Understanding Pathophysiology (Canadian Edition) [1st Edition] 9781771721196, 9781771721189

Table of contents :
Title Page......Page 2
Table of Contents......Page 4
Health Promotion Boxes......Page 17
Copyright......Page 19
Reviewers......Page 21
Contributors......Page 23
Preface......Page 27
Organization and Content......Page 28
Features to Promote Learning......Page 31
Art Program......Page 32
Teaching/Learning Package......Page 33
Acknowledgments......Page 34
Introduction to Pathophysiology......Page 35
Part One Basic Concepts of Pathophysiology......Page 37
Unit 1 The Cell......Page 38
1 Cellular Biology......Page 39
Prokaryotes and Eukaryotes......Page 41
Cellular Functions......Page 42
Structure and Function of Cellular Components......Page 43
Cell-to-Cell Adhesions......Page 55
Cellular Communication and Signal Transduction......Page 60
Cellular Metabolism......Page 63
Membrane Transport: Cellular Intake and Output......Page 67
Cellular Reproduction: The Cell Cycle......Page 78
Tissues......Page 81
Did You Understand?......Page 91
Key Terms......Page 95
References......Page 98
2 Genes and Genetic Diseases......Page 99
DNA, RNA, and Proteins: Heredity at the Molecular Level......Page 101
Chromosomes......Page 109
Elements of Formal Genetics......Page 118
Transmission of Genetic Diseases......Page 119
Linkage Analysis and Gene Mapping......Page 131
Multifactorial Inheritance......Page 134
Did You Understand?......Page 137
Key Terms......Page 140
References......Page 143
3 Epigenetics and Disease......Page 144
Epigenetic Mechanisms......Page 146
Epigenetics and Human Development......Page 149
Genomic Imprinting......Page 150
Inheritance of Epigenetic States......Page 153
Epigenetics and Cancer......Page 157
Future Directions......Page 160
Did You Understand?......Page 161
Key Terms......Page 163
References......Page 164
4 Altered Cellular and Tissue Biology......Page 167
Cellular Adaptation......Page 169
Cellular Injury......Page 176
Manifestations of Cellular Injury: Accumulations......Page 202
Cellular Death......Page 211
Aging and Altered Cellular and Tissue Biology......Page 218
Somatic Death......Page 222
Did You Understand?......Page 223
Key Terms......Page 227
References......Page 229
5 Fluids and Electrolytes, Acids and Bases......Page 234
Distribution of Body Fluids and Electrolytes......Page 236
Alterations in Water Movement......Page 239
Sodium, Chloride, and Water Balance......Page 241
Alterations in Sodium, Chloride, and Water Balance......Page 244
Alterations in Potassium and Other Electrolytes......Page 249
Acid-Base Balance......Page 256
Pediatric Considerations......Page 264
Geriatric Considerations......Page 265
Did You Understand?......Page 266
Key Terms......Page 269
References......Page 271
Unit 2 Mechanisms of Self-Defence......Page 273
6 Innate Immunity......Page 274
Human Defence Mechanisms......Page 276
Acute and Chronic Inflammation......Page 298
Wound Healing......Page 302
Pediatric Considerations......Page 308
Geriatric Considerations......Page 309
Did You Understand?......Page 310
Key Terms......Page 313
References......Page 316
7 Adaptive Immunity......Page 318
Third Line of Defence: Adaptive Immunity......Page 320
Antigens and Immunogens......Page 324
Antibodies......Page 325
Immune Response: Collaboration of B Cells and T Cells......Page 332
Cell-Mediated Immunity......Page 342
Pediatric Considerations......Page 344
Geriatric Considerations......Page 345
Did You Understand?......Page 346
Key Terms......Page 349
References......Page 351
8 Infection and Defects in Mechanisms of Defence......Page 352
Infection......Page 353
Deficiencies in Immunity......Page 371
Hypersensitivity: Allergy, Autoimmunity, and Alloimmunity......Page 386
Did You Understand?......Page 402
Key Terms......Page 405
References......Page 408
9 Stress and Disease......Page 412
Historical Background and General Concepts......Page 414
The Stress Response......Page 418
Stress, Personality, Coping, and Illness......Page 429
Geriatric Considerations......Page 434
Did You Understand?......Page 435
Key Terms......Page 438
References......Page 439
Unit 3 Cellular Proliferation: Cancer......Page 445
10 Biology of Cancer......Page 446
Cancer Terminology and Characteristics......Page 449
The Biology of Cancer Cells......Page 454
Clinical Manifestations of Cancer......Page 479
Diagnosis, Characterization, and Treatment of Cancer......Page 485
Did You Understand?......Page 492
Key Terms......Page 496
References......Page 498
11 Cancer Epidemiology......Page 501
Genetics, Epigenetics, and Tissue......Page 507
Incidence and Mortality Trends......Page 509
In Utero and Early Life Conditions......Page 511
Environmental and Lifestyle Factors......Page 513
Did You Understand?......Page 541
Key Terms......Page 547
References......Page 548
12 Cancer in Children and Adolescents......Page 559
Incidence, Etiology, and Types of Childhood Cancer......Page 561
Prognosis......Page 568
Did You Understand?......Page 570
Key Terms......Page 571
References......Page 572
Part Two Body Systems and Diseases......Page 574
Unit 4 The Neurological System......Page 575
13 Structure and Function of the Neurological System......Page 576
Overview and Organization of the Nervous System......Page 579
Cells of the Nervous System......Page 580
The Nerve Impulse......Page 587
The Central Nervous System......Page 590
The Peripheral Nervous System......Page 613
The Autonomic Nervous System......Page 615
Geriatric Considerations......Page 621
Did You Understand?......Page 622
Key Terms......Page 624
References......Page 628
14 Pain, Temperature, Sleep, and Sensory Function......Page 629
Pain......Page 632
Temperature Regulation......Page 642
Sleep......Page 648
The Special Senses......Page 651
Somatosensory Function......Page 663
Geriatric Considerations......Page 664
Geriatric Considerations......Page 665
Geriatric Considerations......Page 666
Did You Understand?......Page 667
Key Terms......Page 671
References......Page 675
15 Alterations in Cognitive Systems, Cerebral Hemodynamics, and Motor Function......Page 680
Alterations in Cognitive Systems......Page 683
Alterations in Cerebral Hemodynamics......Page 703
Alterations in Neuromotor Function......Page 708
Alterations in Complex Motor Performance......Page 722
Extrapyramidal Motor Syndromes......Page 724
Did You Understand?......Page 725
Key Terms......Page 728
References......Page 731
16 Disorders of the Central and Peripheral Nervous Systems and Neuromuscular Junction......Page 734
Central Nervous System Disorders......Page 736
Peripheral Nervous System and Neuromuscular Junction Disorders......Page 771
Tumours of the Central Nervous System......Page 773
Did You Understand?......Page 779
Key Terms......Page 782
References......Page 784
17 Alterations of Neurological Function in Children......Page 790
Development of the Nervous System in Children......Page 792
References......Page 793
Structural Malformations......Page 795
Alterations in Function: Encephalopathies......Page 805
Cerebrovascular Disease in Children......Page 810
Childhood Tumours......Page 812
Did You Understand?......Page 818
Key Terms......Page 820
References......Page 821
Unit 5 The Endocrine System......Page 824
18 Mechanisms of Hormonal Regulation......Page 825
Mechanisms of Hormonal Regulation......Page 828
Structure and Function of the Endocrine Glands......Page 835
Geriatric Considerations......Page 853
Did You Understand?......Page 854
Key Terms......Page 857
References......Page 859
19 Alterations of Hormonal Regulation......Page 861
Mechanisms of Hormonal Alterations......Page 863
Alterations of the Hypothalamic-Pituitary System......Page 865
Alterations of Thyroid Function......Page 874
Alterations of Parathyroid Function......Page 882
Dysfunction of the Endocrine Pancreas: Diabetes Mellitus......Page 885
Alterations of Adrenal Function......Page 902
Did You Understand?......Page 910
Key Terms......Page 914
References......Page 916
Unit 6 The Hematological System......Page 921
20 Structure and Function of the Hematological System......Page 922
Components of the Hematological System......Page 924
Development of Blood Cells......Page 935
Mechanisms of Hemostasis......Page 945
Pediatric Considerations......Page 953
Geriatric Considerations......Page 955
Did You Understand?......Page 956
Key Terms......Page 958
References......Page 960
21 Alterations of Hematological Function......Page 961
Alterations of Erythrocyte Function......Page 964
Myeloproliferative Red Blood Cell Disorders......Page 975
Alterations of Leukocyte Function......Page 979
Alterations of Lymphoid Function......Page 991
Alterations of Splenic Function......Page 1004
Hemorrhagic Disorders and Alterations of Platelets and Coagulation......Page 1006
Did You Understand?......Page 1022
Key Terms......Page 1026
References......Page 1029
22 Alterations of Hematological Function in Children......Page 1034
Disorders of Erythrocytes......Page 1036
Disorders of Coagulation and Platelets......Page 1048
Neoplastic Disorders......Page 1051
Did You Understand?......Page 1056
Key Terms......Page 1058
References......Page 1059
Unit 7 The Cardiovascular and Lymphatic Systems......Page 1061
23 Structure and Function of the Cardiovascular and Lymphatic Systems......Page 1062
The Circulatory System......Page 1064
The Heart......Page 1065
The Systemic Circulation......Page 1089
The Lymphatic System......Page 1104
Did You Understand?......Page 1107
Key Terms......Page 1111
References......Page 1114
24 Alterations of Cardiovascular Function......Page 1116
Diseases of the Veins......Page 1119
Diseases of the Arteries......Page 1122
Disorders of the Heart Wall......Page 1158
Manifestations of Heart Disease......Page 1175
Shock......Page 1185
Did You Understand?......Page 1200
Key Terms......Page 1204
References......Page 1206
25 Alterations of Cardiovascular Function in Children......Page 1215
Congenital Heart Disease......Page 1217
Acquired Cardiovascular Disorders......Page 1238
Did You Understand?......Page 1245
Key Terms......Page 1247
References......Page 1248
Unit 8 The Pulmonary System......Page 1249
26 Structure and Function of the Pulmonary System......Page 1250
Structures of the Pulmonary System......Page 1252
Function of the Pulmonary System......Page 1259
Geriatric Considerations......Page 1273
Did You Understand?......Page 1275
Key Terms......Page 1277
References......Page 1278
27 Alterations of Pulmonary Function......Page 1279
Clinical Manifestations of Pulmonary Alterations......Page 1281
Disorders of the Chest Wall and Pleura......Page 1288
Pulmonary Disorders......Page 1292
Did You Understand?......Page 1326
Key Terms......Page 1329
References......Page 1331
28 Alterations of Pulmonary Function in Children......Page 1337
Disorders of the Upper Airways......Page 1339
Disorders of the Lower Airways......Page 1345
Sudden Unexpected Infant Death......Page 1360
Did You Understand?......Page 1362
Key Terms......Page 1364
References......Page 1365
Unit 9 The Renal and Urological Systems......Page 1370
29 Structure and Function of the Renal and Urological Systems......Page 1371
Structures of the Renal System......Page 1374
Renal Blood Flow......Page 1383
Kidney Function......Page 1386
Tests of Renal Function......Page 1396
Pediatric Considerations......Page 1399
Geriatric Considerations......Page 1400
Did You Understand?......Page 1401
Key Terms......Page 1403
References......Page 1405
30 Alterations of Renal and Urinary Tract Function......Page 1406
Urinary Tract Obstruction......Page 1409
Urinary Tract Infection......Page 1419
Glomerular Disorders......Page 1424
Acute Kidney Injury......Page 1431
Chronic Kidney Disease......Page 1436
Did You Understand?......Page 1443
Key Terms......Page 1445
References......Page 1447
31 Alterations of Renal and Urinary Tract Function in Children......Page 1452
Structural Abnormalities......Page 1455
Glomerular Disorders......Page 1459
Nephroblastoma......Page 1462
Bladder Disorders......Page 1464
Urinary Incontinence......Page 1467
Did You Understand?......Page 1469
Key Terms......Page 1471
References......Page 1472
Unit 10 The Reproductive Systems......Page 1475
32 Structure and Function of the Reproductive Systems......Page 1476
Development of the Reproductive Systems......Page 1479
The Female Reproductive System......Page 1484
Structure and Function of the Breast......Page 1496
The Male Reproductive System......Page 1499
Aging and Reproductive Function......Page 1506
Did You Understand?......Page 1509
Key Terms......Page 1512
References......Page 1514
33 Alterations of the Female Reproductive System......Page 1517
Abnormalities of the Female Reproductive Tract......Page 1520
Alterations of Sexual Maturation......Page 1522
Disorders of the Female Reproductive System......Page 1526
Disorders of the Female Breast......Page 1565
Did You Understand?......Page 1590
Key Terms......Page 1594
References......Page 1596
34 Alterations of the Male Reproductive System......Page 1607
Alterations of Sexual Maturation......Page 1610
Disorders of the Male Reproductive System......Page 1613
References......Page 1633
Disorders of the Male Breast......Page 1649
Sexually Transmitted Infections......Page 1651
Did You Understand?......Page 1658
Key Terms......Page 1660
References......Page 1661
Unit 11 The Digestive System......Page 1667
35 Structure and Function of the Digestive System......Page 1668
The Gastro-Intestinal Tract......Page 1671
Accessory Organs of Digestion......Page 1689
Geriatric Considerations......Page 1701
Did You Understand?......Page 1703
Key Terms......Page 1706
References......Page 1709
36 Alterations of Digestive Function......Page 1710
Disorders of the Gastro-Intestinal Tract......Page 1713
Disorders of the Accessory Organs of Digestion......Page 1750
Cancer of the Digestive System......Page 1767
Did You Understand?......Page 1777
Key Terms......Page 1782
References......Page 1785
37 Alterations of Digestive Function in Children......Page 1796
Disorders of the Gastro-Intestinal Tract......Page 1798
Disorders of the Liver......Page 1817
Gastro-Intestinal Malignancies in Children......Page 1823
Did You Understand?......Page 1824
Key Terms......Page 1826
References......Page 1828
Unit 12 The Musculo-skeletal and Integumentary Systems......Page 1835
38 Structure and Function of the Musculo-skeletal System......Page 1836
Structure and Function of Bones......Page 1838
Structure and Function of Joints......Page 1849
Structure and Function of Skeletal Muscles......Page 1855
Aging and the Musculo-skeletal System......Page 1868
Did You Understand?......Page 1870
Key Terms......Page 1872
References......Page 1875
39 Alterations of Musculo-skeletal Function......Page 1877
Musculo-skeletal Injuries......Page 1880
Disorders of Bones......Page 1897
Disorders of Joints......Page 1913
Disorders of Skeletal Muscle......Page 1932
Musculo-skeletal Tumours......Page 1943
Did You Understand?......Page 1950
Key Terms......Page 1952
References......Page 1955
40 Alterations of Musculo-skeletal Function in Children......Page 1969
Congenital Defects......Page 1972
Bone Infection......Page 1978
Juvenile Idiopathic Arthritis......Page 1981
Osteochondroses......Page 1983
Scoliosis......Page 1987
Muscular Dystrophy......Page 1988
Musculo-skeletal Tumours......Page 1993
Nonaccidental Trauma......Page 1997
Did You Understand?......Page 1999
Key Terms......Page 2001
References......Page 2002
41 Structure, Function, and Disorders of the Integument......Page 2004
Structure and Function of the Skin......Page 2007
Disorders of the Skin......Page 2019
Disorders of the Hair......Page 2053
Disorders of the Nail......Page 2054
Geriatric Considerations......Page 2055
Did You Understand?......Page 2056
Key Terms......Page 2059
References......Page 2061
42 Alterations of the Integument in Children......Page 2067
Acne Vulgaris......Page 2070
Dermatitis......Page 2072
Infections of the Skin......Page 2075
Insect Bites and Parasites......Page 2084
Cutaneous Hemangiomas and Vascular Malformations......Page 2087
Other Skin Disorders......Page 2090
Did You Understand?......Page 2091
Key Terms......Page 2093
References......Page 2094
Index......Page 2097
Prefixes and Suffixes Used in Medical Terminology......Page 2332
Word Roots Commonly Used in Medical Terminology......Page 2334

