal Cancer: Screening. U.S. Preventive Services Task Force. June 2017. https://www.uspreventiveservices taskforce.org/Page/Document/RecommendationState mentFinal/colorectal-cancer-screening2. [Online]. Fisher DA, Galanko J, Dudley TK, Shaheen NJ. Impact of comorbidity on colorectal cancer screening in the veterans healthcare system. Clin Gastroenterol Hepatol. 2007;5:991–6. Froehlich F, Wietlisbach V, Gonvers JJ, Burnand B, Vader JP. Impact of colonic cleansing on quality and diagnostic yield of colonoscopy: the European Panel of Appropriateness of Gastrointestinal Endoscopy European multicenter study. Gastrointest Endosc. 2005;61:378–84. Goodwin JS, Singh A, Reddy N, Riall TS, Kuo YF. Overuse of screening colonoscopy in the Medicare population. Arch Intern Med. 2011;171:1335–43. Gross CP, Mcavay GJ, Krumholz HM, Paltiel AD, Bhasin D, Tinetti ME. The effect of age and chronic illness on life expectancy after a diagnosis of colorectal cancer:

1961 implications for screening. Ann Intern Med. 2006;145:646–53. Haggstrom DA, Klabunde CN, Smith JL, Yuan G. Variation in primary care physicians’ colorectal cancer screening recommendations by patient age and comorbidity. J Gen Intern Med. 2013;28:18–24. Hardcastle JD, Chamberlain JO, Robinson MH, Moss SM, Amar SS, Balfour TW, James PD, Mangham CM. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet. 1996;348: 1472–7. Harewood GC, Lieberman DA. Colonoscopy practice patterns since introduction of medicare coverage for average-risk screening. Clin Gastroenterol Hepatol. 2004; 2:72–7. Hoffman RM, Walter LC. Colorectal cancer screening in the elderly: the need for informed decision making. J Gen Intern Med. 2009;24:1336–7. https://www.census.gov/prod/cen2010/briefs/c2010br-09. pdf. [Online]. Imperiale TF, Ransohoff DF, Itzkowitz SH. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;371:187–8. Kahi CJ. Screening relevance of sessile serrated polyps. Clin Endosc. 2019;52:235. Kahi CJ, Azzouz F, Juliar BE, Imperiale TF. Survival of elderly persons undergoing colonoscopy: implications for colorectal cancer screening and surveillance. Gastrointest Endosc. 2007;66:544–50. Kahi CJ, Van Ryn M, Juliar B, Stuart JS, Imperiale TF. Provider recommendations for colorectal cancer screening in elderly veterans. J Gen Intern Med. 2009; 24:1263–8. Kahi CJ, Myers LJ, Slaven JE, Haggstrom D, Pohl H, Robertson DJ, Imperiale TF. Lower endoscopy reduces colorectal cancer incidence in older individuals. Gastroenterology. 2014;146:718–725 e3. Knudsen AB, Zauber AG, Rutter CM, Naber SK, DoriaRose VP, Pabiniak C, Johanson C, Fischer SE, Lansdorp-Vogelaar I, Kuntz KM. Estimation of benefits, burden, and harms of colorectal cancer screening strategies: modeling study for the US Preventive Services Task Force. JAMA. 2016;315:2595–609. Ko CW, Sonnenberg A. Comparing risks and benefits of colorectal cancer screening in elderly patients. Gastroenterology. 2005;129:1163–70. Koretz RL. Polyp surveillance in patients with limited life expectancy. JAMA. 1996;275:327. Kronborg O, Fenger C, Olsen J, Jorgensen OD, Sondergaard O. Randomised study of screening for colorectal cancer with faecal-occult-blood test. Lancet. 1996;348:1467–71. Lee SJ, Boscardin WJ, Stijacic-Cenzer I, Conell-Price J, O’Brien S, Walter LC. Time lag to benefit after screening for breast and colorectal cancer: meta-analysis of survival data from the United States, Sweden, United Kingdom, and Denmark. BMJ. 2013;346:e8441. Lewis CL, Griffith J, Pignone MP, Golin C. Physicians’ decisions about continuing or stopping colon cancer

1962 screening in the elderly: a qualitative study. J Gen Intern Med. 2009;24:816–21. Lieberman DA, Williams JL, Holub JL, Morris CD, Logan JR, Eisen GM, Carney P. Colonoscopy utilization and outcomes 2000 to 2011. Gastrointest Endosc. 2014; 80:133–43. Lin OS, Kozarek RA, Schembre DB, Ayub K, Gluck M, Drennan F, Soon MS, Rabeneck L. Screening colonoscopy in very elderly patients: prevalence of neoplasia and estimated impact on life expectancy. JAMA. 2006;295:2357–65. Lin JS, Piper MA, Perdue LA, Rutter CM, Webber EM, O’Connor E, Smith N, Whitlock EP. Screening for colorectal cancer: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2016;315:2576–94. Lukens FJ, Loeb DS, Machicao VI, Achem SR, Picco MF. Colonoscopy in octogenarians: a prospective outpatient study. Am J Gastroenterol. 2002;97:1722–5. Mandel JS, Bond JH, Church TR, Snover DC, Bradley GM, Schuman LM, Ederer F. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med. 1993;328:1365–71. Miller KM, Waye JD. Approach to colon polyps in the elderly. Am J Gastroenterol. 2000;95:1147–51. Miller K, Waye JD. Colorectal polyps in the elderly: what should be done? Drugs Aging. 2002;19:393–404. Miyakura Y, Sugano K, Konishi F, Ichikawa A, Maekawa M, Shitoh K, Igarashi S, Kotake K, KOYAMA Y, NAGAI H. Extensive methylation of hMLH1 promoter region predominates in proximal colon cancer with microsatellite instability. Gastroenterology. 2001;121:1300–9. Murphy CC, Sandler RS, Grubber JM, Johnson MR, Fisher DA. Underuse and overuse of colonoscopy for repeat screening and surveillance in the Veterans Health Administration. Clin Gastroenterol Hepatol. 2016;14: 436–444 e1. Ransohoff DF, Lang CA. Sigmoidoscopic screening in the 1990s. JAMA. 1993;269:1278–81. Rex DK, Ahnen DJ, Baron JA, Batts KP, Burke CA, Burt RW, Goldblum JR, Guillem JG, Kahi CJ, Kalady MF, O’BRIEN MJ, Odze RD, Ogino S, Parry S, Snover DC, Torlakovic EE, Wise PE, Young J, Church J. Serrated lesions of the colorectum: review and recommendations from an expert panel. Am J Gastroenterol. 2012;107:1315–29; quiz 1314, 1330 Rex DK, Boland CR, Dominitz JA, Giardiello FM, Johnson DA, Kaltenbach T, Levin TR, Lieberman D, Robertson DJ. Colorectal cancer screening: recommendations for

C. J. Kahi and D. K. Rex physicians and patients from the U.S. Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2017;153:307–23. Schoenborn NL, Lee K, Pollack CE, Armacost K, Dy SM, Bridges JFP, Xue QL, Wolff AC, Boyd C. Older adults’ views and communication preferences about cancer screening cessation. JAMA Intern Med. 2017;177: 1121–8. Sheffield KM, Han Y, Kuo YF, Riall TS, Goodwin JS. Potentially inappropriate screening colonoscopy in Medicare patients: variation by physician and geographic region. JAMA Intern Med. 2013;173:542–50. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34. Stevens T, Burke CA. Colonoscopy screening in the elderly: when to stop? Am J Gastroenterol. 2003;98: 1881–5. Tang V, Boscardin WJ, Stijacic-Cenzer I, Lee SJ. Time to benefit for colorectal cancer screening: survival metaanalysis of flexible sigmoidoscopy trials. BMJ. 2015;350:h1662. Tran AH, Man Ngor EW, Wu BU. Surveillance colonoscopy in elderly patients: a retrospective cohort study. JAMA Intern Med. 2014;174:1675–82. U.S. Census Bureau, Statistical Abstract of the United States: 2012. Van Hees F, Habbema JD, Meester RG, Lansdorp-Vogelaar I, VAN Ballegooijen M, Zauber AG. Should colorectal cancer screening be considered in elderly persons without previous screening? A cost-effectiveness analysis. Ann Intern Med. 2014;160:750–9. Walter LC, Covinsky KE. Cancer screening in elderly patients: a framework for individualized decision making. JAMA. 2001;285:2750–6. Walter LC, Lewis CL, Barton MB. Screening for colorectal, breast, and cervical cancer in the elderly: a review of the evidence. Am J Med. 2005;118:1078–86. Walter LC, Lindquist K, Nugent S, Schult T, Lee SJ, Casadei MA, Partin MR. Impact of age and comorbidity on colorectal cancer screening among older veterans. Ann Intern Med. 2009;150:465–73. Warren JL, Klabunde CN, Mariotto AB, Meekins A, Topor M, Brown ML, Ransohoff DF. Adverse events after outpatient colonoscopy in the Medicare population. Ann Intern Med. 2009;150:849–57, W152 Winawer SJ, Zauber AG, Ho MN, O’Brien MJ, Gottlieb LS, Sternberg SS, Waye JD, Schapiro M, Bond JH, Panish JF, et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med. 1993;329:1977–81.

Colorectal Cancer

89

C. S. Pitchumoni

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1964 Epidemiology of CRC in Relevance to the Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . Worldwide Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology of CRC in the USA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Morphology of Colon Polyps and CRC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1964 1965 1965 1967

The Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1970 Modifiable Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1971 Clinical Features of CRC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Screening for CRC in the Older Adults (When to Do, What to Do, and When to Stop) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment Options of CRC in Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Preoperative Management of CRC in Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1974 1974 1978 1978

Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1982 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1982

Abstract

C. S. Pitchumoni (*) Department of Medicine, Robert Wood Johnson School of Medicine, Rutgers University, New Brunswick, NY, USA Department of Medicine, New York Medical College, Valhalla, NY, USA Division of Gastroenterology, Hepatology and Clinical Nutrition, Saint Peters University Hospital, New Brunswick, NJ, USA e-mail: [email protected]

According to the World Health Organization (WHO), colorectal cancer (CRC) is the second most common tumor among both men and women, after lung tumors. CRC is one of the most common age-related cancers and a common cause of cancer-related deaths. Approximately 60% of individuals with CRC are >70 years of age at the time of diagnosis, and 43% are >65. The risk is higher in women, with 27% of cases over age 80 years. It is not surprising that the incidence is increasing since there is a global increase in the number of older adults. Rectal cancer predominantly affects persons >70 years, with a peak incidence at age 80–85 years.

© Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_80

1963

1964

There is a marked difference in the incidence of CRC between the affluent nations with a High Developmental Index (HDI) with a high incidence and low incidence in developing nations. The modifiable risk factors are many for the sporadic type of CRC, which accounts for over 90% of the cancers in older adults, in contrast to genetic types of CRC. Many screening options are available. Colonoscopic screening for CRC is advocated for all healthy adults above the age of 50 and even for healthy older adults irrespective of chronological age but based on anticipated life expectancy. Treatment modalities, in general, are surgery for stage I or II; surgery followed by adjuvant chemotherapy for stage III colon cancer, and in cases of metastatic CRC (mCRC) systemic chemotherapy alone or with targeted biologics. The goals of surgery in rectal cancer include removal of the tumor, avoid local recurrence, and, if possible, preserve sphincter function. With appropriate geriatric and nutritional assessment, the prognosis of CRC in the older adult has improved. Solely based on older age, a patient should not be excluded from any advanced treatment options available to the younger patients. Keywords

Colon · Rectum · Adenoma · Villous adenoma · Serrated adenoma · Microsatellite instability · Hereditary nonpolyposis colon cancer syndrome (HNPCC) · Familial adenomatous polyposis syndromes · PeutzJeghers disease · Juvenile polyposis chemotherapy · Colostomy · Hereditary CRC · Radiation · Adjuvant chemotherapy · 5-Fluorouracil (5-FU) · Capecitabine · Irinotecan · Oxaliplatin · Trifluridine and Tipiracil · Palliative care · Nutrition · Laparoscopic surgery · Hepatic metastasis · Duke’s classification · Obesity · Colonoscopy · Screening · Dietary fiber

C. S. Pitchumoni

Introduction Older age is well recognized to be the number one cause of most cancers, importantly that of colon and rectum. Globally the most common cancers are lung (2.09 million cases), breast (2.09 million cases), colorectal (1.80 million cases), and prostate (1.28 million cases). Thus worldwide, colorectal cancer (CRC), the third most commonly diagnosed malignancy, is the fourth leading cause of cancer death, accounting for about 1.8 million new cases and almost 881,000 deaths in 2018 (Bray et al. 2018). The incidence of CRC is markedly different from country to country (Figs. 1 and 2). Almost all epidemiological studies agree on the following. There is (i) a high incidence of CRC in many affluent nations with a High Developmental Index (HDI, a composite index of life expectancy, education, and per capita income indicators), (ii) a relatively low incidence in many Afro-Asian countries with a low developmental index, and (iii) a slow increase in areas where previously it was low. The change is in parallel with an advance in HDI and to the western type of lifestyle changes in diet, sedentary life, and increase in BMI. Most of the sporadic CRC (in contrast to hereditary polyposis and hereditary nonpolyposis colon cancer (HNPCC)) syndromes are either preventable or can be diagnosed at a curable stage (favorable “stage shifting”) by routine screening examinations (Arnold et al. 2017; Center et al. 2009). Older adults are often given suboptimal treatment because of ill-conceived notions. The primary goal of this chapter is to emphasize the unique issues concerning screening for CRC and management n older adults. The details on clinical features, diagnostic studies, staging, and screening options are only briefly discussed.

Epidemiology of CRC in Relevance to the Older Adults Data on community-based estimates of the prevalence of colorectal neoplasms (adenomatous polyps and cancer) widely varies depending on

89

Colorectal Cancer

1965

Fig. 1 Incidence and mortality of colorectal cancer – SEER incidence and US death rates for invasive colon and rectal cancer (2001–2005), by age group. SEER ¼ Surveillance, Epidemiology and End Results. Adapted from SEER Cancer Statistics Review. Available at http:// seer.cancer.gov. Accessed January 16, 2009

the country. Screening colonoscopy based data is the best in predicting the prevalence of asymptomatic adenomas which are the leading precursors to CRC. However, screening colonoscopies are not performed in most countries.

Worldwide Epidemiology Older age is the number one risk factor for CRC as for many other cancers in adults. Epidemiologists predict an increase in the incidence of CRC world over with improved longevity and change in lifestyle. The incidence and mortality rates vary up to ten-fold worldwide. In highly developed countries, the rates are stabilizing but yet remain the highest in the world (Arnold et al. 2017; Mattiuzzi et al. 2019). There are many interesting observations in the epidemiology of CRC suggesting clues to the etiology. The incidence is 18% higher in the highly industrialized and affluent nations in comparison with many developing nations in Asia and Africa. According to a 2012 report, the highest age-standardized incidence rates (per 100,000 population) are in Australia/New Zealand (44.8 and 32.2 cases in men and women, respectively), and the lowest is in western Africa (4.5 and 3.8 cases in

men and women, respectively). More than two-thirds of all cases and about 60% of all deaths are occurring in countries with distinct gradients across HDI levels, the highest incidence in rich countries, lowest in emerging nations, and in between rates in countries in transition (China, India, Brazil, etc.). The highest estimated 2012 mortality rates (per 100,000 population) were in central and eastern Europe (20.3 deaths in men and 11.7 in women), and the lowest in western Africa (3.5 deaths in men and 3.0 in women). The rates are rising rapidly in many low-income and middleincome countries attributed to a western lifestyle mostly in the form of changes in diet (from high fiber to low fiber, high fat, mostly of animal origin), increasing obesity, and other environmental changes (Figs. 2 and 3).

Epidemiology of CRC in the USA CRC is the fourth leading cause of cancers and the second leading cause of cancer death among men and women combined in the United States. According to the American Cancer Society, 147,950 people will be diagnosed with CRC and 53,200 could die from this disease in 2020. In

1966

C. S. Pitchumoni

Fig. 2 Global incidence of CRC. High incidence in countries with High human development index (HDI) and lower incidence in countries with low HDI. GLOBOCAN 2018. WHO International Agency for Research on Cancer. Source GLOBOCAN 2018

previous years the incidence and death rates were highest among persons aged >75 years (Siegel et al. 2019). Centers for Disease Control and Prevention (CDC) analyzed the CRC incidence and mortality data in 2008 from the US Cancer Statistics (USCS). Men had higher CRC incidence rates (51.6 versus 38.7 per 100,000 population) and death rates (19.7 vs. 13.8 per 100,000 population) compared to women. Relevant to this chapter on “CRC in older adults” is the data that the incidence and mortality increased with advancing age (Fig. 1). A more significant number of men (23,720) than women (16,190) would develop CRC. Non-Hispanic blacks had the highest CRC incidence and death rates compared to non-Hispanic whites, Asians/Pacific Islanders, and American Indians/Alaska Natives.

The American Cancer Society (ACS), in 2019, estimated the number of new CRC cases to be 101,420, with about 51,020 deaths. Advanced stage CRC and reduced survival after diagnosis in comparison to Whites are also notable (Alexander et al. 2007). Current screening guidelines recommending the first colonoscopy at age 45 in African Americans is a reflection of the above. Irrespective of the race there is an increase in proximal cancers noted in older age groups, the take-home message being that a screening sigmoidoscopy is inadequate in firmly xcluding colon cancer in the older adults. The trend of a decrease in CRC incidence (Fig. 4) may be due to effective implementation of CRC screening and surveillance procedures. In the USA, the incidence rates have dropped

89

Colorectal Cancer

1967

Fig. 3 GLOBOCAN. CDC Colorectal Cancer Incidence and Screening – United States, 2008 and 2010. Shows the increasing incidence as age advances. CDC data. Supplements: November 22, 2013/62(03); 53–60

from 298.3 per 100,999 to 186.8 per 100,000 from 2000 to 2013 (Nee et al. 2020).

Morphology of Colon Polyps and CRC Majority of CRC are sporadic, more so in the older age groups. Hereditary colon cancers make up less than 5% of all colon cancer cases worldwide (Kwong and Dove 2009). There is a high morphological heterogeneity in terms of size, grade, and type of the CRC. The variability is also seen in clinical presentation, the likelihood of cure, a pattern of extension, and response to treatment (Fearon 2011; Sadanandam et al. 2013; de Sousa E Melo et al. 2013). Although in this chapter, we have used the common term “CRC” to discuss the entities of the

colon and rectal cancers, there are a few differences between the two. The median age at diagnosis for colon cancer is 68 in men and 72 in women; for rectal cancer, it is 63 years of age in both men and women (American Cancer Society 2017). Other differences are presented in the discussions. CRC cancer mortality rates are declining in the USA and some other developed nations (Arnold et al. 2017; Center et al. 2009). Rectal cancers (R.C.) are histologically adenocarcinomas but because of the location below the peritoneal reflection, differ in certain respects from colon cancer. In the USA, there were an estimated 39,910 cases of rectal cancers in 2017 (Goldenberg et al. 2018). Nearly 90% of the cases were in those >50 years of age. There are anatomical differences, blood supply, drainage, and innervation resulting in variations in the behavior of colon and rectal cancers, invasive

1968

C. S. Pitchumoni

Fig. 4 Data shows a trend of decrease in CRC in the USA. US Cancer Statistics Data Visualizations Tool. CDC data

growth of the primary tumor and the surgical approaches and treatment outcomes (van der Sijp et al. 2016). Rectal cancers differ from colon cancer in their risk for local recurrence, survival, and management issues (Goldenberg et al. 2018; van der Sijp et al. 2016). Because of its location, in the distal colon, the clinical manifestations of rectal cancers are somewhat different. Change in bowel habits may occur early and is present in nearly 75% of cases, bright red blood in stool in 50%, rectal mass in 25%, iron deficiency anemia in 10%, and abdominal pain in 4% (Thompson et al. 2017). Rectal cancers have about a 20% risk of local recurrence, versus about two percent with colon cancers. Some studies suggest that the high body mass index (BMI), low physical activity, and dietary parameters such as high intake of beef, pork or lamb, processed meat, and alcohol are risk factors for colon cancers but not for rectal cancer (Wei et al. 2004; Terry et al. 2002; Colditz et al. 1997; National Institutes of Health 2020). There are two types of CRC: genetic and sporadic. Nearly all CRCs arise from adenomatous polyps, excluding cases from inflammatory bowel diseases. Epidemiologic data indicate that as many as 30–50% of individuals >50 years of age harbor one or more polyps (tubular, tubulovillous, villous,

and serrated) during their life and a small percentage of them may transform into CRC. Polyps >1 cm in size may contain villous features denoting a higher risk for cancer. There are multiple steps taking place in ten or more years in the transformation of normal colonic epithelium to colon polyp and colonic adenocarcinoma. The process involves a series of histological, morphological, and genetic and epigenetic factors (Tenesa and Dunlop 2009; Pino and Chung 2010; Simon 2016). The histological types of colon polyps are tabulated. All polyps are not precancerous. The various histological types of premalignant polyps are: (i) adenomatous (tubular), (ii) villous, (iii) tubulovillous, and (iv) sessile serrated adenoma a type of hyperplastic polyp, especially on the right side of the colon. The pathways to CRC are summarized in Fig. 5. Adenomatous polyps are seen in routine screening colonoscopies, with a lifetime risk of around 5% in the western world. A recent population-based study noted that at least one polyp was detected in 34.3% of asymptomatic patients undergoing screening colonoscopy (Reinhart et al. 2013). The goal of a colon cancer screening program is to recognize the neoplastic polyps at a sufficiently early stage when an outpatient colonoscopy and polypectomy would

89

Colorectal Cancer

1969

Fig. 5 Sessile serrated adenoma Right side of colon

likely prevent the later development of CRC. The long latent period of more than a decade allows for periodic screening and detection, and removal of early-stage precancerous polyps before they become cancerous. Colonic adenomas may be flat, sessile, subpedunculated, or pedunculated. The prevalence of adenomas increases sharply with age. The malignant potential of polyps is influenced by the size, shape, pedunculated or sessile, and histopathology. Precancerous colon polyps are related to size (>10 mm), shape (more with sessile), and histology (villous and tubulovillous types), and they are more prevalent in older adults. In contrast, the prevalence of serrated lesions (discussed later) increases only modestly with age (Kim et al. 2014). The prevalence and severity of neoplastic changes from adenoma through advanced adenoma to invasive carcinoma are substantially related to aging (Nee et al. 2020; Strul et al. 2006). Strul and associates (Strul et al. 2006) reported that healthy older adults aged 76–80 years at average risk have twice the risk for advanced neoplasia and CRC (14.3% and 2.6%, respectively) compared to the age group of 50–75 years. The adenoma detection rate is an indicator of the quality of a colonoscopy. The multiple steps in the development of colon cancer from epithelium to benign adenomatous polyps to more advanced premalignant polyps with foci of high-grade dysplasia, to locally invasive cancer, and eventually to metastatic disease (see Fig. 5) take place in many years, usually more than 10– 15 years. The complicated process is driven by the

accumulation of mutations that perturb specific genetic pathways at each step in the tumorigenic process (Vogelstein et al. 1988; Muto et al. 1975; Miyoshi et al. 1992; Nagase and Nakamura 1993). CRC arises from three different pathways: (1) “adenoma to carcinoma pathway” (about 50–70% of cancers, (2) recently described “the serrated pathway “(30–35%), and (3) through the mutator “Lynch syndrome” route (3–5%) (Erichsen et al. 2016). The concept of serrated adenoma and its malignant potential is relatively new. The serrated polyps are a heterogeneous group of hyperplastic polyps with serrated architecture of the epithelium. This group includes hyperplastic polyps and sessile serrated adenomas and traditional serrated polyps. Small hyperplastic polyps (50 2. Personal history of CRC or polyps 3. Personal history of inflammatory bowel disease (IBD) 4. Family history or personal history of CRC or polyps 5. Lynch syndrome, an inherited condition 6. Racial and ethnic backgrounds. The incidence is higher among African Americans than among whites (15% higher and 40% higher, respectively). And lower in Asian Americans, Hispanics/Latinos, and American Indians/ Alaskan natives. 7. Type 2 diabetes mellitus. Modifiable 8. Obesity 9. Diet reduced risk with a high fiber diet. High in red meats (beef, pork, lamb, or liver), processed meats, cooking meats at high temperatures (frying, broiling, or grilling) 10. Cigarette smoking 11. Heavy alcohol use 12. Sedentary lifestyle Risk reducing factors. Use of ASA and NSAIDS

the older adult would have been already exposed to the risk factors for decades.

Modifiable Risk Factors Obesity, high- fat diets, cigarette smoking, alcoholism, sedentary lifestyles are modifiable risk factors for CRC. Diabetes, family history of colon cancer, and/or family history of HNPCC-related cancers (ovary, stomach, small bowel, pancreas, hepatobiliary tract, upper uroepithelial tract, brain (Turcot variant)) and sebaceous adenomas/carcinomas (Muir-Torre variant) and inflammatory bowel diseases are nonmodifiable risk factors. Current smoking increases the risk of proximal colon and rectal cancer (Murphy et al. 2019). Individuals with a history of more than three drinks per day have about a 40% increased risk for CRC and 20% higher risk with regular drinking of 2–3 drinks per day. Obesity and obesogenic diets are implicated in the epidemiology. An obesogenic diet is quite prevalent in the western world and segments of poor nations. There is good evidence that “diabesity” (overweight, obesity, and diabetes) is

1971

associated with increased risks of many cancers (Lauby-Secretan et al. 2016; Jochem and Leitzmann 2016), including endometrial, esophageal adenocarcinoma, gastric cardiac, liver, pancreatic, and gallbladder. Individuals who are obese are slightly (about 30%) more likely to develop CRC than normal-weight people (Ma et al. 2013). A higher BMI is associated with increased risks of colon and rectal cancers in both men and women, probably attributed to chronic low-level inflammation and DNA damage. Some dietary components are considered proinflammatory. Consumption of diets high in fat added sugar and protein is associated with increased inflammation and increased risk of CRC. A high-fat consumption in particular from animal sources increases bile acid secretion. High bile acid levels in the colon increase cell loss and proliferation in the mucosa (Bruce 1987; Aykan 2015). That chronic inflammation may predispose to cancers, including CRC, is not new, but the pathophysiology is being expanded (Harmon et al. 2017). Several recent studies have looked at the Dietary Inflammatory Index (DII index) and its association with CRC. A more proinflammatory diet was associated with an increased risk of CRC in men and, to a lesser degree, in women. Increased consumption of red meat (beef, pork, lamb, and horse) and processed meat (red meat preserved by smoking, curing, salting, or by adding preservatives) increases the risk of CRC63 by 20–30%. White meat (poultry and fish) is not associated with increased cancer risk (Aykan 2015). The most extensive study is in the EPIC trial (The European Prospective Investigation into Cancer and Nutrition), which prospectively followed 478,040 men and women from 10 European countries between 1992and 1998, and the authors observed 1329 CRCs. CRC risk was positively associated with the intake of red and processed meat (Norat et al. 2005). In red meat, the heme molecule is present in high concentrations. Heme iron can promote cancer pathways by increased liberation of reactive oxygen species (ROS), which induces genetic mutations. At least 70% of sporadic colon cancers may be preventable by moderate changes in diet and lifestyle. Since the prescribed diet and lifestyle factors for CRC prevention are the same for the

1972

prevention of cardiovascular disease, type 2 diabetes mellitus, and obesity, a change in the current western pattern of diet is expected to improve overall health and reduce the incidence of cancers (Song et al. 2015; Roslan et al. 2019; Dreher 2018). These factors discussed below contribute to overall good health. In addition to a high fiber diet, many individual nutrients are noted to reduce CRC. The following is a review of some specific nutrients and the reduced risk for CRC. a) Dietary fiber (D.F.). Since Burkitt and associates in the 1970s first observed an inverse but close relationship between colon cancer and fiber-rich diet (Burkitt 1987), a large number of experimental and clinical studies have corroborated the findings. D.F. is defined as carbohydrates not digested in the small bowel but fermented by colonic bacteria. Details on D.F. are offered elsewhere in the book (EFSA Panel on Dietetic Products N and A (NDA) 2010). Dietary fiber in addition to increasing the stool bulk and diluting the carcinogens in the colon functions as a prebiotic that facilitates the growth of beneficial gut microbiota. In the colon, D.F. is fermented by gut microbiota producing short-chain fatty acids (SCFA) butyrate, acetate, and propionate. SCFA are the main fuel for colonocytes. Butyrate plays a pivotal role in maintaining normal colonic function (Fung et al. 2013; Leonel and Alvarez-Leite 2012; Shaw et al. 2017; Jacobs et al. 2006). Consumption of adequate diets rich in fruits and vegetables are superior to other fiber-rich diets because they are rich in polyphenols. Polyphenols are natural compounds rich in fruits, vegetables, whole grains, and plant-derived beverages (Alsolmei et al. 2019; Mileo et al. 2019; Little et al. 2017; Waluga et al. 2018; Nolfo et al. 2013). Polyphenols (flavonoids and non-flavonoids) reduce the risk of many kinds of cancer, including CRC (Mileo et al. 2019; Chang et al. 2018). In addition to reducing the risk for CRC, polyphenols potentiate the efficacy of chemo/radiotherapy, reduce the risk of tumor recurrence (Asensi et al. 2011), and promote good gut microbiome (Li et al. 2018).

C. S. Pitchumoni

b) Calcium intake and risk of colorectal cancer. Low levels of dietary calcium have been linked with an increased risk of CRC, although controversy exists (Bonovas et al. 2016; Lipkin and Newmark 1995; Pence 1993; Keum et al. 2014). A meta-analysis by Keum et al. in 2014 showed a positive relationship with calcium supplementation and CRC incidence (Keum et al. 2014). Each 300 mg/day of increase of calcium intake was associated with an approximately 8% reduced risk of CRC (summary RR ¼ 0.92, 95% CI ¼ 0.89–0.95, I ¼ 47% (Arnold et al. 2017), 15 studies with 12,305 cases, intake ¼ 250–1,900 mg/day, followup ¼ 3.3–16 years). The mechanism of action is not clear, but it is postulated that calcium signaling may enhance T-cell proliferation and differentiation and contribute to T-cell mediated antitumor immunity (Yang et al. 2019). c) Folic acid. B vitamins, in particular folate and B6, have been noted to have a protective role (Kok et al. 2020; Ting et al. 2019). Low folate and vitamin B6 intake was associated with an increased risk of p53-overexpressing colon cancers but not wild-type tumors (Schernhammer et al. 2008). d) Antioxidants. Several vitamins and trace elements participate in scavenging the free radicals (F.R.) implicated in carcinogenesis. The significant vitamins necessary in scavenging F.R. are beta carotene, vitamin A, vitamin C, and vitamin E. The essential trace elements are zinc (Zn), copper (Cu), manganese (Mn), iron (Fe), and selenium (Se). A small number of studies have reported a protective value for antioxidant supplements in preventing CRC. However, a recent meta-analysis of eight placebo controlled trials demonstrated no convincing evidence for antioxidant supplements in the prevention of CRC (Bjelakovic et al. 2006). e) Other nutrients. Dairy products contain many vital nutrients and may be associated with a decreased risk of CRC. Omega (ω)-3 polyunsaturated fatty acids (PUFAs) are naturally occurring substances recognized to have anticancer activity. There is also evidence for improved efficacy and tolerability of

89

Colorectal Cancer

conventional cancer chemotherapy when administered with ω-3 PUFAs (Cockbain et al. 2012). f) Cooking red meats at very high temperatures (frying, broiling, or grilling) is reported to result in chemicals that might raise the risk for CRC. The World Health Organization (WHO)’s International Agency for Research on Cancer (IARC) announced in a monograph evaluating the consumption of red meat and processed meat in Lyon, France, 2015, that processed meat (meat that has been transformed through salting, curing, fermentation, smoking, or other processes to enhance flavor or improve preservation) is carcinogenic. Non-modifiable risk factors. Many risk factors are nonmodifiable, such as older age, a personal, or familial history of colorectal polyps or CRC, racial and ethnic backgrounds. The average age at the time of diagnosis for colon cancer in men is 68 and in women 72 years. For rectal cancer, it is age 63 for both men and women. For reasons not clear, men have a slightly higher risk of developing CRC than women. Probably race is an added risk factor. African Americans in the USA have the highest rates of sporadic, or nonhereditary, colorectal cancer. Further African Americans are more likely to be diagnosed with CRC at a younger age (Williams et al. 2016). Although over the past 10 years, the incidence and mortality rates of CRC in the USA has steadily declined as a result of early screening, the benefits are strikingly lower among African Americans who continue to have the highest rate of mortality and lowest survival when compared with all other racial groups. The American College of Gastroenterology recommends that African Americans begin screening with colonoscopies at age 45 instead of age 50 (Wei et al. 2004; Chan and Giovannucci 2010). Hereditary factors. A brief description of hereditary CRC is not out of place since such cancers may occur in older age groups also (Lee et al. 2017). According to Lynch, while the lifetime risk of CRC in the general population is about 5–6%, the patients with a familial risk, those who have two or more first- or seconddegree relatives (or both) with CRC, make up

1973

approximately 20% of all patients with CRC. CRC has one of the largest proportions of familial cases (about 25%), although only 5–6% of cases of CRC is associated with germline mutations that confer an inherited predisposition for cancer (Boland et al. 2018). The important hereditary syndromes are Lynch syndrome or hereditary nonpolyposis colorectal cancer [HNPCC]), familial adenomatous polyposis (FAP), attenuated FAP, MUTYH-associated polyposis (MAP), and Peutz Jeghers (Song et al. 2015; Yamauchi et al. 2012). All of these conditions are inherited autosomal dominant disorders, except MAP, which is autosomal recessive (Witold et al. 2018). The possibility of a hereditary cancer syndrome should be assessed for every patient irrespective of age at the time of initial CRC diagnosis because screening and management guidelines differ from sporadic cases (Jasperson et al. 2010; Stoffel et al. 2015). An association with a specific bacterial disease and CRC is the finding of a strong relationship with Streptococcus bovis sepsis. S. bovis is currently named S. gallolyticus. 25–80% of patients with S. bovis/gallolyticus bacteremia have concomitant colorectal tumors. Cancer may arise years after the presentation of bacteremia or infectious endocarditis relating in S. bovis/gallolyticus (Abdulamir et al. 2011). Beneficial Medications in risk reduction of CRC. Chemoprevention refers to the use of pharmaceutical or natural agents to prevent or delay the development of cancer in healthy patients. The agents used should be well-tolerated, low in toxicity, inexpensive, and effective (Kim and Giardiello 2011). Regular use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, lowers the risk of CRC and polyps. Epidemiological and experimental studies and recent randomized, placebo controlled trials suggest that NSAIDS are effective chemopreventive agents in patients with familial adenomatous polyposis. Sulindac, a NSAID, and its metabolites exhibit pronounced pro-apoptotic activity in cancer cell lines and animal models including activation of both extrinsic and intrinsic apoptosis pathways (Li et al. 2015; Veettil et al. 2017; Baron 2003; Logan et al. 2008).

1974

Low-dose aspirin has a moderate chemopreventive effect on adenomas in the large bowel (Baron et al. 2003). There is no strong recommendation for prophylactic ASA therapy to prevent CRC in the general population. A meta-analysis of five primary prevention RCTs examining aspirin chemoprevention in patients without previously detected cardiovascular disease reported that ASA added to a nonsignificant increased risk of hemorrhagic stroke (U.S. Preventive Services Task Force 2007). Many other interesting observations are in the scientific and lay press requiring a brief discussion. Agents under study in this regard are curcumin and eicosapentaenoic acid which show efficacy in small clinical trials of chemoprevention of FAP. The use of statins, extensively used as a class of hypolipidemic agents, was associated with a 47% relative reduction in the risk of colorectal cancer after adjustment for other known risk factors (Poynter et al. 2005). HMG-CoA reductase is overexpressed in CRC cells, and statins have been shown to induce apoptosis in cancer cell lines in vitro (Poynter et al. 2005; Dobrzycka et al. 2018; Lochhead and Chan 2013). The evidence is insufficient evidence to recommend the use of statins for chemoprevention of CRC. Metformin use is likely to reduce the risk of colorectal adenoma, especially in high-risk populations (Jung et al. 2017). The role of gut microbiota and CRC is an important one discussed at length in another chapter. The unhealthy GM, in short, has a decreased variety of bacteria and consists of mostly Firmicutes. The dysbiotic GM is involved in the pathogenesis of many metabolic disorders and cancers including that of CRC in both animal models and human studies (Zhu et al. 2013; Sun and Kato 2016; Sobhani et al. 2011; Wu et al. 2013; Geng et al. 2013; Mima et al. 2016; Kostic et al. 2013). Bacterial fermentation of dietary fiber to SCFA, such as butyrate, is an important metabolic pathway in suppressing oncogenesis via its anti-inflammatory and antiproliferative effects, and carcinogenesis is the ultimate outcome from interactions between the microbiome, the environment, and the epigenetically/genetically vulnerable host. A number of

C. S. Pitchumoni

studies are currently looking at the role of prebiotics and probiotics in the prevention of CRC (Nolfo et al. 2013; Keum et al. 2014).

Clinical Features of CRC In general, the clinical features are the same as in younger individuals, well described in standard textbooks. Iron deficiency anemia, abdominal pain, change in stool caliber, new-onset constipation or less often diarrhea, intestinal obstruction, and hematochezia are the various manifestations depending on the location and size of the tumor. Weight loss is conspicuous in the age group above 80 years. A prominent feature of colon cancer in the older adult is the increasing frequency of right sided cancers, the frequency reaching nearly 50% in patients over 80 years (Itatani et al. 2018; Siegel et al. 2017; Kotake et al. 2015).

Screening for CRC in the Older Adults (When to Do, What to Do, and When to Stop) Screening tests aim to identify CRC in early stages when the curative resectability is high. Guidelines recommend screening of average risk men and women beginning at age 50: flexible sigmoidoscopy to 40 cm or splenic flexure every 5 years, colonoscopy every 10 years, double contrast barium enema every 5 years, and computer tomography colonography every 5 years. There are various recommendations by different professional societies including the American Cancer Society (ACS), US Multi-Society Task Force on Colorectal Cancer, and American College of Radiology, US Preventive Services Task Force (USPSTF), American College of Physicians (ACP), American College of Gastroenterology (ACG), and National Comprehensive Cancer Network (NCCN). The recommendations may slightly differ in details, frequency, and age of initial screening but the most important advice is that any one form of screening and adherence to a guideline is better than no screening at all (Preventive Services Task Force 2016). The US Preventive

89

Colorectal Cancer

Services Task Force (USPSTF) recommends that adults age 50–75 be screened for CRC. The Task Force leaves the decision to the caring physician in older adults age 76–85. Screened for CRC is by using one or more of the following methods: (1) fecal occult blood testing (FOBT) every year, (2) sigmoidoscopy every 5 years (with high-sensitivity FOBT every 3 years), or (3) colonoscopy every 10. Although not included as a screening test, routine digital rectal examination (DRE) is still a useful procedure in excluding rectal cancer. Many modern gastroenterologists defer an initial digital rectal examination when they are sure to perform a colonoscopy within a short period, but if the patient does not return for the scheduled colonoscopy, the patient might become a missed rectal cancer with consequences for the patient and the physician.

Stool Based Tests 1. FOBT the traditional guaiac FOBT (gFOBT) and newer immunochemical FOBT (iFOBT) (Kościelniak-Merak et al. 2018). The gFOBT tests are first-line screening tests, can be performed in the office, low sensitivity, and specificity (50%) and a high false positivity and negativity. False-positivity may result by the presence of animal-derived haem in the stool. The consumption of large amounts of green vegetables may have chlorophyll-mediated pseudo-peroxidase activity (broccoli, cauliflower, cantaloupe, carrots, squashes, figs, horseradish, grapefruit, melons, tomatoes, pumpkins, etc.) or medicines including NSAIDs, vitamin C, and iron. In order to improve the specificity, the patient should be instructed to avoid certain foods and medications for variable periods, usually 2–5 days. A positive gFOBT or iFOBT initiates a diagnostic colonoscopy to examine the entire colon. FIT-DNA. The fecal immunochemical tests (FIT) use antibodies to detect blood in the stool. It should be performed once a year and has higher sensitivity and higher participation rates. It is simpler, does not require dietary restrictions, is not very accurate, and is associated with high false negative and positive results. Once again, FIT is not a highly accurate test. Depending on the

1975

positive cutoff used, no advanced neoplasia is likely to be there in 40–70% of FIT positive patients (de Klerk et al. 2018). CT Colonography, an imaging procedure, requires cathartic bowel preparation, the most disliked part of actual colonoscopy. Sigmoidoscopy is less invasive, time consuming, and can be performed with much less preparation but with very limited observation of the distal colon only; it is a poor substitute for the complete examination of colon by colonoscopy. Sigmoidoscopy is in adequate in detecting the incidence of right-sided advanced adenomas and cancers that increase with age, increasing from 15% of lesions in patients at 50 years of age to over 35% in patients over age 75 (Siegel et al. 2017; Walter et al. 2005; Hoffman and Walter 2009). Colonoscopy. Performed under I V conscious sedation often administered by a qualified anesthesiologist after a thorough cleansing of the colon for 1 or 2 days, colonoscopy has been accepted as the best mode of screening. The procedure permits removal of premalignant polyps and biopsy of suspicious lesions. There are problems in satisfactory cleansing, consequent failed procedures, patient dissatisfaction with the rigid rules, and inconveniences for 1 or 2 days. Most older patients rate the preparation for colonoscopy as worse than the procedure of colonoscopy under sedation. The older adults often even do not remember the procedure because of the amnestic effect of sedation. There are procedure related complications, which are reviewed here. Aging is a highly disparate process, and as such, and given that chronological age does not always correspond with biological age, a patient’s date of birth should not be used as the sole discriminatory element when embarking on a diagnostic process or establishing the best treatment option for a specific neoplastic disease. Aging is a highly disparate process, and as such, and given that chronological age does not always correspond with biological age, a patient’s date of birth should not be used as the sole discriminatory element when embarking on a diagnostic process or establishing the best treatment option for a specific neoplastic disease.

1976

CRC screening in those over age 75 years has been controversial and many guidelines are not clear about the indications (Nee et al. 2020; Wilson 2010). The controversy is particularly pertinent to screening colonoscopy which is invasive, associated with potentially serious complications related to IV sedation and/or the procedure. The American College of Physicians in the “Choosing Wisely” Campaign to control health care costs states that “routine colonoscopies usually aren’t needed after age 75.” The USPSTF recommends discontinuation of screening in average-risk individuals at age 75, an opinion not shared by other major United States gastroenterology societies, the American Gastroenterological Association, American Society of Gastrointestinal Endoscopy, and the American College of Gastroenterology.

C. S. Pitchumoni

Everyone is concerned about the diminishing returns or utility and increasing costs, morbidity and risks to both individual and society (Lin 2014). The controversy here is only about the need for screening colonoscopy in the older adult. There is no controversy about the need for colonoscopy to control lower GI bleeding, remove polyps and small tumors, and relieve colonic obstruction and other indications (Figs. 6 and 7). A pertinent question about colonoscopy in the older adult is regarding the technical difficulties and potential complications. There may be more technical difficulties in performing colonoscopy in the older adult because of various reasons, extensive diverticulosis, stricture, higher incidence of tortuosity, or postsurgical adhesions. Complicating

Fig. 6 (a and b) Sigmoid colon cancer, semi-circular involvement, partial obstruction to colon

Figs. 7 (a and b) Pedunculated polyp

89

Colorectal Cancer

the above, often times, the older adults present for endoscopy with inadequate bowel preparation (Lin 2014). Many are on anticoagulant therapy for a cardiac indication. The need for ensuring that the patient is not on recent anticoagulant therapy is crucial even for screening colonoscopy because of the potential need for polypectomy during the procedure. Obviously the benefits of the screening colonoscopy in the older adult should be weighed against the potential risks of IV sedation, the procedure, as well as the benefits in this age group. A healthy older adult with no serious comorbidity should not be excluded from a screening colonoscopy (Walter and Covinsky 2001). A brief discussion is necessary to evaluate the risks. According to the American Society for Gastrointestinal Endoscopy, serious complications occur in around 2.8% of every 1,000 procedures when done in people of average risk. A major German study reported major complications (bleeding or perforation) in 0.82% of 5527 procedures overall. A recent study specifically looked at the complications in the older adults (Grossberg et al. 2019). The study included a total of 30,409 colonoscopies performed in 27,173 patients (51% male) by 40 endoscopists. After 188 colonoscopies (0.62%), patients required visits to the emergency room. Age over 75 years was independently associated with ED visit (OR 1.58, 95% CI 1.05–2.37, p ¼ 0.027) and hospitalization (OR 3.7, 95% CI 2.03–6.73, p < 0.001) within 7 days of colonoscopy. The identifiable risk factors were a higher number of medication classes, recent ED visit, polypectomy, and endoscopic mucosal resection. The mortality rate at the end of the follow-up (median 4.4; IQR 2.7–6 years) was 1.9, 8.6, and 15.8% for the age-groups 50–75, 76–85, and >85 years, respectively. A very relevant study based on a pooled data is by Day et al. on the incidence rates for adverse events (per 1000 colonoscopies) in patients 65 years of age and older (Day et al. 2011). The cumulative GI adverse events were 26.0 (95% CI, 25.0–27.0). The frequency of adverse events was 1.0 (95% CI, 0.9–1.5) for perforation, 6.3 (95% CI, 5.7–7.0) for GI bleeding, 19.1 (95% CI, 18.0–20.3)

1977

for CV/pulmonary complications, and 1.0 (95% CI, 0.7–2.2) for mortality. In older adults the rate increased. In octogenarians the analysis showed adverse events (per 1000 colonoscopies) of 34.9 (95% CI, 31.9–38.0), perforation rate of 1.5 (95% CI, 1.1–1.9), GI bleeding rate of 2.4 (95% CI, 1.1–4.6), CV/pulmonary complication rate of 28.9 (95% CI, 26.2–31.8), and mortality rate of 0.5 (95% CI, 0.06–1.9). The procedure-related complications such as perforation and bleeding are higher in the older adults (Day et al. 2011). A study by Olaiya B and Adler (Olaiya and Adler 2019) queried the National Inpatient Sample to identify octogenarians who had a colonoscopy during hospitalization from 1998 to 2013. The authors noted a higher risk of adverse GI-related events after colonoscopy in octogenarians as compared with the general population. Even bowel preparation is associated with practical and physiological problems in many older adults although there is no ideal colonoscopic preparation suitable for older adults. Oral sodium phosphate and magnesium citrate are known to increase the risk for renal complications. Volume depletion, renal impairment, and electrolyte abnormalities, in addition to unintended side effects of prolonged “NPO,” are not to be ignored. Hypoglycemia, delirium, and falls are potentially serious problems that cannot be justified in a screening procedure. The occurrence of adverse GI-related events increased the risk of mortality among octogenarians regardless of comorbid status (Olaiya and Adler 2019). The risk of cardiopulmonary events associated with colonoscopy increases with advanced age, higher American Society of Anesthesiologists Physical Status Classification System scores, and the presence of comorbidities (Warren et al. 2009). Colonoscopy has become a routine procedure performed with IV sedation administered mostly by a qualified anesthesiologist with prior and appropriate preprocedure evaluation using the American Society of Anesthesiologists (ASA) criteria. Appropriate assessment of anesthesia risk before colonoscopy may reduce cardiopulmonary complications; high-risk patients are co-managed with other specialists (e.g., cardiology, anesthesiology) (ASGE

1978

Standards of Practice Committee, Sedation related complications but not procedure related issues can be reduced by using anesthesiologists for all endoscopic procedures in the older adults. Many colonoscopy procedures in the older adults are incomplete as a result of poor preparation, tortuous colon, and hypoxemia during the procedure. An optimistic picture is painted in many other reports showing that colonoscopy in the very elderly can be performed safely, successfully, and with considerable benefits to the patients (Lin 2014; Duncan et al. 2006; Zerey et al. 2007; Cha et al. 2016). These results demonstrate that colonoscopy for patients over 85 years of age is safe and effective (Isohata et al. 2018). Considering all the pros and cons, Nee et al. conclude that one should weigh the risks and benefits of a screening colonoscopy in the older adult and an age based cut off and exclusion of older patients from screening procedures can be examples of age-based discrimination.

Treatment Options of CRC in Older Adults Treatment options and outcome are determined by the anatomic location of cancer (proximal rightsided versus left- sided or rectal locations), stage of the disease (see Table 2), and other patientrelated factors. Prognostic factors influencing survival in CRC patients include depth of tumor invasion into and beyond the bowel wall, the number of involved regional nodes, and the presence or absence of distant metastases (American Joint Committee on Cancer 2002). The team of physicians should include the primary care physician, geriatrician, a nutritionist, oncologist, surgeon, gastroenterologist, radiation oncologist, and others based on comorbid conditions. The team needs to carefully plan the management based on several factors. Primary mode of therapy for CRC is surgery with options for chemotherapy and or radiation. The following discussion is meant to highlight some special features in the management of CRC in the older adult, but it is by no means exhaustive or comprehensive. The one time belief that older patients may not tolerate the treatment

C. S. Pitchumoni Table 2 Staging of colon cancer Stage Tumor T1 T2 T3

Characteristics

Tumor invades submucosa Tumor invades muscularis propria Tumor invades through muscularis propria into subserosa or nonperitonealized pericolic or perirectal tissues T4 Tumor directly invades other organs or structures and/or perforates visceral peritoneum Regional nodal metastasis NX Regional lymph nodes cannot be assessed N0 No nodal metastasis N1 Metastasis in one to three pericolic or perirectal nodes N2 Metastasis in four to more pericolic or perirectal nodes N3 Metastasis in any node along course of a named vascular trunk and/or metastasis to apical node Distant metastasis MX Presence of distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis

options has led to exclusion of many older patients solely based on chronological age. Newer data offer much optimism and guidance in determining the choice of treatment. The emphasis is that older age should not be the sole basis for exclusion of patients for curative surgery.

Preoperative Management of CRC in Older Adults Management of CRC in the older adults is associated with unique challenges, and the team of physicians should be ready to offer all the options for treatment dispassionately to the patient and responsible members of the family with their benefits and risks (Itatani et al. 2018; Shank and Balducci 1992; Ng et al. 2016). Many questions may arise. The patient or the family may question the need for surgery, the benefits, life with colostomy (when needed), life expectancy and potential clinical problems with and without surgical, chemotherapeutic and/or radiation treatment and may even opt for a suboptimal management

89

Colorectal Cancer

option. The team should explain the clinical consequences and quality of life of an ostomy be it temporary or permanent, as needed or fecal incontinence that is anticipated (Kim 2017). In general, as age advances the surgical risk increases progressively. In addition to age related risks, another disadvantage is that older patients often present with more advanced disease stage requiring emergency surgery rather than elective curative resection (Au et al. 2018). According to Balducci the three pertinent questions in the assessment of older cancer patients being evaluated for treatment are as follows (Balducci and Extermann 2000): (a) is the patient going to die with cancer or of cancer? (b) Is the patient able to tolerate the stress of antineoplastic therapy? (c) Is the treatment producing more benefits than harm?. Geriatric assessment is superior to oncologists’ clinical judgment in identifying frailty (Balducci and Extermann 2000; Kirkhus et al. 2017; Jolly et al. 2015; Millan et al. 2015). Hence, a Comprehensive Geriatric Assessment (CGA) is essential before any treatment regimen is chosen (see chapter in book). There are many assessment tools that provide useful information on the impact of comorbidities at the initial diagnosis and prospective outcomes. Preoperative evaluations include the use of medications their side effects, functional status, frailty, risk of malnutrition, cognitive impairment, and comorbidities. In 2012, the American College of Surgeons (ACS) and the American Geriatrics Society (AGS) released a guideline to help physicians with preoperative evaluations for elderly patients (Chow et al. 2012; Antonio et al. 2017). The assessment should also include vision, hearing, and ambulatory function. Frailty, frequent in older patients, is not necessarily a contraindication to surgical treatment (Rønning et al. 2016). Solely based on chronological age surgery should not be excluded. With proper selection of patients and preoperative geriatric assessment, the treatment options are surgery preferably with a laparoscopic approach and if necessary chemo and radiation therapy. With proper assessment the operative mortality is low (Biondi et al. 2016; Kazama et al. 2017).

1979

Although it is very difficult to predict life expectancy, various measurable indices help. The Charlson comorbidity index (CCI) predicts the 1-year mortality for a patient who may have a range of comorbid conditions, such as heart disease, AIDS, or cancer (a total of 22 conditions). The CCI scores >3 also increase mortality by 24%, while emergency surgery increases mortality rates by 14.9% (Ng et al. 2016; Morris et al. 2011; Charlson et al. 1987). Charlson et al. (1987) quantify an individual’s burden of disease and corresponding 1-year mortality risk. The frailty index is used to measure the health status of older individuals and serves as a proxy measure of aging and vulnerability to poor outcomes (Burn et al. 2018; Pandit et al. 2018; Schmoll et al. 2012). A recent study from the USA investigated the relationship among age, postoperative complications, 1 year survival, and cause of death following potentially curative colon cancer surgery. Older age was independently associated with higher odds of a complication and a 1-year overall mortality, 1-year colon cancer and cardiovascular disease-specific mortality, and infectious complications (Aquina et al. 2017). The message is that age-associated decline in the functional reserve of multiple organ systems is not related to chronological age. A Cochrane meta-analysis of 10,315 patients from 22 trials compared the benefits of preoperative comprehensive geriatric assessment (CGA) with standard care. Substantial benefits were noted. Those patients who received CGA were less likely to suffer death or deterioration (OR ¼ 0.76, 95% CI ¼ 0.64–0.90), less likely to be institutionalized (OR ¼ 0.79, 95% CI ¼ 0.69– 0.88), and more likely to be alive and in their own homes after 12 months of follow-up (OR ¼ 1.16, 95% CI ¼ 1.05–1.28) (Ellis et al. 2011). To minimize the risk for venous thrombosis appropriate prophylaxis, a combination of mechanical and pharmacologic prophylaxis with low-dose unfractionated heparin or low molecular weight heparin as recommended by several guidelines is appropriate (Emoto et al. 2019; Lee et al. 2016; Hinoi et al. 2015). Management of rectal cancer in the older adult is more complicated than colon cancer because of

1980

the anatomy and the role of rectal sphincter (Montroni et al. 2018). Radical surgery for rectal cancer in older adults was once questioned because of the high rate of complications. Current data suggest that older adults undergoing surgery have a similar life expectancy to their peers without rectal cancer. Therefore, in properly selected patients, rectal cancer surgery is advised. A multidisciplinary task force convened experts from the European Society of Surgical Oncology, European Society of Coloproctology, International Society of Geriatric Oncology, and the American College Surgeons Commission on Cancer, with the goal of identifying the best practice to promote personalized rectal cancer care in older patients (Montroni et al. 2018). The stage of the disease at diagnosis is an important factor in determining life expectancy and the treatment plan. Preoperative staging requires a comprehensive medical history and physical examination, complete blood counts, biochemistry profile including liver tests and serum markers (carcinoembryonic antigen (CEA), abdominal and pelvic computed tomography (CT) scans, and a plain x-ray of the chest (Upadhyay et al. 2015). Endoscopic ultrasound (EUS) and nuclear magnetic resonance (NMR) imaging of the pelvis are required for tumor (T) or lymph node (N) staging. Although surgery cannot be excluded solely based on older age one should anticipate various postoperative complications. The TNM classification for CRC replacing the once popular Duke’s classification (American Joint Committee on Cancer (AJCC)) adds greater precision in the identification of prognostic subgroups and is based on three key pieces of information, the depth of tumor invasion into or beyond the wall of the colorectum (T), invasion of or adherence to adjacent organs or structures (T), the number of regional lymph nodes involved (N), and the presence or absence of distant metastasis (M). Stage of the tumor determines management. For example, a selected few patients with stage II benefit from adjuvant therapy, and patients with stage III benefit from surgery followed by adjuvant chemotherapy. A few patients with stage IV disease require surgery, chemotherapy alone or combined with targeted therapy, preoperative or postoperative, radiotherapy, and/or chemotherapy (Biondi

C. S. Pitchumoni

et al. 2016). Chemotherapy may be adjuvant (chemotherapy in addition to surgery) or neo-adjuvant (adjuvant therapy given before radiation or chemotherapy to reduce the tumor size) (Stintzing 2014; Chang et al. 2012; Ketelaers et al. 2020).

Radiation Therapy Radiation therapy is needed in selected cases of colon cancer before surgery (along with chemotherapy) to reduce the tumor size, to make it easier to remove, after surgery to eliminate residual tumors in adjacent areas. In patients with tumor invading adjacent organs, with perforation or fistula, or are subtotally resected, surgery may not be adequate or technically incomplete. Improved local control and possibly survival with the addition of external irradiation and/or intraoperative radiation is the observation in studies (Willett et al. 1993, 1999; Gunderson et al. 1997; Amos et al. 1996). Chemotherapy A number of patients with stage III CRC and selected patients with stage II disease demonstrate a significant benefit from adjuvant chemotherapy. However, older age is associated with a progressive decline of function, increased prevalence of comorbidity, slower cognition, and progressive sensorial deprivation leading to a decreased functional reserve of multiple organ systems, in particular the kidneys, which influences the pharmacokinetics and pharmacodynamics of drugs (Hurria and Lichtman 2008; Lichtman et al. 2007). The risk for drug toxicity and drug-drug interaction are likely to be higher in incidence and severity. Despite some of the limitations for chemotherapy in the older adults, there is a role for it. Postoperative chemotherapy reduces the risk of tumor recurrence and improves survival for patients with resected CRC. There is good evidence that the older adults tolerate chemotherapy fairly well and hence age alone should not determine candidacy for adjuvant therapy (Antonio et al. 2017; Sargent et al. 2001; Papamichael et al. 2015). The National Institutes of Health (NIH) Consensus Conference in 1990 recommended that patients with stage III colon cancer receive adjuvant chemotherapy (NIH Consensus

89

Colorectal Cancer

Conference 1990). While 5-fluorouracil (5-FU)based chemotherapy, including combination with leucovorin (LV) and oxaliplatin (FOLFOX), has been the cornerstone of treatment in adjuvant setting. The various chemotherapeutic agents available are 5-Fluorouracil (5-FU), Capecitabine (Xeloda), Irinotecan (Camptosar), Oxaliplatin (Eloxatin), and Trifluridine and tipiracil (Lonsurf).

Newer Approaches New and innovative approaches to advanced colon cancer include immunotherapy. The procedure primes the host’s natural immune defenses to recognize, target, and destroy cancer cells effectively. The FDA-approved immunotherapeutic agents for metastatic CRC patients are pembrolizumab, nivolumab plus, or minus ipilimumab for a subset of colorectal cancers (Ganesh et al. 2019). In the management of rectal cancer, the US National Comprehensive Cancer Network recommend either neoadjuvant chemoradiation or neoadjuvant radiation alone, followed by surgery and adjuvant chemotherapy, in select patient populations at high risk of distant recurrence (Folkesson et al. 2005; Benson et al. 2015; Liu et al. 2018). Endoscopic therapy has a welcome role in the management of CRC in the older adults. Polypectomy and endoscopic mucosal resection (EMR) and endoscopic submucosal resections (ESD) are options for the removal of most colorectal neoplasia (Draganov 2018). Endoscopic stenting for inoperative obstructive lesions (Winner et al. 2013) is useful in the management of large bowel obstruction, as well as a bridge to surgery converting an emergency condition to elective situation permitting a more favorable opportunity for staging and optimization of patient’s condition (Winner et al. 2013). Nutritional Support Nutritional support plays an important role although colon cancer itself is much less of a cause for malnutrition compared to the consequences of surgery, and chemotherapy associated with various other causes for malnutrition in the hospitalized patients (Bauer et al. 2002; DobrilaDintinjana et al. 2013; Maurício et al. 2018). The presence of malnutrition in patients with cancer is

1981

influenced by decreased food intake, surgery, psychological problems, prolonged often unwarranted NPO status for tests and procedures. Assessment of malnutrition based on BMI is insufficient to detect changes in body composition associated with malignancy.

Palliative Care Palliative care, as defined by the World Health Organization, applies not only at end of life but throughout cancer care (World Health Organization 2020). The American Academy of Hospice and Palliative Medicine defines palliative care as “focused on alleviating suffering and promoting quality of life.” The major concerns are pain and symptom management, information sharing and advance care planning, psychological and spiritual support, and coordination of care (Gold 2003). The goal of palliative care is to provide relief from the symptoms and stress of the cancer, the goal being to improve quality of life for both the patient and the family members. The administration of palliative care is multidisciplinary. A team-based palliative approach is beneficial for treating patients with advanced CRC, because of the complexity of their coexisting social, psychological, and medical needs (Dixon and Stamos 2004). Palliative care may be needed in patients with colonic obstruction. Malignant colorectal obstruction, a type of large bowel obstruction (LBO), is a frequent and serious complication of advanced cancers, including colorectal cancer or those with near organ (e.g., ovary, vagina, and prostate) or distant metastases (Zhao et al. 2013; Deans et al. 1994; Liu et al. 1997). The goal of colonic stent insertion is to overcome the risks associated with open surgery. Self-expanding metallic stents (SEMS) have been widely applied to patients with incurable malignant obstructions as palliative treatment or as a bridge to elective primary resection and anastomosis (Beets et al. 2017). In summary, CRC is an age related tumor with a tendency to increase in incidence as age advances. CRC will affect 1 in 20 Americans in their lifetime. The population trend with increase in life expectancy and a change of adopting a western type of diet one can project an increase

1982

in incidence in many affluent nations where the incidence is high and even in developing nations where the disease was historically low. The natural history of development of colon polyp from an epithelium and later on to CRC in 10 or more years and the availability of effective screening procedures reflect an optimistic view in reducing the incidence in affluent nations while developed nations should adopt effective preventive measures through a healthy diet and prevention of obesity, cigarette smoking, and alcoholism. With the availability of safe anesthetic procedures and improved surgical techniques, older adults derive excellent results with the surgical management of CRC. Chemotherapeutic management is also safe in the older adults. In view of the above, the older adults should not be excluded from the best available options in treatment solely based on older age alone.

C. S. Pitchumoni

8.

9.

10. 11.

12.

Key Points 13. 1. Colorectal cancer (CRC) is related to older age. Approximately 60% of CRC patients are >70 years of age at the time of diagnosis, and 43% are >65. The risk is higher in women, with 27% of cases over age 80 years. 2. CRC is the second most common tumor in both men and women, after lung tumors (WHO). 3. The incidence of CRC is increasing, along with the global demographic change in population. 4. While a trend for decrease is notable in affluent nations, CRC is increasing in incidence in many Afro-Asian countries where once it was low. 5. Most CRCs are sporadic, probably related to lifestyle factors, diet (low fiber, high fat, high red meat, cigarette smoking, alcoholism, obesity, and others), and are modifiable. 6. Genetic predisposition to CRC is less than 5% and from familial adenomatous polyposis and hereditary nonpolyposis colon cancer (HNPCC). 7. The screening modalities are noninvasive tests (stool-based testing, radiologic testing,

14.

and blood testing) and invasive procedures (colonoscopy) with differing merits. US Preventive Services Task Force recommend against screening individuals over age 85 years. The Task Force is uncertain about the benefits of CRC screening in those between ages 76 and 85 years. Screening for CRC in the older adult needs careful scrutiny based on the general condition and life expectancy. Older adults with CRC are likely to be undertreated and carry a poorer outcome. The stage at presentation, location, and the comorbid conditions of the patient determine the choice of treatment of CRC. A comprehensive geriatric assessment improves therapeutic choices and outcome. Treatment modalities, in general, are surgery for stage I or II; surgery followed by adjuvant chemotherapy for stage III colon cancer, and in cases of metastatic CRC (mCRC) systemic chemotherapy alone or with targeted biologics. The 5-year survival rate for CRC found at the local stage is 90%, regional stage is 71%, and at the distant stage is 14%. The goals of surgery in rectal cancer are to avoid local recurrence and, if possible, preserve sphincter function.

References Abdulamir AS, Hafidh RR, Bakar FA. The association of Streptococcus bovis/gallolyticus with colorectal tumors: the nature and the underlying mechanisms of its etiological role. J Exp Clin Cancer Res. 2011;30 (1):11. https://doi.org/10.1186/1756-9966-30-11. Alexander DD, Waterbor J, Hughes T, Funkhouser E, Grizzle W, Manne U. African-American and Caucasian disparities in colorectal cancer mortality and survival by data source: an epidemiologic review. Cancer Biomark. 2007;3(6):301–13. https://doi.org/10.3233/ CBM-2007-3604. Alsolmei FA, Li H, Pereira SL, Krishnan P, Johns PW, Siddiqui RA. Polyphenol-enriched plum extract enhances myotubule formation and anabolism while attenuating colon cancer-induced cellular damage in C2C12 cells. Nutrients. 2019;11(5):E1077. https://doi. org/10.3390/nu11051077. American Cancer Society. Colorectal cancer facts & figures 2017–2019. Atlanta. 2017. https://www.cancer. org/content/dam/cancer-org/research/cancer-facts-and-

89

Colorectal Cancer

statistics/colorectal-cancer-facts-and-figures/colorectalcancer-facts-and-figures-2017-2019.pdf. Accessed 26 Feb 2020. American Joint Committee on Cancer. Colon and rectum. In: AJCC cancer staging manual. 6th ed. Chicago: American Joint Committee on Cancer; 2002. p. 113–24. https:// cancerstaging.org/references-tools/deskreferences/Docu ments/AJCC6thEdCancerStagingManualPart1.pdf. Amos EH, Mendenhall WM, McCarty PJ, et al. Postoperative radiotherapy for locally advanced colon cancer. Ann Surg Oncol. 1996;3(5):431–6. https://doi.org/ 10.1007/bf02305760. Antonio M, Saldaña J, Carmona-Bayonas A, et al. Geriatric assessment predicts survival and competing mortality in elderly patients with early colorectal cancer: can it help in adjuvant therapy decision-making? Oncologist. 2017;22 (8):934–43. https://doi.org/10.1634/theoncologist.20160462. Aquina CT, Mohile SG, Tejani MA, et al. The impact of age on complications, survival, and cause of death following colon cancer surgery. Br J Cancer. 2017;116(3):389–97. https://doi.org/10.1038/bjc.2016.421. Armaghany T, Wilson JD, Chu Q, Mills G. Genetic alterations in colorectal cancer. Gastrointest Cancer Res. 2012;5(1):19–27. Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2017;66(4):683– 91. https://doi.org/10.1136/gutjnl-2015-310912. Asensi M, Ortega A, Mena S, Feddi F, Estrela JM. Natural polyphenols in cancer therapy. Crit Rev Clin Lab Sci. 2011;48(5–6):197–216. https://doi.org/10.3109/1040 8363.2011.631268. Au S, Ventham NT, Yalamarthi S, Manimaran N. Colorectal cancer outcomes in nonagenarian patients: a case series. Int J Surg. 2018;55:139–44. https://doi.org/10.1016/j.ijsu.2018.05.032. Aykan NF. Red meat and colorectal cancer. Oncol Rev. 2015;9 (1):38–44. https://doi.org/10.4081/oncol.2015.288. Balducci L, Extermann M. Management of cancer in the older person: a practical approach. Oncologist. 2000;5(3):224– 37. https://doi.org/10.1634/theoncologist.5-3-224. Baron JA. Epidemiology of non-steroidal anti-inflammatory drugs and cancer. Prog Exp Tumor Res. 2003;37:1–24. https://doi.org/10.1159/000071364. Baron JA, Cole BF, Sandler RS, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med. 2003;348(10):891–9. https://doi.org/10.1056/NEJM oa021735. Bauer J, Capra S, Ferguson M. Use of the scored patientgenerated subjective global assessment (PG-SGA) as a nutrition assessment tool in patients with cancer. Eur J Clin Nutr. 2002;56(8):779–85. https://doi.org/ 10.1038/sj.ejcn.1601412. Beets G, Sebag-Montefiore D, Andritsch E, et al. ECCO essential requirements for quality Cancer care: colorectal Cancer. A critical review. Crit Rev Oncol Hematol. 2017;110:81–93. https://doi.org/10.1016/j.critrevo nc.2016.12.001.

1983 Benson AB, Venook AP, Bekaii-Saab T, et al. Rectal cancer, version 2.2015: featured updates to the NCCN guidelines. J Natl Compr Cancer Netw. 2015;13 (6):719–28. https://doi.org/10.6004/jnccn.2015.0087. Biondi A, Vacante M, Ambrosino I, Cristaldi E, Pietrapertosa G, Basile F. Role of surgery for colorectal cancer in the elderly. World J Gastrointest Surg. 2016;8 (9):613. https://doi.org/10.4240/wjgs.v8.i9.606. Bjelakovic G, Nagorni A, Nikolova D, Simonetti RG, Bjelakovic M, Gluud C. Meta-analysis: antioxidant supplements for primary and secondary prevention of colorectal adenoma. Aliment Pharmacol Ther. 2006;24 (2):281–91. https://doi.org/10.1111/j.1365-2036.2006. 02970.x. Boland PM, Yurgelun MB, Boland CR. Recent progress in Lynch syndrome and other familial colorectal cancer syndromes. CA Cancer J Clin. 2018;68(3):217–31. https://doi.org/10.3322/caac.21448. Bonovas S, Fiorino G, Lytras T, Malesci A, Danese S. Calcium supplementation for the prevention of colorectal adenomas: a systematic review and meta-analysis of randomized controlled trials. World J Gastroenterol. 2016;22(18):4594–603. https://doi.org/10.3748/wjg. v22.i18.4594. Boparai KS, Mathus-Vliegen EMH, Koornstra JJ, et al. Increased colorectal cancer risk during follow-up in patients with hyperplastic polyposis syndrome: a multicentre cohort study. Gut. 2010;59(8):1094–100. https:// doi.org/10.1136/gut.2009.185884. Bosman FT, Yan P. Molecular pathology of colorectal cancer. Pol J Pathol. 2014;65(4):257–66. https://doi. org/10.5114/pjp.2014.48094. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac. 21492. Bruce WR. Recent hypotheses for the origin of colon cancer. Cancer Res. 1987;47(16):4237–42. http:// www.ncbi.nlm.nih.gov/pubmed/3300962. Accessed 26 Feb 2020. Burkitt DP. Epidemiology of cancer of the colon and rectum. Nutr Rev. 1987;45(9):212–4. https://doi.org/ 10.1111/j.1753-4887.1987.tb02736.x. Burn R, Hubbard RE, Scrase RJ, et al. A frailty index derived from a standardized comprehensive geriatric assessment predicts mortality and aged residential care admission. BMC Geriatr. 2018;18(1):319. https:// doi.org/10.1186/s12877-018-1016-8. Butte JM, Tang P, Gonen M, et al. Rate of residual disease after complete endoscopic resection of malignant colonic polyp. Dis Colon Rectum. 2012;55(2):122–7. https://doi.org/10.1097/DCR.0b013e3182336c38. Center MM, Jemal A, Smith RA, Ward E. Worldwide variations in colorectal cancer. CA Cancer J Clin. 2009;59 (6):366–78. https://doi.org/10.3322/caac.20038. Cha JM, Kozarek RA, la Selva D, et al. Risks and benefits of colonoscopy in patients 90 years or older, compared with

1984 younger patients. Clin Gastroenterol Hepatol. 2016;14 (1):80–86.e1. https://doi.org/10.1016/j.cgh.2015.06.036. Chan AT, Giovannucci EL. Primary prevention of colorectal cancer. Gastroenterology. 2010;138(6):2029–43. https://doi.org/10.1053/j.gastro.2010.01.057. Chang GJ, Kaiser AM, Mills S, Rafferty JF, Buie WD. Practice parameters for the management of colon cancer. Dis Colon Rectum. 2012;55(8):831–43. https:// doi.org/10.1097/DCR.0b013e3182567e13. Chang H, Lei L, Zhou Y, Ye F, Zhao G. Dietary flavonoids and the risk of colorectal cancer: an updated metaanalysis of epidemiological studies. Nutrients. 2018;10 (7):E950. https://doi.org/10.3390/nu10070950. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–83. https://doi.org/10.1016/00219681(87)90171-8. Chow WB, Rosenthal RA, Merkow RP, Ko CY, Esnaola NF. Optimal preoperative assessment of the geriatric surgical patient: a best practices guideline from the American college of surgeons national surgical quality improvement program and the American geriatrics society. J Am Coll Surg. 2012;215(4):453–66. https:// doi.org/10.1016/j.jamcollsurg.2012.06.017. Cockbain AJ, Toogood GJ, Hull MA. Omega-3 polyunsaturated fatty acids for the treatment and prevention of colorectal cancer. Gut. 2012;61:135–49. https://doi. org/10.1136/gut.2010.233718. Colditz GA, Cannuscio CC, Frazier AL. Physical activity and reduced risk of colon cancer: implications for prevention. Cancer Causes Control. 1997;8(4):649–67. https://doi.org/10.1023/a:1018458700185. Day LW, Kwon A, Inadomi JM, Walter LC, Somsouk M. Adverse events in older patients undergoing colonoscopy: a systematic review and meta-analysis. Gastrointest Endosc. 2011;74(4):885–96. https://doi. org/10.1016/j.gie.2011.06.023. de Klerk CM, Vendrig LM, Bossuyt PM, Dekker E. Participant-related risk factors for false-positive and false-negative fecal immunochemical tests in colorectal cancer screening: systematic review and metaanalysis. Am J Gastroenterol. 2018;113(12):1778–87. https://doi.org/10.1038/s41395-018-0212-7. de Sousa E Melo F, Wang X, Jansen M, et al. Poorprognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat Med. 2013;19(5):614–8. https://doi.org/ 10.1038/nm.3174. Deans GT, Krukowski ZH, Irwin ST. Malignant obstruction of the left colon. Br J Surg. 1994;81(9):1270–6. https://doi.org/10.1002/bjs.1800810905. Dixon MR, Stamos MJ. Strategies for palliative care in advanced colorectal cancer. Dig Surg. 2004;21(5– 6):344–51. https://doi.org/10.1159/000081351. Dobrila-Dintinjana R, Trivanovic D, Zelić M, et al. Nutritional support in patients with colorectal cancer during chemotherapy: does it work? HepatoGastroenterology. 2013;60(123):475–80. https://doi. org/10.5754/hge12710.

C. S. Pitchumoni Dobrzycka M, Spychalski P, Łachiński A, Kobiela P, Jędrusik P, Kobiela J. Statins and colorectal cancer – a systematic review. Exp Clin Endocrinol Diabetes. 2018; https://doi.org/10.1055/a-0668-5692. Draganov PV. Endoscopic mucosal resection vs endoscopic submucosal dissection for colon polyps. Gastroenterol Hepatol. 2018;14(1):50–2. Dreher M. Whole fruits and fruit fiber emerging health effects. Nutrients. 2018;10(12):1833. https://doi.org/ 10.3390/nu10121833. Duncan JE, Sweeney WB, Trudel JL, Madoff RD, Mellgren AF. Colonoscopy in the elderly: low risk, low yield in asymptomatic patients. Dis Colon Rectum. 2006;49(5):646–51. https://doi.org/10.1007/s10350005-0306-3. East JE, Atkin WS, Bateman AC, et al. British Society of Gastroenterology position statement on serrated polyps in the colon and rectum. Gut. 2017;66(7):1181–96. https://doi.org/10.1136/gutjnl-2017-314005. EFSA Panel on Dietetic Products N and A (NDA). Scientific opinion on dietary reference values for carbohydrates and dietary fibre. EFSA J. 2010;8(3) https://doi. org/10.2903/j.efsa.2010.1462. Ellis G, Gardner M, Tsiachristas A, et al. Comprehensive geriatric assessment for older adults admitted to hospital. Cochrane Database Syst Rev. 2011;7:CD006211. https://doi.org/10.1002/14651858.CD006211.pub3. Emoto S, Nozawa H, Kawai K, et al. Venous thromboembolism in colorectal surgery: incidence, risk factors, and prophylaxis. Asian J Surg. 2019;42(9):863–73. https://doi.org/10.1016/j.asjsur.2018.12.013. Erichsen R, Baron JA, Hamilton-Dutoit SJ, et al. Increased risk of colorectal cancer development among patients with serrated polyps. Gastroenterology. 2016;150(4):895–902. e5. https://doi.org/10.1053/j.gastro.2015.11.046. Fearnhead NS, Britton MP, Bodmer WF. The ABC of APC. Hum Mol Genet. 2001;10(7):721–33. https:// doi.org/10.1093/hmg/10.7.721. Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol Mech Dis. 2011;6(1):479–507. https://doi. org/10.1146/annurev-pathol-011110-130235. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759–67. https://doi. org/10.1016/0092-8674(90)90186-I. Fidalgo CA, Santos L, Rosa I, et al. Hyperplastic polyp? Look again ... the impact of the new classification for serrated polyps. Gut. 2011;60(Suppl 3):A306. https:// www.researchgate.net/publication/262974251_Hyper plastic_polyp_Look_again_the_impact_of_the_new_ classification_for_serrated_polyps. Accessed 26 Feb 2020. Folkesson J, Birgisson H, Pahlman L, Cedermark B, Glimelius B, Gunnarsson U. Swedish rectal cancer trial: long lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol. 2005;23(24):5644–50. https://doi.org/10.1200/JCO.2005.08.144. Fung KYC, Ooi CC, Zucker MH, et al. Colorectal carcinogenesis: a cellular response to sustained risk environment. Int J Mol Sci. 2013;14(7):13525–41. https:// doi.org/10.3390/ijms140713525.

89

Colorectal Cancer

Ganesh K, Stadler ZK, Cercek A, et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol. 2019;16(6):361–75. https://doi.org/10.1038/s41575-019-0126-x. Geng J, Fan H, Tang X, Zhai H, Zhang Z. Diversified pattern of the human colorectal cancer microbiome. Gut Pathogens. 2013;5(1):2. https://doi.org/10.1186/ 1757-4749-5-2. Gold MF. Comfort, compassion, dignity mark end-of-life care. Provider. 2003;29(12):33. http://www.ncbi.nlm. nih.gov/pubmed/14677249. Accessed 27 Feb 2020. Goldenberg BA, Holliday EB, Helewa RM, Singh H. Rectal cancer in 2018: a primer for the gastroenterologist. Am J Gastroenterol. 2018;113(12):1763–71. https://doi.org/10.1038/s41395-018-0180-y. Grossberg LB, Papamichael K, Leffler DA, Sawhney MS, Feuerstein JD. Patients over age 75 are at increased risk of emergency department visit and hospitalization following colonoscopy. Dig Dis Sci. 2019; https://doi.org/ 10.1007/s10620-019-05962-3. Gryfe R, Kim H, Hsieh ETK, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000;342(2):69–77. https://doi.org/10.1056/NEJM200001133420201. Gunderson LL, Nelson H, Martenson JA, et al. Locally advanced primary colorectal cancer: intraoperative electron and external beam irradiation  5-FU. Int J Radiat Oncol Biol Phys. 1997;37(3):601–14. https:// doi.org/10.1016/S0360-3016(96)00563-9. Harmon BE, Wirth MD, Boushey CJ, et al. The dietary inflammatory index is associated with colorectal cancer risk in the multiethnic cohort. J Nutr. 2017;147(3):430– 8. https://doi.org/10.3945/jn.116.242529. Hemminki A, Peltomäki P, Mecklin JP, et al. Loss of the wild type MLH1 gene is a feature of hereditary nonpolyposis colorectal cancer. Nat Genet. 1994;8(4):405– 10. https://doi.org/10.1038/ng1294-405. Hinoi T, Kawaguchi Y, Hattori M, et al. Laparoscopic versus open surgery for colorectal cancer in elderly patients: a multicenter matched case–control study. Ann Surg Oncol. 2015;22(6):2040–50. https://doi.org/ 10.1245/s10434-014-4172-x. Hoffman RM, Walter LC. Colorectal cancer screening in the elderly: the need for informed decision making. J Gen Intern Med. 2009;24(12):1336–7. https://doi. org/10.1007/s11606-009-1121-7. Huang CS, Farraye FA, Yang S, O’Brien MJ. The clinical significance of serrated polyps. Am J Gastroenterol. 2011;106(2):229–40. https://doi.org/10.1038/ajg.20 10.429. Hurria A, Lichtman SM. Clinical pharmacology of cancer therapies in older adults. Br J Cancer. 2008;98(3):517– 22. https://doi.org/10.1038/sj.bjc.6604201. Isohata N, Shimojima R, Utano K, et al. Colonoscopy in patients aged 85 years or older: an observational study. J Anus Rectum Colon. 2018;2(4):155–61. https://doi. org/10.23922/jarc.2018-014. Itatani Y, Kawada K, Sakai Y. Treatment of elderly patients with colorectal Cancer. Biomed Res Int. 2018;2018:1–8. https://doi.org/10.1155/2018/2176056.

1985 Jacobs ET, Lanza E, Alberts DS, et al. Fiber, sex, and colorectal adenoma: results of a pooled analysis. Am J Clin Nutr. 2006;83(2):343–9. https://doi.org/10.1093/ ajcn/83.2.343. Jasperson KW, Tuohy TM, Neklason DW, Burt RW. Hereditary and familial colon cancer. Gastroenterology. 2010;138(6):2044–58. https://doi.org/10.1053/j. gastro.2010.01.054. Jass JR. Serrated adenoma of the colorectum and the DNA-methylator phenotype. Nat Clin Pract Oncol. 2005;2(8):398–405. https://doi.org/10.1038/ncponc0248. Jochem C, Leitzmann M. Obesity and colorectal cancer. In: Recent results in cancer research, vol. 208. New York: Springer; 2016. p. 17–41. https://doi.org/10.1007/9783-319-42542-9_2. Jolly TA, Deal AM, Nyrop KA, et al. Geriatric assessmentidentified deficits in older cancer patients with normal performance status. Oncologist. 2015;20(4):379–85. https://doi.org/10.1634/theoncologist.2014-0247. Jung YS, Park CH, Eun CS, Park DI, Han DS. Metformin use and the risk of colorectal adenoma: a systematic review and meta-analysis. J Gastroenterol Hepatol (Australia). 2017;32(5):957–65. https://doi.org/ 10.1111/jgh.13639. Kazama K, Aoyama T, Hayashi T, et al. Evaluation of shortterm outcomes of laparoscopic-assisted surgery for colorectal cancer in elderly patients aged over 75 years old: a multi-institutional study (YSURG1401). BMC Surg. 2017;17(1):29. https://doi.org/10.1186/s12893-0170229-7. Ketelaers SHJ, Fahim M, Rutten HJT, Smits AB, Orsini RG. When and how should surgery be performed in senior colorectal cancer patients? Eur J Surg Oncol. 2020;46(3):326–32. https://doi.org/10.1016/j.ejso.20 20.01.007. Keum N, Aune D, Greenwood DC, Ju W, Giovannucci EL. Calcium intake and colorectal cancer risk: doseresponse meta-analysis of prospective observational studies. Int J Cancer. 2014;135(8):1940–8. https://doi. org/10.1002/ijc.28840. Kim YW. Surgical treatment for colorectal cancer in octogenarians and nonagenarians. J BUON. 2017; 22(3):578–85. www.jbuon.com. Accessed 27 Feb 2020. Kim B, Giardiello FM. Chemoprevention in familial adenomatous polyposis. Best Pract Res Clin Gastroenterol. 2011;25(4–5):607–22. https://doi.org/10.1016/j.bpg. 2011.08.002. Kim HY, Kim SM, Seo JH, Park EH, Kim N, Lee DH. Age-specific prevalence of serrated lesions and their subtypes by screening colonoscopy: a retrospective study. BMC Gastroenterol. 2014;14(82) https:// doi.org/10.1186/1471-230X-14-82. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996;87(2):159–70. https://doi.org/ 10.1016/S0092-8674(00)81333-1. Kirkhus L, Benth JŠ, Rostoft S, et al. Geriatric assessment is superior to oncologists’ clinical judgement in identifying frailty. Br J Cancer. 2017;117(4):470–7. https:// doi.org/10.1038/bjc.2017.202.

1986 Kok DE, Steegenga WT, Smid EJ, Zoetendal EG, Ulrich CM, Kampman E. Bacterial folate biosynthesis and colorectal cancer risk: more than just a gut feeling. Crit Rev Food Sci Nutr. 2020;60(2):244–56. https:// doi.org/10.1080/10408398.2018.1522499. Kościelniak-Merak B, Radosavljević B, Zając A, Tomasik PJ. Faecal occult blood point-of-care tests. J Gastrointest Cancer. 2018;49(4):405. https://doi.org/ 10.1007/s12029-018-0169-1. Kostic AD, Chun E, Robertson L, et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe. 2013;14(2):207–15. https://doi.org/ 10.1016/j.chom.2013.07.007. Kotake K, Asano M, Ozawa H, Kobayashi H, Sugihara K. Tumour characteristics, treatment patterns and survival of patients aged 80 years or older with colorectal cancer. Color Dis. 2015;17(3):205–15. https://doi.org/ 10.1111/codi.12826. Kwong LN, Dove WF. APC and its modifiers in colon cancer. Adv Exp Med Biol. 2009;656:85–106. https:// doi.org/10.1007/978-1-4419-1145-2_8. Lauby-Secretan B, Scoccianti C, Loomis D, Grosse Y, Bianchini F, Straif K. Body fatness and cancer – viewpoint of the IARC working group. N Engl J Med. 2016;375(8):794–8. https://doi.org/10.1056/NEJMsr 1606602. Lee E, Kang SB, Choi SII, et al. Prospective study on the incidence of postoperative venous thromboembolism in Korean patients with colorectal cancer. Cancer Res Treat. 2016;48(3):978–89. https://doi.org/10.4143/ crt.2015.311. Lee J, Xiao Y-Y, Sun YY, et al. Prevalence and characteristics of hereditary non-polyposis colorectal cancer (HNPCC) syndrome in immigrant Asian colorectal cancer patients. BMC Cancer. 2017;17(1):843. https:// doi.org/10.1186/s12885-017-3799-y. Leonel AJ, Alvarez-Leite JI. Butyrate: implications for intestinal function. Curr Opin Clin Nutr Metab Care. 2012;15(5):474–9. https://doi.org/10.1097/MCO.0b0 13e32835665fa. Li X, Pathi SS, Safe S. Sulindac sulfide inhibits colon cancer cell growth and downregulates specificity protein transcription factors. BMC Cancer. 2015;15(1):974. https://doi.org/10.1186/s12885-0151956-8. Li Y, Zhang T, Chen GY. Flavonoids and colorectal cancer prevention. Antioxidants. 2018;7(12):187. https://doi. org/10.3390/antiox7120187. Lichtman SM, Balducci L, Aapro M. Geriatric oncology: a field coming of age. J Clin Oncol. 2007;25(14):1821–3. https://doi.org/10.1200/JCO.2007.10.6567. Lin OS. Performing colonoscopy in elderly and very elderly patients: risks, costs and benefits. World J Gastrointest Endosc. 2014;6(6):220–6. https://doi. org/10.4253/wjge.v6.i6.220. Lipkin M, Newmark H. Calcium and the prevention of colon cancer. J Cell Biochem. 1995;59(22S):65–73. https://doi.org/10.1002/jcb.240590810.

C. S. Pitchumoni Little CH, Combet E, McMillan DC, Horgan PG, Roxburgh CSD. The role of dietary polyphenols in the moderation of the inflammatory response in early stage colorectal cancer. Crit Rev Food Sci Nutr. 2017;57(11):2310–20. https://doi.org/10.1080/10408398.2014.997866. Liu SKM, Church JM, Lavery IC, Fazio VW. Operation in patients with incurable colon cancer – is it worthwhile? Dis Colon Rectum. 1997;40(1):11–4. https://doi.org/ 10.1007/BF02055675. Liu SL, O’brien P, Zhao Y, Hopman WM, Lamond N, Ramjeesingh R. Adjuvant treatment in older patients with rectal cancer: a population-based review. Curr Oncol. 2018;25(6):e499–506. https://doi.org/10.3747/ co.25.4102. Lochhead P, Chan AT. Statins and colorectal cancer. Clin Gastroenterol Hepatol. 2013;11(2):109–18. https://doi. org/10.1016/j.cgh.2012.08.037. Logan RFA, Grainge MJ, Shepherd VC, Armitage NC, Muir KR. Aspirin and folic acid for the prevention of recurrent colorectal adenomas. Gastroenterology. 2008;134(1):29–38. https://doi.org/10.1053/j.gastro. 2007.10.014. Lynch HT. Family information service and hereditary cancer. Cancer. 2001;91(4):625–8. https://doi.org/ 10.1002/1097-0142(20010215)91:43.0.CO;2-4. Lynch HT, de la Chapelle A. Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet. 1999;36(11):801–18. https://doi.org/10.1136/jmg.36. 11.801. Lynch HT, de la Chapelle A. Hereditary colorectal Cancer. Guttmacher AE, Collins FS, editors. N Engl J Med. 2003;348(10):919–32. https://doi.org/10.1056/NEJM ra012242. Ma Y, Yang Y, Wang F, et al. Obesity and risk of colorectal cancer: a systematic review of prospective studies. PLoS One. 2013;8(1):e53916. https://doi.org/10.1371/ journal.pone.0053916. Mattiuzzi C, Sanchis-Gomar F, Lippi G. Concise update on colorectal cancer epidemiology. Ann Transl Med. 2019;7(21):609. https://doi.org/10.21037/27916. Maurício SF, Xiao J, Prado CM, Gonzalez MC, Correia MITD. Different nutritional assessment tools as predictors of postoperative complications in patients undergoing colorectal cancer resection. Clin Nutr. 2018;37(5):1505–11. https://doi.org/10.1016/j.clnu. 2017.08.026. Michalopoulos G, Tzathas C. Serrated polyps of right colon: guilty or innocent? Ann Gastroenterol. 2013;26 (3):212–9. http://www.ncbi.nlm.nih.gov/pubmed/ 24714424. Accessed 26 Feb 2020. Mileo AM, Nisticò P, Miccadei S. Polyphenols: immunomodulatory and therapeutic implication in colorectal cancer. Front Immunol. 2019;10(Apr):729. https://doi. org/10.3389/fimmu.2019.00729. Millan M, Merino S, Caro A, Feliu F, Escuder J, Francesch T. Treatment of colorectal cancer in the elderly. World J Gastrointest Oncol. 2015;7(10):220. https://doi.org/ 10.4251/wjgo.v7.i10.204.

89

Colorectal Cancer

Mima K, Nishihara R, Qian ZR, et al. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut. 2016;65(12):1973–80. https://doi.org/ 10.1136/gutjnl-2015-310101. Miyoshi Y, Nagase H, Ando H, et al. Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet. 1992;1 (4):229–33. https://doi.org/10.1093/hmg/1.4.229. Montroni I, Ugolini G, Saur NM, et al. Personalized management of elderly patients with rectal cancer: expert recommendations of the European Society of Surgical Oncology, European Society of Coloproctology, International Society of Geriatric Oncology, and American College of Surgeons Commission on Cancer. Eur J Surg Oncol. 2018;44(11):1685–702. https://doi.org/ 10.1016/j.ejso.2018.08.003. Morris EJA, Taylor EF, Thomas JD, et al. Thirty-day postoperative mortality after colorectal cancer surgery in England. Gut. 2011;60(6):806–13. https://doi.org/ 10.1136/gut.2010.232181. Murphy N, Ward HA, Jenab M, et al. Heterogeneity of colorectal cancer risk factors by anatomical subsite in 10 European countries: a multinational cohort study. Clin Gastroenterol Hepatol. 2019;17(7):1323–1331.e6. https://doi.org/10.1016/j.cgh.2018.07.030. Muto T, Bussey HJR, Morson BC. The evolution of cancer of the colon and rectum. Cancer. 1975;36(6):2251–70. https://doi.org/10.1002/cncr.2820360944. Nagase H, Nakamura Y. Mutations of the APC (adenomatous polyposis coli) gene. Hum Mutat. 1993;2(6):425– 34. https://doi.org/10.1002/humu.1380020602. National Institutes of Health. Colorectal cancer – cancer stat facts. 2020. https://seer.cancer.gov/statfacts/html/ colorect.html. Accessed 26 Feb 2020. Nee J, Chippendale RZ, Feuerstein JD. Screening for Colon Cancer in older adults: risks, benefits, and when to stop. Mayo Clin Proc. 2020;95(1):184–96. https://doi.org/10.1016/j.mayocp.2019.02.021. Ng O, Watts E, Morris R, Acheson A, Banerjea A. Colorectal cancer outcomes in patients aged over 85 years. Ann R Coll Surg Engl. 2016;98:216–21. https://doi.org/10.1308/rcsann.2016.0085. NIH Consensus Conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA. 1990;264 (11):1444–50. https://doi.org/10.1001/jama.264.11. 1444. Nolfo F, Rametta S, Marventano S, et al. Pharmacological and dietary prevention for colorectal cancer. BMC Surg. 2013;13(Suppl 2):S16. https://doi.org/10.1186/ 1471-2482-13-S2-S16. Norat T, Bingham S, Ferrari P, et al. Meat, fish, and colorectal cancer risk: the European prospective investigation into cancer and nutrition. J Natl Cancer Inst. 2005;97 (12):906–16. https://doi.org/10.1093/jnci/dji164. Olaiya B, Adler DG. Adverse events after inpatient colonoscopy in octogenarians. J Clin Gastroenterol. 2019;1 https://doi.org/10.1097/MCG.0000000000001288. Pandit V, Khan M, Martinez C, et al. A modified frailty index predicts adverse outcomes among patients with

1987 colon cancer undergoing surgical intervention. Am J Surg. 2018;216(6):1090–4. https://doi.org/10.1016/j. amjsurg.2018.07.006. Papamichael D, Audisio RA, Glimelius B, et al. Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013. Ann Oncol. 2015;26(3):463–76. https://doi.org/10.1093/annonc/mdu253. Patai ÁV, Molnár B, Tulassay Z, Sipos F. Serrated pathway: alternative route to colorectal cancer. World J Gastroenterol. 2013;19(5):607–15. https://doi.org/ 10.3748/wjg.v19.i5.607. Pence BC. Role of calcium in colon cancer prevention: experimental and clinical studies. Mutat Res Fundam Mol Mech Mutagen. 1993;290(1):87–95. https://doi. org/10.1016/0027-5107(93)90036-F. Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology. 2010;138(6):2059– 72. https://doi.org/10.1053/j.gastro.2009.12.065. Poynter JN, Gruber SB, Higgins PDR, et al. Statins and the risk of colorectal Cancer. N Engl J Med. 2005;352 (21):2184–92. https://doi.org/10.1056/NEJMoa043792. Preventive Services Task Force US. Screening for colorectal cancer: US preventive services task force recommendation statement. JAMA. 2016;315(23):2564–75. https://doi.org/10.1001/jama.2016.5989. Reinhart K, Bannert C, Dunkler D, et al. Prevalence of flat lesions in a large screening population and their role in colonoscopy quality improvement. Endoscopy. 2013;45 (5):350–6. https://doi.org/10.1055/s-0032-1326348. Rønning B, Wyller TB, Nesbakken A, et al. Quality of life in older and frail patients after surgery for colorectal cancer-a follow-up study. J Geriatr Oncol. 2016;7 (3):195–200. https://doi.org/10.1016/j.jgo.2016.03.002. Roslan NH, Makpol S, Mohd Yusof YA. A review on dietary intervention in obesity associated colon cancer. Asian Pacific Journal of Cancer Prevention. 2019;20 (5):1309–19. https://doi.org/10.31557/APJCP.2019. 20.5.1309. Rowan AJ, Lamlum H, Ilyas M, et al. APC mutations in sporadic colorectal tumors: A mutational “hotspot” and interdependence of the “two hits”. Proc Natl Acad Sci U S A. 2000;97(7):3352–7. https://doi.org/10.1073/ pnas.97.7.3352. Sadanandam A, Lyssiotis CA, Homicsko K, et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med. 2013;19(5):619–25. https://doi.org/10.1038/nm.3175. Sargent DJ, Goldberg RM, Jacobson SD, et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med. 2001;345 (15):1091–7. https://doi.org/10.1056/NEJMoa010957. Schernhammer ES, Ogino S, Fuchs CS. Folate and vitamin B6 intake and risk of colon cancer in relation to p53 expression. Gastroenterology. 2008;135(3):770–80. https://doi.org/10.1053/j.gastro.2008.06.033. Schmoll HJ, van cutsem E, Stein A, et al. Esmo consensus guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical

1988 decision making. Ann Oncol. 2012;23(10):2479–516. https://doi.org/10.1093/annonc/mds236. Shank WA, Balducci L. Recombinant hemopoietic growth factors: comparative hemopoietic response in younger and older subjects. J Am Geriatr Soc. 1992;40(2):151–4. https://doi.org/10.1111/j.1532-5415.1992.tb01936.x. Shaw E, Warkentin MT, McGregor SE, Town S, Hilsden RJ, Brenner DR. Intake of dietary fibre and lifetime non-steroidal antiinflammatory drug (NSAID) use and the incidence of colorectal polyps in a population screened for colorectal cancer. J Epidemiol Community Health. 2017;71(10):961–9. https://doi.org/10.1136/ jech-2016-208606. Siegel RL, Miller KD, Fedewa SA, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017;67(3):177–93. https://doi.org/10.3322/caac.21395. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34. https://doi.org/ 10.3322/caac.21551. Simon K. Colorectal cancer development and advances in screening. Clin Interv Aging. 2016;11:967–76. https:// doi.org/10.2147/CIA.S109285. Snover DC, Ahnen DJ, Burt RW, Odze RD. Serrated polyps of the colon and rectum and serrated polyposis. 4th ed. In: Bosman FT, Carneiro F, Hruban RH, et al., editors. Lyon: IARC; 2010. Sobhani I, Tap J, Roudot-Thoraval F, et al. Microbial dysbiosis in colorectal cancer (CRC) patients. PLoS One. 2011;6(1):e16393. https://doi.org/10.1371/journal.pone.0016393. Song M, Garrett WS, Chan AT. Nutrients, foods, and colorectal cancer prevention. Gastroenterology. 2015;148(6):1244–1260.e16. https://doi.org/10.1053/ j.gastro.2014.12.035. Stintzing S. Management of colorectal cancer. F1000Prime Rep. 2014;6(108) https://doi.org/10.12703/P6-108. Stoffel EM, Mangu PB, Gruber SB, et al. Hereditary colorectal cancer syndromes: American society of clinical oncology clinical practice guideline endorsement of familial risk-colorectal cancer: European society for medical oncology clinical practice guidelines. J Clin Oncol. 2015;33(2):209–17. https://doi.org/10.1200/ JCO.2014.58.1322. Strul H, Kariv R, Leshno M, et al. The prevalence rate and anatomic location of colorectal adenoma and cancer detected by colonoscopy in average-risk individuals aged 40–80 years. Am J Gastroenterol. 2006;101 (2):255–62. https://doi.org/10.1111/j.1572-0241.2006. 00430.x. Sun J, Kato I. Gut microbiota, inflammation and colorectal cancer. Genes Dis. 2016;3(2):130–43. https://doi.org/ 10.1016/j.gendis.2016.03.004. Tenesa A, Dunlop MG. New insights into the aetiology of colorectal cancer from genome-wide association studies. Nat Rev Genet. 2009;10(6):353–8. https://doi.org/ 10.1038/nrg2574. Terry PD, Miller AB, Rohan TE. Obesity and colorectal cancer risk in women. Gut. 2002;51(2):191–4. https:// doi.org/10.1136/gut.51.2.191.