Citation preview

Understanding Pathophysiology FIRST CANADIAN EDITION

Mohamed Toufic El-Hussein, RN, PhD Associate Professor, School of Nursing Faculty of Health, Community & Education Mount Royal University Calgary, Alberta

Kelly Power-Kean, MHS, NP, RN Center for Nursing Studies Memorial University St. John's, Newfoundland

Stephanie Zettel, BN, MN Associate Professor School of Nursing and Midwifery Mount Royal University Calgary, Alberta U.S. AUTHORS

Sue E. Huether, MS, PhD Professor Emeritus College of Nursing University of Utah Salt Lake City, Utah

Kathryn L. McCance, MS, PhD Professor Emeritus College of Nursing University of Utah Salt Lake City, Utah U.S. Section Editors

Valentina L. Brashers, MD Professor of Nursing and Woodard Clinical Scholar Attending Physician in Internal Medicine University of Virginia Health System Charlottesville, Virginia

Neal S. Rote, PhD Academic Vice-Chair and Director of Research Department of Obstetrics and Gynecology University Hospitals Case Medical Center William H. Weir, MD, Professor of Reproductive Biology and Pathology Case Western Reserve University School of Medicine Cleveland, Ohio

Table of Contents Cover image Title Page Health Promotion Boxes Copyright Reviewers Contributors Preface Organization and Content Features to Promote Learning Art Program Teaching/Learning Package Acknowledgments

Introduction to Pathophysiology

Part One Basic Concepts of Pathophysiology Unit 1 The Cell 1 Cellular Biology Prokaryotes and Eukaryotes Cellular Functions Structure and Function of Cellular Components Cell-to-Cell Adhesions Cellular Communication and Signal Transduction Cellular Metabolism Membrane Transport: Cellular Intake and Output Cellular Reproduction: The Cell Cycle

Tissues Did You Understand? Key Terms References

2 Genes and Genetic Diseases DNA, RNA, and Proteins: Heredity at the Molecular Level Chromosomes Elements of Formal Genetics Transmission of Genetic Diseases Linkage Analysis and Gene Mapping Multifactorial Inheritance Did You Understand? Key Terms References

3 Epigenetics and Disease Epigenetic Mechanisms Epigenetics and Human Development Genomic Imprinting Inheritance of Epigenetic States Epigenetics and Cancer Future Directions Did You Understand? Key Terms References

4 Altered Cellular and Tissue Biology Cellular Adaptation Cellular Injury Manifestations of Cellular Injury: Accumulations Cellular Death Aging and Altered Cellular and Tissue Biology Somatic Death Did You Understand? Key Terms References

5 Fluids and Electrolytes, Acids and Bases

Distribution of Body Fluids and Electrolytes Alterations in Water Movement Sodium, Chloride, and Water Balance Alterations in Sodium, Chloride, and Water Balance Alterations in Potassium and Other Electrolytes Acid-Base Balance Pediatric Considerations Geriatric Considerations Did You Understand? Key Terms References

Unit 2 Mechanisms of Self-Defence 6 Innate Immunity Human Defence Mechanisms Acute and Chronic Inflammation Wound Healing Pediatric Considerations Geriatric Considerations Did You Understand? Key Terms References

7 Adaptive Immunity Third Line of Defence: Adaptive Immunity Antigens and Immunogens Antibodies Immune Response: Collaboration of B Cells and T Cells Cell-Mediated Immunity Pediatric Considerations Geriatric Considerations Did You Understand? Key Terms References

8 Infection and Defects in Mechanisms of Defence Infection

Deficiencies in Immunity Hypersensitivity: Allergy, Autoimmunity, and Alloimmunity Did You Understand? Key Terms References

9 Stress and Disease Historical Background and General Concepts The Stress Response Stress, Personality, Coping, and Illness Geriatric Considerations Did You Understand? Key Terms References

Unit 3 Cellular Proliferation: Cancer 10 Biology of Cancer Cancer Terminology and Characteristics The Biology of Cancer Cells Clinical Manifestations of Cancer Diagnosis, Characterization, and Treatment of Cancer Did You Understand? Key Terms References

11 Cancer Epidemiology Genetics, Epigenetics, and Tissue Incidence and Mortality Trends In Utero and Early Life Conditions Environmental and Lifestyle Factors Did You Understand? Key Terms References

12 Cancer in Children and Adolescents Incidence, Etiology, and Types of Childhood Cancer Prognosis

Did You Understand? Key Terms References

Part Two Body Systems and Diseases Unit 4 The Neurological System 13 Structure and Function of the Neurological System Overview and Organization of the Nervous System Cells of the Nervous System The Nerve Impulse The Central Nervous System The Peripheral Nervous System The Autonomic Nervous System Geriatric Considerations Did You Understand? Key Terms References

14 Pain, Temperature, Sleep, and Sensory Function Pain Temperature Regulation Sleep The Special Senses Somatosensory Function Geriatric Considerations Geriatric Considerations Geriatric Considerations Did You Understand? Key Terms References

15 Alterations in Cognitive Systems, Cerebral Hemodynamics, and Motor Function Alterations in Cognitive Systems Alterations in Cerebral Hemodynamics Alterations in Neuromotor Function Alterations in Complex Motor Performance Extrapyramidal Motor Syndromes

Did You Understand? Key Terms References

16 Disorders of the Central and Peripheral Nervous Systems and Neuromuscular Junction Central Nervous System Disorders Peripheral Nervous System and Neuromuscular Junction Disorders Tumours of the Central Nervous System Did You Understand? Key Terms References

17 Alterations of Neurological Function in Children Development of the Nervous System in Children References Structural Malformations Alterations in Function: Encephalopathies Cerebrovascular Disease in Children Childhood Tumours Did You Understand? Key Terms References

Unit 5 The Endocrine System 18 Mechanisms of Hormonal Regulation Mechanisms of Hormonal Regulation Structure and Function of the Endocrine Glands Geriatric Considerations Did You Understand? Key Terms References

19 Alterations of Hormonal Regulation Mechanisms of Hormonal Alterations Alterations of the Hypothalamic-Pituitary System Alterations of Thyroid Function Alterations of Parathyroid Function

Dysfunction of the Endocrine Pancreas: Diabetes Mellitus Alterations of Adrenal Function Did You Understand? Key Terms References

Unit 6 The Hematological System 20 Structure and Function of the Hematological System Components of the Hematological System Development of Blood Cells Mechanisms of Hemostasis Pediatric Considerations Geriatric Considerations Did You Understand? Key Terms References

21 Alterations of Hematological Function Alterations of Erythrocyte Function Myeloproliferative Red Blood Cell Disorders Alterations of Leukocyte Function Alterations of Lymphoid Function Alterations of Splenic Function Hemorrhagic Disorders and Alterations of Platelets and Coagulation Did You Understand? Key Terms References

22 Alterations of Hematological Function in Children Disorders of Erythrocytes Disorders of Coagulation and Platelets Neoplastic Disorders Did You Understand? Key Terms References

Unit 7 The Cardiovascular and Lymphatic Systems 23 Structure and Function of the Cardiovascular and Lymphatic Systems The Circulatory System The Heart The Systemic Circulation The Lymphatic System Did You Understand? Key Terms References

24 Alterations of Cardiovascular Function Diseases of the Veins Diseases of the Arteries Disorders of the Heart Wall Manifestations of Heart Disease Shock Did You Understand? Key Terms References

25 Alterations of Cardiovascular Function in Children Congenital Heart Disease Acquired Cardiovascular Disorders Did You Understand? Key Terms References

Unit 8 The Pulmonary System 26 Structure and Function of the Pulmonary System Structures of the Pulmonary System Function of the Pulmonary System Geriatric Considerations Did You Understand? Key Terms References

27 Alterations of Pulmonary Function Clinical Manifestations of Pulmonary Alterations Disorders of the Chest Wall and Pleura Pulmonary Disorders Did You Understand? Key Terms References

28 Alterations of Pulmonary Function in Children Disorders of the Upper Airways Disorders of the Lower Airways Sudden Unexpected Infant Death Did You Understand? Key Terms References

Unit 9 The Renal and Urological Systems 29 Structure and Function of the Renal and Urological Systems Structures of the Renal System Renal Blood Flow Kidney Function Tests of Renal Function Pediatric Considerations Geriatric Considerations Did You Understand? Key Terms References

30 Alterations of Renal and Urinary Tract Function Urinary Tract Obstruction Urinary Tract Infection Glomerular Disorders Acute Kidney Injury Chronic Kidney Disease Did You Understand? Key Terms References

31 Alterations of Renal and Urinary Tract Function in Children Structural Abnormalities Glomerular Disorders Nephroblastoma Bladder Disorders Urinary Incontinence Did You Understand? Key Terms References

Unit 10 The Reproductive Systems 32 Structure and Function of the Reproductive Systems Development of the Reproductive Systems The Female Reproductive System Structure and Function of the Breast The Male Reproductive System Aging and Reproductive Function Did You Understand? Key Terms References

33 Alterations of the Female Reproductive System Abnormalities of the Female Reproductive Tract Alterations of Sexual Maturation Disorders of the Female Reproductive System Disorders of the Female Breast Did You Understand? Key Terms References

34 Alterations of the Male Reproductive System Alterations of Sexual Maturation Disorders of the Male Reproductive System References Disorders of the Male Breast Sexually Transmitted Infections Did You Understand?

Key Terms References

Unit 11 The Digestive System 35 Structure and Function of the Digestive System The Gastro-Intestinal Tract Accessory Organs of Digestion Geriatric Considerations Did You Understand? Key Terms References

36 Alterations of Digestive Function Disorders of the Gastro-Intestinal Tract Disorders of the Accessory Organs of Digestion Cancer of the Digestive System Did You Understand? Key Terms References

37 Alterations of Digestive Function in Children Disorders of the Gastro-Intestinal Tract Disorders of the Liver Gastro-Intestinal Malignancies in Children Did You Understand? Key Terms References

Unit 12 The Musculo-skeletal and Integumentary Systems 38 Structure and Function of the Musculo-skeletal System Structure and Function of Bones Structure and Function of Joints Structure and Function of Skeletal Muscles Aging and the Musculo-skeletal System Did You Understand?