C. S. Pitchumoni Thompson MR, O’Leary DP, Flashman K, Asiimwe A, Ellis BG, Senapati A. Clinical assessment to determine the risk of bowel cancer using symptoms, age, mass and Iron deficiency anaemia (SAMI). Br J Surg. 2017;104 (10):1393–404. https://doi.org/10.1002/bjs.10573. Ting PC, Lee WR, Huo YN, Hsu SP, Lee WS. Folic acid inhibits colorectal cancer cell migration. J Nutr Biochem. 2019;63:157–64. https://doi.org/10.1016/j. jnutbio.2018.09.020. U.S. Preventive Services Task Force. Routine aspirin or nonsteroidal anti-inflammatory drugs for the primary prevention of colorectal cancer: recommendation statement – U.S. Preventive Services Task Force – American Family Physician. American Family Physician. 2007, July 1. https://www.aafp.org/afp/2007/0701/ p109.html. Accessed 26 Feb 2020. Upadhyay S, Dahal S, Bhatt VR, Khanal N, Silberstein PT. Chemotherapy use in stage III colon cancer: a national cancer database analysis. Ther Adv Med Oncol. 2015;7(5):244–51. https://doi.org/10.1177/ 1758834015587867. van der Sijp MPL, Bastiaannet E, Mesker WE, et al. Differences between colon and rectal cancer in complications, short-term survival and recurrences. Int J Color Dis. 2016;31(10):1683–91. https://doi.org/10.1007/ s00384-016-2633-3. Veettil SK, Lim KG, Ching SM, Saokaew S, Phisalprapa P, Chaiyakunapruk N. Effects of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs on the incidence of recurrent colorectal adenomas: a systematic review with meta-analysis and trial sequential analysis of randomized clinical trials. BMC Cancer. 2017;17(1):763. https://doi.org/10.1186/s12885-017-3757-8. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319(9):525–32. https://doi.org/ 10.1056/NEJM198809013190901. Vu HT, Lopez R, Bennett A, Burke CA. Individuals with sessile serrated polyps express an aggressive colorectal phenotype. Dis Colon Rectum. 2011;54 (10):1216–23. https://doi.org/10.1097/DCR.0b013e 318228f8a9. Walter LC, Covinsky KE. Cancer screening in elderly patients a framework for individualized decision making. J Am Med Assoc. 2001;285(21):2750–6. https:// doi.org/10.1001/jama.285.21.2750. Walter LC, Lewis CL, Barton MB. Screening for colorectal, breast, and cervical cancer in the elderly: a review of the evidence. Am J Med. 2005;118(10):1078–86. https://doi.org/10.1016/j.amjmed.2005.01.063. Waluga M, Zorniak M, Fichna J, Kukla M, Hartleb M. Pharmacological and dietary factors in prevention of colorectal cancer. J Physiol Pharmacol. 2018;69 (3) https://doi.org/10.26402/jpp.2018.3.02. Warren JL, Klabunde CN, Mariotto AB, et al. Adverse events after outpatient colonoscopy in the medicare population. Ann Intern Med. 2009;150(12):849–57. https://doi.org/10.7326/0003-4819-150-12-20090616000008.

89

Colorectal Cancer

Wei EK, Giovannucci E, Wu K, et al. Comparison of risk factors for colon and rectal cancer. Int J Cancer. 2004;108(3):433–42. https://doi.org/10.1002/ijc.11540. Willett CG, Fung CY, Kaufman DS, Efird J, Shellito PC. Postoperative radiation therapy for high-risk colon carcinoma. J Clin Oncol. 1993;11(6):1112–7. https://doi.org/10.1200/JCO.1993.11.6.1112. Willett CG, Goldberg S, Shellito PC, et al. Does postoperative irradiation play a role in the adjuvant therapy of stage T4 colon cancer? Cancer J Sci Am. 1999;5 (4):242–7. http://www.ncbi.nlm.nih.gov/pubmed/10 439171. Accessed 27 Feb 2020. Williams R, White P, Nieto J, Vieira D, Francois F, Hamilton F. Colorectal cancer in African Americans: an update. Clin Transl Gastroenterol. 2016;7(7):e185. https://doi.org/10.1038/ctg.2016.36. Wilson JAP. Colon cancer screening in the elderly: when do we stop? Trans Am Clin Climatol Assoc. 2010;121:94–103. Winner M, Mooney SJ, Hershman DL, et al. Incidence and predictors of bowel obstruction in elderly patients with stage IV colon cancer: a population-based cohort study. JAMA Surg. 2013;148(8):715–22. https://doi.org/ 10.1001/jamasurg.2013.1. Witold K, Anna K, Maciej T, Jakub J. Adenomas – genetic factors in colorectal cancer prevention. Rep Pract Oncol Radiother. 2018;23(2):75–83. https://doi.org/ 10.1016/j.rpor.2017.12.003.

1989 World Health Organization. WHO definition of palliative care. World Health Organization. 2020. https://www.who.int/ cancer/palliative/definition/en/. Accessed 27 Feb 2020. Wu N, Yang X, Zhang R, et al. Dysbiosis signature of fecal microbiota in colorectal cancer patients. Microb Ecol. 2013;66(2):462–70. https://doi.org/10.1007/s00248013-0245-9. Yamauchi M, Morikawa T, Kuchiba A, et al. Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut. 2012;61(6):847–54. https://doi.org/10.1136/gutjnl-2011-300865. Yang W, Liu L, Keum NN, et al. Calcium intake and risk of colorectal cancer according to tumor-infiltrating T cells. Cancer Prev Res. 2019;12(5):283–93. https://doi.org/ 10.1158/1940-6207.CAPR-18-0279. Zerey M, Paton BL, Khan PD, et al. Colonoscopy in the very elderly: a review of 157 cases. Surg Endosc Other Interv Tech. 2007;21(10):1806–9. https://doi.org/ 10.1007/s00464-007-9269-x. Zhao XD, Cai BB, Cao RS, Shi RH. Palliative treatment for incurable malignant colorectal obstructions: a metaanalysis. World J Gastroenterol. 2013;19(33):5565–74. https://doi.org/10.3748/wjg.v19.i33.5565. Zhu Q, Gao R, Wu W, Qin H. The role of gut microbiota in the pathogenesis of colorectal cancer. Tumor Biol. 2013;34(3):1285–300. https://doi.org/10.1007/s13277013-0684-4.

Chemoradiotherapy for Gastrointestinal Malignancies

90

Jonathan B. Wallach and Michael J. Nissenblatt

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1992 Assessment Tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1993 Tumor-Agnostic Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1994 Colorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1994 Gastric Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1995 Esophageal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1996 Pancreatic Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1998 Biliary Tract Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1999 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2000 Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2001 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2001

Abstract

There is a paucity of data from randomized controlled trials for evidence-based decisionmaking for older patients. Many gastrointestinal malignancies require trimodality therapy with surgery, chemotherapy, and radiotherapy,

J. B. Wallach (*) Department of Radiation Oncology, Saint Peter’s University Hospital, New Brunswick, NJ, USA e-mail: [email protected] M. J. Nissenblatt Regional Cancer Care Associates, East Brunswick, NJ, USA e-mail: [email protected]

but physicians have historically undertreated older patients who may have benefitted from more aggressive approaches, leading to suboptimal outcomes. The comprehensive geriatric assessment (CGA) has been developed to stratify older adults into tiers based upon their level of fitness to receive oncologic therapy and to assess appropriate goals of care. As with all age cohorts, immunotherapy is dramatically changing survival, and stereotactic body radiotherapy (SBRT) performs very powerful, targeted treatments to a variety of sites. Treatment recommendations should be made at an interdisciplinary tumor board represented by all pertinent specialties. Shared decision-

© Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_102

1991

1992

J. B. Wallach and M. J. Nissenblatt

making is important to balance the benefits and risks. Prospective studies should enroll more older patients, enabling physicians to best know how to evaluate and treat this expanding cohort of the oncology population. Keywords

Gastrointestinal cancer · Geriatric · Surgery · Chemotherapy · Radiotherapy

Introduction As the populations of developed nations are aging, and most malignancies increase in incidence with age, the older cancer patient population will continue to grow both in absolute numbers and as a percentage of the total cancer population. Back in 1900, the percentage of the US population 65 years was 4.1% and had reached 13.0% by 2010; it is projected to reach 20.9% by 2050 (West et al. 2014). It has been predicted that by 2030, 70% of all cancers and 85% of all cancer-related deaths will occur in patients aged 65 years (Yancik and Ries 2004). Older patients also tend to have additional medical problems compared to their younger peers, potentially complicating their treatments and leading to inferior outcomes. Aging is not merely an outwardly apparent phenotypic phenomenon; it may be defined as the synchronous progressive decline in the functional reserve of multiple organ systems. This process varies from individual to individual, and will correlate with chronologic age, but in approaching the older patient with gastrointestinal cancer, the physiologic age needs to be determined (Sheridan et al. 2014). Geriatric patients

risk being unnecessarily undertreated, leading to worse oncologic outcomes; however, if they are overtreated, there are increased risks for morbidity and mortality (Sheridan et al. 2014). There is a paucity of data from randomized controlled trials applicable for evidence-based decision-making for gastrointestinal cancers in the aged. The lack of data complicates decisionmaking in selecting which patients would benefit from a curative approach, and for which patients a non-operative and/or less aggressive palliative approach would be more reasonable, even when a cancer is potentially curable. Many clinical trials have even excluded patients >75 years old, as these patients are more likely to have comorbidity that may increase the risk of complications and mortality during treatment. These trials exclude older patients because the trials have largely been designed to demonstrate maximal treatment efficacy with aggressive oncologic therapy in patients with high-performance status (create differences between the trial arms), which tend to be suboptimal in the elderly. Specialized patient assessments and individualized treatment approaches are needed, given the patients’ increased comorbidities, as clinical results from younger patients cannot be directly translated to older adults, with their declining organ function and comorbid conditions. A study by Talarico et al. analyzed the enrollment of cancer patients in clinical trials in the United States, versus the proportion of cancer population, and highlighted this dramatic underrepresentation, as seen in Table 1 (Talarico et al. 2004). Another issue facing elderly oncology patients is polypharmacy. About 80% of patients with newly diagnosed malignancies aged 65 years take 5 medications (Prithviraj et al. 2012). Polypharmacy complicates cancer treatment by

Table 1 Enrollment of elderly cancer patients in clinical trials in the United States, as a proportion of the cancer population (Talarico et al. 2004) Age (years) 65 70 75

Clinical trial enrollment representation (%) 36 20 9

Cancer population percentage 60 46 31

Enrollment repr./cancer population percentage 0.60 0.43 0.29

90

Chemoradiotherapy for Gastrointestinal Malignancies

increasing the risks of drug-drug interactions, adverse effects, and nonadherence. As a result, geriatric oncology patients may have inferior outcomes from the potential side effects, or they may be prescribed less aggressive treatments. Therefore, to limit the risks of polypharmacy, a regular review of a patient’s medications should be part of the treatment plan. While this chapter discusses patients 65 years old with gastrointestinal malignancies, the evidence and recommendations can largely also be applied to younger patients with gastrointestinal malignancies with significant medical comorbidities and thus in effect have a higher physiologic age.

Assessment Tools At the outset, a comprehensive assessment of this heterogenous population is needed to determine the patient’s physiologic age, which is more important than the chronologic age; such an assessment is the first step in providing optimal care. Performance scales such as the Karnofsky performance score (KPS) and Eastern Cooperative Oncology Group (ECOG) score are widely used. However, for geriatric oncology, these scales alone are insufficient, as they do not account for comorbidities that can become quickly problematic, nor do they account for the social support system, usually from the family. Therefore, comprehensive geriatric assessment (CGA) that is used in geriatric medicine is now used in geriatric oncology. The International Society of Geriatric Oncology task force has recommended wider implementation of geriatric assessment prior to treatment (Extermann et al. 2005). The multifaceted, interdisciplinary diagnostic CGA helps determine where along the spectrum an individual is in his ability to tolerate definitive or palliative treatment. It assesses a geriatric patient’s medical, psychosocial, and functional capacities to develop an appropriate treatment plan. Patients are divided into three functional groups, as follows (Balducci and Extermann 2000):

1993

1. Fit – candidates who are healthy and functionally independent may receive the full conventional treatment. 2. Intermediate – candidates in between frail and fit, who may benefit from modified curative treatment. 3. Frail – candidates only for palliation. CGA is currently recommended for all elderly oncology patients (Hamaker et al. 2012); nevertheless, as it is a time-consuming process, the validated VES-13 (Vulnerable Elders Survey-13) is a widely used test that can be used as a quick, supplemental screening tool. It consists of 1 item for age and 12 items that evaluate health, functional capacity, and physical performance. The average time to complete this self-administered questionnaire is 75 years old may be less likely to receive surgery and/or systemic therapy due to medical comorbidities. Indeed, while octogenarians do tend to have higher perioperative mortality rates than patients 4 times and 95

50–80

55

>70

burden downstream from normal hepatic tissue is excessive and mediators enter the systemic circulation leading to symptoms. Carcinoid tumors of the foregut (stomach, duodenum, bronchus, thymus) do have secretory products, but carcinoid syndrome is rare. Hindgut carcinoids have variable secretory activity and are rarely symptomatic. Diagnosis of carcinoid syndrome is made by measurement of: • 24-h urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) is most useful in midgut NENs; care should be taken to avoid certain medications and foods that are rich in tryptophan/ serotonin. • Plasma 5-HIAA is a more convenient test and correlates well with urinary 5-HIAA, but this test needs to be further validated. • Urinary excretion of serotonin (assays not available in the USA) may detect foregut carcinoids in which secretion of 5-HT is seen.

GI dysfunction Abdominal pain Anorexia Nausea Constipation Diarrhea Diverticula Dyspeptic symptoms Fecal incontinence Gall stones Gastroparesis Hepatic dysfunction Intestinal motility Malabsorption Peptic ulcers Vomiting Weight gain Weight loss

+ +

+

+ +

+

+

+

+

Hypothyroidism + +

Acromegaly

+

+

+ +

+

+

+

+ +

Hyperthyroidism

Table 3 Gastrointestinal dysfunction associated with endocrine disorders

+

+ +

+

+

Hyperparathyroidism + + +

+

+

+

Adrenal insufficiency + + +

+

+

Cushing’s +

+ + +

+ +

+ +

+

+

Diabetes + + + + +

+

+ + +

+

+

+

+

Neuroendocrine tumors +

98 Gastrointestinal Manifestations of Endocrine Disease 2179

2180

• Chromogranin A, B, and C concentration: Chromogranin A is the most sensitive and is increased in well-differentiated NENs and with large tumor burden. False-positive elevation is present in several other endocrine, gastrointestinal, and cardiovascular conditions. Treatment of carcinoid syndrome is largely dependent on the somatostatin analogs, octreotide and lanreotide. Surgical resection or hepatic embolization can be a highly effective measure for people with extensive liver disease. Telotristat, the oral tryptophan hydroxylase inhibitor, can limit the synthesis of serotonin and has been shown to reduce bowel movement frequency. Interferon alpha is effective in patients’ refractory to somatostatin analogs but may lead to debilitating side effects. Antidiarrheal agents such as loperamide and diphenoxylate-atropine or even opiates may need to be used concurrently for severe diarrhea. It is important to remember that chronic somatostatin may cause fat malabsorption and steatorrhea, necessitating the use of pancreatic enzyme supplementation with meals.

When to Suspect a Gastroenteropancreatic Neuroendocrine Neoplasm (GEP NEN)? • Unexplained diarrhea • Confirmed hypoglycemia reversed by glucose intake in the absence of pharmacological treatment for diabetes • Recurrent peptic ulceration • Unexplained hypokalemia • Necrolytic migratory erythema • Steatorrhea • Cholelithiasis • Unexplained flushing • Unexplained anemia • Weight loss While each of the above clinical findings can occur in isolation and have a readily identifiable cause, patients with a constellation of typical features which are chronic and do not have an explanation should be evaluated for a neuroendocrine tumor. A possible pitfall is to treat each clinical

N. Pandya and E. Hames

condition in isolation and failure to identify an underlying possibly treatable disorder.

Key Points • Older adults often present with vague and/or atypical signs and symptoms of endocrine disorders, such as weakness, depression, falls, impaired cognition, or functional decline. • Within the gastrointestinal tract, manifestations of underlying endocrine disease may include anorexia, dysphagia, nausea and vomiting, changes in hepatobiliary function, constipation, diarrhea, and weight loss (Table 3). • These changes may be misinterpreted as agerelated physiologic changes, primary gastrointestinal disorders, geriatric syndromes, or as sequelae of underlying morbidities (e.g., heart failure, coronary artery disease, cerebrovascular disease, etc.). • The clinician needs to maintain a high index of suspicion for an endocrine diagnosis in patients with GI symptoms that persist without reasonable explanation. • In patients with a known endocrine disorder, it is important to exclude other causes of GI symptoms (i.e., minimize diagnostic overshadow). • Carefully review medications used for endocrine disorders for appropriateness of dosing and potential GI adverse effects. • Due to fragmentation of care provided by multiple specialists, a brief comprehensive geriatric assessment of the older adult is advised to evaluate all potential contributing causes (to reduce cognitive and anchoring bias). • Management should be appropriate for the patient’s goals of care and to improve quality of life.

References Abboud B, et al. Digestive manifestations of parathyroid disorders. World J Gastroenterol. 2011;17:4063–6. Almogbel RA, Alhussan FA, Alnasser SA. Prevalence and risk factors of gastroparesis-related symptoms among

98

Gastrointestinal Manifestations of Endocrine Disease

patients with type 2 diabetes. Int J Health Sci (Qassim). 2016;10(3):397–404. American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association (AGA) Institute, American Society for Gastrointestinal Endoscopy, Waxler A. The gastroenterology core curriculum. 3rd ed. Gastroenterology 2007;132:2012–18. Bancos I, Hahner S, Tomlinson J, et al. The Lancet Diabetes and Endocrinology. 2015;3(3):216–226. Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 2006;101:2379–400. Bettge K, Kahle M, Abd El Aziz MS, et al. Occurrence of nausea, vomiting and diarrhoea reported as adverse events in clinical trials studying glucagon-like peptide-1 receptor agonists: a systematic analysis of published clinical trials. Diabetes Obes Metab. 2017;19(3):336–47. Bharucha AE, Kudva YC, Prichard DO. Diabetic gastroparesis. Endocr Rev. 2019; https://doi.org/ 10.1210/er.2018-00161. Bhatt H, Smith RJ. Fatty liver disease in diabetes mellitus. Hepatobiliary Surg Nutr. 2015;4(2):101–8. Ch’ng CL, et al. Prospective screening for celiac disease in patients with graves’ hyperthyroidism using anti-gliadin and tissue transglutaminase antibodies. Clin Endocrinol. 2005;62:303–6. Chiu, et al. Dysphagia as a manifestation of thyrotoxicosis: report of three cases and literature review. Dysphagia. 2004;19:120–4. Ciobanu L, Dumitrascu DL. Gastrointestinal motility disorders in endocrine diseases. Pol Arch Med Wewn. 2011;121:129–36. Daher R, et al. Consequences of Dysthyroidism on the digestive tract and viscera. World J Gastroenterol. 2009;15:2834–8. Davis PJ, Davis FB. Hyperthyroidism in patients over the age of 60 years: clinical features in 85 patients. Medicine. 1974;53:161–6. Dickman R, Kislov J, Boaz M, Ron Y, et al. Prevalence of symptoms suggestive of gastroparesis in a cohort of patients with diabetes mellitus. J Diabetes Complicat. 2013;27(4):376–9. Dixon JL, et al. Association between diabetes and esophageal cancer, independent of obesity, in the United States veterans affairs population. Dis Esophagus. 2016;29(7):747–751. Ebert EC. The thyroid and the gut. J Clin Gastroenterol. 2010;44:402–6. Ehehalt F, et al. Neuroendocrine tumors of the pancreas. Oncologist. 2009;14:456. Elfström P, et al. Risk of thyroid disease in individuals with celiac disease. J Clin Endocrinol Metab. 2007;92:3915–9. Ellis C, Nicoloff DM. Hyperparathyroidism and peptic ulcer disease. Arch Surg. 1968;96:114–8. Felderbauer, et al. Mutations in the calcium-sensing receptor: a new genetic risk factor for chronic pancreatitis? Scand J Gastroenterol. 2006;41: 343–8.

2181 Fraenkel M, Kim M, Faggiano A, de Herder WW, Valk GD. Knowledge NETwork. Endocr Relat Cancer. 2014 May 6;21(3):R153–63. Gardner EC, Hersch T. Primary hyperparathyroidism and the gastrointestinal tract. South Med J. 1981;74:197–9. Gibbons D, Camilleri M, Nelson AD, Eckert D. Characteristics of chronic megacolon among patients diagnosed with multiple endocrine neoplasia type 2B. United European Gastroenterol J. 2016;4(3):449–54. Goyal I, Panta R, Chaudhuri A. A rare case of pituitary mediated hypercortisolism (Cushing’s disease) with MEN-1 syndrome. Endocr Pract, suppl. Supplement 3; Jacksonville. 2017;23:188. Harrison B, et al. The Association of Primary Hyperparathyroidism with Pancreatitis. J Clin Gastroenterol. 2012;46:656–61. Hosono K, Endo H, Takahashi H, et al. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res. 2010;3(9):1077–83. Jacob JJ, et al. Does hyperparathyroidism cause pancreatitis? ANZ J Surg. 2006;76:740–4. Jodkowska A, et al. Interdisciplinary aspects of primary hyperparathyroidism: symptomatology in a series of 100 cases. Adv Clin Exp Med. 2016;25:285–93. Jorde R, Saleh F, Sundfjord J, Haug E, et al. Coeliac disease in subjects with secondary hyperparathyroidism. Scand J Gastroenterol 2005;40:178–92. Karaus M, Wienback M, Grussendorf M, Erckenbrecht JF, et al. Intestinal motor activity in experimental hyperthyroidism in conscious dogs. Gastroenterology 1989;97:911–19. Khater D. Endocrinopathies in celiac disease: when the endocrinologist sees what is invisible to the gastroenterologist. Acta Biomed. 2018;9:117–21. Khoo TK, et al. Acute pancreatitis in primary hyperparathyroidism: a population-based study. J Clin Endocrinol Metab. 2009;94:2115–28. Kim D, Ryan J. Gastrointestinal manifestations of systemic diseases. In: Feldman et al, editor. Gastrointestinal and liver disease: pathophysiology/diagnosis/management. 7th ed. 2002. Philadelphia: Saunders Lauritano EC, et al. Association between hypothyroidism and small intestinal bacterial overgrowth. J Clin Endocrinol Metab. 2008;92:4180–5. Lin TY, et al. Incidence of abnormal liver biochemical tests in hyperthyroidism. Clin Endocrinol. 2017;86:755–9. Mantovani A, et al. Association between primary hypothyroidism and NAFLD: a systematic review and metaanalysis. Thyroid. 2018;28:1270–6. Maser C, et al. Gastrointestinal manifestations of endocrine disease. World J Gastroenterol. 2006;12:3174–9. Matsumoto AM, Robertson RP. Commentary: geriatric endocrinology: an important competency for endocrinologists in an aging society. Endocrine News. 2016;1–4. Norton JA, et al. Prospective study of surgery for primary hyperparathyroidism (HPT) in multiple endocrine neoplasia-type 1 and Zollinger-Ellison syndrome: longterm outcome of a more virulent form of HPT. Ann Surg. 2008;247:501–10.

2182 Noto H, et al. Hyperthyroidism presenting as dysphagia. Intern Med. 2000;39:472–3. Rao RH, Vagnucci AH, Amico JA. Bilateral Massive Adrenal Hemorrhage: Early Recognition and Treatment. Ann Intern Med. 1989;110:227–235. Shah VN, et al. Effect of gender, biochemical parameters & parathyroid surgery on gastrointestinal manifestations of symptomatic primary hyperparathyroidism. Indian J Med Res. 2014;139:279–84. Sharma, et al. Colorectal manifestations of endocrine disease. Dis Colon Rectum. 1995;38:318–23. Stepanchick A, et al. Calcium sensing receptor mutations implicated in pancreatitis and idiopathic epilepsy syndrome disrupt an arginine-rich retention motif. Cell Physiol Biochem. 2010;26:363–74.

N. Pandya and E. Hames Tun-Abraham ME, et al. Acute pancreatitis associated with hypercalcemia. Cir Cir. 2015;83:227–31. Valera M, et al. Primary biliary cirrhosis: a thirteen year experience. Rev Clin Med. 2006;134:469–74. Wang X, et al. The effect of periodontal treatment on hemoglobin a1c levels of diabetic patients: a systematic review and meta-analysis. PLoS One. 2014;9:1084. Wegener M, et al. Effect of hyperthyroidism on the transit of a caloric solid-liquid meal through the stomach, the small intestine, and the Colon in man. J Clin Endocrinol Metab. 1992;75:745–9. Zawada, et al. Gastrointestinal complications in patients with diabetes mellitus. Adv Clin Exp Med. 2018;27:567–72.

Rheumatological Manifestations of GI Disorders

99

Mandakolathur R. Murali

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2184 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Relationship Between Mucosal and Systemic Immunity, Genetic Factors, Gut Microbiota, and Dietary Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis Underlying the Gut and Extra-Intestinal Manifestations (EIM) of Rheumatic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rheumatological Manifestations of Gastrointestinal Diseases . . . . . . . . . . . . . . . . . . . . . . . .

2184 2184 2189 2190

Therapeutic Options for Rheumatological (Extra-Intestinal) Manifestations of Gastrointestinal Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2196 Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2197 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2198

Abstract

The gastrointestinal system is unique as it is constantly exposed to the antigenic diversity of the external milieu as well as its own microbiota, interacting with the innate and adaptive mucosal and systemic immune system. The tightly regulated system determines immune tolerance against luminal microbiota (antiinflammatory) versus immune elimination of offending antigens by recruiting diverse

M. R. Murali (*) Division of Rheumatology, Allergy and Clinical Immunology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA e-mail: [email protected]

immune inflammatory pathways (proinflammatory) with potential for causing gastrointestinal diseases. Derangements in the control of homeostatic pathways lead to disordered immunoregulation, resulting in many gastrointestinal disorders such as inflammatory bowel diseases (IBD), celiac disease, Whipple’s disease, bacterial overgrowth syndromes, and others. Further, articular, ocular, cutaneous, hepatobiliary, oral cavity lesions, and even neurological manifestations, often termed as rheumatologic or extraintestinal manifestations (EIM) may be the presenting feature or a manifestation of gastrointestinal disease. This chapter explores the role of the immune inflammatory pathways as it pertains to the rheumatological manifestations of gastrointestinal diseases, in a backdrop of genetic

© Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_89

2183

2184

factors, gut microbiota, and dietary factors that cause altered metabolomics and consequent effect on immune homeostasis. The clinical spectrum and therapeutic options of these EIM are discussed.

M. R. Murali

effect on immune homeostasis. The pathogenetic mechanisms, clinical spectrum, and diagnostic features of these EIM will be described. Therapeutic options that emerge from this understanding will be alluded to as they pertain to these extraintestinal manifestations of gastrointestinal disease.

Keywords

Innate immunity · Dysbiosis · Mucosal immunity · Microbiota · Gut permeability · Immune complexes · T cell heterogeneity · Extraintestinal manifestations · Cell trafficking · Arthropathy · Immunosuppression · Bacteriotherapy · Inflammatory bowel disease · Biologics

Introduction From an immunological angle, the gastrointestinal (GI) system is unique in that it is constantly exposed to the antigenic diversity of the external milieu while interacting with its own luminal microbiota. The latter calls for a balance between the ability to detect and eliminate offending agents while being tolerant to the indigenous microbiota. Further, the interactions between the microbiota and mucosal microenvironment are tightly regulated by the mucosal and systemic immune system. Both innate and adaptive immunity are instrumental in maintaining immune homeostasis (Atarashi et al. 2011). Derangements in the control of the homeostatic pathways leading to disordered immunoregulation result in many gastrointestinal diseases such as inflammatory bowel diseases (IBD), celiac disease, Whipple’s disease, bacterial overgrowth syndromes, and others. Articular, ocular, cutaneous, hepatobiliary, oral cavity lesions, and even neurological manifestations, often termed as extraintestinal manifestations (EIM) or rheumatological manifestations may be the presenting feature or manifestation of gastrointestinal diseases (Vavricka et al. 2015). This chapter explores the role of the immune system and inflammatory pathways as it pertains to the rheumatological manifestations of gastrointestinal diseases, in a backdrop of genetic factors, gut microbiota, and dietary factors that cause altered metabolomics and consequent

Background Relationship Between Mucosal and Systemic Immunity, Genetic Factors, Gut Microbiota, and Dietary Factors 1. MUCOSAL AND SYSTEMIC IMMUNITY: Innate immunity provides a nonspecific and generalized response to infection and/or injury resulting in the induction of a proinflammatory immune response. It is mediated by germ-line encoded receptors. Some of these are pattern recognition receptors or PRRs. The PRRs recognize motifs associated with pathogens that are called pathogen-associated molecular patterns or PAMPs. These PAMPs are uniquely expressed in microbes but not in vertebrates, and allow for initiation of an immune response during the course of an infection. PRRs are strategically expressed on both host cellular membranes as well as in the cytosol, so as to sense threats from external milieu such as bacteria as well as alterations in the internal cytosolic compartment as is a feature of viral infections (Dommett et al. 2005). These receptors are conserved across evolution. Adaptive immunity, on the other hand, is restricted to vertebrates and results in the generation of an antigen-specific immune response to pathogens or external insults. This is achieved by receptors that are generated by random genomic recombination of gene segments, which when assembled during the development of a lymphocyte has the potential to generate 109– 1012 different receptor specificities. The innate immune system includes the epithelial barrier, the lining mucosal blanket, along with an array of innate receptors, which are currently classified into five families: (1) toll-like receptors

99

Rheumatological Manifestations of GI Disorders

(TLR), (2) nucleotide-binding leucine-rich repeatcontaining receptors (NLRs), (3) retinoic acid inducible gene-I (RIG-I)-like receptors (RLRs), (4) C-type lectins (CTLs), and (5) absent-in-melanoma (AIM)-like receptors (ALRs). These receptor families, functioning as sensors or antenna, provide an extensive array of defense receptors that respond to exogenous molecules and endogenous danger signals. TLRs that are expressed on the plasma membrane, including TLR1, 2, 4, 5, and 6, detect a variety of lipidand protein-based ligands that are found in the extracellular milieu. Some TLRs, namely, TLR3 and TLR 7–9, are important initiators of antivirus responses through their recognition of nucleic acids within the endosomal compartment. Threats to the integrity of the gastrointestinal mucosal cells from intracellular microbes and viruses are sensed by cytoplasmic receptors such as the nucleotide binding oligomerization domain (NOD)-like receptors – a member of the NLR family. NLRs are expressed intracellularly and have been shown to respond to a wide variety of classes of ligands, bacterial wall components, toxins, and host-derived ligands (ATPs, uric acids, and damaged membrane). RLRs and ALRs specifically respond to viral RNA and bacterial and viral DNA, respectively. These receptors are thought to be critical players in antiviral immunity. Although these families of innate receptors display a certain degree of specificity, different receptors and their signaling pathways are often simultaneously activated during the course of infection. C type lectins recognize carbohydrate-based ligands and are generally important receptors in the recognition and response to different infections (Janeway and Medzhitov 2002; Meylan et al. 2006; Pichlmair and Reis E Sousa 2007). NOD1 and NOD2 have been shown to be critical receptors of peptidoglycan motifs of gram-negative bacteria and gram-positive bacteria. These proteins are strategically expressed in the intestine, constituting the front line of hostmicrobe interface, and play an important role in maintaining gut homeostasis by preventing exacerbated inflammatory response to commensal bacteria while protecting the host against invasion by

2185

enteric microbial pathogens. Indeed, mutation and polymorphisms in NOD1 and NOD2 have been associated with Crohn’s disease (CD) and other inflammatory bowel disorders, most likely due to altered inflammatory immune response to commensal bacteria and/or enteric pathogens (Ogura et al. 2001). Signaling by these PRR that interact with pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and apoptotic cell-associated molecules (ACAMPs) results in immune elimination of offending stimuli, while at the same time cytokines resulting from this interaction activate the adaptive immune system. It is unclear to what extent the inflammatory response in inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn’s disease, is due to host inflammatory response to gut microbial products or whether the observed alterations in gut microbiota (dysbiosis) are a consequence of the intestinal inflammation. In either case, host tissue damage is the consequence of the activation of the inflammatory cascades initiated by host inflammatory responses, derived from exposure to aberrant concentrations of lipopolysaccharide (LPS) or endotoxin. Engagement of TLR4 receptors by soluble LPS results in intracellular signaling that culminates in nuclear factor kappa beta (NF-kβ) activation and subsequent production of interleukin 1 beta (IL-1β), tumor necrosis factor beta (TNFβ), interleukin 6 (IL-6), and nitric oxide synthetase (iNOS). Nitric oxide (NO) is synthesized from the amino acid L-arginine, via nitric oxide synthetases (Takeda et al. 2003). The immunologic reactivity to dietary and microbial antigens locally is primarily tolerogenic. This is mediated by the innate immune system’s ability to recognize antigenic patterns, antigenic diversity, and quantity which determines the level and direction of T cell reactivity and diversity. Antigens that cannot be eliminated by the intestinal macrophages or other innate lymphoid cells (ILC) via their innate receptor triggered pathways are processed and presented to the members of the adaptive immune system. The macrophages that have trafficked to the regional lymph nodes present antigens to

2186

naïve CD4+ T cells that differentiate into functionally distinct regulatory or effector subsets in the secondary lymph nodes of the spleen and regional nodes. The activated CD4+ T cells differentiate into T cells subtypes (TH1, TH2, TH 17 and Tregs, follicular T helper cells (Tfh), etc.) influenced by the cytokine and microenvironment and regulated by transcription factors. Specifically, IL-12 and IL-18 and the transcription factor T-bet drive cells to the TH1 pathway. These cells are characterized by IFN-γ and IL-2 production and orchestrate a cell-mediated and often granulomatous response. CD4 cells that interact with thymic stromal lymphopoietin (TSLP) activate the transcription factor GATA-3 and evolve into TH2 cells that produce IL-4, IL-5, and IL-13 that contributes to humoral immune responses. While IL-4 and IL-13 induce mast cell and IgE pathways, Il-5 is associated with eosinophilia. Both mast cells and eosinophil derived TGF-β contribute to intestinal smooth muscle remodeling. The transcription factor that presides over the differentiation of CD4+ cells to Tregs is FoxP3 and is mediated by the presence of TGF-β and absence of IL-6. Those CD 4 cells that differentiate into the proinflammatory TH17 cells are influenced by IL22 and the transcription factor RORγ3 (Dong 2006). Studies have expanded the CD4+ T cell differentiation framework to include FoxP3-independent activation of CD4+ T cell-regulatory axis via IL-27, a differentiation factor for regulatory type I cells (Tr 1), a major class of IL-10 producing CD4+ T cells, which despite lack of FoxP3 still exhibit important immunosuppressive functions. It plays a dominant role in regulation of gut immunity. Follicular T helper cells (Tfh) also influence the CD4+ balance by migrating from the T cell area to the B cell follicle via CCR7 downregulation and concurrent expression of the homing chemokine receptor CXCR5. Tfh cells by producing IL-21 through transcription factor BCL-6 promote crosstalk among TH1/TH17 cells. The transcription factor PU.1 works by directly binding to the promoter of IL-9 gene and attracts chromatin-modifying enzymes which reinforce IL9-gene transcription. The resultant IL-9 facilitates the development of the TH9

M. R. Murali

phenotype. The emergence of the TH22 phenotype is promoted by IL-22 produced by the recruitment of aryl hydrocarbon receptor (AHR). This suggests that the T cell populations are highly heterogenous in nature with diverse functions (O’Shea and Paul 2010). This complex and integrated T cell/ B cell interactions along with the innate receptor-mediated immune responses maintain the homeostasis of the gut immune system and the microbiota. (Fig. 1). The immune network of innate and adaptive immunity participates in immune inflammation that contributes to the pathogenesis of the rheumatological manifestations of gastrointestinal diseases. The specific mechanisms contributing to the clinical expression of these manifestations will be addressed under the section of pathogenesis. 2. GENETIC INFLUENCES: A healthy and regulated host-microbe relationship is necessary for the normal development of gut mucosal immunity, to maintain intestinal homeostasis and mitigate against excessive uncontrollable local inflammation. This regulated microenvironment facilitates epithelial-barrier function, by promoting the renewal of epithelial cells. Jacobs and Braun in 2014 commented on how host genetics and gene expression modulate immune mechanisms of microbial molecular pattern recognition to influence the diversity and functionality of the local microbiota. Since the discovery of the NOD2 gene, numerous gene loci associated with abnormal innate immune response (CARD 15/NOD2, TLR4, CARD9, and RAGE), differentiation of TH17 lymphocytes (IL 23R, JAK2, STAT3, CCR6, and ICOSLG), autophagy (ATG16L1, IRGM, LRRK2, and SCL11A), mutations of epithelial barrier function (IBD5, DLG5, PTGER4, INTL1, and DMBTI), and initiation of secondary immune response (HLA region, TNFSF15/ TLIA, IRF5, PTPN2, IL-12B, IL-18 RAP, and MST1) have been recognized for their role in Crohn’s disease (Ogura et al. 2001; Basson et al. 2016). Genome-wide analyses continue to define more gene associations with IBD. These genetic alterations influence immunity by either suppressing or promoting pathogenic

99

Rheumatological Manifestations of GI Disorders

2187

Fig. 1 T cell heterogeneity and GI diseases

microbial colonies. These in turn affect the integrity of the epithelial barrier, host intestinal immunity leading to exacerbations, or remissions of gastrointestinal inflammatory diseases. Inflammatory pathways and mediators resulting from aberrations in systemic immunity resulting from or coexistent with altered mucosal immunity contribute to the rheumatological manifestations of gastrointestinal diseases. 3. GUT MICROBIOTA AND DIETARY FACTORS: The community of microorganisms that live on or inside another organism is termed the “microbiome.” Their interactions with each other and with the host may be beneficial (symbiotic) or detrimental (pathogenic). Alterations in the quantity (bacterial levels) or quality (diversity) are referred to as dysbiosis and regulate immune tolerance or inflammation (Fig. 2). The gut microbiome represents a highly complex and dynamic ecosystem. While a diverse community of bacteria constitutes the

predominant species, it includes eukaryotic fungi and some viruses. Colonization begins in utero and expands in the first 3 years of life. The major phyla are Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria. Its composition is dynamic and dependent on host-associated factors such as age, diet, and environmental conditions. Dietary derived short-chain fatty acids (SCFAs) such as acetate, butyrate, and propionate are derived from fermentation of complex dietary carbohydrates. SCFAs are regarded as mediators in the communication between the intestinal microbiome and the immune system. The signal they produce is transferred to immune cells via free fatty acid receptors (FFARs), which belong to the family of G protein-coupled receptors (GPCRs). SCFAs inhibit the activity of histone deacetylase (HDAC) – an enzyme involved in posttranslational modifications, namely, the process of deacetylation and of histone crotonylation. These properties of SCFAs have an effect on their immunomodulatory potential, i.e., maintaining the anti/proinflammatory balance. SCFAs act not

2188

M. R. Murali

Microbiota and Metabolome modulate the Gastrointestinal – Rheumatic disease axis Infections

Age

Diet

Microbial Dysbiosis

Genetics

Drugs

(Qualitative and Quantitative)

Microbial molecules e.g. LPS, lipids (MAMP’s & PAMP’s)

Microbial metabolites e.g. SCFA’s Glycerolipids, glycospingolipids Modulates epithelial and Mucosal integrity

Activates Innate and adaptive immunity

Commensal

Inflammation Th1 /TH17

Pathogenic

11 - Crohn’s disease 3 - Whipple’s disease 5 – Celiac disease

Tolerance/ T regs

Symbionts

3 4

1 2

5 6

2 – Ulcerative colitis 4 – Bacterial overgrowth 6 – Toxic enterocolitis

Fig. 2 Microbial dysbiosis and rheumatological manifestations

only locally in the intestines colonized by commensal bacteria, but also influence the intestinal immune cells and modulate immune response by multiprotein inflammasome complexes (Round et al. 2011; Kim et al. 2014; Basson et al. 2016). SCFAs exert anti-inflammatory effects by increasing epithelial barrier function, inducing T regs and IL-10 production (Atarashi and Honda 2011; Gonzalves et al. 2018). In addition to SCFA, other metabolites such as tryptophan influence host-microbiome interactions. Tryptophan is an important intermediate metabolite for the activity of the aryl hydrocarbon receptor (AHR) that suppresses immune responses in dendritic cells. The AHR induces indoleamine 2,3 -dioxygenase (IDO), which catabolizes tryptophan to kynurenine (Kyn). A tryptophan-dependent deficiency of AHR causes reduced Kyn, and this results in increased production of proinflammatory TH17 cells (Knights et al. 2013). Excessive and indiscriminate use of antibiotics promotes dysbiosis and contributes to the development of not only allergic diseases (the basic tenant of the hygiene hypothesis) but also to

intestinal bacterial overgrowth syndromes and colitis (Blaser 2016). The net result of microbial dysbiosis is a perturbation of the innate and adaptive immunity, and together with alterations in microbial metabolites, results in loss of immune regulation, epithelial cell dysfunction, mucosal integrity, and emergence of an immune system that is skewed to aberrations in Th1, TH2, and TH17 mediated diseases. Taken together, it is clear that there is a complex and regulated interaction between genetic factors, epigenetics modulated by microbiota, metabolomics, and dietary and nutritional factors, and these impinge on both innate and adaptive immunity. The outcome of these events results in immune tolerance and health versus inflammation and disease states. Given this homeostatic balance of microbiota, could modulation of microbial communities be a therapeutic approach for some gastrointestinal diseases? The answer to this question is best exemplified by studies that document the clinical value and outcomes of carefully chosen microbes used in fecal microbial

99

Rheumatological Manifestations of GI Disorders

transplant or FMT (also known as bacteriotherapy) for C. difficile colitis. Probiotics are defined as “live microorganisms which, when administered in adequate amounts, confer a health benefit to the host.” Prebiotics represent nondigestible food components that benefit the host by selectively stimulating the growth and activity of microorganisms. Foods rich in fibers and oligosaccharides have this property. Beneficial synergism resulting from a combination of prebiotics and probiotics is called synbiotics (Pascal et al. 2018). Early studies using probiotics, prebiotics, and synbiotics shed light on the need to define the optimal time as well as composition of microbiota for these interventions, be it before, during, or after the birth of the child or early childhood (Fig. 2).

Pathogenesis Underlying the Gut and Extra-Intestinal Manifestations (EIM) of Rheumatic Diseases Many pathogenic pathways have been proposed to explain the concurrent inflammation of the gut and its major EIM, namely, the joints as well as other EIM such as the skin, eyes, liver, etc. These encompass genetic predisposition, altered intestinal microbiota, dietary factors, and metabolomics that impact both the innate and adaptive mucosal and systemic immunity. These have been reviewed above, and this section links them together in an attempt to explain the diverse yet unique aspects of the rheumatological aspects of gastrointestinal diseases. A derangement of the gut mucosal barrier is postulated as the primary process. The microbial dysbiosis and altered metabolic products alter the balance from normal tolerogenic and noninflammatory milieu to a proinflammatory environment that impairs the gut epithelial barrier and makes it more permeable to microbial products, cytokines, and toxins. (Fig. 2). An alternative view is that shared genetic or environmental factors predispose individuals to the various inflammatory pathways that link the gut to the joints and other organ system manifestations that constitute the EIM. (Gracey et al. 2019). Intestinal parasitic

2189

infestation, caused by protozoa such as amoeba and giardia, nematods such as strongyloidiasis, platyhelminths such as Tenia Solium causing cysticercosis, and hydatid cyst caused by Echinococcus granulosis, are not rare and lend themselves to anthelminthic therapy to resolve the rheumatological EIM. Circulating microbial antigens may cause reactive arthritis as seen in Yersinia enterocolitica, Shigella, and Salmonella infections. Molecular mimicry, in which an immune response to a gut-derived antigen cross-reacts with normal host protein, has been suggested to explain the role of HLA B27 in postdysenteric reactive arthritis and in some spondyloarthropathies (Gracey et al. 2016). T cells, derived from gut or trafficking (homing) to the gut, express the integrin α4β7 that finds as its address in the adhesion molecule, MAdCAM - 1, expressed in high endothelial venules of Peyers patches and lamina propria venules. The efficacy of vedolizumab in ulcerative colitis and Crohn disease in treating acute exacerbations and maintaining sustained remission bears testimony to this mechanism and represents a highlight of translational medicine in gastrointestinal diseases. Expansion of α4β7 expressing T cells in the joints of patients with ankylosing spondylitis has been documented by molecular profiling and constitutes evidence for gut -joint trafficking T cells expressing α4β7, in causing ankylosing spondylitis (Qaiyum et al. 2019). Cells such as mucosa-associated invariant T cells (MAITS) have been recovered from the synovial fluid of patients from ankylosing spondylitis endorsing the role of gut-derived immunocompetent T cells in the pathophysiology of arthritic manifestations of gastrointestinal diseases (Gracey et al. 2016). Circulating immune complexes, composed of gut bacterial antigens and host antibodies as a consequence of immune response to gut microbes, has been implicated in the arthritis and skin lesions following intestinal bypass surgery and even bacterial overgrowth syndromes resulting from blind loops (Jorizzo et al. 1984). Revision of the blind loops abrogates the inflammation providing indirect evidence for causal mechanisms (Stein et al. 1981).

2190

M. R. Murali

Rheumatological Manifestations of Gastrointestinal Diseases 6. Gastrointestinal diseases that have been linked to inflammatory arthritis as well as other extraintestinal manifestations (EIM) include, but are not limited to, inflammatory bowel disease (IBD) (represented by ulcerative colitis and Crohn disease). Others such as celiac disease or gluten-sensitive enteropathy (GSE), bacterial enteritis, Whipple disease, vasculitides affecting the GI tract such as polyarteritis nodosa (PAN), Henoch-Schonlein purpura (HSP), Behcet syndrome, and microscopic and collagenous colitis are also associated with EIM. Therapy with biologic gents such as infliximab for inflammatory bowel disease can cause arthralgia and induce a positive antinuclear antibody test (ANA). This may be mistaken for EIM of IBD, but a careful history of medication used as well as improvement in IBD with concomitant appearance of arthralgias and positive ANA helps the clinician to recognize this entity. Similarly, immune checkpoint inhibitors such as pembrolizumab, nivolumab, and ipilimumab used to treat advanced malignancy can present with both gastrointestinal, articular, ocular, and dermatological manifestations. Thus, a detailed history, including medication usage and clinical evolution of symptoms, is essential in the total evaluation of a patient. The rheumatological manifestations of gastrointestinal diseases are protean in nature and systemic in their manifestations. They are best considered under the following categories: 1. Arthropathy – axial, peripheral, and reactive. 2. Dermatologic – erythema nodosum (EM), pyoderma gangrenosum (PG), dermatitis herpetiformis (DH), palpable purpura, and vasculitic rash. Sweet’s syndrome, characterized by acute onset of fever, painful rash, and neutrophilia, is a rare manifestation. 3. Ocular – Episcleritis, scleritis, and uveitis. 4. Oral cavity lesions – aphthous stomatitis, pyostomatitis vegetans. 5. Hepatobiliary – primary sclerosing cholangitis (PSC), autoimmune hepatitis

7. 8. 9. 10. 11.

(AIH), gallstones, pancreatitis, and cholangiocarcinoma. Renal injury due to vasculitis or immune complexes. Osseous – Osteoporosis and osteomalacia. Fever – Whipple disease. Vascular – Behcet syndrome, polyarteritis nodosa. Neurological- Whipple disease, celiac disease, and vasculitic syndromes. Hematologic – - Celiac disease, microscopic and collagenous colitis, and polyarteritis nodosa can present with manifestations of iron deficiency anemia.

1. ARTHROPATHY: The arthropathy in IBD patients is generally divided into peripheral and axial involvement. It occurs in up to 40% of patients with IBD, with a higher prevalence in CD than in UC (Vavricka et al. 2015). The peripheral arthropathies in IBD that will be discussed includes both pauciarticular (Type I) as well as polyarticular (Type II). Enthesitis, dactylitis, and arthralgias complete this spectrum. The axial arthropathies associated with IBD include ankylosing spondylitis (AS), sacroiliitis, and inflammatory back pain (IBP) (see Fig. 3). Increased gut mucosal permeability to bacterial antigens may result in the induction of articular symptoms and inflammation, mediated by immune complexes, T cells, and the cytokine milieu (Hollander 1988). AXIAL ARTHROPATHY in IBD includes ankylosing spondylitis (AS), sacroiliitis, and reactive arthritis. The onset of axial involvement frequently precedes that of IBD, its clinical course is independent of the IBD, and bowel surgery does not alter the outcome of AS or sacroiliitis. On the other hand, the course of reactive arthritis parallels IBD activity. ANKYLOSING SPONDYLITIS occurs in about 4–10% of patients with IBD, the prevalence in CD being greater than in UC, and it is also more common in males than females. IBD-associated

99

Rheumatological Manifestations of GI Disorders

2191

ARTHROPATHIES (20 -30% of IBD)

AXIAL ARTHRITIS (3 -25%)

PERPHERAL ARTHRITIS (10 -20%) ENTHESITIS (5-10%) AND

AS (4-10%) M>F

DACTYLITIS (2-4%)

SACROILITIS (4-32%) ARTHRALGIAS CD - 14% and UC - 5%

PAUCIARTICULAR

POLYARTICULAR

TYPE I

TYPE II

Fig. 3 Types of arthropathies in rheumatic diseases

AS has a strong genetic predisposition, with a high correlation with HLA-B 27. CD and AS have also been associated with IL-23 receptor variants (Bianchi and Rogge 2019). Symptoms include thoracic or lumbar pain, buttock or chest pain, often with morning stiffness involving the spine. These symptoms manifest several years before active IBD is detected, and the arthritis is independent of the course of the underlying bowel disease (Vavricka et al. 2015). Pathologically the spinal vertebra of the cervical, thoracic, and lumbar regions often fuses, contributing to the so- called bamboo spine that limits mobility and flexibility resulting in changes in posture. Physical examination reveals limited spinal flexion (Schober’s test) and reduced chest expansion. Radiological imaging reveals that in patients with IBD and advancing AS there is squaring of vertebral bodies, marginal syndesmophytes (bony growth originating in ligaments leading to fusion of vertebrae), bone proliferation and fibrosis of the annulus, and ankylosis, features contributing to the bamboo spine. ISOLATED SACROILIITIS is an inflammation of the sacroiliac (SI) joints, often asymptomatic and may be unilateral or bilateral. Sacroiliitis occurs in 4–32% of patients with IBD, being more common in patients with CD than in patients with UC (Gravellese and Kantrowitz 1988). The varying incidences depend on whether the diagnosis is made by clinical symptoms, plain radiographs, or CT scan. Symptoms consist of pain or stiffness in the buttocks that is worse in the morning or after

rest and often improves with exercise. Spinal mobility decreases with time. Sacroiliitis is diagnosed by imaging methods that include conventional radiographs or CT scans that reveal sclerosis, erosions, and/or ankylosis. MRI confirms acute inflammation with or without structural changes. ARTHRALGIAS occur in about 14% of patients with CD and in about 5% of those with UC. Arthralgia has been attributed to inflammation resulting from deposition of circulating immune complexes, composed of gut microbial antigens and host antibodies, on synovial tissue; migrating T cells that recognize common antigens in microbiota and synovium or just effect of cytokines generated during exacerbation of bowel inflammation in IBD. They are most often polyarticular than monoarticular or oligoarticular. Arthralgia often exacerbates and remits with IBD activity (Gravellese and Kantrowitz 1988). PERIPHERAL ARTHROPATHY in IBD occurs in about 10–20% of patients with IBD, with a higher prevalence in CD than UC. Increased gut permeability to microbial antigens and the ensuing T and B cell responses have been suggested as a mechanism for synovial inflammation. Based on the differences in genetic predisposition, number and types of joints involved, clinical differences in presentation and outcome of the peripheral arthropathy have been classified as pauciarticular - Type I or polyarticular - Type II (Vavricka et al. 2015). These are depicted in the Table 1.

2192

M. R. Murali

Table 1 Characteristics of peripheral arthropathy associated with IBD Features Genetic association Prevalence in UC and CD Number of joints involved Types of joints Pattern of joint involvement Distribution Relationship to IBD Course of disease

Pauciarticular – Type I HLA B27, B 35, and DR 103 35 and 29% 4 or less Large joints Knee>ankle>wrist>elbow> MCP > hip> shoulder Asymmetric, rare erosions Parallels IBD activity Self-limited and resolves in 5 Small joints MCP > knee> PIP > wrist> ankle> elbow> shoulder Symmetric with +/ erosions Independent of IBD and may precede it Persistent inflammation for months or years Only uveitis

to affect the larger joints of the lower extremity than the upper, often asymmetrically, and can be migratory. Enthesitis and sacroiliitis may also be a feature. While in the majority it is selflimited and lasts a few days to months, a chronic relapsing arthritis may rarely occur. In those who are HLA B27 positive, there is an increased association with not only reactive arthritis, but also the likelihood of its severity and chronicity. Unlike infectious arthritis, the inflammation of reactive arthritis does not respond to antibacterial therapy, again endorsing the concept of immune inflammation. This concept is further strengthened by the fact that anti-inflammatory agents do ameliorate this condition. Reactive arthritis has been rarely noted in celiac disease and after intestinal bypass surgery – such as -jejunocolic and jejunoileal -procedures. Bowel bypass syndrome, also called blind loop syndrome, is a well-recognized complication of jejunoileal bypass; the same syndrome was recognized in patients who had not had intestinal bypass surgery, and the term the “bowel-associated dermatosis–arthritis syndrome” (BADAS) is used for this entity (Carubbi et al. 2013). CELIAC DISEASE-associated arthritis can be axial, peripheral, or both (Lubrano et al. 1996). It commonly affects the lumbar spine, hips, and knees and may precede, such as the skin manifestations, the diagnosis of celiac disease.

99

Rheumatological Manifestations of GI Disorders

Arthritis is common in about 65–90% of patients with Whipple disease. About a quarter of patients have axial involvement manifesting as sacroiliitis or spondylitis (Lange and Teichmann 2003). The nondestructive arthritis is migratory, affecting larger joints more often than smaller joints. The arthritis can precede other features of the disease by years, but its duration is transient ranging from hours to days. Response to antibiotics is excellent.

2. DERMATOLOGIC MANIFESTATIONS: Cutaneous manifestations such as erythema nodosum (EM) and pyoderma gangrenosum (PD) often provide a clue to the existence of IBD in patients presenting with bowel manifestations. The presence of palpable purpura signifies a vasculitic pathology and points to the consideration of entities like HenochSchonlein purpura or polyarteritis nodosa in whom the GI presentation is a common

2193

feature, if not the presenting feature. The itchy, papulo-vesicular rash of dermatitis herpetiformis may precede, coincide, or follow manifestations of celiac disease (Farhi et al. 2008). Table 2 summarizes some of the salient features of the dermatological manifestations of gastrointestinal diseases. 3. OCULAR MANIFESTATIONS 5–8% of patients with IBD either present with ocular manifestations or have eye findings on slit lamp examination of the eye (Mintz et al. 2004). Immune complexes and T cells are incriminated in the pathogenesis. The ocular manifestations affect the mesenchymal as well as neuro-vascular tissues and are depicted in Table 3. 4. ORAL MANIFESTATIONS Oral lesions, when present, are a source of great discomfort as they impair dietary intake further exacerbating the awareness of gastrointestinal disease (Vavricka et al. 2015). They are summarized below (Table 4).

Table 2 Dermatological manifestations of gastrointestinal diseases Manifestation Epidemiology Erythema nodosum 6–15% in CD 1–9% in UC F>M Pyoderma 0.5 to2% in IBD gangrenosum F>M

Dermatitis Herpetiformis

Up to 10% in those with celiac disease

Vasculitic syndromes affecting GI tract

Palpable purpura is a sine qua non for Henoch-Schonlein purpura. Variable in ANCA, PAN, Behcet, and cryoglobulinemia Rare association with CD, UC, and rarely malignancy

Sweet’s syndrome or acute febrile neutrophilic dermatosis

Clinical features Red, raised, painful, or tender indurated nodules largely present over the anterior aspects of the legs Painful, characteristic black eschars or ulcers with undermined edges, often purple, on lower limbs, trunk, and adjacent to stomas Intensely itchy, painful, and red papules that have scabs or vesicles, scar, and distributed in extensor surfaces of knees, elbows, buttocks, and rarely trunk Palpable purpura, livedo reticularis, and necrotizing ulcers are present along with distinct vasculitic syndromes affecting the GI tract

Tender or papulosquamous exanthema or nodules over arms, legs, trunk, arms, and face. Fever, arthritis, and conjunctivitis may be present

Correlation with bowel disease Often a marker of disease activity Often not associated with active disease

May precede or coexist with active celiac disease

May precede but often are part of the presentation of the syndrome

Its association with IBD usually parallels the G I disease but may precede it

2194

M. R. Murali

Table 3 Ocular manifestations of gastrointestinal diseases Manifestation Uveitis

Epidemiology 0.5–3% in IBD (CD > UC) 3:1 F to M ratio

Clinical features Ocular pain, blurred vision, photophobia, red eyes, visual loss, and headaches

Episcleritis

5.0–8% in IBD (CD > UC) 3:1 F to M ratio Rare Rare

Acute hyperemia, irritation, burning, and lacrimation

Correlation with bowel disease Anterior uveitis: 30% association with EN. Posterior uveitis: 90% associated with arthritis, particularly AS Associated with active bowel disease

Redness, irritation, and lacrimation Blurred vision to sudden blindness

Behcet syndrome Associated with PAN activity

Conjunctivitis Optic neuritis

Table 4 Oral lesions in inflammatory bowel disease Manifestation Aphthous stomatitis Pyostomatitis vegetans

Epidemiology 3–10% in IBD CD > UC 10% in IBD

Clinical features Well-defined round to oval, painful ulcers on buccal and labial mucosa, floor of mouth, and tongue Multiple pustular or hemorrhagic eruption in oral cavity with a cobblestone appearance. The circinate lesions resemble a “snail track.” pain is variable

Correlation with bowel disease Associated with active bowel disease Associated with active bowel disease

Table 5 Hepatobiliary manifestations in inflammatory bowel disease Manifestation Primary sclerosing cholangitis (PSC)

Epidemiology 2.2–7.5% in UC 3.4% in CD. M>F

Autoimmune hepatitis, gallstones, and pancreatic disease

Rare reports

Clinical features Cholestatic biochemical profile with multifocal bile duct strictures and segmental dilatation on cholangiography. May progress to cirrhosis, portal hypertension and acute decompensation, and often liver transplantation Hepatic dysfunction, biliary symptoms with gallstones on imaging and pancreatitis due to luminal obstruction

5. HEPATOBILIARY MANIFESTATIONS Hepatic and biliary manifestations are a challenge for management and add to the morbidity of the primary gastrointestinal disease (Yarur et al. 2014). They are depicted in Table 5. 6. RENAL MANIFESTATIONS While Henoch-Schonlein purpura is the classical prototype of a rheumatologic manifestation of renal disease, other vasculitis such as

Correlation with bowel disease May precede UC by years. PSC may be diagnosed several years after proctocolectomy for UC. At higher risk of colorectal cancer and cholangiocarcinoma

Variable and unpredictable. IgG4-related disease may be a masquerader

mixed cryoglobulinemia, SLE vasculitis, polyarteritis nodosa, ANCA vasculitis, and microscopic angiitis with colitis also can present with both these organ system manifestations. The mechanisms include circulating and/or in situ immune complexes due to exogenous antigens (bacterial as in bacterial overgrowth syndrome, viral as in Hep B associated PAN and Hep C associated mixed cryoglobulinemia or endogenous antigens

99

Rheumatological Manifestations of GI Disorders

such as dsDNA (SLE), transcriptome proteins such as Scl-70 and topoisomerase as in systemic sclerosis, or proteinase 3 (c-ANCA) or myeloperoxidase or MPO (p-ANCA) in ANCA-associated vasculitis (Jennette and Falk 1997). Innate immunity via TLR 9 for dsDNA and TLR7 for ssRNA also contributes to the interferon signature and inflammation. 7. OSSEOUS MANIFESTATIONS, manifesting with bony pain, arthralgia, fractures, and deformities, are secondary to metabolic derangements in celiac disease, malabsorption syndromes, chronic renal failure, and osteomalacia (Dos Santos and Liote 2017). The constellation of articular and musculoskeletal abnormalities on exam or imaging coupled to studies that include a complete hemogram with vitamin B12 levels and a comprehensive metabolic panel that includes measurements of total protein, albumin, calcium, phosphate, magnesium, alkaline phosphatase, and thyroid hormones will facilitate the diagnosis. Hypertrophic osteoarthropathy is occasionally seen in patients with IBD, being most common in Crohn disease. It is distinguished by the presence of digital clubbing along with the expansion of the lower end of the radius and ulnar and wrist pain. Imaging reveals periosteal thickening of the radius and ulna. 8. FEVER is seldom thought of as a rheumatologic manifestation of gastrointestinal disease. However, low grade fever, arthralgias and even arthritis, diarrhea secondary to fat malabsorption (steatorrhea), and weight loss are features of Whipple disease, and also noted in bacterial overgrowth syndromes (Patil and Fantry 2012). 9. VASCULITIC MANIFESTATIONS most often manifest with cutaneous features such as palpable purpura, livedo reticularis, urticarial vasculitis, nodules, necrotizing ulcers, and rarely gangrene. These are seen in PAN, Behcet syndrome, Henoch-Schonlein purpura, and cryoglobulinemias. Besides the skin, vasculitis manifests as vascular strokes, mononeuritis multiplex, ocular manifestations

2195

ranging from occlusion of central artery of retina or segmental retinal infarcts, and renal, splenic, and visceral infarcts (Jennette and Falk 1997). 10. NEUROLOGIC MANIFESTATIONS are rarely a feature of gastrointestinal diseases, but ataxia and peripheral neuropathy has been reported in celiac disease. Neurological manifestations ranging 5–40% have been reported in Whipple disease, and it can manifest before the gastrointestinal features are noted. Dementia, disturbances of ocular movement, abnormal involuntary movements, particularly myoclonus, and deranged function of the hypothalamus are most often found. Epilepsy, focal cerebral signs, ataxia, and meningitic features may also be present. Myelopathy and involvement of muscle or peripheral nerve have been described. Headache is a very common symptom (Patil and Fantry 2012). 11. HEAMATOLOGICAL MANIFESTATIONS can be the presenting symptom, when the disease is indolent and protracted but not severe enough to draw attention to the impairment in bowel habits, stool consistency, or manifest as diarrhoea. Patients can present with iron deficiency anemia as described in celiac disease, polyarteritis nodosa, Henoch-Schonlein purpura, microscopic colitis (both lymphocytic and collagenous), or due to drug-nduced colonic lesions as seen during prolonged therapy with nonsteroidal anti-inflammatory drug (NSAIDS). Alternatively, they can present with megaloblastic anemia, with or without neurologic manifestations, when the terminal ileum is involved precluding the absorption of Vitamin B12. (Jennette and Falk 1997; Puspok et al. 2000; Leffler et al. 2015). The relationship between the extraintestinal manifestations and gastrointestinal disease activity is variable. Some of the manifestations are markers of disease activity and parallel the course of the disease, while others occur independent of disease activity. A few have

2196

M. R. Murali

Table 6 Relationship between extra-intestinal manifestations and gastrointestinal activity Extra-intestinal manifestation (EIM) Musculoskeletal Axial Peripheral type I Peripheral type II Mucocutaneous Erythema Nodosum (F > M) Pyoderma gangrenosum Sweet’s syndrome Aphthous ulcers OCULAR Episcleritis (F > M) Uveitis (F > M) HEPATOBILIARY Primary sclerosing cholangitis (M > F)

Parallels IBD activity

Independent of IBD activity

Variably associated with IBD activity

No Yes Yes

Yes No Yes

N/A Follows IBD activity Can precede IBD

Yes No Yes Yes

No No No No

No Yes No No

Yes No

No No

No Yes

No

No

Yes

inconsistent relationship to gastrointestinal disease activity. These are best summarized in Table 6 below.

Therapeutic Options for Rheumatological (Extra-Intestinal) Manifestations of Gastrointestinal Diseases The landscape for therapy for many years was focused on mitigating inflammation with anti-inflammatory agents belonging to the prostaglandin pathways, targeting COX-2 pathways preferentially to avoid the GI adverse effects of COX 1 agents, sulfonamide derivatives with anti-inflammatory action and others like dapsone that modulated neutrophil pathways emerged along with colchicine. The multifactorial antiinflammatory action of corticosteroids was initially hailed as a breakthrough, but its systemic adverse reactions led to the use of steroid sparing agents that included immune-suppressives. Steroids are used topically for skin and eyes, rectally as enemas, as well as systemically by oral or parenteral routes. The emergence of long-acting intraarticular steroids had a considerable impact

for selected large joints as well as in some pauciarticular diseases. Later, steroid sparing anti-inflammatory agents such as methotrexate, cyclosporin, and azathioprine emerged but were not without adverse side effects. Understanding the role of immune effector cells and microbiota, in maintaining immune tolerance and homeostatic balance between normal digestive process and inflammation at the mucosal interface of the gastrointestinal tract, led to the development of monoclonal antibodies (called biologics) that modulate these immune effector cells. Biologics such as infliximab, adalimumab, ustekinumab, and vedolizumab emerged as some agents considered as the second line of therapy. They seem to usher in the era of targeted therapy with rapid response and sustained effects. They are not a panacea as therapy with infliximab may cause opportunistic infections and reactivate latent tuberculosis and fungal infections and rarely cause autoimmune inflammation of joints. It behooves the clinician to weigh the pros and cons, to make correct choices, in every clinical situation. While probiotics and prebiotics are being evaluated, the beneficial role of modulating gut microbiota with drugs such as rifaximin or therapy with fecal microbial transplants (bacteriotherapy) is

99

Rheumatological Manifestations of GI Disorders

2197

Table 7 Treatment options for rheumatological (extra-intestinal) manifestations of gastrointestinal diseases Organ involved JOINTS

SKIN

Specific EIM Peripheral- type I (large joints) and type II (small joints) Axial – Ankylosing spondylitis and sacroiliitis Reactive arthritis

Erythema nodosum Pyoderma gangrenousm Pyostomatitis vegetans Sweet’s syndrome Dermatitis herpetiformis Aphthous ulcers

EYES

LIVER

Episcleritis Uveitis Primary sclerosing cholangitis

First-line Rx Treatment of IBD in type I, COX 2 inhibitors, sulphasalazine, intraarticular/oral steroids, and immunomodulators COX-2 inhibitors, sulphasalazine, methotrexate, and physical therapy

Second-line Rx Infliximab, adalimumab

Rx primary disease, rifaximin for bacterial overgrowth, anti-inflammatory agents for enthesitis, and dactylitis Rx IBD flare, colchicine, and antiinflammatory agents Oral and intralesional steroids, doxycycline, immunosuppressives, and ulcer care Rx flare of IBD, topical and oral steroids.

For persistent or recurrent C. Difficile colitis – Fecal microbial transplants (FMT) Infliximab, adalimumab

Topical/systemic steroids Systemic steroids/sulphasalazine, dapsone

Infliximab

Rx IBD flare, topical and oral steroids, and topical lidocaine Rx IBD flare, topical steroids Topical/systemic steroids, intraocular for posterior uveitis, and cyclosporin ERCP for dilatation, stents, and UDCA up to 15 mg/kg.

Infliximab

gaining momentum in well selected cases. Table 7 provides a summary of therapeutic options to treat the rheumatologic manifestations of gastrointestinal diseases (Ardizzone and Porro 2005; Dharmani and Chadee 2008; Monteleone et al. 2011). It is clear that a better understanding of the role of diet, genetics, and epigenetics as influenced by microbial communities will help us to not only understand the immune inflammation causing many gastrointestinal diseases, but also their protean manifestations that clinicians have come to appreciate as rheumatologic or extraintestinal manifestations.

Key Points • Gastrointestinal health and mucosal integrity are mediated by innate and adaptive immune pathways.

Infliximab, adalimumab, Secukinumab, and ixekizumab

Infliximab, adalimumab Infliximab, adalimumab

Infliximab Liver transplant

• Homeostatic immune regulation is a function of genetic predisposition interacting with both external stimuli as well as intrinsic microbiota. • Breaches in mucosal permeability and aberrant immune responses result in both humoral and cellular inflammation resulting in gastrointestinal diseases. • The rheumatologic manifestations or extraintestinal manifestations (EIM) are a reflection of the immune dysregulation and inflammation. • The protean rheumatological manifestations involve the joints and musculoskeletal system, skin, eye, oral cavity, renal, blood vessels, neurological, hematologic, and hepatobiliary systems. • Integrating the pathogenesis of gastrointestinal diseases with a comprehensive clinical examination of the organ systems is the key to the successful diagnosis of this entity.

2198

• The EIM may be the presenting feature of gastrointestinal diseases. • Management includes treatment of the primary gastrointestinal disorder as well as use of antiinflammatory, immunosuppressive drugs, and biologics. • Fecal microbial transplants (FMT) or bacteriotherapy promises to usher in a new era of translational medicine based on microbiota and microbiome.

References Ardizzone S, Porro BG. Biologic therapy for inflammatory bowel disease. Drugs. 2005;65(16):2253–86. Atarashi K, Honda K. Microbiota in autoimmunity and tolerance. Curr Opin Immunol. 2011;23:761–8. Atarashi K, Tanoue T, Shima T, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science. 2011;331:337–41. Basson A, Trotter A, Rodriguez-Palacios A, Cominelli F. Mucosal interactions between genetics, diet, and microbiome in inflammatory bowel disease. Front Immunol. 2016;7:1–34. Bianchi E, Rogge L. The IL-23/IL-17 pathway in human chronic inflammatory diseases—new insight from genetics and targeted therapies. Genes Immun. 2019;20:415–25. Blaser MJ. Antibiotic use and its consequences for the normal microbiome. Science. 2016;352:544–5. Brackenhoff LK, Van der Heijde DM, Hommes DW. IBD and arthropathies: a practical approach to diagnosis and management. Gut. 2011;60:1426–35. Carubbi F, Ruscitti P, Pantano I, Alvaro S, Di Benedetto P, Liakouli V, Giuliani A, et al. Jejunoileal bypass as the main procedure in the onset of immune-related conditions: the model of BADAS. Expert Rev Clin Immunol. 2013;9(5):441–52. Dharmani P, Chadee K. Biologic therapies against inflammatory bowel disease: a dysregulated immune system and the cross talk with gastrointestinal mucosa hold the key. Curr Mol Pharmacol. 2008;1(3):195–212. Dommett R, Zilbauer M, George JT, Bajaj-Elliott M. Innate immune defense in the human gastrointestinal tract. Mol Immunol. 2005;42:903–12. Dong C. Diversification of T- helper cell lineages: finding the family root of IL-17 producing cells. Nat Rev Immunol. 2006;6:329–33. Dos Santos S, Liote F. Osteoarticular manifestations of celiac and non-celiac gluten hypersensitivity. Joint Bone Spine. 2017;84:263–6. Farhi D, Cosnes J, Zizi N, Chosidow O, Seksik P, Beaugerie L, Aractingi S, Khosrotehrani K. Significance of erythema nodosum and pyoderma gangrenosum in inflammatory bowel diseases: a cohort study of 2402 patients. Medicine. 2008;87:281–93.

M. R. Murali Gonzalves P, Arayo JR, DiSanto JP. A crosstalk between microbiota-derived SCFA and the host mucosal immune system regulates homeostasis and inflammatory bowel disease. Inflam Bowel Dis. 2018;24:558– 72. Gracey E, Yao Y, Green B, Qaiyum Z, Baglaenko Y, et al. Sexual dimorphism in the TH 17 signature of ankylosing spondylitis. Arthritis Rheumatol. 2016;68:679–89. Gracey E, Dumas E, Yerushalami M, Qaiyum Z, Inman RD, Elewaut D. The ties that bind: skin, gut and spondyloarthritis. Curr Opin Rheumatol. 2019;31:62–9. Gravellese EM, Kantrowitz PG. Arthritic manifestations of inflammatory bowel disease. Am J Gastroenterol. 1988;83:703–9. Hollander D. Crohn’s disease – a permeability disorder of tight junction. Gut. 1988;29:1621–4. Jacobs JP, Braun J. Immune and genetic gardening of the intestinal microbiome. FEBS let. 2014;588:4102–11. Janeway CA, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002;7:131–7. Jennette JC, Falk RJ. Small vessel vasculitis. N Engl J Med. 1997;337:1512–23. Jorizzo JL, Schmalstieg FC, Dinehart SM, Daniels JC, Cavallo T, Apisarnthanarax P, et al. Bowel-associated dermatitis-arthritis syndrome. Immune complex- mediated vessel damage and increased neutrophil migration. Arch Intern Med. 1984;144:738–40. Kim CH, Park J, Kim M. Gut microbiota derived shortchain fatty acids, T cells and inflammation. Immune Netw. 2014;14:277–88. Knights D, Lassen KG, Xavier RJ. Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome. Gut. 2013;62:3–15. Lange U, Teichmann J. Whipple disease: diagnosis by molecular analysis of synovial fluid- current status of diagnosis and therapy. Rheumatology. 2003;42:473– 80. Leffler DA, Green PH, Fasano A. Extraintestinal manifestations of celiac disease. Nat Rev Gastroenterol Hepatol. 2015;(10):561–71. Lubrano E, Ciacchi C, Ames PR, Mazzacca G, Oriente P, Scarpa R. The arthritis of celiac disease: prevalence and pattern in 200 adult patients. Br J Rheumatol. 1996;35:1314–8. Meylan E, Tschoop J, Karin M. Intracellular pattern recognition receptors in the host response. Nature. 2006;442:39–44. Mintz R, Feller ER, Bahr RL, Shah SA. Ocular manifestations of inflammatory bowel disease. Inflamm Bowel Dis. 2004;10:135–9. Monteleone G, Pallone F, MacDonald TT. Emerging immunological targets in inflammatory bowel disease. Curr Opin Pharmacol. 2011;11(6):640–5. O’Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4+ cells. Science. 2010;327:1098–102. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al. A frameshift mutation in NOD2 is associated with susceptibility to Crohn’s disease. Nature. 2001;411:603–6.

99

Rheumatological Manifestations of GI Disorders

Pascal M, Perez-Gordo M, Caballero T, et al. Microbiome and allergic diseases. Front Immunol. 2018;9:1–9. Patil S, Fantry GT. Connecting the dots: the many systemic manifestations of Whipple disease. Gastroenterol Hepatol (NY). 2012;8:63–6. Pichlmair A, Reis E Sousa C. Innate recognition of viruses. Immunity. 2007;27:370–83. Puspok A, Kiener HP, Oberhuber G. Clinical, endoscopic and histologic spectrum of non-steroidal anti-inflammatory drug-induced lesions in the colon. Dis Colon Rectum. 2000;43:685–91. Qaiyum Z, Gracey E, Yao Y. Integrin and transcriptomic profiles identify a distinctive synovial CD8+ T cell population in spondyloarthritis. Ann Rheu Dis. 2019;78:1566–75.

2199 Round JL, Lee SM, Li J. The toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science. 2011;332:974–7. Stein HB, Schlappner OL, Boyko W, Gourlay RH, Reeve CE. The intestinal bypass: arthritis-dermatitis syndrome. Arthritis Rheum. 1981;24:684–90. Takeda K, Kaisho T, Akira S. Toll-like receptors. Ann Rev Immunol. 2003;21:335–76. Vavricka SR, Schoepfer A, Scharl M, Lakatos PL, Navarini A, Rogler G. Extraintestinal manifestations of inflammatory bowel disease. Inflamm Bowel Dis. 2015;21:1982–92. Yarur AJ, Czul F, Levy C. Hepatobiliary manifestations in inflammatory bowel disease. Inflamm Bowel Dis. 2014;20:1655–67.

Gastrointestinal Disorders in Long-Term Care

100

Roy J. Goldberg and Mahesh Jhurani

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2201 Weight Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Common GI Symptoms Seen in LTC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gastroenterological Conditions with Features Specific to LTC . . . . . . . . . . . . . . . . . . . . . . . End of Life Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2202 2207 2211 2213

Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2215 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2216

Abstract

Gastrointestinal (GI) symptoms are very common in older adults. Residents of long-term facilities face the typical problems of those patients in the community, but also have unique issues related to their multiple comorbidities and to the end of life. GI issues often present atypically, and may be iatrogenic, oftentimes due to prescribed medications. Recognizing symptoms early improves quality of life and helps avoid serious life-threatening complications. Goals of

care conversations and an interdisciplinary approach are mandatory. Keywords

Long-term care · Gastrointestinal disorders in long-term care facilities · Post-acute care · Assisted living facilities · Geriatrics · Older adults · Feeding gastrostomy tubes · PEG tubes · Weight loss · End of life care · Palliative care

Introduction R. J. Goldberg (*) Division of Geriatrics, Albert Einstein College of Medicine, Bronx, NY, USA Kings Harbor Multicare Center, Bronx, NY, USA e-mail: [email protected] M. Jhurani Kings Harbor Multicare Center, Bronx, NY, USA e-mail: [email protected]

Nursing homes, Skilled Nursing Facilities, PostAcute Care Centers, and Assisted Living Facilities, collectively known as long-term care (LTC) facilities, have evolved greatly over the years, and so have the residents who call these facilities home. Although more people are remaining in their households with support from family

© Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_95

2201

2202

members or hired caregivers, the baby boomer population continues to age and the need for long-term care will continue to increase. Long-Term Care facilities provide a variety of medical and personal care services to people who are unable to manage independently in the community. Over four million Americans are admitted to or reside in nursing homes and skilled nursing facilities each year and nearly one million persons reside in assisted living facilities (Centers for Disease Control and Prevention 2017). As with any older patient population the guidelines for screening and care change, but with the multiple comorbidities most LTC residents live with, further issues must be addressed. Some gastroenterological conditions are unique among the aging population, and others unique to the population who require help with their Activities of Daily Living (ADLs). Most times, individual diseases that affect an older population start prior to admission to a LTC facility. Specific entities are addressed in chapters devoted to them. This population experiences expected age-related physiologic declines in function of metabolic, immunologic, and neurologic systems. However, the functional reserve of the gastrointestinal tract, aging per se, has less direct effect on most gastrointestinal functions (Firth and Prather 2002). Regardless, the elderly population has a high prevalence of gastrointestinal disorders of function and motility. It is estimated that in any year, 35–40% of geriatric patients will have at least one GI symptom (American Medical Directors Association 2018a).

Weight Loss Weight loss is a geriatric syndrome commonly seen in the LTC setting. Research has shown that it is associated with an increased risk for mortality, especially if the weight loss is unintentional (Huffman 2002; Thomas and Morley 2002). In clinical practice, it is encountered in up to 41% of the institutionalized elderly (Alibhai et al. 2005; Sloane et al. 2008). Weight loss can lead to a functional decline in ADLs, increased risk of hip fractures in women (Ensrud et al. 2003), and

R. J. Goldberg and M. Jhurani

an increased incidence of pressure ulcers and infections. Unintentional weight loss may reflect disease severity in patients with advanced heart disease, lung disease, malignant disease, or undiagnosed illness. Involuntary weight loss in an older adult may result from a variety of factors including inadequate dietary intake, the inflammatory effects of disease (cachexia), the loss of muscle mass (sarcopenia), or the loss of appetite (anorexia). The Long-Term Care Minimum Data Set (MDS), a standardized, primary screening and assessment tool of health status which forms the foundation of the comprehensive assessment for all residents of long-term care facilities certified to participate in Medicare or Medicaid, defines clinically significant weight loss in the long-term care setting as a loss of 5% of usual body weight in 1 month or 10% over a period of 6 months or longer (Sloane et al. 2008). The MDS plays a key role in the Medicare and Medicaid reimbursement system and in monitoring the quality of care provided to nursing facility residents (Office of Disease Prevention and Health Promotion 2018). The incidence of weight loss in a facility is an important quality indicator and is scrutinized carefully by state and federal surveyors. The simplest ways to screen weight loss is serial weight measurements with Body Mass Index (BMI). However, there are many screening tools to assess nutritional status which assist with the early recognition of undernutrition. These include The Simplified Nutrition Assessment Questionnaire (SNAQ) (Messinger-Rapport et al. 2011, 2012), the Mini Nutritional AssessmentShort Form (MNA-SF) (Kaiser et al. 2009), the Malnutrition Universal Screening Tool (MUST), and NRS-2002 (Nutrition Risk Screening) (Messinger-Rapport et al. 2012). Body composition changes with age. Lean body mass begins to decrease up to 0.7 lb. (0.3 kg) per year from the third decade. This loss is offset by gains in fat mass that continue until 65–70 years of age. Total body weight usually peaks in the 60s with small decreases of 0.2–0.4 lb. (0.1–0.2 kg) per year after around 70 years of age. Therefore, substantial weight changes should not be attributed to normal aging

100

Gastrointestinal Disorders in Long-Term Care

(Gaddey and Holder 2014) and require appropriate evaluation based on individualized goals of care. Cachexia is loss of weight, muscle atrophy, fatigue, weakness, and significant loss of appetite in a patient who is not actively trying to lose weight. It is a hypercatabolic state that is defined by an accelerated loss of skeletal muscle in the context of a chronic inflammatory response. Multiple studies have looked at inflammatory cytokines such as tumor necrosis factor α, interleukin-1β and interleukin-6, and gut hormones such as cholecystokinin, glucagon-like peptide, and ghrelin as they relate to cachexia. Elevated concentrations of tumor necrosis factor α have also been associated with weight loss (Gaddey and Holder 2014). Cachexia is most frequently seen in the setting of malignancy but also seen in other advanced chronic illnesses including infections such as osteomyelitis or AIDS, heart failure, and chronic obstructive pulmonary disease (Kotler 2000). This weight loss is often progressive and irreversible despite all interventions. In 2011, a group of cancer researchers proposed a three-level staging system consisting of precachexia, cachexia, and a refractory stage, based on a study of small cell lung and gastrointestinal cancers. Patients classified as pre-cachectic and cachectic were clinically similar with respect to overall symptom burden, quality of life, tolerance of chemotherapy, and survival, whereas those in the refractory stage were noted to have deteriorating clinical outcomes (Dev et al. 2017). No guidelines or standards of care are universal for the treatment of cachexia. In general, patients should eat small, frequent, calorie dense meals, with supplements used between meals to approximate normal dietary intake, and not use them as a substitute for eating (Dev et al. 2017). Sarcopenia, another cause of unintentional weight loss, occurs in 53–57% of men and 43–60% of women over 80 years old. It is a syndrome characterized by the loss of muscle mass, strength, and performance and is associated with increased risk of functional impairment, disability, falls, and mortality. It can be caused by disuse, endocrine changes (decreased testosterone

2203

and estrogen), chronic disease, inflammation, insulin resistance, and nutritional deficiencies (e.g., inadequate protein intake). Low muscle mass is defined as a decrease in appendicular muscle mass two standard deviations below the mean for young healthy adults and is measured by DEXA or bio-electrical impedance in clinical practice. Unlike cachexia, sarcopenia does not require the presence of an underlying illness. Whereas most people with cachexia are sarcopenic, most sarcopenic individuals are not considered cachectic (Janssen 2011). Anorexia is often multifactorial. Reduced sense of smell and taste contribute to anorexia and decreased weight. Loss of taste, known as ageusia, is the loss of taste functions of the tongue, particularly the inability to detect sweetness, sourness, bitterness, saltiness, and savory taste. Because the tongue can only differentiate between sweet, sour, bitter, salty, and savory, most of what is perceived as the sense of taste is largely derived from smell. Loss of taste is generally associated with loss of smell and results in poor appetite (Bromley 2000). Although some loss of taste and smell is natural with aging, additional common causes are nasal and sinus problems such as allergies, sinusitis, or nasal polyps. Loss of taste may be due to decrease in size and numbers of taste buds or decrease in production of saliva and related to wearing dentures. Kidney and liver diseases can result in loss of taste, as can glossitis or swelling of tongue, and loss of papillae due to vitamin B12 deficiency, zinc deficiency, or thrush. Cigarette smoking, dental problems, head or facial injury or space occupying mass, Parkinson’s disease, or Alzheimer’s disease are other etiologies (Makins and Ballinger 2003). Poor oral hygiene, found frequently in LTC-facilities for a number of reasons, contributes to changes in eating; many medications cause xerostomia (dry mouth) with an associated difficulty swallowing (Weintraub et al. 2018). Medications including beta blockers and angiotensin converting enzyme (ACE) inhibitors are well known to affect taste. Other drugs, such as eszopiclone, can cause an altered sense of taste in significant proportions of patients at normal doses (Goldberg et al. 2005).

2204

The typical LTC resident receives more than seven different medications per day (Farrell et al. 2013). Attempts at medication reduction should be regularly undertaken with educated analysis on both routine assessment and with any change in medical condition to avoid drug-drug interactions. Although some medications that cause anorexia may not be new to a patient’s regimen, the addition of another medication may interact with the existing regimen causing a decrease in appetite. Pill burden and polypharmacy often lead to adverse drug reactions, drug/drug interactions, higher cost, and anorexia. These indirect outcomes from medications are often associated with weight loss, decreased quality of life, decreased mobility, and cognition (Farrell et al. 2013). Medications and their effect on appetite should not be overlooked nor underestimated. Donepezil is well known to cause nausea. For many LTC residents with weight loss, this can be safely discontinued or switched to memantine without affecting outcomes. If depression is a possible etiology of weight loss, mirtazapine may increase appetite and promote weight gain as opposed to selective serotonin-reuptake inhibitors (Huffman 2002; Thomas and Morley 2002). Digoxin can often be tapered, discontinued, or switched to a beta blocker without any deleterious effect for the patient. Nonsteroidal anti-inflammatory drugs may be switched to acetaminophen or low-dose narcotic pain relievers without decreasing pain control. Oral bisphosphonates are not well absorbed and thus must be taken on an empty stomach, oftentimes leading to gastric upset or reflux esophagitis. If this occurs, bisphosphonates can be switched to the intravenous formulations which do not have these side effects, or should be changed to other classes of medication for osteoporosis (Goldberg et al. 2005). Medications can also cause other gastrointestinal ailments that indirectly lead to weight loss. The calcium antagonists, phenytoin, and cyclosporin induce gum hyperplasia, particularly in patients with poor oral hygiene. Many drugs including didanosine, furosemide, corticosteroids, azathioprine, and sodium valproate have been associated with the development of acute pancreatitis. NSAIDs, nitrates, theophylline, calcium channel

R. J. Goldberg and M. Jhurani

blockers, and oral antibiotics can all increase the severity of esophageal reflux (Makins and Ballinger 2003). Many drugs lead to constipation. Some of the more common medications and classes to look for when assessing patients with weight loss are listed in Table 1, including direct and indirect associations with weight loss. It is possible that lower doses of existing regimens may positively affect the weight loss problem. If reduction of medication dosage is not possible, then changing the class of medication for a specific indication may be helpful. Early satiety, the inability to eat a full meal, or feeling full after only a small amount of food intake may also cause weight loss. A common cause for early satiety is gastroparesis, and a leading cause of gastroparesis is diabetes (Camilleri 2007; Parkman et al. 2017). Gastroparesis can also develop after esophageal or abdominal surgery (see ▶ Chap. 48, “Gastroparesis in Older Adults”). Other causes for early satiety are peptic ulcer disease, gastroesophageal reflux disease, obstruction in the upper GI tract, tumors of the abdominal organs, or involvement of the nerves that control the movement of food in the digestive system as a result of surgery or neuropathy. Gastroparesis is a condition that affects the normal spontaneous movement of stomach muscles. This results in slowing down of stomach motility and prevents the stomach from emptying properly. An inability to consume normal-sized meals, feeling of being full after eating very little, nausea, and vomiting are often the presenting complaints. Antral stretch, whereby the fundus of stomach is less compliant, results in rapid filling of antrum and early antral distension. Stretching of the antrum regulates appetite as it signals to the body that the stomach is full. Aging causes decrease in fundic receptive relaxation, leading to early transfer of food to antrum and antral stretching (Pankaj et al. 2018). Viral infection, scleroderma, Parkinson’s disease, multiple sclerosis, autoimmune diseases, some cancers, and hypothyroidism can increase the risk of developing gastroparesis (Waseem et al. 2009). Gastroparesis can result in malnutrition, dehydration, unpredictable blood sugar levels, and decreased quality of life (Parkman et al. 2017).

100

Gastrointestinal Disorders in Long-Term Care

Table 1 Classes of medications that may be directly or indirectly associated with weight loss Drugs that may cause anorexia Acetylcholinesterase (ACh) inhibitors Anticonvulsants Conjugated estrogens Digoxin preparations H2 blockers Hypnotics Narcotics Nonsteroidal antiinflammatory drugs (NSAIDs) Proton-pump inhibitors Psychotropics

Selective serotonin reuptake inhibitors (SSRIs) Thyroid replacements Medications that may alter taste Angiotensin converting enzyme (ACE) inhibitors Antibiotics Antihistamines Antiparaitics Antiseizure medications Beta2 agonists Digoxin Diuretics H2 blockers Hypnotics Mood stabilizers Proton pump inhibitors Selective serotonin reuptake inhibitors (SSRIs)

Drugs associated with dysphagia Angiotensin converting enzyme (ACE) inhibitors Antibiotics Antihistamines Antivirals Ascorbic acids Bisphosphonates Diuretics Narcotics

Nitrates Nonsteroidal antiinflammatory drugs (NSAIDs) Potassium chloride

Psychotropics Theophyllines Medications with gastrointestinal adverse Effects (other than dysphagia) Antiarrhythmics Antibiotics Aspirin Chemotherapy agents Dextromethorphan/ quinidine Digoxin Direct oral anticoagulants (DOACs) Disease modifying antirheumatic drugs (DMARDs) Iron preparations Laxatives Narcotics Nonsteroidal antiinflammatory drugs (NSAIDs) Oral hypoglycemics (all classes)

Any medication with anticholinergic side effects can cause gastroparesis. Some examples include opioid pain relievers, antidepressants,

2205

antihypertensive, and allergy medications. Aluminum hydroxide, found in several over the counter antacids, can lead to gastroparesis and constipation when used over long periods of time. Other causes of anorexia are endocrinological disorders including hyperparathyroidism or Addison’s disease, impairment of masticatory function, swallowing problems, H. pylori, cholecystitis, Clostridium difficile, and tuberculosis. Cytokines cause anorexia, lipolysis, and loss of muscle mass (Landi et al. 2016). Their pathophysiology includes the downregulation of protein synthesis and an overall hypermetabolic state with loss of adenosine triphosphate, further shifting the balance towards catabolism (Dev et al. 2017). Despite all of the physiological reasons noted above for weight loss, the most common cause for anorexia in the LTC setting is depression. Depression increases the anorectic neurotransmitters serotonin and corticotropin releasing hormone. Some depressed individuals manifest increased appetite, although most lose their appetite. Many of the brain regions implicated in appetitive responses to food have also been implicated in depression. Depression-related appetite loss is associated with hypoactivation of insular regions that support monitoring the body’s physiological state (Simmons et al. 2016). Depression is not a normal consequence of aging. Sadness and grief are normal responses to life events that occur with aging such as bereavement, adjustment to changes in social status with retirement and loss of income, transition from independent living to assisted or long-term care, and loss of physical, social, or cognitive function from illness (Birrer and Vemuri 2004). Depression in older adults may be difficult to recognize because these individuals may show different symptoms compared to younger people. Residents of LTC facilities may have other less obvious symptoms of depression, or they may not be willing to talk about their feelings. Complaints of fatigue, insomnia, or irritability may be the only symptoms. Confusion or attention problems caused by depression can sometimes resemble Alzheimer’s disease or other brain disorders. Other medical conditions or medication side effects may contribute to depression.

2206

As many as 50% of nursing home residents are depressed. A study of 634,060 nursing home residents 65 years and older found that during their first year, 54% had physician-diagnosed depression (Hoover et al. 2010). Severe cognitive impairment was associated with lower rates of depression; such impairment may interfere with detecting depression. Depression amplifies disability and lessens quality of life (Unutzer et al. 1997). Depression in late life also tends to be a recurrent or persistent condition and adversely impacts both medical and psychiatric morbidity and mortality. There are many screening instruments available for the early diagnosis of depression, the most commonly used are Geriatric Depression Scale, Patient Health Questionnaire-9 (PHQ9), and Two-Question Screen. The development of depression as a complication of Alzheimer’s disease is increasingly recognized and depression is a common complication in many other dementia syndromes including Parkinson dementia, Lewy Body dementia, frontotemporal dementia, and Huntington’s dementia (Lyketsos and Olin 2002). Approximately 25% of patients with weight loss never have the etiology of their weight loss determined, but a targeted work up is indicated for all residents so that reversible causes can be addressed (Huffman 2002; White 2004). Nonspecific nutritional blood work, in an attempt to discover a reason for decreased appetite, has a low yield and can be misleading (Huffman 2002; Bouras et al. 2001; Lewko et al. 2003). For example, a low albumin level may indicate infection as well as poor oral intake. Checking blood levels for such medications as phenytoin or divalproex when weight loss is noted is prudent, as they may cause nausea or dyspepsia. Thyroid function tests should also be checked to ensure appropriate levothyroxine dosages for patients with hypothyroidism and to diagnose hyperthyroidism. Goals of care must be taken into account for any workup of weight loss. A patient who is neither interested in nor capable of undergoing surgery, need not be worked up for conditions that would require operative interventions. Chest x-rays in former smokers, stool guaiacs, and sonograms may be easily obtained in facilities with little discomfort

R. J. Goldberg and M. Jhurani

or cost to the resident and are appropriate in certain situations. Several medications to stimulate appetite are available, but none have been shown to reduce mortality in older patients with unintentional weight loss. Megestrol, the most commonly studied medication, has been shown to improve appetite and increase weight gain in patients with cancer and AIDS cachexia (Ruiz Garcia et al. 2013), although this weight gain is predominantly adipose tissue (Messinger-Rapport et al. 2011). Adverse effects of megestrol include gastrointestinal upset, insomnia, erectile dysfunction, hypertension, thromboembolic events, and adrenal insufficiency. Therefore, megestrol is not appropriate for all patients, and the risks versus benefits and patient preferences should be considered. Mirtazapine, a serotonin antagonist used to treat depression, is a possible treatment for unintentional weight loss in older patients because 12% of patients who take this drug for depression report weight gain (Fox et al. 2009). Mirtazapine may be considered for older patients with depression who have unintentional weight loss. It should be used with caution in patients with risk of falls due to dizziness and orthostatic hypotension which are possible adverse effects. Cyproheptadine has been studied in patients with cancer and cachexia. Cyproheptadine, used in the past, should no longer be prescribed as it does not cause weight gain and has many side effects (Kardinal et al. 1990). Dronabinol and human growth hormone have been studied in small, limited trials with mixed results for short-term, small weight gains. Dronabinol has been associated with significant adverse effects, particularly central nervous system toxicity. Human growth hormone has been associated with increased mortality (Alibhai et al. 2005) and has not been approved by FDA for weight loss. Selective androgen receptor molecules, ghrelin agonists, and a novel peptide-nucleic acid compound are all currently under development to enhance food intake and improve weight gain (Messinger-Rapport et al. 2011). Many disciplines help evaluate weight loss in the post-acute environment. Nurses and nurse’s aides monitor food intake, dietitians ensure

100

Gastrointestinal Disorders in Long-Term Care

residents receive the appropriate diets and consistencies, social workers may help coordinate with families to ensure culturally sensitive diets are offered, and clinical pharmacists review medication regimens monthly. Studies have shown that when pharmacists review medications, a lower quantity of inappropriate regimens are prescribed, resulting in fewer adverse drug events (Aoyama et al. 2006). Behavioral interventions, such as ensuring adequate feeding assistance and encouraging socialization at meal times are simple ways to improve nutritional status. Encouraging family members to bring in snacks, and supplements between meals are also helpful (Aoyama et al. 2006).

Common GI Symptoms Seen in LTC Constipation Constipation is the most common GI complaint in LTC setting. It leads to decreased quality of life, increased nursing time per patient, and contributes to weight loss as it often leads to anorexia. In the community people 65 years of age or older, the prevalence is 26% for women and 16% for men. This rate increases to 34% for women and 26% for men in those 84 years of age and older. For long-term care residents, the prevalence is as high as 80%. The Bristol Stool Scale is a validated tool that correlates stool consistency with colonic transit time. The scale can be helpful for patient assessment and monitoring, and as a clinical communication aid to help patients discuss their bowel movements with their physicians (Schuster et al. 2015). Constipation may be seen in multiple disease states and is a side effect of numerous medications. Specific diseases such as Parkinson’s disease; colorectal cancer; dehydration; hypothyroidism; diabetes; hyperparathyroidism; diverticulosis; irritable bowel syndrome; rectocele; strictures; metabolic abnormalities like hypercalcemia, hypokalemia, and hypomagnesemia; anxiety; depression; chronic kidney disease; multiple sclerosis; and sexual abuse may all lead to constipation. Lack of fiber in the diet and immobility both exacerbate the problem (Hsieh 2005).