Key Terms References

39 Alterations of Musculo-skeletal Function Musculo-skeletal Injuries Disorders of Bones Disorders of Joints Disorders of Skeletal Muscle Musculo-skeletal Tumours Did You Understand? Key Terms References

40 Alterations of Musculo-skeletal Function in Children Congenital Defects Bone Infection Juvenile Idiopathic Arthritis Osteochondroses Scoliosis Muscular Dystrophy Musculo-skeletal Tumours Nonaccidental Trauma Did You Understand? Key Terms References

41 Structure, Function, and Disorders of the Integument Structure and Function of the Skin Disorders of the Skin Disorders of the Hair Disorders of the Nail Geriatric Considerations Did You Understand? Key Terms References

42 Alterations of the Integument in Children Acne Vulgaris Dermatitis

Infections of the Skin Insect Bites and Parasites Cutaneous Hemangiomas and Vascular Malformations Other Skin Disorders Did You Understand? Key Terms References

Index Prefixes and Suffixes Used in Medical Terminology Word Roots Commonly Used in Medical Terminology

Health Promotion Boxes Gene Therapy, 57 The Percentage of Child Medication–Related Poisoning Deaths Is Increasing, 85 Air Pollution Reported as Largest Single Environmental Health Risk, 86 Low-Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention, 88 Low-Risk Alcohol Drinking Guidelines, 92 Hyponatremia and Older Adults, 122 Potassium Intake: Hypertension and Stroke, 123 Tuberculosis and the Indigenous Population in Canada, 178 Risk of HIV Transmission Associated With Sexual Practices, 196 Glucocorticoids, Insulin, Inflammation, and Obesity, 222 Psychosocial Stress and Progression to Coronary Heart Disease, 223 Acute Emotional Stress and Adverse Heart Effects, 228 Partner's Survival and Spouse's Hospitalizations and/or Death, 228 Global Cancer Statistics and Risk Factors Associated With Causes of Cancer Death, 274 World Health Organization Cancer Prevention Strategies, 275 Increasing Use of Computed Tomography Scans and Associated Risks, 287 Rising Incidence of HPV-Associated Oropharyngeal Cancers, 293 Radiation Risks and Pediatric Computed Tomography: Data from the US National Cancer Institute, 306 Magnetic Fields and Development of Pediatric Cancer, 306 Bone Marrow Transplantation: Improving Outcomes for Canadian Children and Adolescent Cancer Patients, 307 Neuroplasticity, 313 Reducing Risk Factors Associated With Alzheimer's Disease, 376 Tourette Syndrome, 382 Prevention of Stroke in Women, 406 West Nile Virus, 414 Prevention of Fetal Alcohol Spectrum Disorders, 427 Growth Hormone Supplementation in Aging, 451 Vitamin D, 454 Type 1 Diabetes Mellitus, 479 Type 2 Diabetes Mellitus, 481 Sticky Platelets, 511 Prevention of Iron-Deficiency Anemia in Infants and Children, 561 B-type Natriuretic Peptide and Heart Failure, 598 Hypertension, 608 Obesity and Hypertension, 609 Recommendations for Managing Cholesterol, 619 Women and Microvascular Angina, 621 Canadian Heart Failure Statistics, 639 Sepsis Prevention: Central Line–Associated Bloodstream Infection, 651 The Surviving Sepsis Guidelines, 652 Endocarditis Risk, 666 Childhood Obesity in Canada, 676 Asthma, 706 Tips to Keep Lungs Healthy, 709

Ventilator-Associated Pneumonia, 712 Facts on Tobacco Use, 718 Lung Cancer, 720 Exercise-Induced Bronchoconstriction, 734 Cystic Fibrosis, 736 Vitamin D Supplementation, 752 Kidney Failure in Canada, 754 Urinary Tract Infection and Antibiotic Resistance, 766 Childhood Urinary Tract Infections, 789 Nutrition and Premenstrual Syndrome, 824 Nonsurgical Management of Vaginal Prolapse, 828 Screening With the Papanicolaou Test and with the Human Papillomavirus DNA Test, 834 Cervical Cancer Primary Prevention, 836 Breast Cancer Screening Mammography, 847 Acetaminophen and Acute Liver Failure, 915 Clostridium difficile and Diarrhea, 923 The Impact of Inflammatory Bowel Disease in Canada, 936 Promotion of Physical Activity in Canadian Schools, 940 Childhood Obesity and Fatty Liver Disease in Canada, 982 Tendon and Ligament Repair, 1007 Managing Tendinopathy, 1017 The Cost of Osteoporosis: Facts and Figures, 1022 Calcium, Vitamin D, and Bone Health, 1025 New Treatments for Osteoporosis, 1026 Musculo-skeletal Molecular Imaging, 1035 Psoriasis and Comorbidities, 1084 Melanoma in People With Darkly Pigmented Skin, 1094

Copyright UNDERSTANDING PATHOPHYSIOLOGY, FIRST CANADIAN EDITION ISBN: 978-1-77172-117-2 Copyright © 2018 Elsevier Canada, a division of Reed Elsevier Canada, Ltd. This adaptation of Understanding Pathophysiology, Sixth Edition, by Sue E. Huether and Kathryn L. McCance is published by arrangement with Elsevier, Inc. ISBN: 978-0-323-35409-7 Copyright © 2017, Elsevier Inc. All rights reserved. Previous editions copyrighted 2012, 2008, 2004, 2000, 1996. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Reproducing passages from this book without such written permission is an infringement of copyright law. Requests for permission to make copies of any part of the work should be mailed to: College Licensing Officer, access ©, 1 Yonge Street, Suite 1900, Toronto, ON M5E 1E5. Fax: (416) 868-1621. All other inquiries should be directed to the publisher. Every reasonable effort has been made to acquire permission for copyrighted material used in this edition and to acknowledge all such indebtedness accurately. Any errors and omissions called to the publisher's attention will be corrected in future printings.

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

Library and Archives Canada Cataloguing in Publication Huether, Sue E., author Understanding pathophysiology / Sue Huether, Kelly Power-Kean, Mohamed El-Hussein, Kathryn McCance, Stephanie Zettel. – First Canadian edition. ISBN 978-1-77172-117-2 (softcover) 1. Physiology, Pathological–Textbooks. 2. Physiology, Pathological–Canada–Textbooks. I. Title. RB113.H84 2018 616.07 C2017-903057-4 Cover Photo Credits Outer left: Antibody and antigen – © Stefanie Winkler/Dreamstime.com Inner left: Bacteria attacking the immune system – © Science Pics/Dreamstime.com Inner right: Virus in blood – © Rangpl/Dreamstime.com Outer right: T-cell – © Andreus/Dreamstime.com VP Medical and Canadian Education: Madelene J. Hyde Content Strategist (Acquisitions): Roberta A. Spinosa-Millman Content Development Manager: Laurie Gower Content Development Specialist: Martina van de Velde Publishing Services Manager: Julie Eddy Senior Project Manager: Richard Barber Cover Designer: Brett J. Miller, BJM Graphic Design and Communications Book Designer: Maggie Reid Elsevier Canada 420 Main Street East, Suite 636, Milton, ON, Canada L9T 5G3 Phone: 416-644-7053 Printed in Canada Last digit is the print number: 9 8 7 6 5 4 3 2 1

Reviewers Colleen Battista BScN, RN, MN Nursing Faculty Collaborative BScN Program St. Lawrence College/Laurentian University St. Lawrence College, Cornwall Campus Cornwall, Ontario Brenda Dafoe Enns BA, RN, MN Nursing Instructor Baccalaureate Nursing Program School of Health Sciences and Community Services Red River College Winnipeg, Manitoba Daphne Gill BA, PhD Sessional Lecturer Department of Biology University of Prince Edward Island Charlottetown, Prince Edward Island Heather Helpard BN, MN, PhD Assistant Professor School of Nursing Dalhousie University Halifax, Nova Scotia Anne-Marie Kowatsch BSc, MSc Instructor Baccalaureate Nursing Program Red River College Winnipeg, Manitoba Tara Lyster BScN, RN, MN Sessional Lecturer School of Nursing Thompson Rivers University Kamloops, British Columbia Joan Mills RN, MN, CCN(C) Assistant Professor Faculty of Nursing MacEwan University Edmonton, Alberta Deborah Morrison RN, BScN, MN Nursing Chair—Interim School of Health & Community Services

Durham College Oshawa, Ontario Maha Othman MD, MSc, PhD Professor School of Baccalaureate Nursing St. Lawrence College Kingston, Ontario Jennifer Perry RN(EC), NP-PHC, PhD Professor School of Nursing St. Lawrence College Kingston, Ontario Kara Sealock BN, RN, MEd, CNCC(C) Nursing Instructor Faculty of Nursing University of Calgary Calgary, Alberta

Contributors The editors would like to acknowledge the following contributors, whose work is the foundation on which the First Canadian Edition is based: Barbara J. Boss RN, PHD, CFNP, CANP Retired Professor of Nursing University of Mississippi Medical Center Jackson, Mississippi Kristen Lee Carroll MD Chief of Staff Medical Staff/Orthopedics Shriners Hospital for Children Professor of Orthopedics University of Utah Salt Lake City, Utah Margaret F. Clayton PhD, APRN Associate Professor and Assistant Dean for the PhD Program College of Nursing University of Utah Salt Lake City, Utah Christy L. Crowther-Radulewicz RN, MS, CRNP Nurse Practitioner Orthopedic Surgery Anne Arundel Orthopedic Surgeons Annapolis, Maryland Susanna G. Cunningham BSN, MA, PhD, RN, FAHA, FAAN Professor Emeritus Department of Biobehavioral Nursing School of Nursing University of Washington Seattle, Washington Sara J. Fidanza MS, RN, CNS-BC, CPNP-BC Digestive Health Institute Children's Hospital Colorado Clinical Faculty University of Colorado College of Nursing Aurora, Colorado Diane P. Genereux PhD Assistant Professor Department of Biology Westfield State Westfield, Massachusetts

Todd Cameron Grey MD Chief Medical Examiner Office of the Medical Examiner State of Utah Salt Lake City, Utah Robert E. Jones MD, FACP, FACE Professor of Medicine Endocrinology Division University of Utah School of Medicine Salt Lake City, Utah Lynn B. Jorde PhD H.A. and Edna Benning Presidential Professor and Chair Department of Human Genetics University of Utah School of Medicine Salt Lake City, Utah Lynne M. Kerr MD, PhD Associate Professor Department of Pediatrics, Division of Pediatric Neurology University of Utah Medical Center Salt Lake City, Utah Nancy E. Kline PhD, RN, CPNP, FAAN † Director, Nursing Research, Medicine Patient Services/Emergency Department Boston Children's Hospital Boston, Massachusetts Lauri A. Linder PhD, APRN, CPON Assistant Professor College of Nursing University of Utah Clinical Nurse Specialist Cancer Transplant Center Primary Children's Hospital Salt Lake City, Utah Sue Ann McCann MSN, RN, DNC Programmatic Nurse Specialist Nursing Clinical Research Coordinator Dermatology University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Nancy L. McDaniel MD Associate Professor of Pediatrics University of Virginia Charlottesville, Virginia Afsoon Moktar PhD, EMBA, CT (ASCP) Associate Professor School of Physician Assistant Studies

Massachusetts College of Pharmacy and Health Sciences University Boston, Massachusetts Noreen Heer Nicol PhD, RN, FNP, NEA-BC Associate Professor College of Nursing University of Colorado Denver, Colorado Nancy Pike PhD, RN, CPNP-AC, FAAN Assistant Professor UCLA School of Nursing Pediatric Nurse Practitioner Cardiothoracic Surgery Children's Hospital Los Angeles Los Angeles, California Patricia Ring RN, MSN, PNP, BC Pediatric Nephrology Children's Hospital of Wisconsin Wauwatosa, Wisconsin Anna E. Roche MSN, RN, CPNP, CPON Pediatric Nurse Practitioner Dana Farber/Boston Children's Cancer and Blood Disorders Center Boston, Massachusetts George W. Rodway PhD, APRN Associate Clinical Professor Betty Irene Moore School of Nursing at UC Davis Sacramento, California Sharon Sables-Baus PhD, MPA, RN, PCNS-BC Associate Professor University of Colorado College of Nursing and School of Medicine Department of Pediatrics Pediatric Nurse Scientist Children's Hospital Colorado Aurora, Colorado Anna Schwartz PhD, FNP-C, FAAN Associate Professor School of Nursing Northern Arizona University Flagstaff, Arizona Affiliate Associate Professor Biobehavioral Nursing and Health Systems University of Washington Seattle, Washington Joan Shea MSN, RN, CPON Staff Nurse III Hematology/Oncology/Clinical Research Boston Children's Hospital

Boston, Massachusetts Lorey K. Takahashi PhD Professor of Psychology Department of Psychology University of Hawaii at Manoa Honolulu, Hawaii David M. Virshup MD Professor and Director Program in Cancer and Stem Cell Biology Duke-NUS Graduate Medical School Singapore Professor of Pediatrics Duke University School of Medicine Durham, North Carolina †

Deceased.