2207

As with other problems found in LTC facilities, medications are a major factor in contributing to constipation. Narcotic pain killers, calcium channel blockers, and calcium supplementation have constipation as major side effects leading to diminished appetite. Vitamins and iron supplements can also cause constipation and are widely used (American Medical Directors Association 2018a; Pankaj et al. 2018). Constipation can be managed by giving the patient adequate fluids, regular physical activity, and providing a diet with soluble as well as insoluble fiber. Fresh fruit and vegetables are great sources of soluble and insoluble fiber and should be increased in all diets in LTC facilities (Thomas et al. 2003). Fiber should be titrated gradually to minimize gastrointestinal side effects such as flatulence and bloating. However, patients with confirmed slow-transit constipation or pelvic floor dyssynergia respond poorly to a high-fiber diet and fiber supplements. A visual and digital analrectal examination must be done for identifying local anorectal disease, mass, stricture, hemorrhoids, anal fissure sphincter tone, and fecal impaction (American Medical Directors Association 2018a) (see ▶ Chap. 53, “Constipation”). Historically docusate has been the first line treatment for constipation in LTC but this is not the most effective agent, although it is currently frequently used. Its mechanism of action is by causing water retention in the stool, a stool softener. Other interventions include bisacodyl tablets or suppositories which work as stimulants by increasing peristalsis, or sodium phosphate enemas which work by their hyperosmotic effect of sodium drawing excess water into the colon promoting evacuation. Sodium phosphate is no longer used, due to its adverse effects. Lactulose, an osmotic laxative and 70% sorbitol, can also be used for treatment of constipation. Lactulose was found to be more effective in producing a normal stool by day seven compared with laxatives containing senna, or bisacodyl (Schuster et al. 2015). Sorbitol is a natural sugar and is found in apple juice. Patients with anorectal dysfunction and impaired colonic motility can develop fecal impaction, which can be treated with suppositories (glycerin or stimulant) and enemas (American

2208

R. J. Goldberg and M. Jhurani

Table 2 A stepwise approach to constipation Non pharmacological Adequate fluid

Regular exercise

Pharmacological- oral Osmotic laxatives Polyethylene glycol 3350 Lactulose Stimulant laxatives Senna Bisacodyl

Pharmacological- rectal Suppositories Glycerin or stimulant Enemas Tap water Soap suds

Regular diet of soluble and insoluble fiber

Medical Directors Association 2018a; Mounsey et al. 2015) (Table 2).

Diarrhea Diarrhea in the older population is associated with higher mortality than in younger people. Persistent diarrhea of more than 2–3 days associated with fever, and dehydration can be life-threatening. Diarrhea can lead to indirect complications like falls (due to frequent trips to bathroom) and contamination of wounds or pressure ulcers. The most common causes of diarrhea are infectious (viral, bacterial, and parasitic), inflammatory changes of the bowel due to chronic inflammatory bowel diseases, GI malignancies, radiation therapy, or malabsorption. Diarrhea can be caused by medications such as antibiotics, colchicine, lithium, metformin, magnesium supplements, niacin, proton pump inhibitors, selective serotonin reuptake inhibitors, sorbitol, and lactulose (Akhtar 2008; Glass et al. 2009). Clostridium difficile infection (CDI) is one of the most common health care-associated infections and a significant cause of morbidity and mortality, especially among older residents of LTC facilities. A spore-forming, toxin-producing, gram-positive anaerobic bacterium that causes colitis, it colonizes the human intestinal tract after the normal gut flora has been disrupted. Fever is associated with CDI in about 15% cases and a marked leukocytosis may be seen. Typically associated with antibiotic usage, over half of residents admitted to acute care settings have had no antibiotic exposure within the past 45 days. However, current proton pump inhibitor usage is associated with a higher risk of infection. Asymptomatic Clostridium difficile carriers, who

shed the bacterium in their stool but who do not have diarrhea or other clinical symptoms do not require contact precautions and should not be retested. In fact, the rate of asymptomatic colonization may approach 20% in some LTC facilities. Colonized individuals may potentially serve as a reservoir for environmental contamination (Little 2018). The diagnosis of CDI is established by a positive laboratory stool test for C. difficile toxin(s) or C. difficile toxin B gene. There is no role for repeat laboratory testing and no indication to test for cure. Stool assays may remain positive during or after clinical recovery. Treatment guidelines have changed as of 2018 whereby vancomycin now replaces metronidazole as first line treatment for initial outbreaks (The Infectious Disease Society of America (IDSA) 2018). Noroviruses, another infectious agent, can spread by food, water, and air droplets. These viruses are highly resilient and can survive for a long period in the environment and on surfaces of door handles and countertops. It can cause widespread outbreaks in the LTC facility requiring contact precautions or GI isolation. Although usually self-limiting, it frequently may require supportive intravenous therapy to maintain adequate hydration (Akhtar 2008). Fecal incontinence, the inability to control bowel movements, ranges from an occasional leakage of stool while passing gas to a complete loss of bowel control, affects almost half of all LTC residents (Wald 2007). Diarrhea, constipation, leakage around an impaction, and muscle or nerve damage are all etiologies. Muscle or nerve damage may be associated with aging. For many people, there is more than one cause of fecal

100

Gastrointestinal Disorders in Long-Term Care

incontinence. Injury to the rings of muscle at the anal sphincter can make it difficult to hold stool back properly. Injury to the nerves that sense stool in the rectum or those that control the sphincter is another cause and may be the result of surgery, childbirth, constant straining during bowel movements, spinal cord injury, or stroke. Some diseases, such as diabetes and multiple sclerosis, also can affect these nerves and cause damage (Wald 2007). If a hard mass of stool or impacted stool forms in the rectum and becomes too large to pass, the muscles of the rectum and intestines stretch and eventually weaken, allowing watery stool from farther up the digestive tract to move around the impacted stool and leak out. Chronic constipation may also cause nerve damage resulting in fecal incontinence, termed pseudo-diarrhea. Hemorrhoids and rectal prolapse may be contributing factors as these prevent the anus from closing completely. Normally, the rectum stretches to accommodate stool, but cannot if the rectum is scarred or rectal walls have stiffened from surgery, radiation treatment, or inflammatory bowel disease (Wald 2007). Finally, fecal incontinence is often seen in patients with late stage Alzheimer’s disease and dementia as they lose the ability to recognize the signals which indicate the need for a bowel movement. Toileting schedules and treatment regimens to regulate bowel movements may diminish the number of episodes of incontinence. Scheduled toileting or timed toileting involves taking a patient to the toilet on a fixed schedule, generally every 2 h and does not try to reestablish independent toileting. The interval can be increased to 2.5–3 h or more, if incontinence does not resume. For fecal incontinence, patients can be taken to the toilet after waking up or after a meal, as this is the time when patients are most likely to have a bowel movement (National Caregivers Library). Prevention and treatment of fecal incontinence depends on the cause (Mayo Clinic). For cognitively intact residents, Kegel exercises and biofeedback can be recommended (Wald 2007). Surgical interventions are available but not usually indicated or effective in this patient population (Lembo and Camilleri 2003).

2209

Dysphagia Dysphagia, defined as difficulty swallowing, affects 300,000–600,000 persons yearly. Although the exact prevalence of dysphagia across different settings is unclear, conservative estimates suggest that 15% of the elderly population is affected (Sura et al. 2012). Dysphagia is found in 40–60% of LTC residents, and is a result of dementia, stroke, generalized weakness, decreased salivary flow, inflammatory disease, infection, obstruction, Parkinson’s disease, and other neurological disorders (Ensrud et al. 2003). Evaluation by a Speech Language Pathologist, speech and swallowing exams are often amongst the first steps of investigation (Campbell-Taylor 2008). Dysphagia is associated with weight loss, nutritional deficits, and increased risk of pneumonia. In fact, it is thought that approximately 50% of stroke patients with dysphagia experience aspiration, and approximately 35% of these patients will develop pneumonia (Campbell-Taylor 2008). Oropharyngeal dysphagia is most common and is characterized by difficulty initiating a swallow. It is addressed by changing consistencies of solid food as well as liquids. Patients have difficulty transferring food from the mouth into the pharynx and esophagus to initiate the involuntary swallowing process. Swallowing may be accompanied by nasopharyngeal regurgitation, aspiration, and a sensation of residual food remaining in the pharynx. Patients with oropharyngeal dysphagia have difficulty transferring food from the mouth to the pharynx and report a feeling of an obstruction in the neck. Other common complaints include coughing, choking, drooling, and regurgitation when swallowing liquids or solid food (Ensrud et al. 2003). The diagnosis is confirmed by imaging studies, such as Fiberoptic Endoscopic Evaluation of Swallowing (FEES). FEES, which is easy to use, is the preferred method for studying swallowing disorders as it is very well tolerated, allows bedside examination, and is economical. Some discomfort, gagging and/or vomiting, vasovagal syncope, epistaxis, mucosal perforation, adverse reactions to topical anesthetics, and laryngospasm are, however, possible (Nacci et al. 2008). The other imaging study used is Video-fluoroscopic modified barium

2210

swallow, which permits functional evaluation of swallowing by visualization and analysis of the rapid sequence of events that make up a swallow. Video-fluoroscopy serves to detect oropharyngeal dysfunction and to assess the degree of dysfunction and severity of aspiration. This technique allows for a more accurate assessment of laryngeal penetration. Nasopharyngeal laryngoscopy, fiberoptic endoscopic evaluation of swallowing and manometry may be needed for further evaluation. Esophageal dysphagia is associated with difficulty swallowing several seconds after initiating a swallow. Patients may point to the suprasternal notch or to an area behind the sternum as the site of obstruction (Wilcox et al. 1995) and may complain of a sensation that foods and/or liquids are being obstructed in their passage from the upper esophagus to the stomach. Esophageal dysphagia arises within the body of the esophagus, the lower esophageal sphincter, or cardia. Benign tumors, malignancy, stricture, diverticula, pill esophagitis, postsurgery, radiation esophagitis, and lymphocytic esophagitis are associated with esophageal dysphagia. Esophageal motility problems also lead to dysphagia and may be due to neuromuscular disorders such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease, scleroderma, achalasia, or gastroparesis (Payne and Morley 2017).

Nausea Nausea can occur alone or can accompany vomiting, dyspepsia, or other gastrointestinal symptoms. It is often more bothersome and disabling than vomiting. Retching differs from vomiting in the absence of expulsion of gastric content (Singh et al. 2016). Nausea, a gastric rhythm disturbance, correlates with a shift in the normal three cycle per minute gastric myoelectrical activity to increased or reduced frequency. Unexplained vomiting is frequently due to constipation unless other explanations are present. Diabetes, cholelithiasis, gastritis, and viral or bacterial gastroenteritis are also etiologies that may lead to vomiting. Painless jaundice and nausea that accompanies it may be due to biliary

R. J. Goldberg and M. Jhurani

obstruction resulting from a malignancy of the pancreas or biliary tree. Nausea from hepatitis may be due to medications, procedures, or hemolysis. As patients are often unable to give a clear history, diagnosis may be difficult. Abdominal sonograms, done on site in most long-term care facilities, are the preferred way of initial evaluation. Liver function tests and viral hepatitis profiles may offer additional information (Singh et al. 2016). For patients with acute vomiting, physicians should expeditiously exclude life-threatening disorders such as bowel obstruction, mesenteric ischemia, acute pancreatitis, and myocardial infarction. When chronic, the consequences or complications of nausea and vomiting (fluid depletion, hypokalemia, and metabolic alkalosis) should be identified and corrected and finally a targeted therapy should be provided (surgery for bowel obstruction or malignancy) (Payne and Morley 2017). In other cases, the etiology must be sought and the symptoms treated to improve quality of life.

Flatulence Flatulence or intestinal gas is usually released from the anus with sound and/or odor. Although not life threatening, it may be a source of embarrassment for LTC residents. The most common causes of flatulence are swallowed air, breakdown of undigested foods, lactose intolerance, and malabsorption of certain foods. Much of the gas produced is due to microbial breakdown of foods and hydrogen, carbon dioxide, and methane are generated; the odor is from other trace waste gases or compounds such as skatole and sulfur-containing substances. It can be managed by modifying the diet, reassurance, and treating the cause. Probiotics, rifaximin, oral alpha-galactosidase (Beano ®), and oral bismuth subsalicylate (PeptoBismol ®) have all been used with varying effectiveness (Bailey et al. 2009). Chest Pain Gastroesophageal reflux disease (GERD) can be mistaken for cardiac chest pain leading to unnecessary cardiac workup and use of medications. GERD-related chest pain and angina pectoris

100

Gastrointestinal Disorders in Long-Term Care

may both be described as squeezing or burning, located substernly and radiating to the back, neck, jaw, or arms. The pain can last anywhere from minutes to hours and resolve either spontaneously or with antacids. GERD can have a major effect on patients’ well-being and quality of life (Katz 1998). Classic symptoms of gastroesophageal reflux disease are heartburn (pyrosis) and regurgitation. Other symptoms of GERD include dysphagia, odynophagia, nausea, and extraesophageal symptoms such as chronic cough, hoarseness, hiccups, or wheezing (DeVault and Castell 1995; Herman et al. 2001). Otolaryngologic complications of GERD can result from laryngopharyngeal reflux, when the reflux of gastric contents results in contact injury to the pharyngeal and laryngeal mucosa (Richter 1996; Jacob et al. 1991).

Abdominal Pain Abdominal pain in an older patient may be due to temporary conditions or serious life-threatening ones. Although generally due to gastroenterological conditions, renal colic, urinary retention, aortic aneurysms, and early herpes zoster may also mimic similar complaints of pain. As far back as 1947, it has been known that pain receptors in the abdomen respond to both mechanical and chemical stimuli. Stretch is the principal mechanical stimulus involved in visceral nociception, although distention, contraction, traction, compression, and torsion are also perceived. Most digestive tract pain is perceived in the midline because of bilaterally symmetric innervation and visceral pain is perceived in the spinal segment at which the visceral afferent nerves enter the spinal cord (Ray and Neill 1947). Direct abdominal and rectal examination should be performed. Monitoring vital signs including oxygen saturation and changes in mental status are important to note as well. Patients with new onset abdominal pain should have their medications reviewed as possible etiology and a review of their bowel habits. An x-ray of abdomen and upright chest x-ray can help rule out bowel obstruction, perforation, or acute colonic pseudo-obstruction. Sonograms may be necessary to evaluate for biliary, pancreatic, vascular, or renal disease.

2211

Gastroenterological Conditions with Features Specific to LTC Peptic Ulcer Disease Peptic ulcer disease causes significant morbidity and mortality in older adults. It frequently presents in an atypical manner and is associated with a high incidence of complications. The prevalence of Helicobacter pylori (H. pylori) increases with age and can have an important role in the development of ulcers. Nonsteroidal anti-inflammatory drugs (NSAIDs) also contribute to the increased incidence of ulcers and the development of complications in older adults. Although management of ulcer disease is similar to that in the younger population, consideration must be given to the potential for increased incidence of side effects and medication interactions. When endoscopy and surgery are performed, there should be an appreciation for the risks associated with concurrent illnesses due to advanced age (Borum 1999). The main goals for treating peptic ulcer disease in the LTC population are to reduce recurrence of the disease and to prevent complications, especially bleeding and perforation. The available treatments for peptic ulcer are essentially based on gastric acid suppression with antisecretory drugs and the eradication of H. pylori infection. Upper gastrointestinal (UGI) bleeding is described as any blood arising from the alimentary tract above the ligament of Treitz, the suspensory thin muscle of duodenum connecting the junction between the duodenum, jejunum, and duodenojejunal flexure to connective tissue surrounding the superior mesenteric artery and celiac artery. This muscle marks the formal division between the first and second parts of the small intestine, the duodenum, and the jejunum. Hematemesis (either red blood or coffee-ground emesis) suggests bleeding proximal to the ligament of Treitz. The presence of frankly bloody emesis suggests moderate to severe bleeding that may be ongoing, whereas coffee-ground emesis suggests more limited bleeding. Ninety percent of melena originates proximal to the ligament of Treitz and may originate from the oropharynx or nasopharynx but may also be from bleeding in the

2212

small bowel or right-sided colonic lesions (Borum 1999). UGI bleeding is most frequently caused by peptic ulcer disease but may be due to tears or inflammation of the esophagus, stomach, or mouth (Alkhatib et al. 2010). Several drugs increase the likelihood of bleeding, including nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and low molecular weight heparins, and heparin. Chronic liver disease due to excessive use of alcohol can also cause UGI bleeding. UGI bleeding may also precipitate hepatic encephalopathy or hepatorenal syndrome and may present as melena as opposed to hematemesis. Approximately 35–45% of all cases of acute upper GI hemorrhage occur in older persons. Medical literature gives conflicting results in regard to mortality from UGI bleeding, from 5.4% to 44% (Alkhatib et al. 2010; Cappell and Friedel 2008; Kim et al. 2014).

Hepatobiliary Disease Diseases affecting the gall bladder and bile ducts occur commonly in older adults. By the age of 70, cholelithiasis, the most frequently occurring disorder affecting these organ systems, and its sequela, choledocholithiasis, are found in 33% of the United States population (Siegel and Kasmin 1997). Asymptomatic gallstones are a common feature in the old, as time, gall bladder dysfunction and the increasing lithogenicity of bile seem to predispose to precipitation of supersaturated bile and the concomitant crystallization of cholesterol or calcium bilirubinate into stone material. While it has been accepted that prophylactic surgery should not be recommended in asymptomatic patients, the longer the patient has gallstones, the more likely cholecystitis and biliary colic will develop. The health care provider must assess the patient and recommend the best available options for treatment (Siegel and Kasmin 1997). Most patients with gallstones never develop acute cholecystitis, and among those who experience an episode of biliary colic, nearly half will never experience a second episode of colic within 5 years. Such an outcome could justify a “waitand-see” approach for most LTC residents.

R. J. Goldberg and M. Jhurani

However, the presentation of colic in the older patient with diabetes and diabetes-associated neuropathy is atypical. In these patients, gangrenous cholecystitis can present without significant temperature increases, significant leukocytosis, or severe abdominal complaints. Consequently, clinically significant cholecystitis may be misdiagnosed as mild biliary colic. Additionally, comorbidities and potentially life-threatening conditions may discourage a surgeon from performing a necessary cholecystectomy. LTC residents who require emergency cholecystectomies tend to do poorly when compared with the outcomes of younger patients. Older patients must be assessed thoroughly prior to cholecystectomy as emergency surgery is often poorly tolerated. The mortality rates for emergency cholecystectomy among older adults have been reported to range from 6% to 15%. If possible, surgery should be deferred and rescheduled on an elective basis (Siegel and Kasmin 1997). Endoscopic Retrograde Cholangiopancreatography (ERCP) techniques alone can be used for treating patients with cholelithiasis or with stones impacted in the cystic duct. Trans-papillary stents can be placed into the affected gall bladder via the cystic duct, allowing bile and purulent material to drain into the duodenum thus palliating acute cholecystitis. ERCP’s success rate is 98% for choledocholithiasis even including those patients at great risk (Siegel and Kasmin 1997).

Colorectal Disease Diverticular disease of the colon mainly affects older adults and presents in 50–70% of those aged 80 years or older (Comparato et al. 2007). Of patients with diverticula, 80–85% remain asymptomatic. Symptomatic disease includes diverticulosis with diverticular bleeding, diverticulitis, or segmental colitis associated with diverticula (Liu et al. 2009). The causes of colonic diverticula are attributed to alterations in colonic wall resistance, disordered colonic motility, dietary fiber deficiency, and inflammation. For those with symptoms, the goals of therapy are improvement of symptoms, prevention of recurrent attacks, and prevention of the complications such as

100

Gastrointestinal Disorders in Long-Term Care

diverticulitis. Computed tomography is recommended for diagnosis when colonic diverticulitis is suspected. Diverticulitis is the most common clinical complication of diverticular disease. Predictive factors for severe diverticulitis are female sex, obesity, immunodeficiency, and old age. Most patients respond to conservative treatment, although 15–30% requires surgery. Conservative treatment of colonic diverticulitis with antibiotics, bowel rest, and parenteral alimentation are usually utilized for 1–2 weeks in an attempt to decrease the need for surgery, which again has high rates of morbidity and mortality. In the absence of a response to conservative treatment, frequent recurrences, or complications (abscesses, fistulas, bowel obstructions, and free perforations), surgery is indicated (Liu et al. 2009). Younger patients often have more virulent disease and are more frequently male, but older patients are more frequently female and more frequently require hospitalization. Possible hypotheses include testosterone’s protective effect on the weakening of the colonic wall, and the effect of pregnancy, labor, and delivery contributing to the weakening of the wall of the colon (Weizman and Nguyen 2011). Lower GI bleeding may be due to hemorrhoids, angiodysplasia, diverticulosis and diverticulitis, inflammatory bowel disease, colonic polyps, or cancer in the colon. Whereas hemorrhoids and colorectal cancer are the most common causes of minor bleeding in older adults, peptic ulcer disease, diverticular disease, and angiodysplasia are the most common causes of major bleeding. Older patients tolerate massive GI bleeding poorly. Diagnosis must be made rapidly, and treatment started quickly. Fortunately, in most older patients, lower GI bleeding stops spontaneously with resuscitation and supportive therapy (Akhtar 2003). Colorectal cancer is any cancer that affects the colon or the rectum. The American Cancer Society estimates 97,220 new cases of colon cancer and 43,030 new cases of rectal cancer in the United States in 2018. It is the second leading cause of cancer death in women, and the third for men. However, due to advances in screening techniques and improvements in treatments, the

2213

death rate from colorectal cancer has been decreasing (American Cancer Society 2018).

Oral Health A significant number of associations exist between oral and general health. There are significant associations between periodontal disease with atherosclerotic vascular disease, diabetes, and aspiration pneumonia. Whereas oral health impacts dietary intake and food choice, nutrition plays a key role in the etiology of oral diseases such as caries and periodontal disease which can subsequently cause difficulty in eating. Poor oral hygiene increases the risk of rapid oral health deterioration adding to the medical factors of hyposalivation and xerostomia. Oral exams and assessments by health care providers in long-term care are rarely performed, although oral hygiene has recently been more a focus of care for caregivers (Kossioni et al. 2018).

End of Life Care Artificial Nutrition and Hydration Although there are many conditions where artificial nutrition may be indicated, studies have shown they neither decrease morbidity or mortality at the end of life (Finucane et al. 1999). Goals of care with patients who have capacity, family members, or health care proxies should be clarified prior to the need to make this decision acutely. Cultural differences need to be respected as the decision-making process may differ from person to person. Due to religious beliefs, inadequate education, and misinformation, families and physicians often proceed with artificial nutrition in cases of questionable utility (Kuo et al. 2009). Although indicated for some neuromuscular disorders that decrease GI motility or for dysphagia due to strictures or strokes, artificial nutrition is generally not indicated for patients with endstage dementia. The risks of surgery, the possibility of infection, the issues surrounding the dislodging of tubes either intentionally by the patient or accidentally must be considered. Feeding tubes do not decrease the risk of aspiration or pneumonia (Finucane et al. 1999).

2214

Much education is necessary as relates to diminished eating at the end of life. Feeding gastrostomies are never to be used for the convenience of staff. Careful hand feeding by trained staff or family is appropriate for persons with advanced dementia. Hand feeding is at least as good as artificial nutrition for the outcomes of death, aspiration pneumonia, functional status, and patient comfort. Feeding tubes negatively impact a patient’s quality of life and deprive them of the enjoyment of food. In actuality, the majority of feeding gastrostomies are inserted during an acute hospitalization for an unrelated condition, thus questioning whether advance directives are taken into account. Tube feeding is associated with agitation, increased use of physical and chemical restraints, and worsening pressure ulcers. In one study, the incidence of feeding-tube insertion was 53.6/1000 residents. Most (68.1%) feeding-tube insertions were performed in an acute care hospital with the most common reasons for admission being pneumonia, dehydration, and dysphagia. One-year postinsertion mortality was 64.1% with median survival of 56 days. Within 1 year, 19.3% of those who had a feeding tube inserted required a tube replacement or repositioning within a median 145 days after the initial insertion. Over 1 year, tube feeding was associated with an average of 9.1 hospitalized days per person, 1.0 hospitalization, and 0.3 emergency room visits that did not result in a hospital admission. It was concluded that most feeding-tube insertions are associated with poor survival and significant rate of health care use after insertion. Of those who die within a year of receiving a gastrostomy tube, half die within 2 months (Kuo et al. 2009). Several types of feeding tubes exist. Nasogastric (NG) tubes enter the nose and feed into the stomach. Patients who need tube feedings for only a short period of time, often receive NG-tubes. NG-tubes can be easily placed or removed without surgery. Unfortunately, they can also be pulled out easily, be irritating, cause nasal septum erosion, and must be taped to the face. As they are visible at all times they diminish quality of life and impact a patient’s dignity. Gastric or Gastrostomy (G) tubes are the most common type of feeding tubes. They are placed

R. J. Goldberg and M. Jhurani

surgically or endoscopically directly through the skin and into the stomach. Patients who require tube feeding for more than 3 months are likely to receive a G-tube. A G-tube may consist of a long tube, sometimes called a PEG tube, or a skin-level button device. Once the tube tract has healed, the tube or button may be replaced at home. Most feeding regimens occur over evenings or at night so that patients may participate in activities during the day and not be attached to feeds (Feeding Tube Awareness Foundation 2018). Jejunal (J) tubes are tubes that are directly placed into the small intestine. They require surgical placement. Depending on the type of surgery and tube, the J-tube may be easily replaced at home. Feedings must be given slowly for 18–24 h. A jejunal feeding tube which is an alternative to a gastrostomy feeding tube is commonly used when gastric enteral feeding is contraindicated or carries significant risks. The advantage over a gastrostomy is its lower risk of aspiration due to its distal placement. Disadvantages include small bowel obstruction (Pearce and Duncan 2002). Older LTC residents often experience diminished thirst sensation resulting in a reduced fluid consumption leading to dehydration. It may also be caused by warm temperature, inattentive or inadequate staffing, and the use of laxatives or diuretics. Reduced swallowing capacity, decreased mobility, or comprehension and communication disorders all contribute to the problem. Disease-related factors, such as incontinence can increase water losses and make measuring urinary outputs difficult to follow. The risks of Foley catheters for measuring outputs far outweigh the benefits for residents in long-term care (Nicolle 2014). Body water content decreases by approximately 15% (about 6 L) between the ages of 20 and 80 increasing the risk and consequences of prerenal azotemia and dehydration. Additionally, older kidneys have a reduced ability to concentrate urine, retain water during water deprivation, and are less able to conserve or excrete sodium, all exacerbating the risk of dehydration (Silver 1990). With this decrease, the body becomes more susceptible to various morbidities such as impaired cognition or acute confusion, falling, or constipation.

100

Gastrointestinal Disorders in Long-Term Care

Dehydration in residents of LTC facilities can be prevented by ensuring adequate fluid intake, maintaining appropriate doses of diuretics, and educating patients, their families, and caregivers on the risks of dehydration and its consequences. A behavioral intervention consisting of verbal prompts and beverage preference compliance was effective in increasing fluid intake among a sample of incontinent LTC residents. Verbal prompting alone was effective in improving fluid intake in the more cognitively impaired residents, whereas preference compliance was needed to increase fluid intake among less cognitively impaired residents (Simmons et al. 2001).

Long-Term Care Patient Management and the Gastroenterologist Most GI issues are managed by primary care providers including Advance Practice Nurses and Physicians Assistants in LTC and should be addressed promptly by the health care provider. Management of GI disorders involves treatments adapted to the specific nature and symptom of the patient, monitoring patients’ progress, preventing recurrence, and maintaining comfort. Timely recognition of serious life-threatening GI symptoms is crucial. Complicated disease states and the need for artificial nutrition precipitate most gastroenterological consultations, although primary care providers always have the option of GI consultation when desired or when requested by the patient or family. Other clinical situations where GI consultation may be necessary include chronic diarrhea or GERD unresponsive to therapy, dysphagia, GI symptoms not responding to initial treatment, laboratory findings indicative of severe anemia or hepatic dysfunction, occult persistent GI bleeding, suspected surgical abdomen, or suspected cholelithiasis (American Medical Directors Association 2018b). LTC patients are always referred to a GI consultant for endoscopy, colonoscopy, invasive radiological studies, endoscopic retrograde cholangiopancreatography, manometry, breath testing and endoscopic ultrasound. Screening colonoscopies are rare as most residents are older than 70.

2215

Most gastroenterologists have never practiced within the LTC setting and are surprised by the multidisciplinary team that contributes to the care of the resident. Not only are the primary care providers offering guidance, but so are nurses, dietitians, speech therapists, social workers, and therapeutic recreation professionals. Additionally, as many of these residents may be suffering from some form of dementia, living wills, health care proxies, Advance Directives, and Medical or Physician Orders for Life Sustaining Treatment forms (MOLST or POLST) must all be considered. The goals of care conversations are of utmost importance and should be done before an acute emergency occurs. Readmission rates to hospitals are now carefully scrutinized and facilities are penalized for excessive numbers of readmissions. Hospitalization should be used as only a last resort. Good oral hygiene in the nursing home has shown to decrease pneumonia and lead to improved survival. Upper and lower gastrointestinal bleeds can be worked up as outpatients in patients that are hemodynamically stable. Transfusions can be arranged as outpatients to limit the possibility of rehospitalization that often occurs when patients are transferred to the emergency department. If a patient is clinically unstable, a transfer to an emergency room may be necessary if it is consistent with the resident’s goal of care. Acute abdomens require hospitalization, as ischemic bowel, a ruptured viscus, gangrenous cholecystitis, acute GI bleeding, or acute diverticulitis remain potentially life threatening. These conditions require urgent attention and may need more advanced testing than what can be done in a typical LTC setting. A gastroenterological consult as well as a surgical consult are necessary in most instances and are usually deferred until the patient arrives at the hospital.

Key Points • GI symptoms in the LTC population must be recognized by primary care providers at an early stage to improve quality of life and

2216

• •

•

•

•

• •

avoid serious life-threatening complications which may lead to hospitalizations. It is worth recognizing that GI disorders present atypically and may contribute to other potentially serious medical complications. Numerous prescribed medications for concurrent conditions cause GI symptomatology; and medications may complicate the assessment and treatment of GI disorders. Careful recognition, assessment, treatment, and monitoring lead to more effective patientspecific interventions for the common GI symptoms. Members of the interdisciplinary team are integral to recognize common signs and symptoms associated with GI disorders and must report them to the primary care provider in a timely manner. Many gastrointestinal conditions are common in older adults regardless of where they reside, but some issues are more pertinent to residents in post-acute care. Gastroenterology consultations remain a necessary component for top quality care and should be readily available when requested. Collaboration with caregivers who know the resident and their families or health care proxies is vital.

References Akhtar AJ. Lower gastrointestinal bleeding in elderly patients. J Am Med Dir Assoc. 2003;4:320–2. Akhtar AJ. Acute diarrhea in frail elderly nursing home patients. J Am Med Dir Assoc. 2008;9:476–85. 2003;4:34–9 Alibhai SMH, Greenwood C, Payette H. An approach to the management of unintentional weight loss in elderly people. CMAJ. 2005;172(6):773–80. https://www. ncbi.nlm.nih.gov/pmc/articles/PMC552892. Accessed 4 Jan 2019. Alkhatib AA, Alkhatib FA, Abubakr SM, et al. Acute upper gastrointestinal bleeding in elderly people: presentations, endoscopic findings, and outcomes. J Am Geriatr Soc. 2010;58(1):182–5. American Cancer Society. Key statistics for colorectal cancer. 2018. https://www.cancer.org/cancer/colon-rectalcancer/about/key-statistics.html. Accessed 4 Jan 2019. American Medical Directors Association. LTC information series. Constipation and diarrhea in the long-term care setting. Columbia. 2018a. p. 1–31.

R. J. Goldberg and M. Jhurani American Medical Directors Association. Clinical practice guidelines. Gastrointestinal disorders in the long-term care setting. Columbia. 2018b. p. 1–25. Aoyama L, Weintraub N, Reuben DB. Is weight loss in the nursing home a reversible problem? J Am Med Dir Assoc. 2006;6(Suppl):S66–72. Bailey J, Carter NJ, Neher JO. Effective management of flatulence. Am Fam Physician. 2009;79(12):1098–100. Birrer RB, Vemuri SP. Depression in later life: a diagnostic and therapeutic challenge. Am Fam Physician. 2004;69(10):2375–82. Borum ML. Peptic-ulcer disease in the elderly. Clin Geriatr Med. 1999;15(3):457–71. https://www.ncbi.nlm.nih. gov/pubmed/10393735. Accessed 4 Jan 2019. Bouras EP, Lange SM, Scolapio JS. Rational approach to patients with unintentional weight loss. Mayo Clin Proc. 2001;76:923–9. Bromley SM. Smell and taste disorders: a primary care approach. Am Fam Physician. 2000;61(2):427–36. Camilleri M. Diabetic gastroparesis. N Engl J Med. 2007;356:820–9. Campbell-Taylor IC. Oropharyngeal dysphagia in longterm care: misperceptions of treatment efficacy. J Am Med Dir Assoc. 2008;9:523–31. Cappell MS, Friedel D. Initial management of acute upper gastrointestinal bleeding: from initial evaluation up to gastrointestinal endoscopy. Med Clin North Am. 2008;92(3):491–509. Centers for Disease Control and Prevention. Nursing homes and assisted living. 2017. https://www.cdc. gov/longtermcare/index.html. Accessed 4 Jan 2019. Comparato G, Pilotto A, Franze A, Franceschi M, Di Mario F. Diverticular disease in the elderly. Dig Dis. 2007;25(2):151–9. Dev R, Wong A, Hui D, et al. The evolving approach to management of cancer cachexia. Oncology. 2017;31(1):23–32. DeVault KR, Castell DO. Guidelines for the prevention and treatment of gastroesophageal reflux disease. Practice Parameters Committee of the American College of Gastroenterology. Arch Intern Med. 1995;155(920): 2165–73. https://www.ncbi.nlm.nih.gov/pubmed?term= 7487238. Accessed 4 Jan 2019. Ensrud KE, Ewing SK, Stone KL, et al. Intentional and unintentional weight loss increase bone loss and hip fracture risk in older women. J Am Geriatr Soc. 2003;51(12):1740–7. Farrell B, Merkley VF, Ingar N. Reducing pill burden and helping with medication awareness to improve adherence. Can Pharm J. 2013;146(5):262–9. https://www. ncbi.nlm.nih.gov/pmc/articles/PMC3785195. Accessed 3 Jan 2019. Feeding Tube Awareness Foundation. 2018. https://www. feedingtubeawareness.org/tube-feeding-basics/tubetypes. Accessed 4 Jan 2019. Finucane TE, Christmas C, Travis K. Tube feeding in patients with advanced dementia: a review of the evidence. JAMA. 1999;282(14):1365–70. Firth M, Prather CM. Gastrointestinal motility problems in the elderly patient. Gastroenterology. 2002;122 (6):1688–170.

100

Gastrointestinal Disorders in Long-Term Care

Fox CB, Treadway AK, Blaszczyk AT, et al. Megestrol acetate and mirtazapine for the treatment of unplanned weight loss in the elderly. Pharmacotherapy. 2009;29(4):383–97. Gaddey HL, Holder K. Unintentional weight loss in older adults. Am Fam Physician. 2014;89(9):718–72. Glass RI, Parashar UD, Estes MK. Norovirus gastroenteritis. N Engl J Med. 2009;361:1776–85. Goldberg RJ, Kaplan LA, Boucher LJ. Physician’s attentiveness to medication usage as etiology of weight loss. Long-term care. Interface. 2005;9:20–3. Herman, CM, McCarthy DM, Ramirez FC. Identifying and managing GERD in the elderly: optimizing therapy and improving outcomes. J Am Med Dir Assoc. 2001;Symposium Highlights:H30–3. Hoover DR, Siegel M, Lucas J, et al. Depression in the first year of stay for elderly long-term nursing home residents in the USA. Int Psychogeriatr. 2010;22(7):1161–71. https://www.ncbi.nlm.nih.gov/ pubmed?term=20478100. Accessed 4 Jan 2019. Hsieh C. Treatment of constipation in older adults. Am Fam Physician. 2005;72(11):2277–84. Huffman GB. Evaluating and treating unintentional weight loss in the elderly. Am Fam Physician. 2002;65:640–50. Jacob P, Kahrilis PJ, Herzon G. Proximal esophageal pHmetry in patients with ‘reflux laryngitis’. Gastroenterology. 1991;100(2):305–10. https://www.ncbi.nlm.nih. gov/pubmed?term=1985028. Accessed 4 Jan 2019. Janssen I. The epidemiology of sarcopenia. Clin Geriatr Med. 2011;27(3):355–63. https://www.ncbi.nlm.nih. gov/pubmed?term=21824552. Accessed 4 Jan 2019. Kaiser MJ, Bauer JM, Ramsch C, et al. Validation of the Mini Nutritional Assessment Short-Form (MNA-SF): a practical tool for the identification of nutritional status. J Nutr Health Aging. 2009;13(9):782–8. https://www. ncbi.nlm.nih.gov/pubmed/19812868. Accessed 4 Jan 2019. Kardinal CG, Loprinzi CL, Schaid DJ, et al. A controlled trial of cyproheptadine in cancer patients with anorexia and/or cachexia. Cancer. 1990;65(12):2657–62. Katz PO. Gastroesophageal reflux disease. J Am Geriatr Soc. 1998;46:1558–65. Kim BSM, Li BT, Engel A, Samra JS, Clarke S, Norton ID, Li AE. Diagnosis of gastrointestinal bleeding: a practical guide for clinicians. World J Gastrointest Pathophysiol. 2014;5(4):467–78. Kossioni AE, Hajto-Bryk J, Janssens B, et al. Practical guidelines for physicians in promoting oral health in frail older adults. J Am Med Dir Assoc. 2018;19 (12):1039–46. Kotler DP. Cachexia. Ann Intern Med. 2000;133 (8):622–34. Kuo S, Rhodes RL, Mitchell SL, et al. Natural history of feeding tube use in nursing home residents with advanced dementia. J Am Med Dir Assoc. 2009;10(4):264–70. Landi F, Calvani R, Tosato M, et al. Anorexia of aging: risk factors, consequences, and potential treatments. Nutrients. 2016;8(2):69. https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC4772033. Accessed 4 Jan 2019.

2217 Lembo A, Camilleri M. Chronic constipation. N Engl J Med. 2003;348(14):1360–8. Lewko M, Chamseddin A, Zaky M, et al. Weight loss in the elderly: what’s normal and what’s not. PT. 2003;28:734–9. Little M. Treating and preventing Clostridium difficile infection in long-term care facilities. Ann Long Term Care. 2018;26(7):25–9. Liu CK, Hsu HH, Cheng SM. Colonic diverticulitis in the elderly. Int J Gerontol. 2009;3(1):9–15. Lyketsos CG, Olin J. Depression in Alzheimer’s disease: overview and treatment. Biol Psychiatry. 2002;52 (3):243–52. https://www.ncbi.nlm.nih.gov/pubmed? term=12182930. Accessed 4 Jan 2019. Makins R, Ballinger A. Gastrointestinal side effects of drugs. Expert Opin Drug Saf. 2003;4:421–9. https:// www.ncbi.nlm.nih.gov/pubmed/12904098. Accessed 3 Jan 2019. Mayo Clinic. Fecal incontinence. https://www.mayoclinic. org/diseases-conditions/fecal-incontinence/symptomscauses/syc-20351397. Accessed 4 Jan 2019. Messinger-Rapport BJ, Morley JE, Thomas DR, et al. Clinical update on nursing home medicine: 2011. J Am Med Dir Assoc. 2011;12:615–26. Messinger-Rapport BJ, Cruz-Oliver DM, Thomas DR, Morley JE. Clinical update on nursing home medicine: 2012. J Am Med Dir Assoc. 2012;13:581–94. Mounsey A, Raleigh M, Wilson A. Management of older adults with constipation. Am Fam Physician. 2015;92(6):500–4. https://www.aafp.org/afp/2015/091 5/p500.html. Accessed 4 Jan 2019. Nacci A, Ursino F, La Vela R, Matteucci F, Mallardi V, Fattori B. Fiberoptic endoscopic evaluation of swallowing: proposal for informed consent. Acta Otorhinolaryngol Ital. 2008;28(4):206–11. https://www. ncbi.nlm.nih.gov/pmc/articles/PMC2644994. Accessed 4 Jan 2019. National Caregivers Library. Toileting and incontinence. http://www.caregiverslibrary.org/caregivers-resources/ grp-home-care/hsgrp-personal-care-activities/toiletingand-incontinence-article.aspx. Accessed 4 Jan 2019. Nicolle LE. Catheter associated urinary tract infections. Antimicrob Resist Infect Control. 2014;3(23):1–8. Office of Disease Prevention and Health Promotion. Minimum data set. 2018. https://www.healthypeople.gov/ 2020/data-source/minimum-data-set. Accessed 4 Jan 2019. Pankaj J, Pasricha PJ, Yates KP, et al. Aprepitant has mixed effects on nausea and reduces other symptoms in patients with gastroparesis and related disorders. Gastroenterology. 2018;154(1):65–76.e11. https://www.gastrojournal. org/article/S0016-5085(17)36066-3/fulltext. Accessed 4 Jan 2019. Parkman HP, Hallinan EK, Hasler WL, et al. Early satiety and postprandial fullness in gastroparesis correlate with gastroparesis severity, gastric emptying, and water loading testing. Neurogastroenterol Motil. 2017;29(4): e12981. https://www.ncbi.nlm.nih.gov/pubmed/ 27781342. Accessed 4 Jan 2019. Payne MA, Morley JE. Dysphagia: a new geriatric syndrome. J Am Med Dir Assoc. 2017;18:555–7.

2218 Pearce C, Duncan H. Enteral feeding. Nasogastric, nasojejunal, percutaneous endoscopic gastrostomy, or jejunostomy: its indications and limitations. Postgrad Med J. 2002;78(918):198–204. Ray BS, Neill CL. Abdominal visceral sensation in man. Ann Surg. 1947;126(5):709–23. https://www.ncbi.nlm. nih.gov/pubmed?term=17859026. Accessed 4 Jan 2019. Richter JE. Typical and atypical presentations of gastroesophageal reflux disease. The role of esophageal testing in diagnosis and management. Gastroenterol Clin North Am. 1996;25(1):75–102. https://www.ncbi.nlm.nih.gov/ pubmed?term=8682579. Accessed 4 Jan 2019. Ruiz Garcia V, López-Briz E, Carbonell Sanchis R, et al. Megestrol acetate for treatment of anorexia-cachexia syndrome. Cochrane Database Syst Rev. 2013; (3): CD004310. Schuster BG, Kosar L, Kamrul R. Constipation in older adults. Can Fam Physician. 2015;61(2):152–8. https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC4325863. Accessed 3 Jan 2019. Siegel JH, Kasmin FE. Biliary tract diseases in the elderly. Gut. 1997;41:433–5. https://gut.bmj.com/content/41/4/ 433. Accessed 4 Jan 2019. Silver AJ. Aging and risks for dehydration. Cleve Clin J Med. 1990;57(4):341–4. Simmons SF, Alessi C, Schnelle JF. Intervention to increase fluid intake in nursing home residents: prompting and preference compliance. J Am Ger Soc. 2001;49(7):926–33. Simmons WK, Burrows K, Avery JA, et al. Depression related increases and decreases in appetite: dissociable patterns of aberrant activity in reward and interoceptive neurocircuitry. Am J Psychiatry. 2016;173(4):418–28. https://ajp.psychiatryonline.org/doi/abs/10.1176/appi. ajp.2015.15020162. Accessed 4 Jan 2019. Singh P, Yoon SS, Kuo B. Nausea: a review of pathophysiology and therapeutics. Ther Adv Gastroenterol. 2016;9(1):98–112. https://www.ncbi.nlm.nih.gov/pub med?term=26770271. Accessed 3 Jan 2019. Sloane PD, Ivey J, Helton M, et al. Nutritional issues in long-term care. J Am Med Dir Assoc. 2008;9:476–85. Sura L, Madhaven A, Carnaby G, Crary MA. Dysphagia in the elderly: management and nutritional considerations.

R. J. Goldberg and M. Jhurani Clin Interv Aging. 2012;7:287–98. https://www.ncbi. nlm.nih.gov/pmc/articles/PMC3426263. Accessed 3 Jan 2019. The Infectious Disease Society of America (IDSA) Clostridium difficile. 2018;66(7):e1–48. https://www. idsociety.org/practice-guideline/clostridium-difficile/. Accessed 12 Jan 2019. Thomas DR, Morley JE. Regulation of appetite in older adults. Ann Long-Term Care. 2002; (Suppl):1–12. Thomas DR, Forrester L, Gloth MF, Gruber J, Krause RA, Prather C, et al. Clinical consensus: the constipation crisis in long-term care. Ann Long-Term Care. 2003; (Suppl):3–14. Unutzer J, Patrick DL, Simon G, Grembowski D, et al. Depressive symptoms and the cost of health services in HMO patients aged 65 years and older: a four-year prospective study. JAMA. 1997;277(20):1618–23. https://www.ncbi.nlm.nih.gov/pubmed?term=9168292. Accessed 4 Jan 2019. Wald A. Fecal incontinence in adults. N Engl J Med. 2007;356(7):1648–55. Waseem S, Moshiree B, Draganov PV. Gastroparesis: current diagnostic challenges and management considerations. World J Gastroenterol. 2009;15(1):25–37. https://www. ncbi.nlm.nih.gov/pmc/articles/PMC2653292. Accessed 4 Jan 2019. Weintraub JA, Zimmerman S, Ward K, et al. Improving nursing home residents’ oral hygiene: results of a cluster randomized intervention trial. J Am Med Dir Assoc. 2018;19:1086–91. Weizman AV, Nguyen GC. Diverticular disease: epidemiology and management. Can J Gastroenterol. 2011;7:385–9. White HK. Weight loss in advanced Alzheimer’s disease, part 1: contributing factors and evaluation. Ann Long Term Care. 2004;12:33–7. Wilcox CM, Alexander LN, Clark WS. Localization of an obstructing esophageal lesion. Is the patient accurate? Dig Dis Sci. 1995;40(10):2192–6. https://www.ncbi. nlm.nih.gov/pubmed?term=7587788. Accessed 3 Jan 2019.

Mucocutaneous Manifestations in Gastrointestinal Disease

101

Robert A. Norman, Trupal Patel, and Tam H. Nguyen

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2220 Oral Cavity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kaposi’s Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mucocutaneous Candidiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Angular Cheilitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Behçet Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2221 2221 2222 2225 2225

Esophagus and Stomach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Plummer-Vinson Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tylosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidermolysis Bullosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Systemic Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis . . . . . . . . . . . . . . . . . . . . . . . .

2226 2227 2227 2227 2228 2229

Intestines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Peutz-Jeghers Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Blue Rubber Bleb Nevus Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gardner Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dermatitis Herpetiformis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Crohn’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2229 2229 2230 2231 2231 2233

Liver and Pancreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hemochromatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Porphyria Cutanea Tarda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pancreatic Fat Necrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Glucagonoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2233 2233 2234 2235 2236

R. A. Norman (*) Center for Geriatric Dermatology, Integrative Dermatology and Neuro-Dermatology, Nova Southeastern University, Tampa, FL, USA e-mail: [email protected] T. Patel American University of Antigua COM MSIV University of Florida, B.S. Biology, Gainesville, FL, USA T. H. Nguyen Larkin Community Hospital, Miami, FL, USA © Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_90

2219

2220

R. A. Norman et al. Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2237 Acanthosis Nigricans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2238 Visceral Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Muir-Torre Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cowden Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cronkhite-Canada Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2238 2238 2239 2240

Other Manifestations: Parasitic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2240 Strongyloidiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2240 Leishmaniasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2240 Additional Considerations in Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2241 Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2242 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2242

Abstract

The gastrointestinal (GI) system of the human body is influenced by many factors that can cause age related and pathological changes in the skin and organ systems. Several GI disorders are associated with cutaneous manifestations. A thorough understanding of the cutaneous-gastrointestinal relationship can alert the astute clinician to the presence of GI disease in patients presenting with mucocutaneous manifestations. This overview provides insight into mucocutaneous manifestations of GI disorders including signs and symptoms, diagnosis, treatment, and prognosis.

Keywords

Mucocutaneous disease · Geriatric gastrointestinal disease · Mucocutaneous manifestations of gastrointestinal disease · Candidiasis · Dermatitis · Hemachromatosis · Peutz-Jeghers syndrome · Kaposi sarcoma · Plummer-Vinson syndrome · Epidermolysis bullosa · Scleroderma · Sclerodactyly · CREST syndrome · Systemic sclerosis · Morphea · Pemphigus vulgaris · Tylosis · Esophageal cancer · Acanthosis nigricans · Porphyria cutanea tarda · Lichen planus · Blue rubber bleb nevus · Gardner’s syndrome · Dermatitis herpetiformis · Celiac disease · Inflammatory bowel disease · Crohn’s disease · Muir-Torre syndrome · Cowden disease · Cronkhite-Canada syndrome · Glossitis ·

Cheilitis · Mucocutaneous vitamin deficiency · Behcet’s syndrome · Stevens-Johnson syndrome · Toxic epidermal necrolysis · Strongyloidiasis · Leishmaniasis · Necrolytic migratory erythema · Glucagonoma · Pancreatic fat necrosis

Introduction As the human body ages, changes in metabolism and lifestyle occur. These changes often result in conditions affecting the gastrointestinal (GI) system. Aging is associated with gastrointestinal physiological and pathological manifestations (Forciea et al. 2000). Several gastrointestinal disorders have an increased risk for specifically associated mucocutaneous manifestations. A mucocutaneous junction, or boundary, is a region of the body in which mucosa transitions to skin. In humans, mucocutaneous junctions are found at the lips, nostrils, conjunctivae, urethra, genitals, and anus. Dermatological manifestations may be coincidental clinical associations, complications of GI disorders, or secondary to therapy administered for the GI disorder. Mucocutaneous signs and symptoms of various GI diseases will be reviewed for each region of the GI tract including the oral cavity, esophagus, stomach, pancreas, liver, and intestines. This overview will also look into visceral neoplasms, rare parasitic diseases, and nutritional abnormalities that result in mucocutaneous manifestations.

101

Mucocutaneous Manifestations in Gastrointestinal Disease

Understanding of these mucocutaneous-gastrointestinal relationships can alert clinicians to investigate further for the presence of underlying GI disease in a presenting patient.

Oral Cavity The oral cavity is commonly accepted as the beginning of the GI tract and system. Many diseases of the GI system manifest in the oral mucosa. In this section, the disorders which arise from the oral cavity and affect the mucocutaneous areas of the body are discussed. Included are Kaposi’s sarcoma, mucocutaneous (oropharyngeal, esophageal, intertrigo, and vulvovaginal) candidiasis, angular cheilitis, and Behcet’s syndrome. Other diseases which manifest in the oral mucosa, but have their origin elsewhere in the GI tract such as the inflammatory bowel diseases, are discussed in their respective sections.

Kaposi’s Sarcoma Kaposi sarcoma (KS) is an angioproliferative disorder that requires infection with human herpes virus 8 (HHV-8). Kaposi sarcoma-associated herpesvirus (KSHV), also known as HHV-8, is the etiologic agent underlying Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease (Gao et al. 1996; Li et al. 2017; Dittmer and Damania 2016; Soulier et al. 1995). The Hungarian dermatologist, Moritz Kaposi, first described the disease in 1872 as “idiopathic multiple pigmented sarcoma of the skin” (idiopathisches multiples Pigmentsarkom der Haut) (Kaposi 1982). The human gammaherpesvirus was discovered in 1994 by Chang and Moore in AIDS-associated KS tissues (Li et al. 2017). Classic Kaposi’s sarcoma is prevalent in older adults of Mediterranean, Central, and Eastern Europe origin but can manifest in any individual with HHV-8 infection (Schwartz and Cohen 1989; Iscovich et al. 1998; Angeloni et al. 1998; Cattani et al. 2003). HHV-8 has been linked closely with all four types of Kaposi sarcoma, i.e., classic

2221

(traditional), endemic (African), epidemic (AIDS related), and iatrogenic (related to immunosuppression) (Allan et al. 2001). Kaposi sarcoma (KS) is the most common cancer in individuals living with HIV/AIDS today (Silverberg et al. 2015; Robbins et al. 2015). KS incidence has stabilized and remained level, since its initial decline due to effective HIV therapy in the United States (Dittmer and Damania 2016). However, the prevalence of KS in endemic African regions remains high (Stefan et al. 2011; Senba et al. 2011). KS can involve any site in the body, but cutaneous disease is most common and usually the initial presentation of the disease. The lesions of KS appear most often on the lower extremities, face (especially the nose), oral mucosa, and genitalia ranging in size from several millimeters to centimeters in diameter. Cutaneous KS presents itself as rainbow-patterned, blue, red, or purplebrown patches, papules, plaques, or as cutaneous nodules of the mucosa, larynx, lungs, pancreas, heart, trachea, stomach, liver, and colon (Satta et al. 2016; Caponetti et al. 2007). The intra-oral site most commonly affected is the palate followed by the gingiva (Nichols et al. 1993). Oral lesions are more common in those with AIDS acquired through blood transfusion, sexual transmission, or IV drug use, compared to those with traditional KS (Fig. 1). Lymphedema of the face, lower extremities, and genitalia may result from vascular obstruction and cytokine involvement. Gastrointestinal lesions may be asymptomatic or may cause weight loss, abdominal pain, nausea and vomiting, upper or lower gastrointestinal bleeding, malabsorption, intestinal obstruction, and/or diarrhea (Danzig et al. 1991; Laine et al. 1990; Neff et al. 1987; Weprin et al. 1982). The diagnosis of KS should be confirmed by biopsy or PCR of lesions whenever possible. Early lesions can easily be mistaken as purpura, hematomas, angiomas, dermatofibromas, bacillary angiomatosis, extrapulmonary P. jirovecii, Sporothrix schenckii (sporotrichosis) and Mycobacterium marinum skin infections, or nevi. There are three histologic features characteristic of KS that manifest in cutaneous and visceral sites. These include angiogenesis, inflammation, and

2222

R. A. Norman et al.

Fig. 1 Kaposi’s Sarcoma of palate in HIV patient (OLD)

proliferation. The histopathology in the early stage lesions show irregularly dilated, jagged, anastomosing, thin-walled vascular slits containing erythrocytes (Young Jr. et al. 1993). Vascular proliferations surrounded by spindle cells that spread are seen in later plaque and nodular stage lesions. Due to the various stages and manifestations of KS, many strategies have emerged to manage the disease. Major therapeutic goals include alleviating symptoms of pain and lymphedema, decreasing cutaneous and visceral lesions, delaying or preventing disease progression, and improving overall immune function. Excisional surgery is one of the traditional therapies, but is generally time consuming and costly. Curettage followed by the application of H2O2 was recently discovered to be a safe, effective and simple technique for the treatment of KS nodules in elderly patients (Tourlaki et al. 2015). Radiation therapy is an effective treatment modality for classic KS and is associated with minimal toxicity (Hauerstock et al. 2009). Cryotherapy and laser therapy is sometimes used for local control and cosmetic reasons for small lesions (Von Roenn and Cianfrocca 2001). Intralesional therapy with injections of vinblastine, vincristine, bleomycin, doxorubicin, or interferon alpha (IFNa) and interleukin-2 have been studied to eradicate cutaneous KS tumors (Vassallo et al. 2015; Brambilla et al. 2010; Mirza et al. 2015; Ghyka et al. 1992). Chemotherapy is generally reserved for KS with severe systemic or failed prior therapy using various agents such as pegylated liposomal

doxorubicin, vinblastine, bleomycin, paclitaxel, oral etoposide, vinorelbine, and gemcitabine (Di Lorenzo et al. 2008; Castiñeiras et al. 2006; Brambilla et al. 2001, 2006; Fardet et al. 2006; Tas et al. 2013; Zustovich et al. 2013; Brambilla et al. 2015). Recombinant IFNa is approved for treatment of AIDS-associated KS in the United States (Krown 2007). Promising new topical therapies with varied mechanisms of action include imiquimod, rapamycin, timolol, and propranolol (Goiriz et al. 2009; Díaz-Ley et al. 2015; Alcántara-Reifs et al. 2016; Abdelmaksoud et al. 2017; Meseguer-Yebra et al. 2015; Zhang et al. 2014). Electrochemotherapy has also been shown to benefit patients with tumor regression (Di Monta et al. 2014; Curatolo et al. 2012). Novel therapies which target angiogenesis may also prove to be beneficial. Removing immunosuppression therapy and improving immune status with antiretroviral therapy has also been an effective way to improve overall prognosis. A recent study of KSHV suggests a unique approach using a vaccine to ultimately eradicate KS-associated diseases from the human population (Dittmer and Damania 2016).

Mucocutaneous Candidiasis Candida is an opportunistic fungus (yeast) that is a normal part of the human oral microbiome. Various species are found throughout the gastrointestinal tract, skin, and mucous membranes as a

101

Mucocutaneous Manifestations in Gastrointestinal Disease

part of the normal commensal flora. When host immune defenses are compromised, the overgrowth of fungus can invade the mucosa and cause various local or systemic diseases including oropharyngeal, esophageal, and cutaneous (vulvovaginitis) candidiasis (Lewis and Williams 2017). Candida albicans is the most frequently isolated candida species from the oral cavity, although a range of non-C. albicans candida species are being increasingly encountered including C. tropicalis, C. glabrata, C. parapsilosis, and C. krusei (Lewis and Williams 2017; Hani et al. 2015). Oropharyngeal candidiasis, or thrush, is commonly seen in infants, older denture-wearing adults, those on chronic antibiotics, inhaled

Fig. 2 Candiasis of the mouth (OLD) Fig. 3 Candida intertrigo (NEW)

2223

corticosteroid use in asthma, rhinitis, xerostomia, chemotherapy, radiation therapy, and immunocompromised states, such as AIDS (Shay et al. 1997; Iacopino and Wathen 1992; Sangeorzan et al. 1994). Endocrine diseases such as diabetes mellitus, Cushing syndrome, hypoparathyroidism, hypothyroidism, chronic kidney disease, and polyendocrinopathy are associated with increased susceptibility to infection (Lindh et al. 2013). The incidence of oral candidiasis has increased in older adults in recent years (Sakaguchi 2017). Oropharyngeal candidiasis typically manifests in either a pseudomembranous, white plaque form on the buccal mucosa, palate, tongue or oropharynx, or the atrophic erythematic form found in older adults under upper dentures without plaques (Fig. 2; Millsop and Fazel 2016). Angular cheilitis, an inflammatory reaction of candidiasis causes soreness, erythema, and fissuring in the perioral areas (Sharon and Fazel 2010). Esophageal candidiasis presents as dysphagia and odynophagia and is more common in those affected with HIV/AIDS. Intertrigo (intertriginous dermatitis) is an inflammatory condition of skin folds of the axilla, perineum, inframammary creases, and abdominal folds most commonly caused by Candida species in the old who are obese or have diabetes (Fig. 3; Hahler 2006). Diagnosis of oropharyngeal candidiasis is made clinically and confirmed by scraping the

2224

white cottage-cheese like lesions with a tongue depressor and a gram stain or KOH preparation of the scrapings (Fig. 4). Classic budding yeasts with

Fig. 4 Candiasis showing white exudates (OLD) Fig. 5 Candida psudohyphae microscopy (NEW)

R. A. Norman et al.

or without pseudohyphae are evident (Fig. 5). Esophagitis is generally diagnosed via endoscopy when white mucosal plaque-like lesions are evident. Cytomegalovirus, herpes simplex virus, medications, and eosinophilia should be considered during diagnosis of esophagitis, especially in HIV-infected patients with AIDS (Geagea and Cellier 2008). Over the counter antifungal dosage forms such as creams and gels can be used for effective treatment of local candidiasis. Whereas, for preventing spread of the disease to deeper vital organs, candidiasis antifungal chemotherapy is preferred. A recent review by Sakaguchi recommend the use an oral moisturizer containing hinokitiol, an antifungal substance, on a regular basis, to help prevent recurrence of oral candidiasis (Sakaguchi 2017). Takeuchi et al. concluded in a recent study that gel-containing egg yolk anti-CA IgY for 1 month significantly reduces the number of C. albicans CFU present on swabs in elderly nursing home volunteers in Japan and may help prevent recurrent disease (Takeuchi et al. 2016). Other beneficial recommendations for prevention and control of cutaneous manifestations include weight loss, glucose control (in patients with diabetes), good hygiene (in intertrigo), and the need for daily care (proper denture care) and monitoring (American Academy of Family Physicians

101

Mucocutaneous Manifestations in Gastrointestinal Disease

2005). Use of probiotics and development of novel vaccines is an advanced approach for the prevention of candidiasis (Hani et al. 2015). Fluconazole, niconazole, clotrimazole, and nystatin are topical agents that have been commonly used when treating oral, esophageal, and vulvovaginal candidiasis (Millsop and Fazel 2016; Klotz 2006; Pappas et al. 2016). Azole therapy includes fluconazole, itraconazole, posaconazole, and voriconazole (fluconazole-resistant candida species) (Vazquez et al. 2006; Pappas et al. 2016; Pons et al. 1997; Skiest et al. 2007; Perfect et al. 2003). Echinocandins such as caspofungin, micafungin, and anidulafungin are effective for the treatment of Candida esophagitis refractory to azole therapy (Villanueva et al. 2002; Kartsonis et al. 2002; de Wet et al. 2005; Krause et al. 2004). Amphotericin B can also be used for drug-resistant infections as an alternate to azole therapy (Pappas et al. 2016; Lake et al. 1996; Pursley et al. 1996; Benson et al. 2004). Antiretroviral therapy plays an important role in preventing recurrent disease in patients with AIDS (Pappas et al. 2016).

Angular Cheilitis Angular cheilitis is an inflammatory reaction of candidiasis and causes soreness, erythema, and fissuring in the perioral areas (Fig. 6; Sharon and Fazel 2010). Angular cheilitis is also caused by excessive moisture and maceration from saliva. It

2225

is especially common in individuals with poor denture hygiene (Terai and Shimahara 2006; Park et al. 2011a, b). Other causes include nutritional deficiencies, type 2 diabetes, immunodeficiency, Sjogren syndrome, and xerostomia (Park et al. 2011b; Al-Maweri 2013; Serrano 2018). Cheilitis can also be a symptom of a contact reaction to an irritant or allergen, or may be provoked by sun exposure (actinic cheilitis) or drug intake, especially retinoids (Lugović-Mihić et al. 2018). Diagnosis is made clinically and can be confirmed by a potassium hydroxide (KOH) preparation from lesions and oral mucosa to include or rule out candida infection. In patients with recalcitrant cheilitis, a lesion swab for bacterial (associated with Staphylococcus aureus) and fungal culture should be obtained. Treatment includes control of underlying factors such as poor oral hygiene, improper denture care/fitting, and xerostomia caused by Sjogren’s syndrome or medications. Patients with confirmed fungal infection can be treated with topical antifungals such as miconazole, clotrimazole, or fluconazole (Candida stomatitis). Staphylococcal infections are generally treated with topical mupirocin ointment. Underlying nutrient deficiencies such as B12 or iron-deficiency should be addressed if present (Lugović-Mihić et al. 2018; Ayesh 2018). Once cleared, barrier creams such as zinc oxide or petrolatum lip balm are effective in reducing excessive moisture in the corners of the mouth.

Behçet Syndrome

Fig. 6 Angular Cheilitis (NEW)

Behçet syndrome, also known as Behçet disease (BD), named after Hulusi Behçet in 1937, is believed to be due to vasculitis caused by endothelial dysfunction (Mutlu and Scully 1994). Behçet syndrome is characterized by recurrent oral aphthous ulcers and any of several systemic manifestations including genital aphthae, gastrointestinal disease, ocular disease, skin lesions, neurologic disease, vascular disease, or arthritis. Due to the complexity of various manifestations, this review will focus on the mucocutaneous

2226

aspects of the syndrome and their treatment. The disorder is relatively rare in the older age group. Mucocutaneous lesions are considered hallmarks of the disease, and often precede other manifestations (Alpsoy 2016; Rotondo et al. 2015). Research into the pathogenesis of Behçet’s syndrome has shown that the most consistent genetic marker of Behçet’s syndrome is HLA-B5 (Yazici et al. 2007). It is more common in Asia and Mediterranean regions prevalent with the geographical distribution of HLA-B51 along the ancient “silk road” (Yazici et al. 2007). The Thelper 17 and interleukin (IL)-17 pathways along with IL-21 are important factors in the cellular pathophysiology of BD (Alpsoy 2016; Scherrer et al. 2017). It typically affects young adults 2040 years of age. Most patients initially manifest recurrent oral aphthous ulcerations (also known as canker sores). These ulcers are histologically similar to common oral ulcers and recurrent aphthous stomatitis (RAS). Genital ulcers are most commonly found on the scrotum in men and the vulva in women. The cutaneous manifestations may include acneiform lesions, papulo-vesiculopustular eruptions, pseudofolliculitis, nodules, erythema nodosum (septal panniculitis), superficial thrombophlebitis, pyoderma gangrenosumtype lesions, erythema multiforme-like lesions, and palpable purpura (Alpsoy 2016). Anterior and posterior uveitis, neovascularization, cataracts, glaucoma, macular edema, and conjunctival ulceration are ocular manifestations that have been reported in patients (Seyahi et al. 2007; Khanfir et al. 2015; Matsuo et al. 2002; Zamir 2003). Diagnosis is based on the criteria published in 1990 by the International Study Group (ISG). Required features include aphthous (idiopathic) ulceration, observed by clinician or patient, with at least three episodes in any 12-month period, and two of the following: (1) Recurrent genital ulceration or scarring, (2) Anterior or posterior uveitis cells in vitreous in slit-lamp examination; or retinal vasculitis documented by ophthalmologist, (3) Erythema nodosum-like lesions observed by clinician or patient; papulopustular skin lesions or pseudofolliculitis with characteristic acneiform nodules observed by clinician, (4) Pathergy test:

R. A. Norman et al.

Interpreted at 24–48 h by clinician (Criteria for diagnosis of Behçet’s disease 1990). Treatment is mainly based on the suppression of inflammatory attacks of the disease using immunomodulatory and immunosuppressive agents (Alpsoy 2016). The treatment of oral and genital ulcers is guided by the severity of symptoms and the presence of other disease manifestations. Treatments for oral aphthae, genital ulcers, pseudofolliculitis, papulopustular lesions, erythema nodosum-like lesions, and pathergy reaction include colchicine, azathioprine, interferon-alpha (INFa), and TNF-alpha antagonist (Rotondo et al. 2015; Lin and Liang 2006; Saleh and Arayssi 2014; Mazzoccoli et al. 2016; Vitale et al. 2016). Ocular manifestions such as recurrent bilateral uveitis (anterior segment, posterior segment, or both), retinal vasculitis, retinal vein occlusion, and optic neuritis can be treated with azathioprine, local or systemic corticosteroids, cyclosporine, infliximab (in combination with azathioprine and corticosteroids), and interferon-α (Rotondo et al. 2015; Lin and Liang 2006; Saleh and Arayssi 2014; Mazzoccoli et al. 2016; Vitale et al. 2016). Gastrointestinal tract manifestations such as anorexia, vomiting, dyspepsia, diarrhea, abdominal pain, ulcers, ischemic perforation, thrombosis in the terminal ileum, ileocecal region, and colon can be managed with sulfasalazine, corticosteroids, azathioprine, TNF-α antagonista, and thalidomid (Rotondo et al. 2015). Novel therapy includes IL-1 inhibitors such as Gevokizumab, Canakinumab, and Anakinra (Saleh and Arayssi 2014; Vitale et al. 2016; Hatemi et al. 2016; Grayson et al. 2017).

Esophagus and Stomach Esophageal and gastric diseases with cutaneous manifestations include Plummer-Vinson syndrome (PVS), epidermolysis bullosa (EB), scleroderma (systemic sclerosis) (CREST syndrome), Tylosis, Stevens-Johnson syndrome, acanthosis nigricans, and pemphigus vulgaris. Candida has been known to cause esophageal candidiasis also known as esophagitis.

101

Mucocutaneous Manifestations in Gastrointestinal Disease

Plummer-Vinson Syndrome Plummer-Vinson syndrome (PVS) also known as Paterson-Brown-Kelly syndrome is a rare syndrome presenting with the triad of iron deficiency anemia (IDA), post-cricothyroid dysphagia, and cervical esophageal webs. It was named after two physicians – Henry Stanley Plummer and Porter Paisley Vinson, at the Mayo Clinic in the USA and two laryngologists from Britain, Donald Ross Paterson and Adam Brown-Kelly, who described similar clinical descriptions. Patients with PVS are typically Caucasian women in their fourth to seventh decade of life (Novacek 2006). It has been reported in children, adolescents, and males, although uncommon (Novacek 2006; Dinler 2009; Karthikeyan et al. 2017). The improvement of IDA in recent decades with iron supplementation and fortification of diet has coincided with reduced incidence of PVS (Chen and Chen 1994). Signs and symptoms of PVS include the mucocutaneous findings of brittle, spoon-shaped nails, early loss of teeth, angular cheilitis, tongue atrophy, angular stomatitis, along with fatigue, weakness, and the clinical complaint of dysphagia (Hoffman and Jaffe 1995). The exact pathogenesis of PVS or formation of esophageal web remains unclear; however, many attribute the condition to the effects of IDA. Diagnosis is based on the finding of iron deficiency anemia on laboratory testing and by demonstration of an esophageal web on barium swallow, video fluoroscopy, or upper endoscopy. Differential diagnosis includes achalasia, which presents with dysphagia to both solids and liquids, and strictures, which are longer in axial length compared with esophageal webs. Esophageal webs have also been associated with Zenker’s diverticulum. Hematologic tests can confirm IDA, but the underlying cause warrants further investigation. Endoscopy is typically performed to rule out gastrointestinal bleeding or malignancy. Plummer-Vinson syndrome can be treated effectively with iron supplementation and mechanical dilation to relieve dysphagia (Karthikeyan et al. 2017; Goel et al. 2017). Rupture of the esophageal web may be necessary for

2227

severe obstruction (Novacek 2006). Burning and itching in the vulval region, reported by women, is relieved after iron treatment.

Tylosis Tylosis describes a rare group of inherited disorders of keratinization characterized by hyperkeratosis of the palms and soles. Hyperkeratosis of the soles at any age suggests tylosis and calls for evaluation for esophageal squamous cell carcinoma, psoriasis, or eczema (Stevens et al. 1996). The disease has an autosomal-dominant mode of inheritance; a gene locus has been mapped to chromosome 17q25.1, a tumor suppressor gene (Stevens et al. 1996; Iwaya 1998). Clinical signs are diffuse hyperkeratosis of the palms and soles and can lead to the development of esophageal cancer (Harper et al. 1970). Management of esophageal carcinoma is based on tumor extent. Surgery is the standard treatment option for early stages. Mucosal resection is an alternative (May et al. 2003). Surveillance includes annual gastroscopy with biopsy of any suspicious lesion (Ellis 2015). Oral retinoids are helpful for hyperkeratosis but are associated with side effects. Genetic counseling can be offered once a family history has been established (Ellis 2015). The American Society for Gastrointestinal Endoscopy recommends beginning endoscopic surveillance at age 30 in patients with a family history to improve prognosis (Hirota 2006).

Epidermolysis Bullosa Epidermolysis Bullosa (EB) describes a rare group of inherited diseases that cause fragile skin (Woodley and Chen 2004). It is characterized by subepidermal blistering of the skin and mucous membranes. Immunologically, EB is characterized by the presence of immunoglobulin G (IgG) autoantibodies (in most patients) targeting the noncollagenous (NC1) domain of type VII collagen. Clinically there are now four forms (previously 3) of EB depending on the layer of blister formation: dystrophic EB (beneath lamina densa),

2228

junctional EB (within the lamina lucida), simplex EB (intraepidermal), and Kindler syndrome (mixed levels of blistering) (Intong and Murrell 2012). Gastrointestinal manifestations include esophageal strictures, gastroesophageal reflux, rectal tears, anal fissures and stenosis, and constipation leading to malnutrition and anemia. The disorder can be distinguished by electron microscopic localization of the basement membrane layer separation. Nutritional deficiency, anemia, and stunted growth may develop over time. Patients with junctional EB have many of the complications of dystrophic EB and may develop pyloric atresia (Berger et al. 1986). In the more severe EB subtypes, lifelong generalized blistering, chronic ulcerations, and scarring sequelae lead to multiorgan involvement, major morbidity, and life-threatening complications (El Hachem et al. 2014). Management plans for EB patients should be individualized according to age, severity, symptoms, complications, and patient priorities. Currently, there is no effective therapy or cure for EB. Gene therapy, protein replacement therapy, cell therapies [allogeneic fibroblasts, mesenchymal stromal cells (MSCs), bone marrow stem cell transplantation, culturing/grafting revertant mosaic keratinocytes], gene editing/engineering, and clinical application of inducible pluripotent stem cells are recent advances in treatment that are promising (Hsu et al. 2014).

Systemic Sclerosis Scleroderma (morphea) and systemic sclerosis describe a systemic disease of unknown etiology that causes fibrotic change in the skin, blood vessels, lungs, heart, kidneys, and GI tract (Steen and Medsger 2000). Esophageal symptoms can include premature fullness, reflux esophagitis, dysphagia, and epigastric pain. As many as 90% of patients with scleroderma demonstrate GI manifestations (Rose et al. 1998). Manifestations are a result of excess collagen production, enhanced immunologic activity, and improper cellular immunity response. Dermatological manifestations are progressive and begin with edema of face, hands, or feet (Fig. 7).

R. A. Norman et al.

Fig. 7 Scleroderma of face (OLD)

The acronym “CREST” has been associated with scleroderma which stands for the syndrome of calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia. The abnormal build-up of fibrous tissue in the skin can result in sclerodactyly. This skin tightening is so severe that the fingers curl and lose their mobility. Curved nails or periungual telangiectasia may be present. Telangiectasia was present in 56% of patients with systemic sclerosis in a study, and associated with esophageal, heart, and lung disease, calcinosis and pitting scars; the study suggested that telangiectasia may be a marker of esophageal involvement (Ashida et al. 2009). Raynaud’s phenomenon is a vasospastic disorder that causes discoloration of the fingers, toes, and other areas. It is caused by a decrease in blood supply to the various regions. Raynaud’s phenomenon is the initial symptom that presents in 70% of patients with scleroderma. Management of the disease is tailored to the individual patient because of the wide spectrum of disease manifestations and organ involvement. Patients with systemic sclerosis are treated symptomatically. Those with gastrointestinal reflux are treated with proton-pump inhibitors; patients with Raynaud phenomenon are commonly treated with calcium channel blockers; and patients with hypertensive scleroderma renal crisis are treated with angiotensin-converting enzyme (ACE) inhibitors. Topical therapies (e.g., high potency topical corticosteroids, topical vitamin D, topical tacrolimus) are often used as initial treatments for

101

Mucocutaneous Manifestations in Gastrointestinal Disease

localized scleroderma. Phototherapy with Ultraviolet A has been shown to be effective (Kroft 2008). Laser or other light therapy may be useful for particularly large lesions of telangiectasia. Presence of extensive skin involvement, cardiac and/or pulmonary involvement, renal disease, and the presence of anti-topoisomerase I antibodies and/or anti-Th/To antibodies are associated with increased mortality and aggressive treatment with methotrexate, mycophenolate, cyclophosphamide, systemic glucocorticoids, or surgery are warranted (Nikpour and Baron 2014).

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Stevens-Johnson syndrome (SJS) is a mucocutaneous disorder, first described as a febrile erosive stomatitis, severe conjunctivitis, and disseminated cutaneous eruption (Lyell 1956). Toxic epidermal necrolysis (TEN) is more severe and affects greater than 30% of the body surface area. Gastrointestinal complications may result from epithelial necrosis of the esophagus, small bowel, or colon. Infection, vaccination, drugs, systemic diseases, physical agents, and food have been implicated as causes of SJS; however, drugs are most commonly blamed. Antibiotics are the most common cause of Stevens-Johnson syndrome. Other drugs that may cause the disease are analgesics, cough and cold medications, nonsteroidal antiinflammatory drugs (NSAIDs), psychoepileptics, and antigout drugs. Patients with active malignancy have an increased risk of SJS/TEN (Rosen et al. 2014). Most patients are treated symptomatically due to the systemic nature of the disease. The offending drug should be stopped immediately (Garcia-Doval et al. 2000). Fluid management, nutrition, insulin therapy, blood and urine tests are control options (Shiga and Cartotto 2010). Silver sulfadiazine should be avoided and instead 0.5% silver nitrate or 0.05% chlorhexidine should be used to bathe affected areas (Dunn and Edwards-Jones 2004). Pain control is important in initial management as cutaneous pain is common. Skin allotransplantation reduces pain,

2229

minimizes fluid loss, improves heat control, and prevents bacterial infection. Repeated cultures of the skin, as well as blood, catheters, gastric, and urinary tubes, should be obtained at 48-h intervals (Schwartz et al. 2013). Antibiotics should be based on culture studies. Hyperbaric oxygen can improve healing (Palmieri et al. 2002). Systemic corticosteroid treatment should be short-term, high-dose intravenous therapy. The effect of systemic steroids or IV immune globulin on either the development or the outcome of ocular manifestations in SJS and toxic epidermal necrolysis (TEN) remains understudied (Corrick and Anand 2013). Ocular manifestations can be managed with saline rinses. Prevention of gynecologic sequelae such as adenosis, adhesions, and labial agglutination can be managed by the application of intravaginal corticosteroids, regular use of soft vaginal molds (e.g., Milex vaginal dilators), and menstrual suppression during the acute phase of illness (Kaser et al. 2011).

Intestines Intestinal disease Hemochromatosis is common and can display a wide variety of manifestations. Many syndromes have been identified. Intestinal GI diseases that have mucocutaneous manifestations discussed in this section include PeutzJeghers syndrome, Blue rubber bleb nevus syndrome, Gardner syndrome, dermatitis herpetiformis, and Crohn’s disease.

Peutz-Jeghers Syndrome Peutz-Jeghers syndrome (PJS) is an autosomal dominant inherited disorder characterized by intestinal hamartomatous polyps in association with mucocutaneous melanocytic macules. The cause of PJS appears to be a germline mutation of the serine threonine kinase STK11 (LKB1) gene (Hemminki et al. 1998; Jenne et al. 1998). The risk of cancer increases with the presence of the gastrointestinal polyps (Brosens et al. 2007; Hernan et al. 2004). Some individuals do not have a family history and may have de novo

2230

mutations (Hernan et al. 2004). Associated cancers include colorectal, breast, stomach, small bowel, and pancreas (van Lier et al. 2010; Lim et al. 2010). Dermatological manifestations of PJS include mucocutaneous pigmentation and melanin spots, appearing as small, flat, brown spots resembling freckles. The lesions most commonly are found on the lips in 95% of patients. The buccal mucosa, palms, fingers, nose, gingiva, eyelids, and hard palate can also be affected. Cutaneous lesions fade away over time. A clinical diagnosis of Peutz-Jeghers syndrome (PJS) requires the presence of any one of the following: two or more histologically confirmed Peutz-Jeghers (PJ) polyps or any number of PJ polyps detected in an individual who has a family history of PJS in a close relative or characteristic mucocutaneous pigmentation in an individual who has a family history of PJS in a close relative or any number of PJ polyps in an individual who also has characteristic mucocutaneous pigmentation. Individuals who meet clinical criteria for PJS should undergo genetic testing for a germline mutation in the STK11 gene. Individuals with PJS should undergo an annual physical examination with a complete blood count to detect iron-deficiency anemia due to occult bleeding from gastrointestinal tract polyps or cancer. Colonoscopy should be performed every 3 years if polyps are detected at baseline. Mucocutaneous pigmented macules affecting the face and labia that do not fade can be treated with Qswitched alexandrite laser treatment (Li et al. 2012). Patients should be counseled to quit smoking due to increased risk thyroid and lung cancers (Syngal et al. 2015).

R. A. Norman et al.

in detail and coined the term Blue rubber bleb nevus syndrome in 1958 (Bean 1958). The clinical manifestations most often present in birth or early childhood, although some cases may not be identified until adulthood (Gião Antunes et al. 2016). Over time, patients develop multiple venous malformations that affect the skin, soft tissue, and gastrointestinal tract. Recently, somatic mutations in TEK, the gene encoding TIE2, were discovered in 15 of 17 individuals with blue rubber bleb nevus syndrome (Soblet et al. 2017). The skin lesions range from 1 to over 100 and take 3 forms: nontender soft nodules that leave behind a blue empty sac that refills rapidly with blood when compressed (blue rubber nipple, Fig. 8), blue-black tender macular lesions distributed on the extremities (Fig. 9) and trunk, and large hemangiomas (up to 10 cm in diameter) that may interfere with limb or organ function. Differential diagnosis includes KlippelTrénaunay-Weber syndrome, Ehlers-Danlos syndrome, the CREST variant of scleroderma, and hereditary hemorrhagic telangiectasias (OslerWeber-Rendu syndrome). Treatment depends on the severity of the diseases. For mild blood loss over time, management includes monitoring, iron replacement, and blood transfusions as needed; endoscopic therapy with bipolar electrocautery or YAG laser may be necessary. Recurrence is common, especially during puberty and pregnancy. Regular imaging and follow-up is necessary to administer supportive therapy. A report of blue rubber bleb nevus syndrome

Blue Rubber Bleb Nevus Syndrome Blue rubber bleb nevus syndrome (BRBN, Bean syndrome) is a rare sporadic or autosomal dominant disorder characterized by the combination of cutaneous vascular malformations in association with visceral lesions causing GI bleeding (Oranje 1986; Oksüzoglu et al. 1996). Bean described BRBNS, first discovered by Gascoyen in 1860,

Fig. 8 Blue nevus on forehead (OLD)

101

Mucocutaneous Manifestations in Gastrointestinal Disease

2231

Fig. 9 Advanced linear epidermal nevus (OLD)

indicated the successful use of interferon-beta to treat the manifestations of disseminated intravascular coagulation in a patient with disseminated skin and GI venous malformations (Apak et al. 2004). Surgical resection of affected areas may be required (Choi et al. 2012). Antiangiogenic agents such as corticosteroids, propranolol, interferon-α, octreotide, and sirolimus have also been used (Jin et al. 2014).

Gardner Syndrome Gardner syndrome (GS) is a variant of familial adenomatous polyposis (FAP) (Gu et al. 2008), inherited as an autosomal dominant trait and characterized by GI polyps, multiple osteomas, and skin and soft tissue tumors. It was first described by Gardner in the early 1950s. Dermatologic manifestations include osteomas, dental abnormalities, cutaneous lesions, desmoid tumors, congenital hypertrophy of the retinal pigment epithelium, adrenal adenomas, and nasal angiofibromas (Ascari-Raccagni et al. 1999; Ponti et al. 2013). Gardner syndrome is genetically linked to band 5q21, the adenomatous polyposis coli (APC) locus (Elkharwily and Gottlieb 2008).

Treatment of GS requires a multidisciplinary effort. The cutaneous findings of desmoid tumors may require excision if they become severe (Escobar et al. 2012). Prophylactic abdominal colectomy with ileorectal anastomosis may be a treatment option for polyposis. Serial colonoscopy and upper endoscopy should be done for at least 1–2 years to exclude recurrence. Osteomas may be treated by peripheral ostectomy and osteoplasty. Chemotherapy with doxorubicin and radiation therapy may be necessary for those who do not respond to tyrosine kinase inhibitors and NSAIDS in intra-abdominal desmoids (Nieuwenhuis et al. 2011; DE Marchis et al. 2017).

Dermatitis Herpetiformis Dermatitis herpetiformis (DH) is an autoimmune blistering disorder associated with a gluten-sensitive enteropathy (GSE). It is characterized by localized excoriations, erythematous, urticarial plaques, and papules with vesicles. It is extremely pruritic and manifests on the elbows, knees, back, and buttocks (Figs. 10 and 11). Many patients with celiac disease develop dermatitis herpetiformis. Oral mucosal involvement may

2232

R. A. Norman et al.

Fig. 10 Dermatitis herpetiformis on Buttocks (old)

Fig. 11 Dermatitis herpetiformis on Upper Back (OLD)

manifest as vesicles, erosions, or erythematous macules on the oral mucosa or tongue. Celiac disease (CD), also an autoimmune disorder of the small intestine, affects persons of all ages, manifesting as atrophy of intestinal villi with resultant malabsorption and consequent clinical manifestations (Barta et al. 2011). The cause of the dermatitis herpetiformis is the deposition of IgA in the papillary dermis triggering an immunologic response to the chronic stimulation of the gut mucosa by dietary gluten. Virtually, all

patients with DH carry the HLA DQ2 or HLA DQ8 haplotype (Bonciani et al. 2012). Vitiligo, Addison’s disease, alopecia areata, type 1 diabetes mellitus, and pernicious anemia are associated with DH as well. Diagnosis of DH in patients who present with clinical findings mentioned above involves obtaining a 4 mm punch biopsy of cutaneous lesions for routine hematoxylin and eosin (H&E) staining and a perilesional skin biopsy for immunofluorescence microscopy (Witte et al. 2018).

101

Mucocutaneous Manifestations in Gastrointestinal Disease

Treatment includes a gluten-free diet and pharmacotherapy with dapsone (Smith et al. 1992; Mendes et al. 2013).

2233

are recent treatments showing promise for disease management (Sandborn et al. 2012, 2013).

Liver and Pancreas Crohn’s Disease Hemochromatosis Several cutaneous changes occur in the course of inflammatory bowel disease (IBD) including pyoderma gangrenosum, erythema nodosum, urticaria, and purpura; rarely the lesions occur before the development of colitis, with leukocytoclastic vasculitis reported several months before the intestinal manifestations became overt (Akbulut et al. 2008). While Crohn’s disease affects the intestines, metastatic Crohn’s disease is a rare skin manifestation, with granulomatous changes occurring at sites distant from the bowel. Erythema nodosum refers to nodular, tender inflammatory lesions involving the subcutaneous fat, occurring typically in the legs, especially anterior tibia, more often in women. Lesions are nonspecific and occur with a variety of infections, such as tuberculosis and at times with Yersinia, Campylobacter, and Shigella. B12 deficiency due to ileal involvement is seen in severe disease. Ocular involvement is rare and includes uveitis, iritis, and episcleritis. The differential diagnosis includes irritable bowel syndrome (IBS), lactose intolerance, infectious colitis, and ulcerative colitis. The diagnosis of Crohn disease (CD) is usually established with endoscopic findings via colonoscopy. Management involves the use of NSAIDs and addressing the underlying etiology. The inflammatory skin lesions resolve with corticosteroid therapy, such as prednisone (Eames et al. 2009; Laube et al. 2018). Azathioprine and 6-mercaptopurine are recommended in patients who do not respond or become glucocorticoid dependent. Anti-TNF with or without a thiopurine or methotrexate is preferred in geriatric patients. These patients should avoid NSAIDS due to risk of increased bleeding. Surgical intervention is reserved for complications or failed pharmacotherapy (Laube et al. 2018). Monoclonal antibodies such as Ustekinumab, Vedolizumab, and Natalizumab

Hemochromatosis is a disease due to an underlying metabolic dysfunction in iron absorption. Too much iron is absorbed into the body, leading to excessive iron deposition in organs, most commonly the liver, myocardium, and visceral cells. This can lead to cirrhosis, cardiac failure, arthritis, hypogonadism, hypothyroidism, and diabetes. Excess iron often builds up in the skin as well, leading to cutaneous findings. The most common dermatologic manifestation seen in hemochromatosis is skin hyperpigmentation. The term “bronze diabetes” is often used to describe this pigment change seen in the skin. It is characterized by diffuse gray- or bronze-colored darkening of the skin and can occur on the face, neck, arms, genitalia, buccal mucosa, or conjunctiva. It is believed that the interaction between biologically active iron in the skin and Ultraviolet A wavelengths induce oxidative stress through the production of reactive oxygen species (ROS). Thus, iron in high amounts can be especially harmful to the skin and promote the aging process more rapidly (Pouillot et al. 2013). Other dermatologic findings in hemochromatosis include ichthyosis, alopecia (especially around the pubic region), koilonychia, reduced wound healing, and skin atrophy (Pouillot et al. 2013; Chevrant-Breton et al. 1977; Wright et al. 2014). Hereditary hemochromatosis is due to a mutation in the HFE gene which codes for a protein involved in iron absorption; it is estimated that approximately 10% of people in the United States carry this mutation. The disease is inherited in an autosomal recessive fashion. Most cases are due to the C282Y mutation, wherein tyrosine is substituted for cysteine at amino acid position 282. Another mutation, H63D, has also been described. In this case, there is a substitution of aspartic acid for histidine in the amino acid position 63 26. It is expressed more in males than

2234

females, influenced by the menstrual cycle and typically manifests clinically after 40 years of age when body iron stores reach 15–40 g or more (Brandhagen et al. 2002). Symptoms can include chronic fatigue, weakness, lethargy, and apathy. Those patients homozygous for C282Y often have higher occurrences of fatigue. In hereditary hemochromatosis, the hyperpigmentation seen on the skin is due primarily to melanin rather than iron (Chevrant-Breton et al. 1977). The iron deposits within the skin can damage its structure, leading to increased synthesis of melanin by melanocytes and thus resulting in the increased pigmentation. Hepatomegaly is the most common GI manifestation seen in hemochromatosis. It is seen in up to 95% of patients with the disease. The excess iron deposits leading to liver enlargement can eventually result in cirrhosis if patients are untreated. Long-term cirrhosis can lead to hepatocellular carcinoma and complications resulting in mortality. The primary treatment options for hemochromatosis include phlebotomy and iron chelating agents. Reducing iron levels through both phlebotomy and oral iron chelation therapy can improve the quality of life and often improves their skin changes as well (Lescano et al. 2017). However, treatment does not reduce hyperpigmentation immediately. The efficacy of treatment is influenced by ferritin levels; it is recommended that ferritin levels are monitored monthly during therapy until the values reach the upper limits of normal (300 mcg/L in men and 200 mcg/L in women) (Drobnik and Schwartz n.d.). In patients with anemia who cannot undergo phlebotomy, iron chelating agents (deferoxamine, deferiprone, deferasirox) can be used (Hazin et al. 2009). The patient’s nutritional status can also influence the treatment progress and prognosis of the disease. For example, interactions between alcohol intake and dietary iron increase hydroxyl free radicals that can cause liver cancer (Asare et al. 2008). Topical iron chelators are novel agents that are currently being explored in the treatment of the deleterious cutaneous effects of iron overload and in preventing the resulting skin aging (Pouillot et al. 2013).

R. A. Norman et al.

Porphyria Cutanea Tarda Porphyria cutanea tarda (PCT) is the most common porphyria, making up greater than 80% of cases, and the form primarily affecting the skin (Vossen et al. 2016). It is due to a deficiency in the heme synthetic enzyme uroporphyrinogen decarboxylase (UROD). PCT can be inherited or acquired (Kappas et al. 1995). Sporadic cases often occur during adulthood while genetically inherited cases with double mutations are usually more severe and manifest early on in childhood (Elder et al. 1981). Patients with acquired PCT have normal UROD DNA sequences. It is thought that the acquired form is due to exposure to large amounts of polyhalogenated cyclic hydrocarbons. Alcohol abuse, oral contraceptive use, estrogen hormonal therapy, and environmental pollutants have been associated with the acquired disease. Alcohol abuse has also been reported to induce cases of sporadic PCT. Biochemically, alcohol increases the absorption of iron, resulting in iron accumulation in the liver. In addition, due to the UROD gene mutation, increased levels of uroporphyrin in the skin can react with ultraviolet light, inducing the production of ROS, and in addition, collagenase, which has been suggested to contribute to many of the skin manifestations of PCT (Yang et al. 2017). There is a strong association between PCT and a coexisting hepatitis C infection. In some cases, however, no causative agent has been found in patients with sporadic PCT. Familial PCT is inherited most often in an autosomal dominant fashion. It is due to a mutation in a single UROD gene locus. There exists a more rare recessive type of PCT called hepatoerythropoietic porphyria in which both UROD alleles are mutated (MoranJimenez et al. 1996). Excess iron enhances formation of toxic oxygen species, increasing oxidative stress, and apparently facilitating porphyrinogenesis by catalyzing the formation of oxidation products that inhibit UROD (Rocchi et al. 1991). The diagnosis of PCT can be made by analyzing the patient’s urine, which will show increased levels of porphyrins. These elevated levels can also cause the urine to appear red-

101

Mucocutaneous Manifestations in Gastrointestinal Disease

brown when exposed to sunlight. In PCT, the ratio of uroporphyrins to coproporphyrins in the urine can also aid in the diagnosis. Blood and stool samples can also be analyzed for porphyrins, and skin biopsies may be taken as well. Patients diagnosed with PCT should been tested for underlying hepatitis C as well. Hepatitis C has also been associated with lichen planus, necrolytic acral erythema, and mixed cryoglobulinemia. Because the disease can be both acquired and inherited, and is associated with a multitude of risk factors, initial workup involving several diagnostic modalities should be utilized both for evaluation and treatment response (Vossen et al. 2016). The major morbidity from PCT is due to skin damage and blistering (Fig. 12). PCT often presents as blisters especially on sun exposed regions like the dorsum of the hands. Secondary erosions can lead to epidermal loss and subsequent infections. The lesions can be painful and often heal very slowly, resulting in atrophic scars. Because of this, daily activities may be severely hampered. Other cutaneous findings are characterized by skin photosensitivity with increased skin fragility, facial hypertrichosis, scarring with milia formation, and skin hyperpigmentation on the hands and other sun-exposed areas. Treatment options for PCT first include the removal of potential offending agents. Cessation of alcohol intake for several months usually reduces the severity of skin lesions in those with Fig. 12 Porphyria cutanea tarda (OLD)

2235

a history of alcohol abuse. Iron and estrogen supplementation may also reduce symptoms. Avoiding sunlight exposure and regular use of sunscreen and other sun protective clothing can reduce the photosensitivity patients may experience. Many cases in the medical literature have reported the successful resolution of PCT with treatment of the coexisting hepatitis C infection. Direct acting antivirals such as ledipasvir/ sofosbuvir and boceprevir are currently being investigated as potential therapeutic agents in treating PCT patients (Singal et al. 2017; Tong et al. 2016; Aguilera et al. 2014; Bruzzone et al. 2017). Phlebotomy in severe cases may decrease the total iron load and lead to improvement. It may improve scleroderma like skin manifestations, but not liver cell function. In addition, in many Asian countries, the glycyrrhiza glaba root has been used for liver protection as additional therapy in hepatitis patients (Yang et al. 2017). Chelation with deferroxamine is an alternative means of iron mobilization when phlebotomy is not practical (Bonkovsky et al. 2003). Human recombinant erythropoietin (EPO) can stimulate erythropoiesis in anemic patients (Hamzi et al. n.d.).

Pancreatic Fat Necrosis Pancreatic fat necrosis describes the association of skin nodules with pancreatic disease. It affects

2236

roughly 0.3–3% of patients with pancreatic disorders (Rongioletti and Caputo 2013). The skin lesions may occur before the onset of clinical pancreatic disease by up to 1–7 months (Rongioletti and Caputo 2013). Painful or painless cutaneous lesions are seen on the legs, buttocks, and trunk (Bonkovsky et al. 1998; Lambiase et al. 1996). Pruritus of lower extremities progresses to skin nodules with tenderness. The nodules drain white, pus-like exudates. An atrophic scar and hyperpigmentation usually results after healing. Patients with pancreatic cancer and pancreatitis have a tendency to manifest pancreatic fat necrosis. Lipolytic enzymes may contribute to development of subcutaneous nodules. The fat necrosis will in many instances resemble pancreatic panniculitis upon histologic examination (Ichiki et al. 2017). Treatment of skin lesions is treatment of the underlying pancreatic disease. Prognosis is most poor in cases of pancreatic cancer; in patients with a very prolonged course of disease, ulceration and frequent recurrences, an occult pancreatic cancer should be considered in the differential diagnosis of etiology. In instances of pancreatic malignancy, removal of the cancer may result in resolution of the skin lesions (Sing et al. 2018). In patients with non-resectable malignancy, chemotherapy is an option and can also reduce severity of the skin lesions (Sing et al. 2018). It is advised that due to the rarity of the condition, definitive diagnosis should be done with an incisional biopsy of more developed lesions.

Glucagonoma Glucagonoma, a rare tumor of the alpha cells of the pancreas, is characterized by a constellation of symptoms including normocytic normochromic anemia, psychological illness, glucose intolerance, hyperglucagonemia, hypoaminoacidemia, and necrolytic migratory erythema (Fig. 13). Necrolytic migratory erythema is often a paraneoplastic condition and can be one of the first clinical manifestations of a glucagonoma. Morphologically, it appears as migrating erythematous scaly patches and plaques with superficial

R. A. Norman et al.

Fig. 13 Glucagonoma (courtesy C.S. Pitchumoni MD) (OLD)

necrosis of the epidermis. Lesions commonly occur in intertriginous regions. Biopsy of affected areas will show vacuolar changes in the epidermis with epidermal necrosis. Initial workup for a pancreatic mass can include an abdominal ultrasound which may show a mass in the pancreas; 85% are in the body or tail of the pancreas (Al-Faouri et al. 2016). Blood tests can show signs of anemia, hyperglycemia, and elevated glucagon levels. Removal of the tumor is the first line treatment for glucagonomas (Tremblay and Marcil 2017). Awareness by physicians is very important in leading to an early diagnosis, as a delay in diagnosis can lead to liver metastasis. Most patients are diagnosed after long periods of the rash. New advancements in the treatment of metastatic pancreatic tumors are liver transplantation and complex liver resections, targeted radiotherapy (radioembolization, peptide ligand receptor radionuclide therapy), and somatostatin analogues with longer half-lives (Al-Faouri et al. 2016). Some patients have shown great improvement in their skin lesions after treatment with octreotide (Tolliver et al. 2018). In some cases, skin lesions disappeared within 2 weeks of initiation of octreotide therapy (Kimbara et al. 2014). In

101

Mucocutaneous Manifestations in Gastrointestinal Disease

some reports, skin symptoms disappeared as early as 10 days after the tumor was surgically excised (Rodríguez et al. 2016). The treatment approach can consist of surgical removal for definitive treatment, somatostatin analogues to treat excess glucagon, administration of IV amino acids to help with the hypoaminoacidemia, and systemic steroids or cyclosporine to treat inflammatory process in skin. Success in treatment with cyclosporine for a metastatic glucagonoma refractory to octreotide and chemotherapy has been described in recent literature (Jiménez-Gallo et al. 2017). Skin lesions underwent complete remission after oral cyclosporine therapy. Treatment approaches for metastatic disease include capecitabine and temozolomide (Jiménez-Gallo et al. 2017).