Preface Based on the sixth US edition of Understanding Pathophysiology, the first Canadian edition has been updated and revised with consideration of the rapid advances in molecular and cellular biology. Many sections have been rewritten or reorganized to provide a foundation for better understanding of the mechanisms of disease. Integrated throughout the text are concepts from the basic sciences, including genetics, epigenetics, gene–environment interaction, immunity, and inflammation. The text has been written to assist students with the translation of the concepts and processes of pathophysiology into clinical practice and to promote lifelong learning. All laboratory values were changed to measure results in SI units and to fit the Canadian context. Canadian statistics were also embedded, based on updated data from Health Canada, the Canadian Institute for Health Information, and other relevant governmental organizations. Furthermore, Indigenous perspectives were integrated and explored in relation to the epidemiology of pathophysiological conditions in Canada. Lastly, feedback from Canadian reviewers was addressed with a critical appreciation of relevant issues and application in current nursing practice. Although the primary focus of the text is pathophysiology, we include discussions of the following interconnected topics to highlight their importance for clinical practice:

• A lifespan approach that includes special sections on aging and separate chapters on children • Epidemiology and incidence rates showing regional and worldwide differences that reflect the importance of environmental and lifestyle factors on disease initiation and progression • Sex differences that affect epidemiology and pathophysiology • Molecular biology—mechanisms of normal cell function and how their alteration leads to disease • Clinical manifestations, summaries of treatment, and health promotion/risk reduction

Organization and Content The book is organized into two parts: Part One, Basic Concepts of Pathophysiology, and Part Two, Body Systems and Diseases.

Part One: Basic Concepts of Pathophysiology Part One introduces basic principles and processes that are important for a contemporary understanding of the pathophysiology of common diseases. The concepts include descriptions of cellular communication; forms of cell injury; genes and genetic disease; epigenetics; fluid and electrolytes and acid and base balance; immunity and inflammation; mechanisms of infection; stress, coping, and illness; and tumour biology. Chapter 3, Epigenetics and Disease explains the way heritable changes in gene expression—phenotype without a change in genotype—are influenced by several factors, including age, environment and lifestyle, and disease state. The first Canadian edition includes significant revisions to Part One, incorporating new or updated information on the following topics:

• Updated content on cell membranes, cell junctions, intercellular communication, transport by vesicles, and stem cells (Chapter 1) • Updated content on epigenetics and disease (Chapter 3) • Updated content on cellular adaptations, oxidative stress, chemical injury, types of cell death, and aging, with a focus on Canadian epidemiology (Chapter 4) • Updates regarding mechanisms of human defence—characteristics of innate and adaptive immunity (Chapters 6 and 7) • Updated content on mechanisms of infection, antibiotic-resistant disease, and alterations in immune defence (Chapter 8) • Updated content on stress, inflammation, hormones, and disease (Chapter 9) • Updated chapter on tumour biology (after an extensive reorganization in the sixth US edition) (Chapter 10) • Updated chapters on the epidemiology of cancer (after an extensive reorganization in the sixth US edition) (Chapters 11 and 12) Part Two: Body Systems and Diseases Part Two presents the pathophysiology of the most common alterations according to body system. To promote readability and comprehension, we have used a logical sequence and uniform approach in presenting the content of the units and chapters. Each unit focuses on a specific organ system and contains chapters related to anatomy and physiology, the pathophysiology of the most common diseases, and common alterations in children. The anatomy and physiology content is presented as a review to enhance the learner's understanding of the structural and functional changes inherent in pathophysiology. A brief summary of normal aging effects is included at the end of these review chapters. The general organization of each disease or disorder discussion includes an introductory paragraph on relevant risk factors and epidemiology, a significant focus on pathophysiology and clinical manifestations, and then a brief review of evaluation and treatment.

The information on reproductive pathophysiology is presented in two chapters, with a new chapter, Alterations of the Male Reproductive System. Other significant revisions to Part Two, which have been retained in the first Canadian edition, include new and/or updated information on the following topics:

• Mechanisms of pain transmission, pain syndromes, and categories of sleep disorders (Chapter 14) • Alterations in levels of consciousness, seizure disorders, and delirium. Pathogenesis of degenerative brain diseases, the dementias, movement disorders, traumatic brain and spinal cord injury, stroke syndromes, headache, and infections and structural malformations of the central nervous system (Chapters 15, 16, 17) • The pathogenesis of type 2 diabetes mellitus (Chapter 19) • Platelet function and coagulation; anemias, alterations of leukocyte function and myeloid and lymphoid tumours (Chapters 20 and 21) • Extensive chapter revisions of alterations of hematological function in children (Chapter 22) • Extensive chapter revisions on structure and function of the cardiovascular and lymphatic systems (Chapter 23) • Mechanisms of atherosclerosis, hypertension, coronary artery disease, heart failure, and shock (Chapter 24) • Pediatric valvular disorders, heart failure, hypertension, obesity, and heart disease (Chapter 25) • Pathophysiology of acute lung injury, asthma, pneumonia, lung cancer, respiratory distress in the newborn, and cystic fibrosis (Chapters 27 and 28) • Mechanisms of kidney stone formation, immune processes of glomerulonephritis, and acute and chronic kidney injury (Chapters 30 and 31) • Female and male reproductive disorders, female and male reproductive cancers, breast diseases and mechanisms of breast cancer, prostate cancer, male breast cancer, and sexually transmitted infections (Chapters 33 and 34) • Gastroesophageal reflux, nonalcoholic liver disease, inflammatory bowel disease, viral hepatitis, obesity, gluten-sensitive enteropathy, and necrotizing enterocolitis (Chapters 36 and 37) • Bone cells, bone remodelling, joint and tendon diseases, osteoporosis, rheumatoid arthritis, and osteoarthritis (Chapters 38 and 39) • Congenital and acquired musculo-skeletal disorders, and muscular dystrophies in children (Chapter 40) • Psoriasis, discoid lupus erythematosus, and atopic dermatitis

(Chapters 41 and 42) • Cancer of the various organ systems was updated for all chapters.

Features to Promote Learning A number of features are incorporated into this text that guide and support learning and understanding, including:

• Chapter Outlines including page numbers for easy reference • Quick Check questions strategically placed throughout each chapter to help readers confirm their understanding of the material; answers are included on the textbook's Evolve website • Health Promotion boxes with a strategic focus on evidence-informed health promotion and current health practices • Risk Factors boxes for selected diseases • End-of-chapter Did You Understand? summaries that condense the major concepts of each chapter into an easy-to-review list format; printable versions of these are available on the textbook's Evolve website • Key Terms set in blue boldface in text and listed, with page numbers, at the end of each chapter • Special boxes for Aging and Pediatrics content that highlight discussions of lifespan alterations

Art Program All of the figures and photographs have been carefully reviewed, and some have been revised or updated. This edition features approximately 1 000 images. The figures are designed to help students visually understand sometimes difficult and complex material. Hundreds of high-quality photographs show clinical manifestations, pathological specimens, and clinical imaging techniques. Micrographs show normal and abnormal cellular structure. The combination of illustrations, algorithms, photographs, and use of colour for tables and boxes allows a more precise understanding of essential information.

Teaching/Learning Package For Students The free electronic Student Resources on Evolve include review questions and answers, numerous animations, answers to the Quick Check questions in the book, printable key points, and bonus case studies with questions and answers. A comprehensive Glossary of pathophysiological conditions for the textbook of more than 600 terms helps students with the often difficult terminology related to pathophysiology; this is available both on Evolve and in the electronic version of the textbook. These electronic resources enhance learning options for students. Go to http://evolve.elsevier.com/Canada/Huether/pathophysiology.

For Instructors The electronic Instructor Resources on Evolve are available free to instructors with qualified adoptions of the textbook and include the following: TEACH Lesson Plans with case studies to assist with clinical application; a Test Bank of more than 1 200 items; PowerPoint Presentations for each chapter, with integrated images, audience response questions, and case studies; and an Image Collection of approximately 1 000 key figures from the text. All of these teaching resources are also available to instructors on the book's Evolve website. Plus the Evolve Learning System provides a comprehensive suite of course communication and organization tools that allow you to upload your class calendar and syllabus, post scores and announcements, and more. Go to http://evolve.elsevier.com/Canada/Huether/pathophysiology. The most exciting part of the learning support package is Pathophysiology Online, a complete set of online modules that provide thoroughly developed lessons on the most important and difficult topics in pathophysiology supplemented with illustrations, animations, interactive activities, interactive algorithms, self-assessment reviews, and exams. Instructors can use it to enhance traditional classroom lecture courses or for distance and online-only courses. Students can use it as a self-guided study tool.

Acknowledgments This book would not be possible without the knowledge and expertise of the contributors to the previous US editions. Their reviews and synthesis of the evidence and clear and concise presentation of information are strengths of this text, and facilitated the adaptation of this information for the Canadian context. The reviewers for this edition provided excellent recommendations for focus of content and revisions, based on the Canadian context, with thoughtful consideration of Indigenous perspectives on health, wellness, and disease. We appreciate their insightful work. We are thankful to Martina van de Velde, our Content Development Specialist, for overseeing this wonderful project, providing insights regarding formatting, and suggesting content to maintain a streamlined manuscript that flows seamlessly from one section to another. We are also thankful to Roberta A. Spinosa-Millman, Content Strategist, for recruiting such a great team! Collaborating with one another on this project has been a great learning experience, and one that would not have been possible without Roberta having brought us all together. We have respected the contributions from US authors, Sue E. Huether and Kathryn L. McCance, in this first Canadian edition and recognize the innovation and clarity that these authors bring to pathophysiology. Lastly, we would like to thank our families for their undying support. They are what makes this work possible! Mohamed El-Hussein Kelly Power-Kean Stephanie Zettel

Introduction to Pathophysiology The word root “patho” is derived from the Greek word pathos, which means suffering. The Greek word root “logos” means discourse or, more simply, system of formal study, and “physio” refers to functions of an organism. Altogether, pathophysiology is the study of the underlying changes in body physiology (molecular, cellular, and organ systems) that result from disease or injury. Important, however, is the inextricable component of suffering and the psychological, spiritual, social, cultural, and economic implications of disease. The science of pathophysiology seeks to provide an understanding of the mechanisms of disease and to explain how and why alterations in body structure and function lead to the signs and symptoms of disease. Understanding pathophysiology guides health care providers in the planning, selection, and evaluation of therapies and treatments. Knowledge of human anatomy and physiology and the interrelationship among the various cells and organ systems of the body is an essential foundation for the study of pathophysiology. Review of this subject matter enhances comprehension of pathophysiological events and processes. Understanding pathophysiology also entails the utilization of principles, concepts, and basic knowledge from other fields of study including pathology, genetics, epigenetics, immunology, and epidemiology. A number of terms are used to focus the discussion of pathophysiology; they may be used interchangeably at times, but that does not necessarily indicate that they have the same meaning. Those terms are reviewed here for the purpose of clarification. Pathology is the investigation of structural alterations in cells, tissues, and organs, which can help identify the cause of a particular disease. Pathology differs from pathogenesis, which is the pattern of tissue changes associated with the development of disease. Etiology refers to the study of the cause of disease. Diseases may be caused by infection, heredity, gene–environment interactions, alterations in immunity, malignancy, malnutrition, degeneration, or trauma. Diseases that have no identifiable cause are termed idiopathic. Diseases that occur as a result of medical treatment are termed iatrogenic (e.g., some antibiotics can injure the kidney and cause kidney failure). Diseases that are acquired as a consequence of being in a hospital environment are called health care–associated diseases. An infection that develops as a result of a person's immune system being depressed after receiving cancer treatment during a hospital stay would be defined as a health care–associated infection. Diagnosis is the naming or identification of a disease. A diagnosis is made from an evaluation of the evidence accumulated from the presenting signs and symptoms, health and medical history, physical examination, laboratory tests, and imaging. A prognosis is the expected outcome of a disease. Acute disease is the sudden appearance of signs and symptoms that last only a short time. Chronic disease develops more slowly, and the signs and symptoms last for a long time, perhaps for a lifetime. Chronic diseases may have a pattern of remission and exacerbation. Remissions are periods when symptoms disappear or diminish significantly. Exacerbations are periods when the symptoms become worse or more severe. A complication is the onset of a disease in a person who is already coping with another existing disease (e.g., a person who has undergone surgery to remove a diseased appendix may develop the complication of a wound infection or pneumonia). Sequelae are unwanted outcomes of having a disease or are the result of trauma, such as paralysis resulting from a stroke or severe scarring resulting from a burn. Clinical manifestations are the signs and symptoms or evidence of disease. Signs are objective alterations that can be observed or measured by another person, measures of bodily functions such as pulse rate, blood pressure, body temperature, or white blood cell count. Some signs are local, such as redness or swelling, and other signs are systemic, such as fever. Symptoms are subjective experiences reported by the person with disease, such as pain, nausea, or shortness of breath; and they vary from person to person. The prodromal period of a disease is the time during which a person experiences vague

symptoms such as fatigue or loss of appetite before the onset of specific signs and symptoms. The term insidious symptoms describes vague or nonspecific feelings and an awareness that there is a change within the body. Some diseases have a latent period, a time during which no symptoms are readily apparent in the affected person, but the disease is nevertheless present in the body; an example is the incubation phase of an infection or the early growth phase of a tumour. A syndrome is a group of symptoms that occur together and may be caused by several interrelated problems or a specific disease; severe acute respiratory syndrome (SARS), for example, presents with a set of symptoms that include headache, fever, body aches, an overall feeling of discomfort, and sometimes dry cough and difficulty breathing. A disorder is an abnormality of function; this term also can refer to an illness or a particular problem such as a bleeding disorder. Epidemiology is the study of tracking patterns or disease occurrence and transmission among populations and by geographical areas. Incidence of a disease is the number of new cases occurring in a specific time period. Prevalence of a disease is the number of existing cases within a population during a specific time period. Risk factors, also known as predisposing factors, increase the probability that disease will occur, but these factors are not the cause of disease. Risk factors include heredity, age, gender, race, environment, and lifestyle. A precipitating factor is a condition or event that does cause a pathological event or disorder. For example, asthma is precipitated by exposure to an allergen, or angina (pain) is precipitated by exertion. Pathophysiology is an exciting field of study that is ever-changing as new discoveries are made. Understanding pathophysiology empowers health care providers with the knowledge of how and why disease develops and informs their decision making to ensure optimal health care outcomes. Embedded in the study of pathophysiology is understanding that suffering is a personal, individual experience and a major component of disease.