Lichen Planus Lichen planus (LP) is a cutaneous manifestation of a variety of liver diseases. It is a pruritic and papular eruption. Papules are purple, polygonal, and have flat surfaces that affect the skin and mucous membranes. Microscopic examination may detect the presence of white or gray linear marks known as Wickham striae, found anywhere on the epidermis, commonly affecting the wrists, ankles, shins, lower back, and genitalia. Genital involvement is common in men with LP. Vulvar involvement in women can include reticulated papules and severe erosions. Hyperpigmentation, subungual hyperkeratosis, onycholysis, and Fig. 14 Oral lichen planus (OLD)

2237

longitudinal melanonychia can result from lichen planus (Chuang and Stitle n.d.). Lichen planus is most likely an immunologically mediated reaction. Its origin is unknown but may be associated with ulcerative colitis, alopecia areata, vitiligo, dermatomyositis, morphea, lichen sclerosis, and myasthenia gravis. In a meta-analysis, 16% of patients with lichen planus had hepatitis-C infection (Shengyuan et al. 2009). Hepatitis should be considered in patients with widespread or unusual presentations of lichen planus. Atrophy and scarring are seen in the hypertrophic lesions and lesions of the scalp. Cutaneous lichen planus does not have a higher risk of skin cancer, but ulcerative lesions in the mouth, particularly in men, have a higher incidence of malignant transformation (Fig. 14; Ingafou et al. 2006). More than two thirds of patients are aged 30–60 years; however, lichen planus can occur at any age (Balasubramaniam et al. 2008). LP usually resolves by itself within 8–12 months. Fluorinated topical steroids can be used to treat mild cases. Class I or II ointments are generally used for them. Systemic steroids can be used for symptom control. Many practitioners prefer intramuscular triamcinolone 40–80 mg every 6–8 weeks. Oral acitretin has been shown to be effective (Cribier et al. 1998). Ultraviolet B (UVB) therapy has been a safe established treatment option for skin lesions as well (Liu et al. 2017). LP of the oral mucosa can be treated with topical steroids like clobetasol 0.025–0.05%,

2238

0.1% tacrolimus, and 1% pimecrolimus. Topical immunomodulators and systemic immunosuppressives are used for more severe cases. These include thalidomide, azathioprine, mycophenolate mofetil, and systemic retinoids. Advancements in therapy have also included the use of diode and excimer lasers for oral lesions (Liu et al. 2017; García-Pola et al. 2017). The use of photodynamic therapy has been studied as well for oral lichen planus (Akram et al. 2018).

Acanthosis Nigricans Acanthosis Nigricans (AN) is an ill-defined, brown-to-black velvety hyperpigmentation of the skin, found in the posterior and lateral folds of the neck, the axilla, and groin (Fig. 15). It is associated with several endocrine disorders such as diabetes, hypo and hyperthyroidism, Cushing’s syndrome, and internal malignancy, typically an adenocarcinoma in the GI tract. This relatively common skin disorder manifests as hyperpigmented patches that can progress into palpable plaques. Patients usually present with a thickened, dark skin with pruritus. Skin markings on the palmar surface of the hands are seen, termed acanthosis palmaris. AN can be benign and malignant. Lesions of benign AN may occur at any age, including at birth, but more commonly in the adult population. Malignant acanthosis nigricans occurs more frequently in the elderly (Miller and Rapini n.d.).

R. A. Norman et al.

There are speculations as to the etiology of AN; a plethora of systemic diseases have been associated with AN. Tissue resistance to insulin and factors that stimulate epidermal keratinocyte and dermal fibroblast proliferation may play an important role in the pathogenesis of AN. The definitive cause for AN is not clear, with several possibilities researched. Tumors may activate insulin-like growth factors or their receptors in the epidermis. Many syndromes of AN have been identified sharing common features, including obesity, hyperinsulinemia, and craniosynostosis. These have been subdivided into insulinresistance syndromes and fibroblast growth factor defects (Miller and Rapini n.d.). At low concentrations, insulin binds to insulin receptors; at high concentrations, it binds to insulin-like growth factor receptors on keratinocytes or fibroblasts (Verrando and Ortonne 1985). Another possibility may be that lytic factors produced by cancer cells may weaken the extracellular matrix. The possibility of an intra-abdominal malignancy should always be considered, especially in the absence of an obvious predisposing condition (Longshore et al. 2003). There is no gender difference for AN (Sinha and Schwartz 2007). AN is commonly associated with obesity. Recent studies have also reported an association with atherosclerosis, especially of the carotid arteries (Guevara-Gutiérrez et al. 2017). The primary treatment option for AN is first to correct the underlying disease process. Other therapies used to lighten the hyperpigmented regions include topical retinoids, topical vitamin D analogues, oral retinoids, and chemical peels (Patel et al. 2018; Ozdemir et al. 2006; Darmstadt et al. 1991).

Visceral Neoplasms Muir-Torre Syndrome

Fig. 15 Acanthosis nigricans on neck (OLD)

Muir-Torre syndrome (MTS) is a syndrome that combines sebaceous neoplasms with visceral malignancies. These include sebaceous adenoma, sebaceous epithelioma, sebaceous carcinoma, and gastrointestinal or genitourinary carcinomas. Sebaceous adenoma is the characteristic marker

101

Mucocutaneous Manifestations in Gastrointestinal Disease

of MTS. These fairly rare benign tumors usually appear as yellow papules or nodules in adults. Sebaceous carcinomas most commonly occur on the eyelids, where they generally arise from the meibomian glands and the glands of Zeiss. They also occur on ears, feet, penis, and the labia. MTS has an autosomal dominant pattern of inheritance in 59% of cases and a high degree of penetrance with variable expression. This condition is associated with an inherited defect in one copy of a DNA mismatch repair gene (MMR), which eventually leads to microsatellite instability (MSI) (Honchel et al. 1994). The two major MMR proteins involved are hMLH1 and hMSH2. Approximately 70% of tumors associated with the MTS have MSI. While germline disruption of hMLH1 and hMSH2 is evenly distributed in HNPCC, disruption of hMSH2 occurs in over 90% of MTS patients (Ponti et al. 2006). Although the majority of cases are inherited in an autosomal dominant manner, a new subtype has been described recently that does not have defects in microsatellite instability but may be inherited in a autosomal recessive pattern (John and Schwartz 2016). The diagnosis of MTS is multidisciplinary and involves a team approach between the dermatologist, dermatopathologist, and geneticist (Kim et al. 2016). Because sebaceous neoplasms are so prevalent in patients with MTS, immunohistochemical staining for mismatch repair enzymes in sebaceous tumors can be used to screen for the disease (Kim et al. 2016; Everett et al. 2014). Clinical genetics evaluation is recommended for patients with abnormal immunohistochemical testing of sebaceous neoplasms (Everett et al. 2014). Treatment of MTS involves regular screening for GI and genitourinary cancers. In many patients, the skin cancers associated with MTS tend to have a nonaggressive course. However, approximately 60% of patients reportedly develop metastatic disease, with a 50% survival rate calculated at 12 years. Lesions outside the head and neck may take a more aggressive course. Age at presentation of MTS ranges from young adulthood to elderly patients, with a median age of 53 years (Burger and Itin 2008). Recent advancements have included a greater role of

2239

immunohistochemical and genetic testing on tumors to confirm the diagnosis (John and Schwartz 2016; Lee et al. 2017).

Cowden Disease Cowden disease isa rare disease of autosomal dominant inheritance is characterized by hamartomas in various tissues. Cutaneous manifestations include trichilemmomas, acral keratoses, and oral papillomas. Oral lesions are common. Papules are 1–3 mm with a smooth surface and a whitish appearance and are present in the gingival, labial, and palatal surfaces of the mouth in over 80% of patients and acral keratoses are flesh-colored or slightly pigmented smooth or verrucoid papules on the dorsal hands and feet, occurring in over 60% of patients (Adkisson and Fiala n.d.). The disease is associated with a variety of malignancies, including breast, thyroid, endometrial, cervical, and colon cancer. GI polyposis occurs in at least 35% of patients with Cowden disease. The common sites of polyposis are colon and rectum, although polyps can occur in the esophagus, stomach, gallbladder, and small bowel. Cowden disease (multiple hamartoma syndrome) is caused by a mutation in the PTEN tumor suppressor gene (also termed MMAC1 or TEP1) on band 10q23.3. Identical mutations in PTEN have been described in BannayanRuvulcaba-Riley syndrome (BRRS). Cutaneous manifestations of Cowden disease are similar in both sexes. Systemic treatments (i.e., acitretin) may control some cutaneous manifestations of the disease; however, recurrence of lesions is typical after treatment is discontinued (Cnudde et al. 1996). A thorough initial GI evaluation is indicated, with appropriate follow-up care. Management of Cowden disease is multidisciplinary. It involves periodic screening for other cancers including breast, thyroid, endometrial cancer, colorectal cancer, and renal cancer (Agarwal et al. 2015). Because the gene defect in PTEN can affect PI3K, AKT, and mTOR pathway, new medications inhibiting mTOR pathway have been reported. No therapies are approved for Cowden, but clinical trials for Sirolimus are underway

2240

(PIK3CA/mTOR) (Agarwal et al. 2015). Clinical trials targeting other specific pathways within the pathogenesis sequence are currently being investigated for future therapy (Agarwal et al. 2015; Nathan et al. 2017; Noreuil et al. 2016).

Cronkhite-Canada Syndrome Cronkhite-Canada syndrome (CCS) is a rare, sporadically occurring, non-inherited disorder reported in 1955 by Leonard Cronkhite Jr. and Wilma Canada. Affected patients often have generalized gastrointestinal polyps, cutaneous pigmentation, alopecia, hypocalcemia, hypoproteinemia, and onychodystrophy (Wen et al. 2014). Ectodermal changes (i.e., hyperpigmentation, alopecia, and nail dystrophy) result from malabsorption and protein loss. Its estimated incidence is approximately one in a million (Zhao et al. 2016). Most patients are over 50 years old at presentation. As the etiology is unknown, treatment is mainly symptomatic, with the goals to correct fluid, electrolyte, and protein loss and regulate stool frequency. Due to its low incidence, no standard therapy has been proposed. However, effective treatments have been combination therapy composed of systemic corticosteroids with an antiplasmin, an elemental diet, antibiotics, and hyperalimentation (nutritional supplements). Treatment with corticosteroids as mainstay can lead to partial remission. Treatments include prednisone, nutritional support, antibiotics, and polypectomy. Other medications such as albendazole and sulfasalazine have also been used. Reports have showed success with oral prednisone at a dosage of 1 mg/kg per day for 2–8 weeks, which resulted in improvement of skin pigmentation, diarrhea, and nail atrophy (Wen et al. 2014). CCS may be associated with carcinoma of the GI tract. Advancements in diagnosis have included the use of a magnifying single balloon enteroscopes, in addition to conventional techniques like balloon-assisted enteroscopy and capsule endoscopy (Murata et al. 2017).

R. A. Norman et al.

Other Manifestations: Parasitic Diseases Strongyloidiasis Strongyloides is a helminthic pathogen associated with infection that is clinically characterized by watery diarrhea, abdominal cramping, and urticarial rash. Strongyloides stercoralis infection is acquired when an individual walks barefoot in contaminated soil. The infective filariform larvae enter the body through the feet by burrowing into the skin. Skin manifestations present as erythematous pustules at the site of entry. The associated rash caused by Strongyloides is called larva currens. It is a very pruritic, erythematous serpiginous lesion, which is due to an IgE-mediated response to larva migration. The cutaneous symptoms usually resolve when larvae enter circulation and migrate to the lungs. Periumbilical purpura, also referred to as the “thumbprint purpura sign,” is pathognomonic and can be seen in disseminated forms; its presence usually indicates a poorer prognosis (Randi et al. 2016). Strongyloidiasis generally presents with diffuse nonspecific GI, dermatologic, or respiratory symptoms and can cause diarrhea and cachexia in immunocompromised patients, who are at a higher risk of systemic disease. The use of serology aids in diagnosis is slowly replacing microbiological techniques (Martinez-Perez et al. 2018). However, its sensitivity can often be very low in immunosuppressed patients. Definitive diagnosis is made by identification of larvae in stool samples. Treatment options include ivermectin, albendazole, and thiabendazole. Ivermectin is usually first line therapy, as it has less adverse effects than thiabendazole and higher cure rates than albendazole based on recent studies (Henriquez-Camacho et al. 2016).

Leishmaniasis Leishmaniasis is another parasitic mucocutaneous disease. Sandfly bites transmit leishmaniasis; however, infection potentially may be transmitted

101

Mucocutaneous Manifestations in Gastrointestinal Disease

via a congenital route, through blood transfusions or through contaminated needle sticks. Mucocutaneous leishmaniasis is considered a New World disease and includes infection by L. mexicana, L amazonensis, L.braziliensis, L, guyanensis, and L. panamensis. More than 20 species of parasite causing leishmaniasis have been identified. Mucocutaneous disease affects the mucous membranes of the mouth, nose, and soft palate. Mucocutaneous leishmaniasis with extensive midfacial mutilation can result in death from airway or nutritional compromise. Skin lesions can appear weeks to years following the sand fly bite. The cutaneous symptoms present as a pustule which progresses to a nodular plaque and then to persistent ulcerative lesion. It is important that physicians consider the possibility of Leishmaniasis in any patient in an endemic region with a chronic skin lesion refractory to standard therapy (Burnett 2015). Diagnosis can be challenging because it can look clinically like both malignant and infectious conditions. Diagnosis consists of culture, histologic analysis, and PCR testing. Because different strains have different sensitivities, identifying the species may be practical because some species have a higher risk of systemic involvement. Parenteral antimonial drugs like sodium stibogluconate are first line (Handler et al. 2015). Other treatment options for cutaneous symptoms include cryotherapy, local heat therapy, and various topical paromomycin preparations. In 2014, the FDA approved miltefosine, an oral agent for cutaneous, visceral, and mucosal leishmanisis caused by certain species. Medications such as parenteral amophotericin B and pentamidine and oral itraconazole are also used (CDC ParasistesLeishmaniasis (page) n.d.).

Additional Considerations in Older Adults Nutritional deficiencies are common in the geriatric population, especially in those individuals with poor caretaker support. Vitamin C deficiency can cause scurvy, resulting in follicular keratosis (outgrowth of the hair), bleeding of gums and teeth, and

2241

Fig. 16 Glossitis due to B2 Deficiency (OLD)

delayed wound healing. Ariboflavinosis, caused by lack of vitamin B2 can result in magenta tongue, seborrhea, cheliosis, and conjunctivitis (Fig. 16). Dermatologic manifestations of zinc deficiency include hair loss, skin lesions, diarrhea, and wasting of body tissue, besides acne; cutaneous signs include hair loss and white spots, bands, or lines on fingernails, termed leukonychia. Supplementation of vitamins and minerals is recommended in those who do not receive adequate nutrition. Older patients are on medications for numerous disorders, including gastrointestinal; adverse drug events may present as a variety of skin lesions warranting a careful medication review. Older adults, especially those bedbound and in institutions, often have fecal or urinary incontinence, with perianal incontinence-associated dermatitis, a disorder that has received little attention; the disorder must be distinguished from often coexisting pressure ulcers (Gray 2010). Treatment goals of incontinence dermatitis include removal of irritants from the skin, eradication of associated infections such as candidiasis and contain or divert incontinent urine and stool (Gray 2010). And finally, several skin manifestations may be the result of intestinal malabsorption and motility disorders, rather than a primary immunologic or genetic disorders; the skin may thus be considered “the mirror of the gut” (Abenavoli et al. 2008).

2242

Key Points • Skin manifestations are common in GI disease and vary in severity. • Topical therapy, pharmacotherapy, changes in diet, topical steroids, systemic steroids, and surgery are options in treatment for these dermal disorders. • Several systemic disorders such as malnutrition, diabetes, hypo and hyperthyroidism, obesity, and immunosuppressed states can manifest as a variety of mucocutaneous manifestations. • A careful skin examination may be the clue to presence of underlying disease such as a malignancy in the GI tract. • Medications used for these skin disorders include topical and systemic steroids, in combination with topical or oral antifungals. • Other treatments include nonintervention, surgical removal of severely affected areas, radiotherapy, chemotherapeutic agents, nonspecific immunotherapy, and cessation of immunosuppressive therapy in those who are iatrogenically immunosuppressed. • For geriatric patients with malnutrition, supplementation of vitamins and minerals is recommended in those who do not receive adequate nutrition, as skin manifestations are common in this group.

References Abdelmaksoud A, et al. Classic and HIV-related Kaposi sarcoma treated with 0.1% topical timolol gel. J Am Acad Dermatol. 2017;76(1):153. Abenavoli L, Proietti I, Vonghia L, et al. Intestinal malabsorption and skin disorders. Dig Dis. 2008;26(2): 167–74. Adkisson K, Fiala KH. Cowden disease (Multiple hamartoma syndrome). n.d. Retrieved from http:// wemedicine.medscape.com/article/1093383-overview. Accessed 15 Mar 2011. Agarwal R, Liebe S, Turski ML, Vidwans SJ, Janku F, Garrido-Laguna I, Munoz J, Schwab R, Rodon J, Kurzrock R, Subbiah V, Pan-Cancer Working Group. Targeted therapy for genetic cancer syndromes: Von Hippel-Lindau disease, Cowden syndrome, and Proteus syndrome. Discov Med. 2015;19(103):109–16. Aguilera P, Laguno M, To-Figueras J. Treatment of chronic hepatitis with boceprevir leads to remission of

R. A. Norman et al. porphyria cutanea tarda. Br J Dermatol. 2014;171(6): 1595–6. Akbulut S, Ozaslan E, Topal F, et al. Ulcerative colitis presenting as leukocytoclastic vasculitis of skin. World J Gastroenterol. 2008;14(15):2448–50. Akram Z, Javed F, Hosein M, Al-Qahtani MA, Alshehri F, Alzahrani AI, Vohra F. Photodynamic therapy in the treatment of symptomatic oral lichen planus: a systematic review. Photodermatol Photoimmunol Photomed. 2018;34(3):167–74. Alcántara-Reifs CM, et al. Classic Kaposi’s sarcoma treated with topical 0.5% timolol gel. Dermatol Ther. 2016;29(5):309. Al-Faouri A, Ajarma K, Alghazawi S, Al-Rawabdeh S, Zayaeen A. Glucagonoma and Glucagonoma syndrome: a case report with review of recent advances in management. Case Rep Surg. 2016;2016: 1484089. Allan AE, Shoji T, Li N, Burlage A, Davis B, Bhawan J. Two cases of Kaposi’s sarcoma mimicking StewartTreves syndrome found to be human herpesvirus-8 positive. Am J Dermatopathol. 2001;23(5):431–6. Al-Maweri SA. Prevalence of oral mucosal lesions in patients with type 2 diabetes attending hospital universiti sains Malaysia. Malays J Med Sci. 2013;20(4):39–46. Alpsoy E. Behçet’s disease: a comprehensive review with a focus on epidemiology, etiology and clinical features, and management of mucocutaneous lesions. J Dermatol. 2016;43(6):620–32. American Academy of Family Physicians. Information from your family doctor. Intertrigo: what you should know. Am Fam Physician. 2005;72(5):840. Angeloni A, Heston L, Uccini S, Sirianni MC, Cottoni F, Masala MV, Cerimele D, Lin SF, Sun R, Rigsby M, Faggioni A, Miller G. High prevalence of antibodies to human herpesvirus 8 in relatives of patients with classic Kaposi’s sarcoma from Sardinia. J Infect Dis. 1998;177(6):1715. Apak H, Celkan T, Ozkan A, et al. Blue rubber bleb nevus syndrome associated with consumption coagulopathy: treatment with interferon. Dermatology. 2004;208(4): 345–8. Asare GA, Bronz M, Naidoo V, Kew MC. Synergistic interaction between excess hepatic iron and alcohol ingestion in hepatic mutagenesis. Toxicology. 2008; 254(1–2):11–8. Ascari-Raccagni A, Baldari U, Righini MG. Cutaneous symptoms of Gardner’s syndrome. J Eur Acad Dermatol Venereol. 1999;12(1):80–1. Ashida R, Ihn H, Mimura Y, et al. Clinical and laboratory features of Japanese patients with scleroderma and telangiectasia. Clin Exp Dermatol. 2009;34(7):761–3. Ayesh MH. Angular cheilitis induced by iron deficiency anemia. Cleve Clin J Med. 2018;85(8):581–2. Balasubramaniam P, Ogboli M, Moss C. Lichen planus in children: review of 26 cases. Clin Exp Dermatol. 2008;33(4):457–9. Barta Z, Zold E, Nagy A, Zeher M, Csipo I. Celiac disease and microscopic colitis: a report of 4 cases. World J Gastroenterol. 2011;17(16):2150–4.

101

Mucocutaneous Manifestations in Gastrointestinal Disease

Bean WB. Blue rubber bleb nevi of the skin and gastrointestinal tract. In: Bean WB, editor. Vascular spiders and related lesions of the skin. Springfield: Charles C Thomas; 1958. p. 178–85. Benson CA, et al. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the national institutes of health, and the HIV medicine association/infectious diseases society of America. MMWR Recomm Rep. 2004;53(RR15):1. Berger TG, Detlefs RL, Donatucci CF. Junctional epidermolysis bullosa, pyloric atresia, and genitourinary disease. Pediatr Dermatol. 1986;3(2):130–4. Bonciani D, et al. Dermatitis herpetiformis: from the genetics to the development of skin lesions. Clin Dev Immunol. 2012;2012:239691. Bonkovsky HL, Poh-Fitzpatrick M, Pimstone N, et al. Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America. Hepatology. 1998;27(6): 1661–9. Bonkovsky HL, Lambrecht RW, Shan Y. Iron as a comorbid factor in nonhemochromatotic liver disease. Alcohol. 2003;30(2):137–44. Brambilla L, Labianca R, Ferrucci SM, Taglioni M, Boneschi V. Treatment of classical Kaposi’s sarcoma with gemcitabine. Dermatology. 2001;202(2):119. Brambilla L, et al. Combination of vinblastine and bleomycin as first line therapy in advanced classic Kaposi’s sarcoma. Eur Acad Dermatol Venereol. 2006;20(9):1090. Brambilla L, Bellinvia M, Tourlaki A, Scoppio B, Gaiani F, Boneschi V. Intralesional vincristine as first-line therapy for nodular lesions in classic Kaposi sarcoma: a prospective study in 151 patients. Br J Dermatol. 2010;162(4):854. Brambilla L, Recalcati S, Tourlaki A. Vinorelbine therapy in classic Kaposi’s sarcoma: a retrospective study of 20 patients. Eur J Dermatol. 2015;25(6):535. Brandhagen DJ, Fairbanks VF, Baldus W. Recognition and management of hereditary hemochromatosis. Am Fam Physician. 2002;65:853–60. Brosens LA, van Hattem WA, Jansen M, et al. Gastrointestinal polyposis syndromes. Curr Mol Med. 2007;7(1):29–46. Bruzzone B, Magnani O, Sticchi L, Canepa P, Rappazzo E, Icardi G, Setti M. Resolution of porphyria cutanea tarda in HIV and mixed HCV coinfection after direct-acting antiviral (DAA) therapy. J Antimicrob Chemother. 2017;72(10):2955–8. Burger B, Itin P. Muir-Torre syndromee. Dermatology. 2008;217(1):56–7. Burnett MW. Cutaneous leishmaniasis. J Spec Oper Med. 2015;15(1):128–9. Caponetti G, Dezube BJ, Restrepo CS, Pantanowitz L. Kaposi sarcoma of the musculoskeletal system: a review of 66 patients. Cancer. 2007;109(6):1040. Castiñeiras I, et al. Disseminated classic Kaposi’s sarcoma. Two cases with excellent response to pegylated liposomal doxorubicin. J Dermatolog Treat. 2006;17(6):377. Cattani P, Cerimele F, Porta D, Graffeo R, Ranno S, Marchetti S, Ricci R, Capodicasa N, Fuga L, Amico

2243

R, Cherchi G, Gazzilli M, Zanetti S, Fadda G. Agespecific seroprevalence of human herpesvirus 8 in Mediterranean regions. Clin Microbiol Infect. 2003;9 (4):274. CDC Parasistes-Leishmaniasis (page). Website title resources for health professionals. n.d. https://www.cd c.gov/parasites/leishmaniasis/health_professionals/ind ex.html Updated 15 Oct 2018. Chen TS, Chen PS. Rise and fall of the Plummer-Vinson syndrome. J Gastroenterol Hepatol. 1994;9(6):654–8. Chevrant-Breton J, Simon M, Bourel M, Ferrand B. Cutaneous manifestations of idiopathic hermochromatosis. Study of 100 cases. Arch Dermatol. 1977;113(2):161–5. Choi KK, et al. Radical resection of intestinal blue rubber bleb nevus syndrome. J Korean Surg Soc. 2012;83(5):316–20. Chuang, T, Stitle L. Lichen planus. n.d. Retrieved from http://emedicine.medscape.com/article/1123213overview. Accessed 1 Mar 2011. Cnudde F, Boulard F, Muller P, et al. Cowden disease: treatment with acitretine. Ann Dermatol Venereol. 1996;123(11):739–41. Corrick F, Anand G. Question 2: would systemic steroids be useful in the management of Stevens-Johnson syndrome? Arch Dis Child. 2013;98(10):828–30. Cribier B, Frances C, Chosidow O. Treatment of lichen planus. An evidence-based medicine analysis of efficacy. Arch Dermatol. 1998;134(12):1521–30. Criteria for diagnosis of Behçet’s disease. International study Group for Behçet’s disease. Lancet. 1990;335(8697):1078. Curatolo P, et al. Electrochemotherapy in the treatment of Kaposi sarcoma cutaneous lesions: a two-center prospective phase II trial. Ann Surg Oncol. 2012;19(1): 192. Danzig JB, Brandt LJ, Reinus JF, Klein RS. Gastrointestinal malignancy in patients with AIDS. Am J Gastroenterol. 1991;86(6):715. Darmstadt GL, Yokel BK, Horn TD. Treatment of acanthosis nigricans with tretinoin. Ach Dermatol. 1991;127:1139–40. DE Marchis ML, et al. Desmoid tumors in familial adenomatous polyposis. Anticancer Res. 2017;37(7):3357. de Wet NT, et al. A randomized, double blind, comparative trial of micafungin (FK463) vs. fluconazole for the treatment of oesophageal candidiasis. Aliment Pharmacol Ther. 2005;21(7):899. Di Lorenzo G, et al. Activity and safety of pegylated liposomal doxorubicin as first-line therapy in the treatment of non-visceral classic Kaposi’s sarcoma: a multicenter study. J Invest Dermatol. 2008;128(6):1578. Di Monta G, et al. Electrochemotherapy as “new standard of care” treatment for cutaneous Kaposi’s sarcoma. Eur J Surg Oncol. 2014;40(1):61. Díaz-Ley B, et al. Classic Kaposi’s sarcoma treated with topical rapamycin. Dermatol Ther. 2015;28(1):40. Dinler G. Plummer-Vinson syndrome in a 15-year-old boy. Turk J Pediatr. 2009;51(4):384. Dittmer DP, Damania B. Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy. J Clin Invest. 2016;126(9):3165–75.

2244 Drobnik J, Schwartz RA. Hemochromatosis. n.d. Retrieved from http://emedicine.medscape.com/arti cle/1104743-overview. Accessed 24 Feb 2011. Dunn K, Edwards-Jones V. The role of Acticoat with nanocrystalline silver in the management of burns. Burns. 2004;30(Suppl 1):S1. Eames T, Landthaler M, Karrer S. Crohn’s disease: an important differential diagnosis of granulomatous skin diseases. Eur J Dermatol. 2009;19(4):360–4. El Hachem M, et al. Multicentre consensus recommendations for skin care in inherited epidermolysis bullosa. Orphanet J Rare Dis. 2014;9:76. Elder GH, Smith SG, Herrero C, et al. Hepatoerythropoietic porphyria: a new uroporphyrinogen decarboxylase defect or homozygous porphyria cutanea tarda? Lancet. 1981;1(8226):916–9. Elkharwily A, Gottlieb K. The pancreas in familial adenomatous polyposis. J Pancreas. 2008;9(1):9–18. Ellis A. Tylosis with oesophageal cancer: diagnosis, management and molecular mechanisms. Orphanet J Rare Dis. 2015;10:126. Escobar C, et al. Update on desmoid tumors. Ann Oncol. 2012;23(3):562–9. Everett JN, Raymond VM, Dandapani M, Marvin M, Kohlmann W, Chittenden A, Koeppe E, Gustafson SL, Else T, Fullen DR, Johnson TM, Syngal S, Gruber SB, Stoffel EM. Screening for germline mismatch repair mutations following diagnosis of sebaceous neoplasm. JAMA Dermatol. 2014;150 (12):1315–21. Fardet L, et al. Treatment with taxanes of refractory or life-threatening Kaposi sarcoma not associated with human immunodeficiency virus infection. Cancer. 2006;106(8):1785. Forciea MA, Lavizzo-Mourne R, Schwab EP. Geriatric secrets. 2nd ed. Philadelphia: Hanley and Belfus; 2000. p. 127. Gao SJ, Kingsley L, Hoover DR, Spira TJ, Rinaldo CR, Saah A, Phair J, Detels R, Parry P, Chang Y, Moore PS. Seroconversion to antibodies against Kaposi’s sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi’s sarcoma. N Engl J Med. 1996;335(4):233. Garcia-Doval I, et al. Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol. 2000;136(3):323. García-Pola MJ, González-Álvarez L, Garcia-Martin JM. Treatment of oral lichen planus. Systematic review and therapeutic guide. Med Clin (Barc). 2017;149(8): 351–62. Geagea A, Cellier C. Scope of drug-induced, infectious and allergic esophageal injury. Curr Opin Gastroenterol. 2008;24(4):496. Ghyka G, Alecu M, Halalau F, Coman G. Intralesional human leukocyte interferon treatment alone or associated with IL-2 in non-AIDS related Kaposi’s sarcoma. J Dermatol. 1992;19(1):35–9.

R. A. Norman et al. Gião Antunes AS, Peixe B, Guerreiro H. Blue rubber bleb nevus syndrome: a delayed diagnosis. GE Port J Gastroenterol. 2016;24(2):101–3. Goel A, Bakshi SS, Soni N, Chhavi N. Iron deficiency anemia and Plummer-Vinson syndrome: current insights. J Blood Med. 2017;8:175–84. Goiriz R, et al. Treatment of classic Kaposi’s sarcoma with topical imiquimod. Dermatol Surg. 2009;35(1):147. Gray M. Optimal management of incontinence-associated dermatitis in the elderly. Am J Clin Dermatol. 2010;11(3):201–10. Grayson PC, et al. Treatment of mucocutaneous manifestations in Behçet’s disease with anakinra: a pilot openlabel study. Arthritis Res Ther. 2017;19(1):69. Gu GL, Wang SL, Wei XM, Bai L. Diagnosis and treatment of Gardner syndrome with gastric polyposis: a case report and review of the literature. World J Gastroenterol. 2008;14(13):2121–3. Guevara-Gutiérrez E, Tlacuilo-Parra A, Gutiérrez-Fajardo P, Sánchez-Tenorio T, Barba-Gómez F, Miranda-Díaz A. A study of the association of acanthosis nigricans with subclinical atherosclerosis. Indian J Dermatol Venereol Leprol. 2017;83(2):190–4. Hahler B. An overview of dermatological conditions commonly associated with the obese patient. Ostomy Wound Manage. 2006;52(6):34–6, 38, 40. Hamzi MA, Alayoud A, Asseraji M, Akhmouch I, Oualim Z. Porphyria cutanea tarda in a hemodialysis patient with hepatitis C virus: efficacy of treatment with multiple phlebotomies and erythropoietin. n.d. Handler MZ, Patel PA, Kapila R, Al-Qubati Y, Schwartz RA. Cutaneous and mucocutaneous leishmaniasis: differential diagnosis, diagnosis, histopathology, and management. J Am Acad Dermatol. 2015;73(6): 911–26. Hani U, Shivakumar HG, Vaghela R, Osmani RA, Shrivastava A. Candidiasis: a fungal infection-current challenges and progress in prevention and treatment. Infect Disord Drug Targets. 2015;15(1):42–52. Harper PS, Harper RMJ, Howell Evans AW. Carcinoma of the oesophagus with tylosis. Q J Med. 1970;39:317–33. Hatemi G, et al. One year in review 2016: Behçet’s syndrome. Clin Exp Rheumatol. 2016;34(6 Suppl 102): 10–22. Hauerstock D, Gerstein W, Vuong T. Results of radiation therapy for treatment of classic Kaposi sarcoma. J Cutan Med Surg. 2009;13(1):18. Hazin R, Abu-Rajab Tamimi TI, et al. Recognizing and treating cutaneous signs of liver disease. Cleve Clin J Med. 2009;76(10):599–606. Hemminki A, Markie D, Tomlinson I, et al. A serine/ threonine kinase gene defective in Peutz-Jeghers syndrome. Nature. 1998;391(6663):184–7. Henriquez-Camacho C, Gotuzzo E, Echevarria J, White AC Jr, Terashima A, Samalvides F, PérezMolina JA, Plana MN. Ivermectin versus albendazole or thiabendazole for Strongyloides stercoralis infection. Cochrane Database Sys Rev. 2016;1:CD007745.

101

Mucocutaneous Manifestations in Gastrointestinal Disease

Hernan I, et al. De novo germline mutation in the serinethreonine kinase STK11/LKB1 gene associated with Peutz-Jeghers syndrome. Clin Genet. 2004;66(1): 58–62. Hirota WK. ASGE guideline: the role of endoscopy in the surveillance of premalignant conditions of the upper GI tract. Gastrointest Endosc. 2006;63(4):570. Hoffman RM, Jaffe PE. Plummer-Vinson syndrome. A case report and literature review. Arch Intern Med. 1995;155(18):2008–11. Honchel R, Halling KC, Schaid DJ, et al. Microsatellite instability in Muir-Torre syndrome. Cancer Res. 1994;54(5):1159–63. Hsu CK, et al. Treatment of hereditary epidermolysis bullosa: updates and future prospects. Am J Clin Dermatol. 2014;15(1):1–6. Iacopino AM, Wathen WF. Oral candidal infection and denture stomatitis: a comprehensive review. J Am Dent Assoc. 1992;123(1):46. Ichiki T, Jnnai S, Nakagawa R, Kohda F, Furue M. Case of widespread fat necrosis that was caused by severe pancreatitis and histologically resembled pancreatic panniculitis. J Dermatol. 2017;44(8):979–81. Ingafou M, Leao JC, Porter SR, Scully C. Oral lichen planus: a retrospective study of 690 British patients. Oral Dis. 2006;12(5):463–8. Intong LR, Murrell DF. Inherited epidermolysis bullosa: new diagnostic criteria and classification. Clin Dermatol. 2012;30(1):70–7. Iscovich J, Boffetta P, Winkelmann R, Brennan P, Azizi E. Classic Kaposi’s sarcoma in Jews living in Israel, 1961–1989: a population-based incidence study. AIDS. 1998;12(15):2067. Iwaya T. Tylosis esophageal cancer locus on chromosome 17q25.1 is commonly deleted in sporadic human esophageal cancer. Gastroenterology. 1998;114(6): 1206. Jenne DE, Reimann H, Nezu J, et al. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet. 1998;18(1):38–43. Jiménez-Gallo D, Ossorio-García L, de la Varga-Martínez R, Arjona-Aguilera C, Linares-Barrios M. Necrolytic migratory erythema associated with glucagonoma treated successfully with cyclosporine. Dermatol Ther. 2017;30(4):e12498. Jin XL, Wang ZH, Xiao XB, Huang LS, Zhao XY. Blue rubber bleb nevus syndrome: a case report and literature review. World J Gastroenterol. 2014;20(45): 17254–9. John AM, Schwartz RA. Muir-Torre syndrome (MTS): an update and approach to diagnosis and management. J Am Acad Dermatol. 2016;74(3):558–66. Kaposi M. Idiopathic multiple pigmented sarcoma of the skin. [English translation from Archiv Für Dermatolgie Und Syphillis 1872;4:265–273] CA Cancer J Clin 1982;32:342. Kappas A, Sassa S, Galbraith RA, et al. The porphyrias. In: Scriver CR, et al., editors. The metabolic basis of

2245

inherited disease. New York: McGraw-Hill; 1995. p. 2103–59. Karthikeyan P, Aswath N, Kumaresan R. Plummer Vinson syndrome: a rare syndrome in male with review of the literature. Case Rep Dent. 2017;2017:6205925. Kartsonis N, et al. Efficacy of caspofungin in the treatment of esophageal candidiasis resistant to fluconazole. J Acquir Immune Defic Syndr. 2002;31(2):183. Kaser DJ, Reichman DE, Laufer MR. Prevention of vulvovaginal sequelae in stevens-johnson syndrome and toxic epidermal necrolysis. Rev Obstet Gynecol. 2011;4(2):81. Khanfir MS, et al. Inflammatory optic neuropathy in Behçet’s disease. Reumatismo. 2015;67(4):156. Kim RH, Nagler AR, Meehan SA. Universal immunohistochemical screening of sebaceous neoplasms for Muir-Torre syndrome: putting the cart before the horse? J Am Acad Dermatol. 2016;75(5):1078–9. Kimbara S, Fujiwara Y, Toyoda M, Chayahara N, Imamura Y, Kiyota N, Mukohara T, Fukunaga A, Oka M, Nishigori C, Minami H. Rapid improvement of glucagonoma-related necrolytic migratory erythema with octreotide. Clin J Gastroenterol. 2014;7(3):255–9. Klotz SA. Oropharyngeal candidiasis: a new treatment option. Clin Infect Dis. 2006;42(8):1187. Krause DS, et al. A randomized, double-blind trial of anidulafungin versus fluconazole for the treatment of esophageal candidiasis. Clin Infect Dis. 2004;39(6):770. Kroft EB. Ultraviolet a phototherapy for sclerotic skin diseases: a systematic review. J Am Acad Dermatol. 2008;59(6):1017. Krown SE. AIDS-associated Kaposi’s sarcoma: is there still a role for interferon alfa? Cytokine Growth Factor Rev. 2007;18(5–6):395. Laine L, Amerian J, Rarick M, Harb M, Gill PS. The response of symptomatic gastrointestinal Kaposi’s sarcoma to chemotherapy: a prospective evaluation using an endoscopic method of disease quantification. Am J Gastroenterol. 1990;85(8):959. Lake DE, et al. Fluconazole versus amphotericin B in the treatment of esophageal candidiasis in cancer patients. Chemotherapy. 1996;42(4):308. Lambiase P, Seery JP, Taylor-Robinson SD, et al. Resolution of panniculitis after placement of pancreatic duct stent in chronic pancreatitis. Am J Gastroenterol. 1996;91(9):1835. Laube R, et al. Oral and upper gastrointestinal Crohn’s disease. J Gastroenterol Hepatol. 2018;33(2):355. Lee JB, Litzner BR, Vidal CI. Review of the current medical literature and assessment of current utilization patterns regarding mismatch repair protein immunohistochemistry in cutaneous Muir-Torre syndrome-associated neoplasms. J Cutan Pathol. 2017;44(11):931–7. Lescano MA, Tavares LC, Santos PCJL. Juvenile hemochromatosis: HAMP mutation and severe iron overload treated with phlebotomies and deferasirox. World J Clin Cases. 2017;5(10):381–3.

2246 Lewis MAO, Williams DW. Diagnosis and management of oral candidosis. Br Dent J. 2017;223(9):675–81. Li Y, et al. Q-switched alexandrite laser treatment of facial and labial lentigines associated with Peutz-Jeghers syndrome. Photodermatol Photoimmunol Photomed. 2012;28(4):196–9. Li S, Bai L, Dong J, Sun R, Lan K. Kaposi’s sarcomaassociated herpesvirus: epidemiology and molecular biology. In: Cai Q, Yuan Z, Lan K, editors. Infectious agents associated cancers: epidemiology and molecular biology. Advances in experimental medicine and biology, vol. 1018. Singapore: Springer; 2017. Lim W, et al. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol. 2010;105(6):1258. Lin P, Liang G. Behçet disease: recommendation for clinical management of mucocutaneous lesions. J Clin Rheumatol. 2006;12(6):282–6. Lindh E, et al. Autoimmunity and cystatin SA1 deficiency behind chronic mucocutaneous candidiasis in autoimmune polyendocrine syndrome type 1. J Autoimmun. 2013;42:1–6. Liu WB, Sun LW, Yang H, Wang YF. Treatment of oral lichen planus using 308-nm excimer laser. Dermatol Ther. 2017;30(5):e12510. Longshore SJ, Taylor JS, Kennedy A, Nurko S. Malignant acanthosis nigricans and endometrioid adenocarcinoma of the parametrium: the search for malignancy. J Am Acad Dermatol. 2003;49(3):541–3. Lugović-Mihić L, et al. Differential diagnosis of cheilitis – how to classify cheilitis? Acta Clin Croat. 2018;57(2): 342–51. Lyell A. Toxic epidermal necrolysis: an eruption resembling scalding of the skin. Br J Dermatol. 1956;68(11): 355–61. Martinez-Perez A, Roure Díez S, Belhassen-Garcia M, Torrús-Tendero D, Perez-Arellano JL, Cabezas T, Soler C, Díaz-Menéndez M, Navarro M, Treviño B, Salvador F, Soil-Transmitted Helminths’ Study Group of the Spanish Society of Tropical Medicine and International Health (SEMTSI). Management of severe strongyloidiasis attended at reference centers in Spain. PLoS Negl Trop Dis. 2018;12(2): e0006272. Matsuo T, Itami M, Nakagawa H, Nagayama M. The incidence and pathology of conjunctival ulceration in Behçet’s syndrome. Br J Ophthalmol. 2002;86(2):140. May A, Gossner L, Behrens A, et al. A prospective randomized trial of two different endoscopic resection techniques for early stage cancer of the esophagus. Gastrointest Endosc. 2003;58(2):167–75. Mazzoccoli G, et al. Behçet syndrome: from pathogenesis to novel therapies. Clin Exp Med. 2016;16(1):1–12. Mendes FB, Hissa-Elian A, Abreu MA, Gonçalves VS. Review: dermatitis herpetiformis. An Bras Dermatol. 2013;88(4):594–9. Meseguer-Yebra C, et al. Successful treatment of classic Kaposi sarcoma with topical timolol: report of two cases. Br J Dermatol. 2015;173(3):860.

R. A. Norman et al. Miller JH, Rapini RP. Acanthosis nigricans. n.d. Retrieved from http://emedicine.medscape.com/article/1102488overview. Accessed 20 Feb 2011. Millsop JW, Fazel N. Oral candidiasis. Clin Dermatol. 2016;34(4):487–94. Mirza YA, Altamura D, Hirbod T, Verdolini R. Long-term response of classic Kaposi’s sarcoma to intralesional doxorubicin: a case report. Case Rep Dermatol. 2015;7(1):17. Moran-Jimenez MJ, Ged C, Romana M, et al. Uroporphyrinogen decarboxylase: complete human gene sequence and molecular study of three families with hepatoerythropoietic porphyria. Am J Hum Genet. 1996;58(4):712–21. Murata M, Bamba S, Takahashi K, Imaeda H, Nishida A, Inatomi O, Tsujikawa T, Kushima R, Sugimoto M, Andoh A. Application of novel magnified single balloon enteroscopy for a patient with Cronkhite-Canada syndrome. World J Gastroenterol. 2017;23(22):4121. Mutlu S, Scully C. The person behind the eponym: Hulûsi Behçet (1889–1948). J Oral Pathol Med. 1994;23(7): 289. Nathan N, Keppler-Noreuil KM, Biesecker LG, Moss J, Darling TN. Mosaic disorders of the PI3K/PTEN/AKT, TSC/mTORC1 signaling pathway. Dermatol Clin. 2017;35(1):51–60. Neff R, Kremer S, Voutsinas L, Waxman M, Mitty W Jr. Primary Kaposi’s sarcoma of the ileum presenting as massive rectal bleeding. Am J Gastroenterol. 1987;82(3):276. Nichols CM, Flaitz CM, Hicks MJ. Treating Kaposi’s lesions in the HIV-infected patient. J Am Dent Assoc. 1993;124(11):78. Nieuwenhuis MH, et al. Evaluation of management of desmoid tumours associated with familial adenomatous polyposis in Dutch patients. Br J Cancer. 2011;104(1):37. Nikpour M, Baron M. Mortality in systemic sclerosis: lessons learned from population-based and observational cohort studies. Curr Opin Rheumatol. 2014;26(2):131–7. Noreuil KM, Parker VE, Darling TN, Martinez-Agosto JA. Somatic overgrowth disorders of the PI3K/AKT/ mTOR pathway & therapeutic strategies. Am J Med Genet C Semin Med Genet. 2016;172(4):402–21. Novacek G. Plummer-Vinson syndrome. Orphanet J Rare Dis. 2006;1:36. Oksüzoglu BC, Oksüzoglu G, Cakir U, et al. Blue rubber bleb nevus syndrome. Am J Gastroenterol. 1996;91 (4):780–2. Oranje AP. Blue rubber bleb nevus syndrome. Pediatr Dermatol. 1986;3(4):304–10. Ozdemir M, Toy H, Mevlitoglu I, et al. Generalized idiopathic acanthosis nigricans treated with acitreitn. J Dermatolog Treat. 2006;17:54–6. Palmieri TL, et al. A multicenter review of toxic epidermal necrolysis treated in U.S. burn centers at the end of the twentieth century. J Burn Care Rehabil. 2002;23(2):87. Pappas PG, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the

101

Mucocutaneous Manifestations in Gastrointestinal Disease

Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1. Park KK, Brodell RT, Helms SE. Angular cheilitis, Part 1: local etiologies. Cutis. 2011a;87(6):289. Park KK, Brodell RT, Helms SE. Angular cheilitis, Part 2: nutritional, systemic, and drug-related causes and treatment. Cutis. 2011b;88(1):27. Patel NU, Roach C, Alinia H, Huang WW, Feldman SR. Current treatment options for acanthosis nigricans. Clin Cosmet Investig Dermatol. 2018;11:407–13. Perfect JR, et al. Voriconazole treatment for less-common, emerging, or refractory fungal infections. Clin Infect Dis. 2003;36(9):1122. Pons V, et al. Oropharyngeal candidiasis in patients with AIDS: randomized comparison of fluconazole versus nystatin oral suspensions. Clin Infect Dis. 1997;24(6):1204. Ponti G, Losi L, Pedroni M, et al. Value of MLH1 and MSH2 mutations in the appearance of Muir-Torre syndrome phenotype in HNPCC patients presenting sebaceous gland tumors or keratoacanthomas. J Invest Dermatol. 2006;126(10):2302–7. Ponti G, et al. Cancer-associated genodermatoses: skin neoplasms as clues to hereditary tumor syndromes. Crit Rev Oncol Hematol. 2013;85(3):239–56. Pouillot A, Polla A, Polla BS. Iron and iron chelators: a review on potential effects on skin aging. Curr Aging Sci. 2013;6(3):225–31. Pursley TJ, et al. Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis. 1996;22(2):336. Randi BA, Felício MF, Lázari CS, Duarte MI, Halpern I, Ho YLA. Woman with AIDS and a neglected disease presenting with coma, periumbilical purpuric rash, and Alveolar Hemorrhage. Clin Infect Dis. 2016;63(9): 1262–3. Robbins HA, Pfeiffer RM, Shiels MS, Li J, Hall HI, Engels EA. Excess cancers among HIV-infected people in the United States. J Natl Cancer Inst. 2015;107(4): pii:dju503. Rocchi E, Cassanelli M, Borghi A, et al. Liver iron overload and desferrioxamine treatment of porphyria cutanea tarda. Dermatologica. 1991;182(1):27–31. Rodríguez G, Vargas E, Abaúnza C, Cáceres S. Necrolytic migratory erythema and pancreatic glucagonoma. Biomedica. 2016;36(2):176–81. Rongioletti F, Caputo V. Pancreatic panniculitis. G Ital Dermatol Venereol. 2013;148(4):419–25. Rose S, Young MA, Reynolds JC. Gastrointestinal manifestations of scleroderma. Gastroenterol Clin N Am. 1998;27(3):563–94. Rosen AC, et al. Life-threatening dermatologic adverse events in oncology. Anti-Cancer Drugs. 2014;25(2):225. Rotondo C, et al. Mucocutaneous involvement in Behçet’s disease: how systemic treatment has changed in the last decades and future perspectives. Mediat Inflamm. 2015;2015:451675. Sakaguchi H. Treatment and prevention of oral candidiasis in elderly patients. Med Mycol J. 2017;58(2):J43–9.

2247

Saleh Z, Arayssi T. Update on the therapy of Behçet disease. Ther Adv Chronic Dis. 2014;5(3):112–34. Sandborn WJ, et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med. 2012;367(16):1519–28. Sandborn WJ, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369(8):711. Sangeorzan JA, et al. Epidemiology of oral candidiasis in HIV-infected patients: colonization, infection, treatment, and emergence of fluconazole resistance. Am J Med. 1994;97(4):339. Satta R, Biondi G, Cottoni F. Rainbow pattern: practical applications of dermoscopy in Kaposi’s sarcoma. G Ital Dermatol Venereol. 2016;107(2):206–7. Scherrer MAR, Rocha VB, Garcia LC. Behçet’s disease: review with emphasis on dermatological aspects. An Bras Dermatol. 2017;92(4):452–64. Schwartz RA, Cohen PF. Kaposi’s sarcoma. In: Newcomer VD, Young Jr EM, editors. Geriatric dermatology: clinical diagnosis and practical therapy. New York: Igaku-Shoin; 1989. p. 645–52. Schwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis: Part II. Prognosis, sequelae, diagnosis, differential diagnosis, prevention, and treatment. J Am Acad Dermatol. 2013;69(2):187.e1. Senba M, Buziba N, Mori N, Morimoto K, Nakamura T. Increased prevalence of Kaposi΄s sarcoma-associated herpesvirus in the Kaposi΄s sarcoma-endemic area of western Kenya in 1981–2000. Acta Virol. 2011;55(2): 161–4. Serrano J. Oral lesions in Sjogren’s syndrome: a systematic review. Med Oral Patol Oral Cir Bucal. 2018;23(4):e391. Seyahi E, Melikoglu M, Yazici H. Clinical features and diagnosis of Behcet’s syndrome. Int J Adv Rheumatol. 2007;5:8. Sharon V, Fazel N. Oral candidiasis and angular cheilitis. Dermatol Ther. 2010;23(3):230. Shay K, Truhlar MR, Renner RP. Oropharyngeal candidosis in the older patient. J Am Geriatr Soc. 1997;45(7):863. Shengyuan L, Songpo Y, Wen W, et al. Hepatitis C virus and lichen planus: a reciprocal association determined by a meta-analysis. Arch Dermatol. 2009;145 (9):1040–7. Shiga S, Cartotto R. What are the fluid requirements in toxic epidermal necrolysis? J Burn Care Res. 2010;31(1):100–4. Silverberg MJ, et al. Cumulative incidence of cancer among persons with HIV in North America: a cohort study. Ann Intern Med. 2015;163(7):507–18. Sing S, Gorouhi F, Konia T, Burrall B. Pancreatic acinar cell carcinoma-induced panniculitis. JAAD Case Rep. 2018;4(7):719–21. Singal AK, Venkata KVR, Jampana S, Islam FU, Anderson KE. Hepatitis C treatment in patients with porphyria cutanea tarda. Am J Med Sci. 2017;353(6): 523–8.

2248 Sinha S, Schwartz RA. Juvenile acanthosis nigricans. J Am Acad Dermatol. 2007;57(3):502–8. Skiest DJ, et al. Posaconazole for the treatment of azole-refractory oropharyngeal and esophageal candidiasis in subjects with HIV infection. Clin Infect Dis. 2007;44(4):607. Smith JB, Taylor TB, Zone JJ. The site of blister formation in dermatitis herpetiformis is within the lamina lucida. J Am Acad Dermatol. 1992;27(2 Pt 1):209–13. Soblet J, et al. Blue rubber bleb nevus (BRBN) syndrome is caused by somatic TEK (TIE2) mutations. J Invest Dermatol. 2017;137(1):207. Soulier J, et al. Kaposi’s sarcoma-associated herpesviruslike DNA sequences in multicentric Castleman’s disease. Blood. 1995;86(4):1276–80. Steen VD, Medsger TA Jr. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum. 2000;43(11):2437–44. Stefan DC, Stones DK, Wainwright L, Newton R. Kaposi sarcoma in south African children. Pediatr Blood Cancer. 2011;56(3):392–6. Stevens HP, et al. Linkage of an American pedigree with palmoplantar keratoderma and malignancy (palmoplantar ectodermal dysplasia type III) to 17q24. Literature survey and proposed updated classification of the keratodermas. Arch Dermatol. 1996;132(6):640. Syngal S, et al. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015;110(2):223. Takeuchi S, et al. Effects of oral moisturising gel containing egg yolk antibodies against Candida albicans in older people. Gerodontology. 2016;33(1): 128–34. Tas F, Sen F, Keskin S, Kilic L. Oral etoposide as first-line therapy in the treatment of patients with advanced classic Kaposi’s sarcoma (CKS): a single-arm trial (oral etoposide in CKS). J Eur Acad Dermatol Venereol. 2013;27(6):789–92. Terai H, Shimahara M. Cheilitis as a variation of Candidaassociated lesions. Oral Dis. 2006;12(3):349. Tolliver S, Graham J, Kaffenberger BH. A review of cutaneous manifestations within glucagonoma syndrome: necrolytic migratory erythema. Int J Dermatol. 2018;57(6):642–5. Tong Y, Song YK, Tyring S. Resolution of porphyria cutanea tarda in patients with hepatitis C following ledipasvir-sofosbuvir combinatino therapy. JAMA Dermatol. 2016;152(12):1393–5. Tourlaki A, Bellinvia M, Brambilla L. Recommended surgery of Kaposi’s sarcoma nodules. J Dermatolog Treat. 2015;26(4):354. Tremblay C, Marcil I. Necrolytic migratory erythema: a forgotten paraneoplastic condition. J Cutan Med Surg. 2017;21(6):559–61. van Lier MG, et al. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol. 2010;105(6):1258.

R. A. Norman et al. Vassallo C, Carugno A, Derlino F, Ciocca O, Brazzelli V, Borroni G. Intralesional vinblastine injections for treatment of classic Kaposi sarcoma in diabetic patients. Cutis. 2015;95(5):E28. Vazquez JA, et al. A multicenter randomized trial evaluating posaconazole versus fluconazole for the treatment of oropharyngeal candidiasis in subjects with HIV/ AIDS. Clin Infect Dis. 2006;42(8):1179. Verrando P, Ortonne JP. Insulin binding properties of normal and ransformed human epidermal cultured keratinocytes. J Invest Dermatol. 1985;85:328–32. Villanueva A, et al. A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis. Am J Med. 2002;113(4):294. Vitale A, et al. New therapeutic solutions for Behçet’s syndrome. Expert Opin Investig Drugs. 2016;25(7): 827–40. Von Roenn JH, Cianfrocca M. Treatment of Kaposi’s sarcoma. Cancer Treat Res. 2001;104:127. Vossen AR, Boesten LS, Siersema PD, Nellen RG. Porphyria cutanea tarda: the benefit of additional diagnostics. Ned Tijdschr Geneeskd. 2016;160:A9166. Wen XH, Wang L, Wang YX, Qian JM. Cronkhite-Canada syndrome: report of six cases and review of literature. World J Gastroenterol. 2014;20(23):7518–22. Weprin L, Zollinger R, Clausen K, Thomas FB. Kaposi’s sarcoma: endoscopic observations of gastric and colon involvement. J Clin Gastroenterol. 1982;4(4):357. Witte M, Zillikens D, Schmidt E. Diagnosis of autoimmune blistering diseases. Front Med (Lausanne). 2018;5:296. Woodley DT, Chen M. Epidermolysis bullosa: then and now. J Am Acad Dermatol. 2004;51(1 Suppl):S55–7. Wright JA, Richards T, Srai SK. The role of iron in the skin and cutaneous wound healing. Front Pharmacol. 2014;5:156. Yang XM, Zhang Y, Wang T, Liu YH. Sporadic porphyria cutanea tarda induced by alcohol abuse. Chin Med J. 2017;130(16):2011–2. Yazici H, Fresko I, Yurdakul S. Behçet’s syndrome: disease manifestations, management, and advances in treatment. Nat Clin Pract Rheumatol. 2007;3(3):148–55. Young EM Jr, Newcomer VD, Kligman AM. Kaposi’s sarcoma. In: Geriatric dermatology: color atlas and practitioner’s guide. Philadelphia: Lea & Febiger; 1993. p. 202–3. Zamir E. Conjunctival ulcers in Behçet’s disease. Ophthalmology. 2003;110(6):1137. Zhang L, et al. Propranolol inhibits angiogenesis via downregulating the expression of vascular endothelial growth factor in hemangioma derived stem cell. Int J Clin Exp Pathol. 2014;7(1):48. Zhao R, Huang M, Banafea O, Zhao J, Cheng L, Zou K, Zhu L. Cronkhite-Canada syndrome: a rare case report and literature review. BMC Gastroenterol. 2016;16:23. Zustovich F, Ferro A, Toso S. Gemcitabine for the treatment of classic Kaposi’s sarcoma: a case series. Anticancer Res. 2013;33(12):5531.

Atlas of Dermatological Manifestations in Gastrointestinal Disease

102

Holly Kanavy, Steven R. Cohen, and Alana Deutsch

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2250 Cutaneous Manifestations of Hereditary GI Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2250 Familial Colorectal Cancer Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2250 Hamartomatous Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2251 Paraneoplastic Syndromes Associated with GI Malignancies . . . . . . . . . . . . . . . . . . . . 2251 Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2252 Immune-Mediated Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2254 Vascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2254 Genodermatoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2255 Nutritional Deficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2255 Cutaneous Side Effects of GI Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2256 Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2257 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2274

Abstract

Photographs courtesy of Steven R. Cohen MD, MPH, M. H. Samitz MD, and Montefiore Medical Center Department of Medicine Division of Dermatology H. Kanavy (*) · S. R. Cohen · A. Deutsch Department of Medicine, Division of Dermatology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA e-mail: hkanavy@montefiore.org; [email protected]; [email protected]

Dermatologists closely assess the skin for primary disease; however cutaneous manifestations of underlying systemic disorders are also of great clinical significance. Such findings offer clinicians visible clues to pathological disorders affecting the gastrointestinal (GI) system, otherwise imperceptible without more invasive investigation. Due to the close embryologic origins of the skin and the GI system, GI disorders fre-

© Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_100

2249

2250

quently manifest concomitant dermatologic features. Dermatologic findings can occur before or concurrently with systemic disease and may aid in accelerating diagnosis of underlying GI disorders. This atlas will provide figures of common manifestations with brief descriptions to highlight the mucocutaneous manifestations of GI disorders in older adults, focusing on GI cancers, paraneoplastic syndromes associated with GI malignancies, inflammatory bowel disorders, vascular disorders, genodermatoses, nutritional deficiencies, and medication-related adverse events. Keywords

Dermatology · Skin · Gastrointestinal disorders · Mucocutaneous manifestations of GI disorders · Hereditary GI cancers · Familial colorectal cancer syndromes · Muir-Torre syndrome · Gardner syndrome · Peutz-Jeghers syndrome · Hamartomatous GI syndromes · Cowden syndrome · Bannayan-RileyRuvalcaba syndrome · Cronkhite-Canada syndrome · Neurofibromatosis · Paraneoplastic syndromes · Acanthosis nigricans · Sign of Leser-Trélat · Acrokeratosis paraneoplastica · Tylosis · Plummer-Vinson syndrome · Necrolytic migratory erythema · Carcinoid syndrome · Paraneoplastic dermatomyositis · Paraneoplastic pemphigus · Cutaneous metastasis of GI malignancy · Inflammatory bowel disease · Cutaneous Crohn’s disease · Erythema nodosum · Pyoderma gangrenosum · Aphthous ulcers · Cutaneous polyarteritis nodosa · Epidermolysis bullosa acquisita · Bowelassociated dermatosis-arthritis syndrome · Henoch-Schönlein purpura · Dermatitis herpetiformis · Degos disease · Kaposi’s sarcoma · Genodermatoses · Pseudoxanthoma elasticum · Ehlers-Danlos syndrome · Hereditary hemorrhagic telangiectasia · Blue rubber bleb nevus · Nutritional deficiencies · Glossitis · Angular cheilitis · Pellagra · Scurvy · Drug rash · Xerosis · Psoriasis · Erysipelas · Herpes zoster · Basal cell carcinoma · Steroid acne · Urticaria

H. Kanavy et al.

Introduction Cutaneous findings are common in patients with gastrointestinal (GI) disorders likely due to the close embryologic origins of these systems (Shah et al. 2013; Rahvar and Kerstetter 2016). In such disorders, dermatological manifestations can precede GI symptoms; therefore, dermatologists and gastroenterologists have a critically collaborative role in diagnosing occult GI disease (Rahvar and Kerstetter 2016). Early diagnosis is particularly important as many of these disorders are associated with an increased risk for malignancy and require timely referral for diagnostic screening (Shah et al. 2013). This visual atlas will highlight the cutaneous manifestations of GI disease focusing on hereditary GI cancers, paraneoplastic syndromes associated with GI malignancies, inflammatory bowel disorders, vascular disorders, genodermatoses, and nutritional deficiencies.

Cutaneous Manifestations of Hereditary GI Cancers Early identification of hereditary GI cancer syndromes is essential, such that patients and their affected family members can establish care with multidisciplinary teams to assess risk, structure individualized screening regimens, and initiate suitable surveillance and preventative measures. Early diagnosis of these hereditary cancer syndromes is frequently facilitated by identification of their specific cutaneous signatures by dermatologists.

Familial Colorectal Cancer Syndromes Colorectal cancer (CRC) affects 130,000 individuals per year in the USA (Shah et al. 2013; Erbe 1976), with a disproportionate number of patients over the age of 50 (Boardman 2002). Nearly onefifth of these patients have a family history of CRC, with many being attributed to one of the four clinically and genetically distinct familial CRC syndromes: hereditary nonpolyposis

102

Atlas of Dermatological Manifestations in Gastrointestinal Disease

2251

CRC (HNPCC), familial adenomatous polyposis (FAP), juvenile polyposis syndrome (JPS), and Peutz-Jeghers syndrome. Gardner’s syndrome and Muir-Torre are variants of FAP and HNPCC, respectively, with shared genetic etiology but distinctive cutaneous manifestations (Boardman 2002). Genetic mutations underlying HNPCC are also shared by 25% of patients with neurofibromatosis 1 resulting in classic cutaneous, ocular, neural, and skeletal disease along with GI manifestations (Shah et al. 2013).

Hamartomatous Syndromes A faction of the hereditary GI cancer syndromes is a group of hamartomatous disorders including Peutz-Jeghers syndrome, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Cronkhite-Canada syndrome. While GI tract polyposis is common among this group, an increased risk of GI cancer only definitively exists in Cowden syndrome and is conjectured in Cronkhite-Canada syndrome. Other malignancies associated with this group of hamartomatous disorders include those of uterine endometrium, breast, and thyroid (Figs. 1, 2, 3, 4, 5, 6, and 7).

Fig. 1 Muir-Torre syndrome. Multiple sebaceous adenomas on the lateral face and ear. Less common lesions seen in this syndrome include sebaceous epitheliomas, sebaceous carcinomas, and multiple keratoacanthomas (Banse-Kupin et al. 1984)

Paraneoplastic Syndromes Associated with GI Malignancies Paraneoplastic syndromes are disorders involving nonmetastatic systemic effects triggered by an altered immune system in response to malignancy. A cutaneous paraneoplastic syndrome, thus, is a cutaneous finding associated with an underlying malignancy but without any direct malignant cellular infiltration of the skin (McLean 1993). These cutaneous manifestations are often the earliest signs of malignancy, and familiarization of these findings by dermatologists, and clinicians alike, will aid in earlier diagnosis and treatment rendering improved prognosis. The paraneoplastic syndromes associated with GI malignancies that will be shown below are malignant acanthosis nigricans, sign of Leser-trelat, acrokeratosis paraneoplastica, tylosis, Plummer-

Fig. 2 Gardner syndrome. Epidermoid cysts on the lateral eyebrow. Multiple epidermoid cysts are a characteristic manifestation of Gardner syndrome. These benign lesions are most frequently seen on the face or extremities. Other associated dermatologic findings include lipomas and desmoid tumors (Boardman 2002)

Vinson syndrome, glucagonoma syndrome with necrolytic migratory erythema, perianal extramammary Paget’s disease, carcinoid syndrome,

2252

H. Kanavy et al.

Fig. 3 Peutz-Jeghers syndrome. Perioral melanocytic macules. Multiple lentigines commonly cluster on the oral mucosa as well as in periorofacial and perineal/anogenital regions (Erbe 1976)

Fig. 5 Bannayan-Riley-Ruvalcaba syndrome. Genital lentigines (tan brown macules) are the most specific cutaneous finding of BRRS. Others include facial verrucae, vascular malformations, lipomas, acanthosis nigricans, and multiple acrochordons (Fargnoli et al. 1996)

Fig. 4 Cowden syndrome (multiple hamartoma syndrome). Trichilemmomas, or benign hamartomas of the outer sheath of the hair, on the face (Brownstein et al. 1977). Patients can have oral papillomatosis which gives a classic cobblestone appearance to the gingival mucosa (Jornayvaz and Philippe 2008; Plauchu et al. 1989). This syndrome is also associated with acral keratoses, lipomas, and café au lait spots (Farooq et al. 2010)

paraneoplastic dermatomyositis, and paraneoplastic pemphigus. Additionally, cutaneous metastasis of GI malignancy is included to

demonstrate the contrast between cutaneous paraneoplastic syndromes and cutaneous infiltration by the primary tumor (Figs. 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 22).

Inflammatory Bowel Disease Crohn’s disease (CD) and ulcerative colitis (UC) are responsible for the majority of cases of inflammatory bowel disease (IBD). Many similarities exist between the pathogenesis and clinical

102

Atlas of Dermatological Manifestations in Gastrointestinal Disease

2253

Fig. 6 Cronkhite-Canada syndrome (CCS). (a) Nail thinning, splitting, and onycholysis, as well as surrounding diffuse hyperpigmentation. (b) Beau’s lines – horizontal,

linear indentations spanning the width of the nails. Nail dystrophy in CCS is likely due to malabsorption and malnutrition from diffuse GI polyposis (Shah et al. 2013)

Fig. 7 Neurofibromatosis. (a) Café au lait spots – multiple irregular brown macules and patches. (b) Neurofibromas – peripheral nerve sheath tumors presenting as dome shaped nodules on the trunk. Patients also frequently

exhibit Crowe sign, or axillary freckling, as well as Lisch nodules, which are hamartomas of the iris (Shah et al. 2013)

presentation of the two entities; however, each has distinctive features including some of their cutaneous manifestations. Skin findings are present in ~20% of patients with IBD, and the lesions have been classified into three groups based on pathogenesis (Rahvar and Kerstetter 2016). Specific lesions are caused by direct involvement of the skin by a pathologic process akin to that of lesions in the GI tract. As UC is restricted to partial thickness involvement of the colon, specific lesions do not affect these patients.

Specific lesions seen in patients with CD include fissures and fistulae, oral CD, and metastatic CD (Rahvar and Kerstetter 2016; Thrash et al. 2013). Reactive lesions are induced by the underlying IBD likely through cross-antigenicity of the skin and gut mucosa. However, pathologic features of these cutaneous lesions are different than those in the GI tract. Erythema nodosum, a reactive lesion, is the most common cutaneous manifestation of IBD. Other reactive lesions include pyoderma

2254

gangrenosum and pyostomatitis vegetans (Rahvar and Kerstetter 2016; Thrash et al. 2013). Associated conditions are disorders that are more incident in patients with IBD due to the

H. Kanavy et al.

chronic inflammatory state and a hypothesized HLA linkage. Associated conditions include psoriasis, vitiligo, eczema, and acrodermatitis enteropathica; therefore, patients presenting with these dermatologic conditions should, at the minimum, have a thorough review of systems to exclude concurrent IBD (Rahvar and Kerstetter 2016; Thrash et al. 2013) (Figs. 23, 24, 25, 26, 27, and 28).

Immune-Mediated Conditions The displayed immune-mediated conditions, bowelassociated dermatosis-arthritis syndrome, HenochSchönlein purpura, dermatitis herpetiformis, and Degos disease, have concomitant involvement of the skin and GI tract due to cross-antigenicity of the skin and GI mucosa (Figs. 29, 30, 31, and 32).

Vascular Disease Fig. 8 Acanthosis nigricans (AN). Hyperpigmented and hyperkeratotic velvety plaques in the axilla. Typical locations include intertriginous areas and overlying acrochordons are frequently present. Benign AN is commonly associated with endocrinopathies and metabolic syndrome (Stone and Buescher 2005)

Kaposi’s sarcoma (KS) is a tumor of lymphatic endothelial cells, which occurs primarily in the skin and GI tract. There are three main populations of individuals with KS: patients with

Fig. 9 Malignant acanthosis nigricans in a patient with gastric adenocarcinoma. Clinically identical in appearance and distribution to benign AN; however lesions can

progress to mammary, umbilical, and anogenital regions, as seen. Disease progression frequently parallels neoplastic activity (Dourmishev and Draganov 2009)

102

Atlas of Dermatological Manifestations in Gastrointestinal Disease

2255

Fig. 10 Palmoplantar keratoderma (PPK). Hyperkeratosis producing a wrinkled appearance with broad ridges and deep sulci within the palms, soles (as shown), and digits (Dourmishev and Draganov 2009). PPK is associated with AN in the setting of gastric adenocarcinoma (Pentenero et al. 2004)

AIDS, elderly Mediterranean men, and endemic Africans.

Fig. 11 Sign of Leser-Trélat. Multiple, eruptive seborrheic keratoses on the trunk. Lesions grow rapidly in size and number and spread outward from the trunk to the extremities. One-third of patients with this cutaneous paraneoplastic phenomenon have underlying GI adenocarcinomas (Ponti et al. 2010)

Genodermatoses Genodermatoses are genetic conditions with cutaneous involvement, although many have multisystem signs and symptoms. Although many genodermatoses are detected during childhood, GI manifestations may not present for decades; thus knowledge of these conditions is important when treating patients of all ages. Genodermatoses with mutual involvement of the skin and GI tract include pseudoxanthoma elasticum, Ehlers-Danlos syndrome, hereditary hemorrhagic telangiectasia, and blue rubber bleb nevus syndrome (Figs. 33, 34, 35, 36, and 37).

Nutritional Deficiencies Nutritional deficiencies in developed countries are widespread, and their prevalence and importance are often overlooked (Miller 1989).

Primary malnutrition results from a failure to intake adequate nutrition through diet, while secondary malnutrition is due to chronic illness of which a large part is GI disease due to impaired digestion and absorption. Elderly individuals are particularly susceptible to malnutrition due to increasing burden of chronic disease, declining cognitive abilities, and deteriorating dentition (Agarwal et al. 2013). While patients with nutritional deficiencies often have distinct clinical presentations, when not being actively considered, they are easily missed. Each individual micronutrient deficiency has characteristic cutaneous manifestations, although commonly a mixed picture is seen as nutritional deficiencies occur concurrently. The nutritional deficiencies detailed below are vitamin B complex deficiency, vitamin B3 deficiency (pellagra), vitamin C deficiency (scurvy), and vitamin K deficiency (Figs. 38, 39, 40, and 41).

2256

Fig. 12 Acrokeratosis paraneoplastica (Bazex syndrome). Keratoderma of the (a) palms and (b) soles with diffuse surrounding hyperpigmentation. Involved nails are commonly dystrophic. The presence of Bazex syndrome

H. Kanavy et al.

should prompt investigation for an internal malignancy, most commonly squamous cell carcinoma of the upper aerodigestive tract (Sharma et al. 2006)

Fig. 13 Acrokeratosis paraneoplastica (Bazex syndrome). Characteristic erythematous to violaceous plaques with adherent psoriasiform scale symmetrically distributed on the elbows (Sharma et al. 2006)

Cutaneous Side Effects of GI Medications

Fig. 14 Tylosis (Howel-Evans syndrome). Focal, nonfrictional, and non-epidermolytic palmoplantar hyperkeratosis. There is a high lifetime incidence of esophageal cancer in patients with tylosis; thus anyone with this cutaneous finding should undergo appropriate radiologic imaging to screen for malignancy (Patel et al. 2007)

Patients with GI disease commonly require the use of one or more medications for acute or chronic indications. Like with all medications, even when tremendously efficacious for prescribed indications,

adverse events are common and must be considered with use. Almost all medications can cause a rash, which can range from benign to life threatening (Mockenhaupt 2017). Benign cutaneous adverse

102

Atlas of Dermatological Manifestations in Gastrointestinal Disease

Fig. 15 Plummer-Vinson syndrome. Patients present with a triad of dysphagia, iron deficiency anemia, and esophageal webs, which are associated with an increased risk of esophageal cancer. Related cutaneous manifestations include glossitis (as shown), brittle nail koilonychias, angular cheilitis, and leukoplakia (Shah et al. 2013)

2257

Fig. 17 Perianal extramammary Paget’s disease. A unilateral eczematous lesion in the perianal region that extends locally. This cutaneous manifestation represents a rare intraepithelial adenocarcinoma around the anal verge often associated with an underlying anorectal malignancy (Shah et al. 2013)

are acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis, which require immediate medical attention and have up to a 35% mortality rate (Hoetzenecker et al. 2016). Shown below are cutaneous adverse drug reactions due to commonly used GI medications include antacids, corticosteroids, analgesics, and TNF-alpha inhibitors (Figs. 42, 43, 44, 45, 46, 47, 48, and 49).

Key Points

Fig. 16 Necrolytic migratory erythema. Annular, erythematous, painful, pruritic eruption with blisters favoring areas of friction and pressure progressing to secondary erosions, crusting, and hyperpigmentation. Characteristic cutaneous finding of glucagonoma syndrome (Lobo et al. 2010)

drug reactions include exanthematous reactions, urticaria, photosensitivity, and fixed drug eruptions. The most severe cutaneous adverse drug reactions

• GI disorders frequently manifest concomitant dermatologic features. • Mucocutaneous manifestations can be the presenting sign of GI disease. • Recognition of cutaneous signatures specific to hereditary GI cancer syndromes and paraneoplastic syndromes associated with GI malignancies is critical for early diagnosis and intervention. • Inflammatory bowel disease is associated with three categories of dermatologic manifestations: specific lesions, reactive lesions, and associated conditions.

2258

H. Kanavy et al.

Fig. 18 Carcinoid syndrome. Bright red flushing, as seen, is the most common cutaneous presentation of carcinoid syndrome. Other presentations include pellagra-like changes, a sclerodermoid variant, and cutaneous metastases. Carcinoid syndrome occurs secondary to release of

vasoactive substances, like serotonin, from a carcinoid tumor, which is most commonly located in the small intestine or appendix. Clinical manifestations that accompany cutaneous symptoms include diarrhea, wheezing, and abdominal pain (Braverman 2002)

Fig. 19 Paraneoplastic dermatomyositis (DM). Cutaneous manifestations of paraneoplastic DM are similar to classic DM including Gottron papules over the finger joints (a) and violaceous poikiloderma overlying the knees (b)

and elbows. The most common sites of underlying malignancies include the ovaries, pancreas, stomach, colon, rectum, and lungs (Chakroun et al. 2011)

102

Atlas of Dermatological Manifestations in Gastrointestinal Disease

2259

Fig. 20 Paraneoplastic dermatomyositis. (a) “V-neck” sign – confluent macular erythema on the photodistributed area of the anterior chest. (b) Heliotrope rash – violaceous plaques on the upper eyelids. Malar rash – macular erythema in the butterfly distribution involving the nasolabial

folds. These dermatologic findings are all characteristic of paraneoplastic DM, and their presence warrants a workup for underlying malignancy (Chakroun et al. 2011)

Fig. 21 Paraneoplastic pemphigus. Painful erosions and ulcerations of the tongue (a) and buccal mucosa (b) demonstrative of the acantholytic mucocutaneous blistering pathology of paraneoplastic pemphigus. The most

common types of tumors that produce this cutaneous phenomenon are lymphomatoid and hematologic (Zhu and Zhang 2007)

• Awareness of genodermatoses is important in the geriatric population as GI manifestations present at older ages and can have high morbidity and mortality. • The geriatric population is at high risk for developing nutritional deficiencies, which can

easily be overlooked despite characteristic mucocutaneous manifestations. • Medications taken for GI disease can cause a range of mucocutaneous adverse events; thus, routine dermatologic surveillance is recommended for these patients.

2260

H. Kanavy et al.

Fig. 22 Cutaneous metastasis of GI malignancy. A Sister Mary Joseph nodule is a periumbilical cutaneous metastasis classically associated with gastric adenocarcinoma. Another common site for cutaneous metastases of GI malignancy is along surgical incisions (Cidon 2010) Fig. 23 Cutaneous Crohn’s disease. Ulcerations due to metastatic Crohn’s disease. Lesions are a direct extension of the inflammatory pathology of IBD and predominantly found on the extremities or intertriginous areas (Hawryluk et al. 2010). The pathogenic transmural inflammation also frequently results in the presence of perianal abscesses and acrochordons (Thrash et al. 2013), labial swelling, and cobblestoning of the oral mucosa (Plauth et al. 1991)

102

Atlas of Dermatological Manifestations in Gastrointestinal Disease

2261

Fig. 24 Erythema nodosum (EN). Painful, erythematous, subcutaneous nodules on the extensor surfaces of the lower extremities (Greenstein et al. 1976)

Fig. 25 Pyoderma gangrenosum. Rapidly enlarging ulcers with a gunmetal gray hue, undermined borders, and granulated bases. Ulcers often arise at sites of trauma (Powell et al. 1985)

2262

H. Kanavy et al.

Fig. 26 Oral aphthous ulcers. Round edematous ulcers with fibrinous exudate coating the bases on the gingival mucosa (a) and tongue (b) (Plauth et al. 1991)

Fig. 27 Cutaneous polyarteritis nodosa. Tender, erythematous nodules on the lower extremities mimicking EN. This chronic and recurring small- and medium-vessel

vasculitis localizes to the dermis and subcutaneous tissue unlike its more common cousin polyarteritis nodosa which involves the viscera (Borrie 1972)

102

Atlas of Dermatological Manifestations in Gastrointestinal Disease

Fig. 28 Epidermolysis bullosa acquisita (EBA). Mechanical damage leads to tense bullae and erosions, as seen on the elbow. Disease is typically distributed over acral areas and associated with skin fragility, nail dystrophies, and contractures of the fingers. There is a rare association with IBD, specifically CD, due to cross-antigenicity of the skin and intestinal mucosa (Thrash et al. 2013; Kim et al. 2016)

2263

Fig. 29 Bowel-associated dermatosis-arthritis syndrome (BADAS). Pink to erythematous macules and papules on the lower extremity of a patient 1-month status post bariatric surgery. Macules and papules can evolve into vesicopustules and inflammatory pustules. Episodic flulike symptoms and polyarthralgias are associated with the rash, all of which spontaneously remit (Dicken 1986)

2264

H. Kanavy et al.

Fig. 30 Henoch-Schönlein purpura (HSP). Palpable purpura on the lower extremities (a), with clustered vesiculobullous lesions (b). This IgA-mediated

leukocytoclastic vasculitis primarily exhibits cutaneous manifestations on dependent regions, which fade quickly leaving behind brown macules (Saulsbury 1999)

Fig. 31 Dermatitis herpetiformis (DH). Small vesicles on an erythematous background with secondary erosions and grouped, crusted papules on the buttocks (a) and knees

(b). This distribution with symmetric involvement of extensor surfaces is characteristic. DH is strongly associated with celiac disease (Collin and Reunala 2003)

102

Atlas of Dermatological Manifestations in Gastrointestinal Disease

2265

Fig. 32 Degos disease (DD). Small umbilicated lesions with porcelain white centers, erythematous rims, and surrounding telangiectasia. 50% of patients with DD have

vasculopathy affecting the GI tract, and the leading cause of death is intestinal perforation (Thrash et al. 2013)

Fig. 33 Kaposi’s sarcoma (KS). (a) Violaceous plaque formed by coalescing papules with a solitary nodule on the lower extremity of a patient with HIV. (b) Erythematous-

violaceous ulcerated papules with crust on the penis in a patient with AIDS (Antman and Chang 2000). These cases both represent the HIV-associated variant of KS

2266

H. Kanavy et al.

Fig. 34 Hereditary hemorrhagic telangiectasia (HHT). Punctate telangiectasia and vascular papules on the (a) lips and (b) ear. Lesions favor the oral region; however involvement of the nose, ears, hands, and feet can also be seen (Romer et al. 1992). Oftentimes the lesions are very

faint due to the tendency for anemia in these patients. Visceral arteriovenous malformations predispose these individuals to acute and chronic GI bleeding (Plauchu et al. 1989)

Fig. 35 Blue rubber bleb nevus syndrome. Dark blue cutaneous hemangiomas on the (a) chest and (b) cheek. These lesions can be compressed easily into a blue sac that rapidly refills once pressure is removed (Munkvad 1983).

Similar lesions can exist throughout the GI tract, and these frequently hemorrhage, which can lead to fatal exsanguination (Ertem et al. 2001)

102

Atlas of Dermatological Manifestations in Gastrointestinal Disease

2267

Fig. 36 Ehlers-Danlos syndrome (EDS). Joint hyperextensibility (a) and wrinkled, redundant, hyperextensible skin (b) are classic features of EDS. Due to poor collagen formation, other cutaneous findings include translucent

skin, varicosities, widened atrophic scarring, and keloids (Thrash et al. 2013). GI complications, such as perforation and ischemia, occur in 19% of cases due to fragility of vessel walls (Sharma et al. 2009)

Fig. 37 Pseudoxanthoma elasticum (PXE). Small yellow papules producing a fine-cobblestone appearance on the lateral neck (a) and axilla (a, b). Like EDS, PXE is

associated with abnormal vasculature and resultant GI bleeding (Finger et al. 2009)

2268

H. Kanavy et al.

Fig. 38 Vitamin B complex deficiency. Angular cheilitis-erythematous-violaceous inflammation and fissures of the bilateral labial commissures. Glossitis and stomatitis are other findings common to all B vitamin deficiencies (Miller 1989)

Fig. 39 Vitamin B3 (niacin) deficiency (pellagra). Sharply demarcated photosensitive eruption with keratotic, hyperpigmented plaques on sun-exposed areas including

the (a) neck (Casal’s necklace) and (b) hands. Look for diarrhea and dementia for complete diagnostic triad (Galimberti and Mesinkovska 2016)

102

Atlas of Dermatological Manifestations in Gastrointestinal Disease

2269

Fig. 40 Vitamin C deficiency (scurvy). (a) Follicular hyperkeratosis with “corkscrew hairs” and perifollicular hemorrhages. (b) Gingival erythema, edema, and hypertrophy (Galimberti and Mesinkovska 2016)

Fig. 41 Vitamin K deficiency. Ecchymoses and purpura. Vitamin K comes from dietary intake and synthesis by gut bacteria; therefore, be aware of this condition in ill patients who are receiving antibiotics and not eating (Miller 1989)

2270

Fig. 42 Drug rash. As mentioned, any medication can cause a drug rash, with the most common presentation being eczematous. This pruritic, erythematous, maculopapular eruption occurs due to hypersensitivity typically starting on the trunk and spreading peripherally.

H. Kanavy et al.

Proton-pump inhibitors, used by ~15 million individuals per year in the USA alone, can cause this eruption, with 78.1% of cases due specifically to omeprazole (Chularojanamontri et al. 2012)

102

Atlas of Dermatological Manifestations in Gastrointestinal Disease

2271

Fig. 43 Dry skin (xerosis). H2 blockers, another class of antacids, as well as pro-motility agents like metoclopramide, have anticholinergic activity. Anticholinergic agents decrease sweating and cause drying of the skin, which can be intensely pruritic (Collamati et al. 2016). Thick ointments such as petroleum jelly are best for hydration and can be applied as often as needed

Fig. 44 Psoriasis vulgaris. Erythematous plaques with thick silvery scale on bilateral knees. Plaque, palmoplantar, and pustular psoriasis can paradoxically manifest after initiation of a TNF-alpha inhibitor, such as for inflammatory bowel disease (IBD). This immune-mediated cutaneous reaction can cause an exacerbation of previously

indolent psoriatic lesions or trigger the development of new lesions altogether. If the TNF-alpha inhibitor is managing the patient’s IBD well and the psoriasis is mild, topical treatment can be initiated or an alternate drug in the class can be trialed (Lindhaus et al. 2017)

2272

Fig. 45 Erysipelas. Sharply demarcated, beefy red erythema of the anterior shin. This superficial cutaneous infection is common secondary to anti-TNF-alpha therapy. Older patients have an increased risk of infection with these immunosuppressing biologic agents, which, besides erysipelas, can cause cellulitis and abscesses in the skin and soft tissue. Most infections develop within 6 months of anti-TNF-alpha therapy initiation and require hospitalization for adequate antibiotic administration (Lindhaus et al. 2017)

H. Kanavy et al.

Fig. 46 Herpes zoster. Painful erythematous plaques with overlying vesicles in a dermatomal distribution. “Shingles” is most commonly seen in immunocompromised individuals such as the elderly or those on TNFalpha inhibitors. Before initiation of a TNF-alpha inhibitor, patients should be informed that reactivation of the latent herpes zoster virus can cause this painful rash. While immunosuppressing medications should not be started during an active infection, history of herpes zoster infection should not preclude use when appropriate (Lindhaus et al. 2017)

102

Atlas of Dermatological Manifestations in Gastrointestinal Disease

Fig. 47 Basal cell carcinoma. An ulcerated pink pearly papule with rolled-up borders and telangiectasia. There is an increased incidence of non-melanoma skin cancers in patients on anti-TNF-alpha therapy. The majority of these malignancies are basal cell carcinomas, but squamous cell carcinomas can also occur (Lindhaus et al. 2017). Therefore, patients on TNF-alpha inhibitors should undergo regular dermatologic evaluation

2273

Fig. 48 Steroid acne. Inflammatory papules and pustules with open and closed comedones densely aggregated on the chest. Corticosteroids are a mainstay of treatment for inflammatory GI disease such as inflammatory bowel disease and Henoch-Schönlein purpura (Hyams 2000). High doses of steroids can precipitate an eruption of acne on the face, chest, and back (Mills Jr. et al. 1973)

Fig. 49 Urticaria (wheals). Pruritic, edematous, erythematous, flat-topped plaques and wheals. Urticaria, or hives, can be caused by a hypersensitivity reaction to many medications. Additionally, opioid analgesics can act as non-immunologic stimuli for mast cell degranulation and produce an identical clinical presentation (Hennino et al. 2006)

2274

References Agarwal E, Miller M, Yaxley A, Isenring E. Malnutrition in the elderly: a narrative review. Maturitas. 2013;76(4):296–302. Antman K, Chang Y. Kaposi’s sarcoma. N Engl J Med. 2000;342(14):1027–38. Banse-Kupin L, Morales A, Barlow M. Torre’s syndrome: report of two cases and review of the literature. J Am Acad Dermatol. 1984;10(5 Pt 1):803–17. Boardman LA. Heritable colorectal cancer syndromes: recognition and preventive management. Gastroenterol Clin N Am. 2002;31(4):1107–31. Borrie P. Cutaneous polyarteritis nodosa. Br J Dermatol. 1972;87(2):87–95. Braverman IM. Skin manifestations of internal malignancy. Clin Geriatr Med. 2002;18(1):1–19. Brownstein MH, Mehregan AH, Bilowski JB. Trichilemmomas in Cowden’s disease. JAMA. 1977;238 (1):26. Chakroun A, Guigay J, Lusinchi A, Marandas P, Janot F, Hartl DM. Paraneoplastic dermatomyositis accompanying nasopharyngeal carcinoma: diagnosis, treatment and prognosis. Eur Ann Otorhinolaryngol Head Neck Dis. 2011;128(3):127–31. Chularojanamontri L, Jiamton S, Manapajon A, et al. Cutaneous reactions to proton pump inhibitors: a case-control study. J Drugs Dermatol. 2012;11(10): e43–7. Cidon EU. Cutaneous metastases in 42 patients with cancer. Indian J Dermatol Venereol Leprol. 2010;76(4):409–12. Collamati A, Martone AM, Poscia A, et al. Anticholinergic drugs and negative outcomes in the older population: from biological plausibility to clinical evidence. Aging Clin Exp Res. 2016;28(1):25–35. Collin P, Reunala T. Recognition and management of the cutaneous manifestations of celiac disease: a guide for dermatologists. Am J Clin Dermatol. 2003;4(1):13–20. Dicken CH. Bowel-associated dermatosis-arthritis syndrome: bowel bypass syndrome without bowel bypass. J Am Acad Dermatol. 1986;14(5 Pt 1):792–6. Dourmishev LA, Draganov PV. Paraneoplastic dermatological manifestation of gastrointestinal malignancies. World J Gastroenterol. 2009;15(35):4372–9. Erbe RW. Inherited gastrointestinal-polyposis syndromes. N Engl J Med. 1976;294(20):1101–4. Ertem D, Acar Y, Kotiloglu E, Yucelten D, Pehlivanoglu E. Blue rubber bleb nevus syndrome. Pediatrics. 2001;107 (2):418–20. Fargnoli MC, Orlow SJ, Semel-Concepcion J, Bolognia JL. Clinicopathologic findings in the Bannayan-Riley-Ruvalcaba syndrome. Arch Dermatol. 1996;132(10):1214–8. Farooq A, Walker LJ, Bowling J, Audisio RA. Cowden syndrome. Cancer Treat Rev. 2010;36 (8):577–83. Finger RP, Charbel Issa P, Ladewig MS, et al. Pseudoxanthoma elasticum: genetics, clinical

H. Kanavy et al. manifestations and therapeutic approaches. Surv Ophthalmol. 2009;54(2):272–85. Galimberti F, Mesinkovska NA. Skin findings associated with nutritional deficiencies. Cleve Clin J Med. 2016;83(10):731–9. Greenstein AJ, Janowitz HD, Sachar DB. The extra-intestinal complications of Crohn’s disease and ulcerative colitis: a study of 700 patients. Medicine (Baltimore). 1976;55(5):401–12. Hawryluk EB, Izikson L, English JC 3rd. Non-infectious granulomatous diseases of the skin and their associated systemic diseases: an evidence-based update to important clinical questions. Am J Clin Dermatol. 2010;11(3):171–81. Hennino A, Berard F, Guillot I, Saad N, Rozieres A, Nicolas JF. Pathophysiology of urticaria. Clin Rev Allergy Immunol. 2006;30(1):3–11. Hoetzenecker W, Nageli M, Mehra ET, et al. Adverse cutaneous drug eruptions: current understanding. Semin Immunopathol. 2016;38(1):75–86. Hyams JS. Corticosteroids in the treatment of gastrointestinal disease. Curr Opin Pediatr. 2000;12(5):451–5. Jornayvaz FR, Philippe J. Mucocutaneous papillomatous papules in Cowden’s syndrome. Clin Exp Dermatol. 2008;33(2):151–3. Kim M, Borradori L, Murrell DF. Autoimmune blistering diseases in the elderly: clinical presentations and management. Drugs Aging. 2016;33(10):711–23. Lindhaus C, Tittelbach J, Elsner P. Cutaneous side effects of TNF-alpha inhibitors. J Dtsch Dermatol Ges. 2017;15(3):281–8. Lobo I, Carvalho A, Amaral C, Machado S, Carvalho R. Glucagonoma syndrome and necrolytic migratory erythema. Int J Dermatol. 2010;49(1):24–9. McLean DI. Toward a definition of cutaneous paraneoplastic syndrome. Clin Dermatol. 1993;11(1):11–3. Miller SJ. Nutritional deficiency and the skin. J Am Acad Dermatol. 1989;21(1):1–30. Mills OH Jr, Leyden JJ, Kligman AM. Tretinoin treatment of steroid acne. Arch Dermatol. 1973;108(3):381–4. Mockenhaupt M. Epidemiology of cutaneous adverse drug reactions. Allergol Select. 2017;1(1):96–108. Munkvad M. Blue rubber bleb nevus syndrome. Dermatologica. 1983;167(6):307–9. Patel S, Zirwas M, English JC 3rd. Acquired palmoplantar keratoderma. Am J Clin Dermatol. 2007;8(1):1–11. Pentenero M, Carrozzo M, Pagano M, Gandolfo S. Oral acanthosis nigricans, tripe palms and sign of leser-trelat in a patient with gastric adenocarcinoma. Int J Dermatol. 2004;43(7):530–2. Plauchu H, de Chadarevian JP, Bideau A, Robert JM. Agerelated clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet. 1989;32(3):291–7. Plauth M, Jenss H, Meyle J. Oral manifestations of Crohn’s disease. An analysis of 79 cases. J Clin Gastroenterol. 1991;13(1):29–37. Ponti G, Luppi G, Losi L, Giannetti A, Seidenari S. LeserTrelat syndrome in patients affected by six multiple

102

Atlas of Dermatological Manifestations in Gastrointestinal Disease

metachronous primitive cancers. J Hematol Oncol. 2010;3:2. Powell FC, Schroeter AL, Su WP, Perry HO. Pyoderma gangrenosum: a review of 86 patients. Q J Med. 1985;55(217):173–86. Rahvar M, Kerstetter J. Cutaneous manifestation of gastrointestinal disease. J Gastrointest Oncol. 2016;7(Suppl 1):S44–54. Romer W, Burk M, Schneider W. Hereditary hemorrhagic telangiectasia (Osler’s disease). Dtsch Med Wochenschr. 1992;117(17):669–75. Saulsbury FT. Henoch-Schonlein purpura in children. Report of 100 patients and review of the literature. Medicine (Baltimore). 1999;78(6):395–409. Shah KR, Boland CR, Patel M, Thrash B, Menter A. Cutaneous manifestations of gastrointestinal disease: part I. J Am Acad Dermatol. 2013;68(2):189 e1–189.e21; quiz 210.

2275

Sharma V, Sharma NL, Ranjan N, Tegta GR, Sarin S. Acrokeratosis paraneoplastica (Bazex syndrome): case report and review of literature. Dermatol Online J. 2006;12(1):11. Sharma NL, Mahajan VK, Gupta N, Ranjan N, Lath A. Ehlers-Danlos syndrome – vascular type (ecchymotic variant): cutaneous and dermatopathologic features. J Cutan Pathol. 2009;36(4):486–92. Stone SP, Buescher LS. Life-threatening paraneoplastic cutaneous syndromes. Clin Dermatol. 2005;23(3):301–6. Thrash B, Patel M, Shah KR, Boland CR, Menter A. Cutaneous manifestations of gastrointestinal disease: part II. J Am Acad Dermatol. 2013;68(2):211 e1–211.e33; quiz 244-216. Zhu X, Zhang B. Paraneoplastic pemphigus. J Dermatol. 2007;34(8):503–11.

HIV in Older Adults

103

C. S. Pitchumoni and Mitesh A. Desai

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2278 Epidemiology of HIV/AIDS in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2282 Gastrointestinal System and HIV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2284 Anorexia and Weight Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2285 Esophagus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2286 Stomach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2287 Small and Large Bowel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2288 Biliary Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2291 Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2293 Malignancy in HIV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2294 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2295

C. S. Pitchumoni Department of Medicine, Robert Wood Johnson School of Medicine, Rutgers University, New Brunswick, NJ, USA Department of Medicine, New York Medical College, Valhalla, NY, USA Division of Gastroenterology, Hepatology and Clinical Nutrition, Saint Peters University Hospital, New Brunswick, NJ, USA e-mail: [email protected] M. A. Desai (*) Centers for Disease Control and Prevention, Atlanta, GA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2021 C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology, https://doi.org/10.1007/978-3-030-30192-7_91

2277

2278

C. S. Pitchumoni and M. A. Desai Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2295 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2295

Abstract

Human immunodeficiency virus (HIV) infection is the cause of acquired immunodeficiency syndrome (AIDS). HIV disease continues to be a significant public health problem, although highly active antiretroviral therapy (HAART) has changed the dismal prognosis that existed in the 1980s. Life expectancy for people living with HIV (PLHIV) in the USA has significantly improved in the HAART era. Globally, 5.8 million (16%) PLHIV were older than age 50 years in 2015; the proportion of older PLHIV will rise to 22% in 2020. The burden of the epidemic differs between countries and regions within countries. Sub-Saharan Africa remains most severely affected. Older age with HIV infection presents unique challenges because both older age and HIV disease increases the risk for cardiovascular disease, bone loss, and certain cancers. Older HIV patients have multimorbidity. Opportunistic infections are currently rarer mostly seen in newly diagnosed patients, but drug-related liver toxicities and age-related comorbid conditions have increased. The gastrointestinal (GI) manifestations are rare since the advent of HAART except in individuals not on treatment either because the diagnosis was missed earlier or the treatment was not offered. Profound involuntary weight loss or wasting (cachexia, a wasting syndrome) indicative of severe protein-energy malnutrition is a frequent complication of AIDS. In HIV, mucosal tissues are the primary sites of viral transmission and significant sites for viral replication. Hence various opportunistic infections, bacterial, viral, and parasitic of the gastrointestinal tract predominate in the clinical manifestations. Keywords

Human immunodeficiency virus, HIV-1 and HIV-2 · Acquired immunodeficiency syndrome (AIDS) · People living with HIV (PLHIV) · Highly active antiretroviral

treatment (HAART) · AIDS cholangiopathy · CD4+ T cells · Hepatocellular carcinoma (HCC), · Kaposi’s sarcoma · Hepatitis c · Acalculous cholecystitis · Cryptosporidium, microsporidia, and isospora · Tuberculosis, syphilis, and Bartonella henselae · AIDS enteropathy · Diarrheal diseases · Opportunistic infections

Introduction Human immunodeficiency virus (HIV) infection is the cause of acquired immunodeficiency syndrome (AIDS). The epidemic was identified in the 1980s; since then, more than 76 million people have been infected with the retrovirus, and over 39 million people have died of HIV. In 2017, almost 37 million people were living with HIV infection, of whom 1.8 million were incident cases that year. With the advent of effective combination antiretroviral therapy (HAART) over the last two decades, AIDSrelated deaths peaked at 1.9 million in 2006 and have since declined to under one million (940,000 in 2017) for the first time since 1996. With life expectancy for people living with HIV (PLHIV) retained on ART and with sustained viral load now approaching that for those not infected with HIV, there is an apparent increase in HIV prevalence. In the USA, almost half (48%) of the PLHIV were over age 50 years (Table 1; Figs. 1 and 2). Globally, whereas 5.8 million (16%) PLHIV were older than age 50 years in 2015, the proportion of older PLHIV will rise to 22% in 2020. Over 80% of older PLHIV (over age 50 years) will continue to be in lower and middle income countries, where age-related noncommunicable diseases, locally prevalent opportunistic coinfections, as well as certain HIV-associated cancers may amplify the interaction between aging and HIV, each, in turn, exacerbating the harms of the other, specifically vis-a-vis the gastrointestinal tract (Roser and Ritchie 2018). When HIV epidemics started than in the 1980s, people who were diagnosed with HIV or AIDS had only 1–2 years of life expectancy after the diagnosis. There was not much

103

HIV in Older Adults

2279

Table 1 Changing patterns of HIV demographics in the USA. Data complied from the 1998, 2008, and 2017 CDC Surveillance Reports (Centers for Disease Control and Prevention 2017, 2018) Parameter New diagnosis of HIV infection

1999 Data not available

New diagnosis of AIDS

46,4000

Death of persons with a diagnosis of HIV infection

Data not available

Deaths of persons with an AIDS diagnosis

16,432

Persons living with a diagnosis of HIV infection

11,020

Persons livings with an AIDS diagnosis

290,547

2008 41,269