PA R T O N E

Basic Concepts of Pathophysiology OUTLINE Unit 1 The Cell Unit 2 Mechanisms of Self-Defence Unit 3 Cellular Proliferation: Cancer

UNIT 1

The Cell OUTLINE 1 Cellular Biology 2 Genes and Genetic Diseases 3 Epigenetics and Disease 4 Altered Cellular and Tissue Biology 5 Fluids and Electrolytes, Acids and Bases

Cellular Biology Kathryn L. McCance, Stephanie Zettel

CHAPTER OUTLINE Prokaryotes and Eukaryotes, 1 Cellular Functions, 2 Structure and Function of Cellular Components, 2 Nucleus, 2 Cytoplasmic Organelles, 2 Plasma Membranes, 2 Cellular Receptors, 9 Cell-to-Cell Adhesions, 10 Extracellular Matrix, 10 Specialized Cell Junctions, 12 Cellular Communication and Signal Transduction, 12 Cellular Metabolism, 14 Role of Adenosine Triphosphate, 16 Food and Production of Cellular Energy, 16 Oxidative Phosphorylation, 16 Membrane Transport: Cellular Intake and Output, 17 Electrolytes as Solutes, 18 Transport by Vesicle Formation, 21 Movement of Electrical Impulses: Membrane Potentials, 24 Cellular Reproduction: The Cell Cycle, 25 Phases of Mitosis and Cytokinesis, 25 Rates of Cellular Division, 26 Growth Factors, 26 Tissues, 27 Tissue Formation, 27 Types of Tissues, 27

All body functions depend on the integrity of cells. Therefore an understanding of cellular biology is increasingly necessary to comprehend disease processes. An overwhelming amount of information reveals how cells behave as a multicellular “social” organism. At the heart of it all is cellular communication (cellular “crosstalk”)—how messages originate and are transmitted, received, interpreted, and used by the cell. Streamlined conversation between, among, and within cells maintains cellular function and specialization. Cells communicate with other cells in a way to promote the integrity of the entire organism (i.e., they are well differentiated), and cells that resemble each other interact with each other more effectively. For example, prokaryotic and eukaryotic cells are organized differently, which accounts for the difference in response to pharmacotherapy. Anti-infectives, such as penicillin, are only effective against bacteria. Pharmacotherapy against eukaryotic cells results in more severe adverse effects, because the cells that are being targeted with the therapy more closely resemble human cells. When cells become less differentiated (as a result of injury or mutation) or less like the surrounding cells, the conversation breaks down, and cells either adapt (sometimes altering function) or become vulnerable to isolation, injury, or diseases such as cancer.

Prokaryotes and Eukaryotes Living cells generally are divided into eukaryotes and prokaryotes. The cells of higher animals and plants are eukaryotes, as are the single-celled organisms, fungi, protozoa, and most algae. Prokaryotes include cyanobacteria (blue-green algae), bacteria, and rickettsiae. Prokaryotes traditionally were studied as core subjects of molecular biology. Today, emphasis is on the eukaryotic cell; much of its structure and function have no counterpart in bacterial cells. Eukaryotes (eu = good; karyon = nucleus; also spelled eucaryotes) are larger and have more extensive intracellular anatomy and organization than prokaryotes. Eukaryotic cells have a characteristic set of membrane-bound intracellular compartments, called organelles, that includes a well-defined nucleus. The prokaryotes contain no organelles, and their nuclear material is not encased by a nuclear membrane. Prokaryotic cells are characterized by lack of a distinct nucleus. Besides having structural differences, prokaryotic and eukaryotic cells differ in chemical composition and biochemical activity. The nuclei of prokaryotic cells carry genetic information in a single circular chromosome, and they lack a class of proteins called histones, which in eukaryotic cells bind with deoxyribonucleic acid (DNA) and are involved in the supercoiling of DNA. Eukaryotic cells have several or many chromosomes. Protein production, or synthesis, in the two classes of cells also differs because of major structural differences in ribonucleic acid (RNA)–protein complexes. Other distinctions include differences in mechanisms of transport across the outer cellular membrane and in enzyme content.

Cellular Functions Cells become specialized through the process of differentiation, or maturation, so that some cells eventually perform one kind of function and other cells perform other functions. Cells with a highly developed function, such as movement, often lack some other property, such as hormone production, which is more highly developed in other cells. The eight chief cellular functions are as follows: 1. Movement. Muscle cells can generate forces that produce motion. Muscles that are attached to bones produce limb movements, whereas those muscles that enclose hollow tubes or cavities move or empty contents when they contract (e.g., the colon). 2. Conductivity. Conduction as a response to a stimulus is manifested by a wave of excitation, an electrical potential that passes along the surface of the cell to reach its other parts. Conductivity is the chief function of nerve cells. 3. Metabolic absorption. All cells can take in and use nutrients and other substances from their surroundings. 4. Secretion. Certain cells, such as mucous gland cells, can synthesize new substances from substances they absorb and then secrete the new substances to serve as needed elsewhere. 5. Excretion. All cells can rid themselves of waste products resulting from the metabolic breakdown of nutrients. Membrane-bound sacs (lysosomes) within cells contain enzymes that break down, or digest, large molecules, turning them into waste products that are released from the cell. 6. Respiration. Cells absorb oxygen, which is used to transform nutrients into energy in the form of adenosine triphosphate (ATP). Cellular respiration, or oxidation, occurs in organelles called mitochondria. 7. Reproduction. Tissue growth occurs as cells enlarge and reproduce themselves. Even without growth, tissue maintenance requires that new cells be produced to replace cells that are lost normally through cellular death. Not all cells are capable of continuous division (see Chapter 4). 8. Communication. Communication is vital for cells to survive as a society of cells. Appropriate communication allows the maintenance of a dynamic steady state.

Structure and Function of Cellular Components Figure 1-1, A, shows a “typical” eukaryotic cell, which consists of three components: an outer membrane called the plasma membrane, or plasmalemma; a fluid “filling” called cytoplasm (Figure 1-1, B); and the “organs” of the cell—the membrane-bound intracellular organelles, among them the nucleus.

FIGURE 1-1 Typical Components of a Eukaryotic Cell and Structure of the Cytoplasm. A, Artist's interpretation of cell structure. Note the many mitochondria known as the “power plants of the cell.” B, Colour-enhanced electron micrograph of a cell. The cell is crowded. Note, too, the innumerable dots bordering the endoplasmic reticulum. These are ribosomes, the cell's “protein factories.” mRNA, messenger RNA; tRNA, transfer RNA. (B, from Patton, K.T., & Thibodeau, G.A. [2013]. Anatomy & physiology [8th ed.]. St. Louis: Mosby.)

Nucleus The nucleus, which is surrounded by the cytoplasm and generally is located in the centre of the cell, is the largest membrane-bound organelle. Two pliable membranes compose the nuclear envelope (Figure 1-2, A). The nuclear envelope is pockmarked with pits, called nuclear pores, which allow chemical messages to exit and enter the nucleus (Figure 1-2, B). The outer membrane is continuous with membranes of the endoplasmic reticulum (see Figure 1-1). The nucleus contains the nucleolus (a small, dense structure composed largely of RNA), most of the cellular DNA, and the DNA-binding proteins (i.e., the histones) that regulate its activity. The DNA “chain” in eukaryotic cells is so long that it is easily broken. Therefore

the histones that bind to DNA cause DNA to fold into chromosomes (Figure 1-2, C), which decreases the risk of breakage and is essential for cell division in eukaryotes.

FIGURE 1-2 The Nucleus. The nucleus is composed of a double membrane, called a nuclear envelope, that encloses the fluid-filled interior, called nucleoplasm. The chromosomes are suspended in the nucleoplasm (illustrated here much larger than actual size to show the tightly packed DNA strands). Swelling at one or more points of the chromosome, shown in A, occurs at a nucleolus where genes are being copied into RNA. The nuclear envelope is studded with pores. B, The pores are visible as dimples in this freeze-etch of a nuclear envelope. C, Histone-folding DNA in chromosomes. (B, from Raven, P.H., & Johnson, G.B. [1992]. Biology. St. Louis: Mosby.)

The primary functions of the nucleus are cell division and control of genetic information. Other functions include the replication and repair of DNA and the transcription of the information stored in DNA. Genetic information is transcribed into RNA, which can be processed into messenger, transport, and ribosomal RNAs and introduced into the cytoplasm, where it directs cellular activities. Most of the processing of RNA occurs in the nucleolus. (The roles of DNA and RNA in protein synthesis are discussed in Chapter 2.)

Cytoplasmic Organelles Cytoplasm is an aqueous solution (cytosol) that fills the cytoplasmic matrix—the space between the nuclear envelope and the plasma membrane. The cytosol represents about half the volume of a eukaryotic cell. It contains thousands of enzymes involved in intermediate metabolism and is crowded with ribosomes making proteins (see Figure 1-1, B). Newly synthesized proteins remain in the cytosol if they lack a signal for transport to a cell organelle.1 The organelles suspended in the cytoplasm are enclosed in biological membranes, so they can simultaneously carry out functions requiring different biochemical environments. Many of these functions are directed by coded messages carried from the nucleus by RNA.

The functions include synthesis of proteins and hormones and their transport out of the cell, isolation and elimination of waste products from the cell, performance of metabolic processes, breakdown and disposal of cellular debris and foreign proteins (antigens), and maintenance of cellular structure and motility. The cytosol is a storage unit for fat, carbohydrates, and secretory vesicles. Table 1-1 lists the principal cytoplasmic organelles. TABLE 1-1 Principal Cytoplasmic Organelles Organelle Characteristics and Description Ribosomes Endoplasmic reticulum Golgi complex

RNA-protein complexes (nucleoproteins) synthesized in nucleolus and secreted into cytoplasm. They provide sites for cellular protein synthesis. Network of tubular channels (cisternae) that extend throughout outer nuclear membrane. It specializes in synthesis and transport of protein and lipid components of most organelles. Network of smooth membranes and vesicles located near nucleus. It is responsible for processing and packaging proteins onto secretory vesicles that break away from the complex and migrate to various intracellular and extracellular destinations, including the plasma membrane. Best-known vesicles are those that have coats largely made of the protein clathrin. Proteins in the complex bind to the cytoskeleton, generating tension that helps organelle function and keep its stretched shape intact. Lysosomes Saclike structures that originate from the Golgi complex and contain enzymes for digesting most cellular substances to their basic form, such as amino acids, fatty acids, and carbohydrates (sugars). Cellular injury leads to release of lysosomal enzymes that cause cellular self-destruction. Peroxisomes Structures similar to lysosomes, but contain several oxidative enzymes (e.g., catalase, urate oxidase) that produce or use hydrogen peroxide; reactions detoxify various wastes. Mitochondria Structures that contain metabolic machinery needed for cellular energy metabolism. Enzymes of respiratory chain (electron-transport chain), found in the inner membrane of mitochondria, generate most of a cell's ATP (oxidative phosphorylation). They have a role in osmotic regulation, pH control, calcium homeostasis, and cell signalling. Cytoskeleton “Bone and muscle” of a cell. It is composed of a network of protein filaments, including microtubules and actin filaments (microfilaments); it forms cell extensions (microvilli, cilia, flagella). Caveolae Tiny indentations (caves) that can capture extracellular material and shuttle it inside the cell or across the cell. Vaults Cytoplasmic ribonucleoproteins shaped like octagonal barrels. They are thought to act as “trucks,” shuttling molecules from the nucleus to elsewhere in the cell.

Quick Check 1-1 1. Why is the process of differentiation essential to specialization? Give an example. 2. Describe at least two cellular functions.

Plasma Membranes Every cell is contained within a membrane with gates, channels, and pumps. Membranes surround the cell or enclose an intracellular organelle and are exceedingly important to normal physiological function because they control the composition of the space, or compartment, they enclose. Membranes can allow or exclude various molecules and, because of selective transport systems, they can move molecules in or out of the space (Figure 1-3). By controlling the movement of substances from one compartment to another, membranes exert a powerful influence on metabolic pathways. Directional transport is facilitated by polarized domains, distinct apical and basolateral domains. Cell polarity, the direction of cellular transport, maintains normal cell and tissue structure for numerous functions (e.g., movement of nutrients in and out of the cell) and becomes altered with diseases (Figure 1-4). The plasma membrane also has an important role in cell-to-cell recognition. Other functions of the plasma membrane include cellular mobility and the maintenance of cellular shape (Table 1-2).

FIGURE 1-3 Functions of Plasma Membrane Proteins. The plasma membrane proteins illustrated here show a variety of functions performed by the different types of plasma membranes. (From Raven, P.H., & Johnson, G.B. [1995]. Understanding biology [3rd ed.]. Dubuque, IA: Brown.)

FIGURE 1-4 Cell Polarity of Epithelial Cells. Schematic of cell polarity (cell direction) of epithelial cells. Shown are the directions of the basal side and the apical side. Organelles and cytoskeleton are also arranged directionally to enable, for example, intestinal cell secretion and absorption. (Adapted from Life science web textbook, The University of Tokyo.)

TABLE 1-2 Plasma Membrane Functions Cellular Mechanism Structure

Protection Activation of cell

Storage

Cell-to-cell interaction

Membrane Functions Usually thicker than membranes of intracellular organelles Containment of cellular organelles Maintenance of relationship with cytoskeleton, endoplasmic reticulum, and other organelles Maintenance of fluid and electrolyte balance Outer surfaces of plasma membranes in many cells are not smooth but are dimpled with cavelike indentations called caveolae; they are also studded with cilia or even smaller cylindrical projections called microvilli; both are capable of movement Barrier to toxic molecules and macromolecules (proteins, nucleic acids, polysaccharides) Barrier to foreign organisms and cells Hormones (regulation of cellular activity) Mitogens (cellular division; see Chapter 2) Antigens (antibody synthesis; see Chapter 6) Growth factors (proliferation and differentiation; see Chapter 10) Storage site for many receptors Transport Diffusion and exchange diffusion Endocytosis (pinocytosis, phagocytosis) Exocytosis (secretion) Active transport Communication and attachment at junctional complexes Symbiotic nutritive relationships Release of enzymes and antibodies to extracellular environment Relationships with extracellular matrix

Modified from King, D.W., Fenoglio, C.M., & Lefkowitch, J.H. (1983). General pathology: Principles and dynamics. Philadelphia: Lea & Febiger.

Membrane Composition The basic structure of cell membranes is the lipid bilayer, composed of two apposing leaflets and proteins that span the bilayer or interact with the lipids on either side of the two leaflets (Figure 1-5). Lipid research is growing, and principles of membrane organization are being overhauled.2 In short, the main constituents of cell membranes are lipids and proteins. Historically, the plasma membrane was described as a fluid lipid bilayer (fluid mosaic model) composed of a uniform lipid distribution with inserted moving proteins. It now appears that the lipid bilayer is a much more complex structure where lipids and proteins are not uniformly distributed but can separate into discrete units called microdomains, differing in their protein and lipid compositions.3 Different membranes have varying percentages of lipids and proteins. Intracellular membranes may have a higher percentage of proteins than do plasma membranes, presumably because most enzymatic activity occurs within organelles. The membrane organization is achieved through noncovalent bonds that allow different physical states called phases. The lipid bilayer can be structured in three main phases: solid gel phase, fluid liquid-crystalline phase, and liquid-ordered phase (Figure 1-5, B). These phases can change under physiological factors such as temperature and pressure fluctuations. Carbohydrates are mainly associated with plasma membranes, in which they are chemically combined with lipids, forming glycolipids, and with proteins, forming glycoproteins (see Figure 1-5).

FIGURE 1-5 Lipid Bilayer Membranes. A, Concepts of biological membranes have markedly changed in the last two decades, from the classic fluid mosaic model to the current model that lipids and proteins are not evenly distributed but can isolate into microdomains, differing in their protein and lipid composition. B, An example of a microdomain is lipid rafts (yellow). Rafts are dynamic domain structures composed of cholesterol, sphingolipids, and membrane proteins important in different cellular processes. Various models exist to clarify the functions of domains. The three major phases of lipid bilayer organization include a solid gel phase (e.g., with low temperatures), a liquid-ordered phase (high temperatures), and a fluid liquid-crystalline (or liquid-disordered) phase. Some membraneassociated proteins are integrated into the lipid bilayer; other proteins are loosely attached to the outer and inner surfaces of the membrane. Transmembrane proteins protrude through the entire outer and inner surfaces of the membrane, and they can be attracted to microdomains through specific interactions with lipids. Interaction of the membrane proteins with distinct lipids depends on the hydrophobic thickness of the membrane, the lateral pressures of the membrane (mechanical force may shift protein channels from an open to closed state), the polarity or electrical charges at the lipid-protein interface, and the presence on the protein side of amino acid side chains. Important for pathophysiology is the proposal that protein-lipid interactions can be critical for correct insertion, folding, and orientation of membrane proteins. For example, diseases related to lipids that interfere with protein folding are becoming more prevalent. C, The cell membrane is not static but is always moving. Observed for the first time from measurements taken at the National Institute of Standards and Technology (NIST) and France's Institut Laue-Langevin (ILL). (Adapted from Bagatolli, L.A., Ipsen, J.H., Simonsen, A.C., et al. [2010]. Prog Lipid Res, 49[4], 378–389; Contreras, F.X., Ernst, A.M., Wieland, F., et al. [2011]. Cold Spring Harb Perspect Biol, 3[6], pii: a004705; Cooper, G.M. [2000]. The cell—a molecular approach [2nd ed.]. Sunderland (MA): Sinauer Associates; Defamie, N., & Mesnil, M. [2012]. Biochim Biophys Acta, 1818[8], 1866–1869; Woodka, A.C., Butler, P.D., Porcar, L. et al. [2012]. Phys Rev Lett, 109[5], 058102.)

The outer surface of the plasma membrane in many types of cells, especially endothelial cells and adipocytes, is not smooth but dimpled with flask-shaped invaginations known as caveolae (“tiny caves”). Caveolae serve as a storage site for many receptors, provide a route for transport into the cell, and act as the initiator for relaying signals from several extracellular chemical messengers into the cell's interior (see p. 23).

Lipids. Each lipid molecule is said to be polar, or amphipathic, which means that one part is hydrophobic

(uncharged, or “water hating”) and another part is hydrophilic (charged, or “water loving”) (Figure 1-6). The membrane spontaneously organizes itself into two layers because of these two incompatible solubilities. The hydrophobic region (hydrophobic tail) of each lipid molecule is protected from water, whereas the hydrophilic region (hydrophilic head) is immersed in it. The bilayer serves as a barrier to the diffusion of water and hydrophilic substances, while allowing lipid-soluble molecules, such as oxygen (O2) and carbon dioxide (CO2), to diffuse through the membrane readily. The structure of the cell membrane also makes it more difficult for water-soluble medications and ionized medications to enter the cell.

FIGURE 1-6 Structure of a Phospholipid Molecule. A, Each phospholipid molecule consists of a phosphate functional group and two fatty acid chains attached to a glycerol molecule. B, The fatty acid chains and glycerol form nonpolar, hydrophobic “tails,” and the phosphate functional group forms the polar, hydrophilic “head” of the phospholipid molecule. When placed in water, the hydrophobic tails of the molecule face inward, away from the water, and the hydrophilic head faces outward, toward the water. (From Raven, P.H., & Johnson, G.B. [1995]. Understanding biology [3rd ed.]. Dubuque, IA: Brown.)

A major component of the plasma membrane is a bilayer of lipid molecules—glycerophospholipids, sphingolipids, and sterols (e.g., cholesterol). The most abundant lipids are phospholipids. Phospholipids have a phosphate-containing hydrophilic head connected to a hydrophobic tail. Phospholipids and glycolipids form self-sealing lipid bilayers. Lipids along with protein assemblies act as “molecular glue” for the structural integrity of the membrane. Investigators are studying the concept of lipid rafts. Membrane lipid rafts (MLRs) appear to be structurally and functionally distinct regions of the plasma membrane4,5 and consist of cholesterol and sphingolipid-dependent microdomains that form a network of lipid–lipid, protein–protein, and protein–lipid interactions (Figures 1-5, B, and 1-7) Although discrepancies between experimental results exist, two main types of MLRs are hypothesized: those that contain the cholesterol-binding protein caveolin (see p. 24) and those that do not.4 Researchers hypothesize that there are lipid rafts that have several functions, including (1) providing cellular polarity and organization of signalling trafficking; (2) acting as platforms for extracellular matrix (ECM) adhesion and intracellular cytoskeletal tethering to the plasma membrane through cell adhesion molecules (CAMs); (3) enabling signalling across the membrane, which can rearrange cytoskeletal architecture and regulate cell growth, migration, and other functions; and (4) allowing entry of viruses, bacteria, toxins, and nanoparticles.4

FIGURE 1-7 Lipid Rafts. The plasma membrane is composed of many lipids, including sphingomyelin (SM) and cholesterol, shown here as a small raft in the external leaflet. GS, glycosphingolipid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PS, phosphatidylserine. (From Pollard, T.D., & Ernshaw, W.C. [2004]. Cell biology. St. Louis: Saunders Elsevier.)

Proteins. A protein is made from a chain of amino acids known as polypeptides. There are 20 types of amino acids in proteins, and each type of protein has a unique sequence of amino acids. Proteins are the major workhorses of the cell. After translation (the synthesis of protein from RNA, see Chapter 2) of a protein, post-translational modifications (PTMs) are the methods used to diversify the limited numbers of proteins generated. These modifications alter the activity and functions of proteins and have become very important in understanding diseases. Researchers have known for decades that pathogens interfere with the host's PTMs.6 New approaches are being used to understand changes in proteins—a field called proteomics is the study of the proteome, or entire set of proteins expressed by a genome from synthesis, translocation, and modification (e.g., folding), and the analysis of the roles of proteomes in a staggering number of diseases. Membrane proteins associate with the lipid bilayer in different ways (Figure 1-8), including (1) transmembrane proteins that extend across the bilayer and are exposed to an aqueous environment on both sides of the membrane (Figure 1-8, A); (2) proteins located almost entirely in the cytosol and are associated with the cytosolic half of the lipid bilayer by an α helix exposed on the surface of the protein (Figure 1-8, B); (3) proteins that exist outside the bilayer, on one side or the other, and are attached to the membrane by one or more covalently attached lipid groups (Figure 1-8, C); and (4) proteins bound indirectly to one or the other bilayer membrane face and are held in place by their interactions with other proteins (Figure 1-8, D).1

FIGURE 1-8 Proteins Attach to the Plasma Membrane in Different Ways. A, Transmembrane proteins extend through the membrane as a single α helix, as multiple α helices, or as a rolled-up barrel-like sheet called a β barrel. B, Some membrane proteins are anchored to the cytosolic side of the lipid bilayer by an amphipathic α helix. C, Some proteins are linked on either side of the membrane by a covalently attached lipid molecule. D, Proteins are attached by weak noncovalent interactions with other membrane proteins. COOH, carboxyl group; NH2, amino group; P, protein. (D, adapted from Alberts, B. [2014]. Essential cell biology [4th ed.]. New York: Garland.)

Proteins directly attached to the membrane bilayer can be removed by dissolving the bilayer with

detergents called integral membrane proteins. The remaining proteins that can be removed by gentler procedures that interfere with protein–protein interactions but do not dissolve the bilayer are known as peripheral membrane proteins. Proteins exist in densely folded molecular configurations rather than straight chains; so most hydrophilic units are at the surface of the molecule, and most hydrophobic units are inside. Membrane proteins, like other proteins, are synthesized by the ribosome and then make their way, called trafficking, to different membrane locations of a cell.7 Trafficking places unique demands on membrane proteins for folding, translocation, and stability.7 Thus, much research is now being done to understand misfolded proteins (e.g., as a cause of disease; Box 1-1).

Box 1-1

Endoplasmic Reticulum, Protein Folding, and ER Stress Protein folding in the endoplasmic reticulum (ER) is critical for us. As the biological workhorses, proteins perform vital functions in every cell. To do these tasks, proteins must fold into complex threedimensional structures (see figure). Most secreted proteins fold and are modified in an error-free manner, but ER or cell stress, mutations, or random (stochastic) errors during protein synthesis can decrease the folding amount or the rate of folding. Pathophysiological processes, such as viral infections, environmental toxins, and mutant protein expression, can perturb the sensitive ER environment. Natural processes also can perturb the environment, such as the large protein-synthesizing load placed on the ER. These perturbations cause the accumulation of immature and abnormal proteins in cells, leading to ER stress. Fortunately, the ER is loaded with protective ways to help folding; for example, protein chaperones facilitate folding and prevent the formation of off-pathway types. Because specialized cells produce large amounts of secreted proteins, the movement or flux through the ER is tremendous. Therefore misfolded proteins not repaired in the ER are observed in some diseases and can initiate apoptosis or cell death. It has recently been shown that the endoplasmic reticulum mediates intracellular signalling pathways in response to the accumulation of unfolded or misfolded proteins; collectively, the pathways are known as the unfolded-protein response (UPR). Investigators are studying UPRassociated inflammation and how the UPR is coupled to inflammation in health and disease. Specific diseases include Alzheimer's disease, Parkinson's disease, prion disease, amyotrophic lateral sclerosis, and diabetes mellitus. Additionally being studied is ER stress and how it may accelerate age-related dysfunction.

Protein Folding. Each protein exists as an unfolded polypeptide (left) or a random coil after the process of translation from a sequence of mRNA to a linear string of amino acids. From amino acids interacting with each other they produce a three-dimensional structure called the folded protein (right) that is its native state.

Data from Brodsky, J., & Skach, W.R. (2011). Curr Opin Cell Biol, 23, 464–475; Jäger, R., Bertrand, M.J.M., Gorman, A.M., et al. (2012). Biol Cell, 104(5), 259–270; Ron, D., & Walter, P. (2007). Nat Rev Mol Cell Biol, 8, 519–529.

Although membrane structure is determined by the lipid bilayer, membrane functions are determined largely by proteins. Proteins act as (1) recognition and binding units (receptors) for substances moving into and out of the cell; (2) pores or transport channels for various electrically charged particles, called ions or electrolytes, and specific carriers for amino acids and monosaccharides; (3) specific enzymes that drive active pumps to promote concentration of certain ions, particularly potassium (K+), within the cell while keeping concentrations of other ions (e.g., sodium, Na+) less than concentrations found in the extracellular environment; (4) cell surface markers, such as glycoproteins (proteins attached to carbohydrates), that identify a cell to its neighbour; (5) cell adhesion molecules (CAMs), or proteins that allow cells to hook together and form attachments of the cytoskeleton for maintaining cellular shape; and (6) catalysts of chemical reactions (e.g., conversion of lactose to glucose; see Figure 1-3). Membrane proteins are key components of energy transduction, converting chemical energy into electrical energy, or electrical energy into either mechanical energy or synthesis of ATP.7 Investigators are studying ATP enzymes and the changes in shape of biological membranes, particularly mitochondrial membranes, and their relationship to aging and disease.8-10 In animal cells, the plasma membrane is stabilized by a meshwork of proteins attached to the underside of the membrane called the cell cortex. Human red blood cells have a cell cortex that maintains their flattened biconcave shape.1

Protein regulation in a cell: protein homeostasis. The cellular protein pool is in constant change or flux. The number of copies of a protein in a cell depends on how quickly it is made and how long it survives or is broken down. This adaptable system of protein homeostasis is defined by the “proteostasis” network that comprises ribosomes (makers); chaperones (helpers); and two protein breakdown systems or proteolytic systems—lysosomes and the ubiquitin– proteasome system (UPS). These systems regulate protein homeostasis under a large variety of conditions, including variations in nutrient supply, the existence of oxidative stress or cellular differentiation, changes in temperature, and the presence of heavy metal ions and other sources of stress.11 Malfunction or failure of the proteostasis network is associated with human disease12 (Figure 1-9).

FIGURE 1-9 Protein Homeostasis System and Outcomes. A main role of the protein homeostasis network (proteostasis) is to minimize protein misfolding and protein aggregation. The network includes ribosome-mediated protein synthesis, chaperone- (folding helpers in the endoplasmic reticulum) and enzyme-mediated folding, breakdown systems of lysosome- and proteasome-mediated protein degradation, and vesicular trafficking. The network integrates biological pathways that balance folding, trafficking, and protein degradation depicted by arrows b, d, e, f, g, h, and i. (Adapted from Lindquist, S.L., & Kelly, J.W. [2011]. Cold Spring Harb Perspect Biol, 3[12], pii: a004507.)

Carbohydrates. The short chains of sugars or carbohydrates (oligosaccharides) contained within the plasma membrane are generally bound to membrane proteins (glycoproteins) and lipids (glycolipids). Long polysaccharide

chains attached to membrane proteins are called proteoglycans. All of the carbohydrate on the glycoproteins, proteoglycans, and glycolipids is located on the outside of the plasma membrane, and the carbohydrate coating is called the glycocalyx. The glycocalyx helps protect the cell from mechanical damage.1 Additionally, the layer of carbohydrate gives the cell a slimy surface that assists the mobility of other cells, like leukocytes, to squeeze through the narrow spaces.1 The functions of carbohydrates are more than protection and lubrication and include specific cell–cell recognition and adhesion. Intercellular recognition is an important function of membrane oligosaccharides; for example, the transmembrane proteins called lectins, which bind to a particular oligosaccharide, recognize neutrophils at the site of bacterial infection. This recognition allows the neutrophil to adhere to the blood vessel wall and migrate from the blood into the infected tissue to help eliminate the invading bacteria.1

Cellular Receptors Cellular receptors are protein molecules on the plasma membrane, in the cytoplasm, or in the nucleus that can recognize and bind with specific smaller molecules called ligands (from the Latin ligare, “to bind”) (Figure 1-10). The region of a protein that associates with a ligand is called its binding site. Hormones, for example, are ligands. Recognition and binding depend on the chemical configuration of the receptor and its smaller ligand, which must fit together somewhat like pieces of a jigsaw puzzle (see Chapter 18). Binding selectively to a protein receptor with high affinity to a ligand depends on formation of weak, noncovalent interactions—hydrogen bonds, electrostatic attractions, and van der Waals attractions—and favourable hydrophobic forces.1 Numerous receptors are found in most cells, and ligand binding to receptors activates or inhibits the receptor's associated signalling or biochemical pathway.

FIGURE 1-10 Cellular Receptors. (A) 1, Plasma membrane receptor for a ligand (here, a hormone molecule) on the surface of an integral protein. A neurotransmitter can exert its effect on a postsynaptic cell by means of two fundamentally different types of receptor proteins: 2, channel-linked receptors, and 3, non–channel-linked receptors. Channel-linked receptors are also known as ligand-gated channels. (B) Example of ligand-receptor interaction. Insulinlike growth factor 1 (IGF-1) is a ligand and binds to the insulinlike growth factor 1 receptor

(IGF-1R). With binding at the cell membrane the intracellular signalling pathway is activated, causing translation of new proteins (P) to act as intracellular communicators. This pathway is important for cancer growth. Researchers are developing pharmacological strategies to reduce signalling at and downstream of the IGF-1R, hoping this will lead to compounds useful in cancer treatment.

Plasma membrane receptors protrude from or are exposed at the external surface of the membrane and are important for cellular uptake of ligands (see Figure 1-10). The ligands that bind with membrane receptors include hormones, neurotransmitters, antigens, complement components, lipoproteins, infectious agents, medications, and metabolites. Many new discoveries concerning the specific interactions of cellular receptors with their respective ligands have provided a basis for understanding disease. Although the chemical nature of ligands and their receptors differs, receptors are classified based on their location and function. Cellular type determines overall cellular function, but plasma membrane receptors determine which ligands a cell will bind with and how the cell will respond to the binding. Specific processes also control intracellular mechanisms. Receptors for different medications are found on the plasma membrane, in the cytoplasm, and in the nucleus. Membrane receptors have been found for certain anaesthetics, opiates, endorphins, enkephalins, antibiotics, cancer chemotherapeutic agents, digitalis, and other medications. Membrane receptors for endorphins, which are opiatelike peptides isolated from the pituitary gland, are found in large quantities in pain pathways of the nervous system (see Chapters 13 and 14). With binding to the receptor, the endorphins (or medications such as morphine) change the cell's permeability to ions, increase the concentration of molecules that regulate intracellular protein synthesis, and initiate molecular events that modulate pain perception. Receptors for infectious microorganisms, or antigen receptors, bind bacteria, viruses, and parasites to the cell membrane. Antigen receptors on white blood cells (lymphocytes, monocytes, macrophages, granulocytes) recognize and bind with antigenic microorganisms and activate the immune and inflammatory responses (see Chapter 6).

Cell-to-Cell Adhesions Cells are small and squishy, not like bricks. They are enclosed only by a flimsy membrane, yet the cell depends on the integrity of this membrane for its survival. How can cells be connected strongly, with their membranes intact, to form a muscle that can lift this textbook? Plasma membranes not only serve as the outer boundaries of all cells but also allow groups of cells to be held together robustly, in cell-to-cell adhesions, to form tissues and organs. Once arranged, cells are linked by three different means: (1) CAMs in the cell's plasma membrane, (2) the ECM, and (3) specialized cell junctions.

Extracellular Matrix Cells can be united by attachment to one another or through the extracellular matrix (ECM) (including the basement membrane), which the cells secrete around themselves. The ECM is an intricate meshwork of fibrous proteins embedded in a watery, gel-like substance composed of complex carbohydrates (Figure 1-11). The matrix is similar to glue; however, it provides a pathway for diffusion of nutrients, wastes, and other water-soluble substances between the blood and tissue cells. Interwoven within the matrix are three groups of macromolecules: (1) fibrous structural proteins, including collagen and elastin; (2) adhesive glycoproteins, such as fibronectin; and (3) proteoglycans and hyaluronic acid.

FIGURE 1-11 Extracellular Matrix. A, Tissues are not just cells but also extracellular space. The extracellular space is an intricate network of macromolecules called the extracellular matrix (ECM). The macromolecules that constitute the ECM are secreted locally (by mostly fibroblasts) and assembled into a meshwork in close association with the surface of the cell that produced them. Two main classes of macromolecules include proteoglycans, which are bound to polysaccharide chains called glycosaminoglycans, and fibrous proteins (e.g., collagen, elastin, fibronectin, and laminin), which have structural and adhesive properties. Together the proteoglycan molecules form a gel-like ground substance in which the fibrous proteins are embedded. The gel permits rapid diffusion of nutrients,

metabolites, and hormones between the blood and the tissue cells. Matrix proteins modulate cell-matrix interactions, including normal tissue remodelling (which can become abnormal, e.g., with chronic inflammation). Disruptions of this balance result in serious diseases such as arthritis, tumour growth, and other pathological conditions. B, Scanning electron micrograph of a chick embryo where a portion of the epithelium has been removed, exposing the curtainlike ECM. (A, adapted from Kumar, V., Abbas, A.K., & Aster, J.C. [Eds.]. [2015]. Robbins and Cotran pathologic basis of disease [9th ed.]. Philadelphia: Saunders; B, © Robert L Trelstad; from Gartner, L.P., & Hiatt, J.L. [2006]. Color textbook of histology [3rd ed.]. St. Louis: Saunders/Elsevier.)

• Collagen forms cablelike fibres or sheets that provide tensile strength or resistance to longitudinal stress. Collagen breakdown, such as occurs in osteoarthritis, destroys the fibrils that give cartilage its tensile strength. • Elastin is a rubberlike protein fibre most abundant in tissues that must be capable of stretching and recoiling, such as tissues found in the lungs. • Fibronectin, a large glycoprotein, promotes cell adhesion and cell anchorage. Reduced amounts have been found in certain types of cancerous cells; the reduced amount of this substance allows cancer cells to travel, or metastasize, to other parts of the body. All of these macromolecules occur in intercellular junctions and cell surfaces and may assemble into two different components: interstitial matrix and basement membrane (see Figure 1-11). The basement membrane is a thin, tough layer of ECM (connective tissue) underlying the epithelium of many organs and is also called the basal lamina (Figure 1-11, B). The ECM is secreted by fibroblasts (“fibre formers”) (Figure 1-12), local cells that are present in the matrix. The matrix and the cells within it are known collectively as connective tissue because they interconnect cells to form tissues and organs. Human connective tissues are enormously varied. They can be hard and dense, like bone; flexible, like tendons or the dermis of the skin; resilient and shock absorbing, like cartilage; or soft and transparent, similar to the jellylike substance that fills the eye. In all these examples, the majority of the tissue is composed of ECM, and the cells that produce the matrix are scattered within it like raisins in a pudding (see Figure 1-12).

FIGURE 1-12

Fibroblasts in Connective Tissue. This micrograph shows tissue from the cornea of a rat. The extracellular matrix surrounds the fibroblasts (F). (From Nishida, T., Yasumoto, K., Otori, T., et al. [1988]. Invest Ophthalmol Vis Sci, 29, 1887–1890.)

The matrix not only acts as passive scaffolding for cellular attachment but also helps regulate the function of the cells with which it interacts. The matrix helps regulate such important functions as cell growth and differentiation.

Specialized Cell Junctions Cells in direct physical contact with neighbouring cells are often interconnected at specialized plasma membrane regions called cell junctions. Cell junctions are classified by their function: (1) some hold cells together and form a tight seal (tight junctions); (2) some provide strong mechanical attachments (adherens junctions, desmosomes, hemidesmosomes); (3) some provide a special type of chemical communication (e.g., inorganic ions and small water-soluble molecules to move from the cytosol of one cell to the cytosol of another cell), such as those causing an electrical wave (gap junctions); and (4) some maintain apicobasal polarity of individual epithelial cells (tight junctions) (Figure 1-13). Overall, cell junctions make the epithelium leak-proof and mediate mechanical attachment of one cell to another, allowing communicating tunnels and maintaining cell polarity.

FIGURE 1-13 Junctional Complex. A, Schematic drawing of a belt desmosome between epithelial cells. This junction, also called the zonula adherens, encircles each of the interacting cells. The spot desmosomes and hemidesmosomes, like the belt desmosomes, are adhering junctions. This tight junction is an impermeable junction that holds cells together but seals them in such a way that molecules cannot leak between them. The gap junction, as a communicating junction, mediates the passage of small molecules from one interacting cell to the other. B, Connexons. The connexin gap junction proteins have four transmembrane domains and they play a vital role in maintaining cell and tissue function and homeostasis. Cells connected by gap junctions are considered ionically (electrically) and metabolically coupled. Gap junctions coordinate the activities of adjacent cells; for example, they are important for synchronizing contractions of heart muscle cells through ionic coupling and for permitting action potentials to spread rapidly from cell to cell in neural tissues. The reason gap junctions occur in tissues that are not electrically active is unknown. Although most gap junctions are associated with junctional complexes, they sometimes exist as independent structures. C, Electron micrograph of desmosomes. (A and C, from Raven, P.H., & Johnson, G.B. [1992]. Biology. St. Louis: Mosby; B, adapted from Gartner, L.P., & Hiatt, J.L. [2006]. Color textbook of histology [3rd ed.]. St. Louis: Saunders Elsevier; Sherwood, L. [2013]. Learning [8th ed.]. Belmont, CA: Brooks/Cole CENGAGE.)

Cell junctions can be classified as symmetrical and asymmetrical. Symmetrical junctions include tight junctions, the belt desmosome (zonula adherens), desmosomes (macula adherens), and gap junctions (also called intercellular channels or communicating junctions).13 An asymmetrical junction is the hemidesmosome (see Figure 1-13). Together they form the junctional complex. Desmosomes unite cells either by forming continuous bands or belts of epithelial sheets or by developing buttonlike points of contact. Desmosomes also act as a system of braces to maintain structural stability. Tight junctions are barriers to diffusion, prevent the movement of substances through transport proteins in the plasma membrane, and prevent the leakage of small molecules between the plasma membranes of adjacent cells. Gap junctions are clusters of communicating tunnels or connexons that allow small ions and molecules to pass directly from the inside of one cell to the inside of another. Connexons are hemichannels that extend outward from each of the adjacent plasma membranes (Figure 1-13, C). Multiple factors regulate gap junction intercellular communication, including voltage across the junction, intracellular pH, intracellular Ca++ concentration, and protein phosphorylation. The most abundant human connexin is connexin 43 (Cx43).14 Investigators recently showed that loss of Cx43

expression in colorectal tumours is correlated with a shorter cancer-free survival rate.15 This study is the first evidence that Cx43 acts as a tumour suppressor for colorectal cancer (enhances apoptosis) and therefore may be an important prognostic marker and target for therapy.15 Investigators also recently reported that glycyrrhizic acid (GA), a glycoside of licorice root extracts, may be a strong chemopreventive agent against carcinogens; induced colon cancer in rats and Cx43 is one target.16 Too much GA often in humans may lead to hypokalemia and hypertension.17 The junctional complex is a highly permeable part of the plasma membrane. Its permeability is controlled by a process called gating. Increased levels of cytoplasmic calcium cause decreased permeability at the junctional complex. Gating enables uninjured cells to protect themselves from injured neighbours. Calcium is released from injured cells.

Cellular Communication and Signal Transduction Cells need to communicate with each other to maintain a stable internal environment, or homeostasis; to regulate their growth and division; to oversee their development and organization into tissues; and to coordinate their functions. Cells communicate by using hundreds of kinds of signal molecules, for example, insulin (Figure 1-10, B). Cells communicate in three main ways: (1) they display plasma membrane–bound signalling molecules (receptors) that affect the cell itself and other cells in direct physical contact (Figure 1-14, A); (2) they affect receptor proteins inside the target cell and the signal molecule has to enter the cell to bind to them (Figure 1-14, B); and (3) they form protein channels (gap junctions) that directly coordinate the activities of adjacent cells (Figure 1-14, C). Alterations in cellular communication affect disease onset and progression. In fact, if a cell cannot perform gap junctional intercellular communication, normal growth control and cell differentiation is compromised, thereby favouring cancerous tumour development (see Chapter 10). Secreted chemical signals involve communication locally and at a distance. Primary modes of intercellular signalling are contact-dependent, paracrine, hormonal, neurohormonal, and neurotransmitter. Autocrine stimulation occurs when the secreting cell targets itself (Figure 1-15).

FIGURE 1-14

Cellular Communication. Three primary ways cells communicate with one another. (B, adapted from Alberts, B., Johnson, A., Lewis, J., et al. [2008]. Molecular biology of the cell [5th ed.]. New York: Garland.)

FIGURE 1-15 Primary Modes of Chemical Signalling. Five forms of signalling mediated by secreted molecules. Hormones, paracrines, neurotransmitters, and neurohormones are all intercellular messengers that accomplish communication between cells. Autocrines bind to receptors on the same cell. Not all neurotransmitters act in the strictly synaptic mode shown; some act in a contact-dependent mode as local chemical mediators that influence multiple target cells in the area.

Contact-dependent signalling requires cells to be in close membrane–membrane contact. In paracrine signalling, cells secrete local chemical mediators that are quickly taken up, destroyed, or immobilized. Paracrine signalling usually involves different cell types; however, cells also can produce signals to which they alone respond, called autocrine signalling (see Figure 1-15). For example, cancer cells use this form of signalling to stimulate their survival and proliferation. The mediators act only on nearby cells. Hormonal signalling involves specialized endocrine cells that secrete chemicals called hormones; hormones are released by one set of cells and travel through the bloodstream to produce a response in other sets of cells (see Chapter 18). In neurohormonal signalling, hormones are released into the blood by neurosecretory neurons. Like endocrine cells, neurosecretory neurons release bloodborne chemical messengers, whereas ordinary neurons secrete short-range neurotransmitters into a small discrete space (i.e., synapse). Neurons communicate directly with the cells they innervate by releasing chemicals or neurotransmitters at specialized junctions called chemical synapses; the neurotransmitter diffuses across the synaptic cleft and acts on the postsynaptic target cell (see Figure 1-15). Many of these same signalling molecules are receptors used in hormonal, neurohormonal, and paracrine signalling. Important differences lie in the speed and selectivity with which the signals are delivered to their targets.1 Plasma membrane receptors belong to one of three classes that are defined by the signalling (transduction) mechanism used. Table 1-3 summarizes these classes of receptors. Cells respond to external stimuli by activating a variety of signal transduction pathways, which are communication pathways, or signalling cascades (Figure 1-16, C). Signals are passed between cells when a particular type of molecule is produced by one cell—the signalling cell—and received by another—the target cell—by means of a receptor protein that recognizes and responds specifically to the signal molecule (Figure 1-16, A and B). In turn, the signalling molecules activate a pathway of intracellular protein kinases that results in various responses, such as grow and reproduce, die, survive, or differentiate (Figure 1-16, D). If deprived of appropriate signals, most cells undergo a form of cell suicide known as programmed cell death, or apoptosis (see p. 105). TABLE 1-3 Classes of Plasma Membrane Receptors

Type of Description Receptor Ion channel coupled Enzyme coupled G-protein coupled

Involve rapid synaptic signalling between electrically excitable cells; also called transmitter-gated ion channels. Channels open and close briefly in response to neurotransmitters, changing ion permeability of plasma membrane of postsynaptic cell. Once activated by ligands, function directly as enzymes or associate with enzymes. Indirectly activate or inactivate plasma membrane enzyme or ion channel; interaction mediated by GTP-binding regulatory protein (G-protein). May also interact with inositol phospholipids, which are significant in cell signalling, and with molecules involved in inositol-phospholipid transduction pathway.

FIGURE 1-16 Schematic of a Signal Transduction Pathway. Like a telephone receiver that converts an electrical signal into a sound signal, a cell converts an extracellular signal, A, into an intracellular signal, B. C, An extracellular signal molecule (ligand) bonds to a receptor protein located on the plasma membrane, where it is transduced into an intracellular signal. This process initiates a signalling cascade that relays the signal into the cell interior, amplifying and distributing it during transit. Amplification is often achieved by stimulating enzymes. Steps in the cascade can be modulated by other events in the cell. D, Different cell behaviours rely on multiple extracellular signals.

Cellular Metabolism All of the chemical tasks of maintaining essential cellular functions are referred to as cellular metabolism. The energy-using process of metabolism is called anabolism (ana = upward), and the energy-releasing process is known as catabolism (kata = downward). Metabolism provides the cell with the energy it needs to produce cellular structures. Dietary proteins, fats, and starches (i.e., carbohydrates) are hydrolyzed in the intestinal tract into amino acids, fatty acids, and glucose, respectively. These constituents are then absorbed, circulated, and incorporated into the cell, where they may be used for various vital cellular processes, including the production of ATP. The process by which ATP is produced is one example of a series of reactions called a metabolic pathway. A metabolic pathway involves several steps whose end products are not always detectable. A key feature of cellular metabolism is the directing of biochemical reactions by protein catalysts or enzymes. Each enzyme has a high affinity for a substrate, a specific substance converted to a product of the reaction.

Role of Adenosine Triphosphate Best known about ATP is its role as a universal “fuel” inside living cells. This fuel or energy drives biological reactions necessary for cells to function. For a cell to function, it must be able to extract and use the chemical energy in organic molecules. When 1 mol of glucose metabolically breaks down in the presence of oxygen into carbon dioxide and water, 686 kcal of chemical energy are released. The chemical energy lost by one molecule is transferred to the chemical structure of another molecule by an energycarrying or energy-transferring molecule, such as ATP. The energy stored in ATP can be used in various energy-requiring reactions and in the process is generally converted to adenosine diphosphate (ADP) and inorganic phosphate (Pi). The energy available as a result of this reaction is about 7 kcal/mol of ATP. The cell uses ATP for muscle contraction and active transport of molecules across cellular membranes. ATP not only stores energy but also transfers it from one molecule to another. Energy stored by carbohydrate, lipid, and protein is catabolized and transferred to ATP (Box 1-2).

Box 1-2

Role of Adenosine Triphosphate Outside Cells Emerging understandings are the role of adenosine triphosphate (ATP) outside cells—as a messenger. In animal studies, using the newly developed ATP probe, ATP has been measured in pericellular spaces. New research is clarifying the role of ATP as an extracellular messenger and its role in many physiological processes, including inflammation. From Burnstock, G. (2007). Physiol Rev, 87(2), 659–797. doi:10.1152/physrev.00043.2006; Falzoni, S., Donvito, G., & Di Virgilio, F. (2013). Interface Focus, 3(3), 20120101. doi:10.1098/rsfs.2012.0101; Nurse, C.A., & Piskuric, N.A. (2012). Semin Cell Dev Biol, 24(1), 22–30. doi:10.1016/j.semcdb.2012.09.006.

Food and Production of Cellular Energy Catabolism of the proteins, lipids, and polysaccharides found in food can be divided into the following three phases (Figure 1-17):

FIGURE 1-17 Three Phases of Catabolism, Which Lead from Food to Waste Products. These reactions produce adenosine triphosphate (ATP), which is used to power other processes in the cell. CO2, carbon dioxide; CoA, coenzyme A; H2O, water; NADH, reduced nicotinamide adenine dinucleotide; NH3, ammonia; O2, oxygen.

Phase 1: Digestion. Large molecules are broken down into smaller subunits: proteins into amino acids, polysaccharides into simple sugars (i.e., monosaccharides), and fats into fatty acids and glycerol. These processes occur outside the cell and are activated by secreted enzymes. Phase 2: Glycolysis and oxidation. The most important part of phase 2 is glycolysis, the splitting of glucose. Glycolysis produces two molecules of ATP per glucose molecule through oxidation, or the removal and transfer of a pair of electrons. The total process is called oxidative cellular metabolism and involves 10 biochemical reactions (Figure 1-18).

Glycolysis. Sugars are important for fuel or energy and they are oxidized in small steps to carbon dioxide (CO2) and water (H2O). Glycolysis is the process for oxidizing sugars or glucose. Breakdown of glucose. A, Anaerobic catabolism, to lactic acid and little adenosine triphosphate (ATP). B, Aerobic catabolism, to carbon dioxide, water, and lots of ATP. (From Herlihy,

FIGURE 1-18

B. [2015]. The human body in health and illness [5th ed.]. St. Louis: Saunders.)

Phase 3: Citric acid cycle (Krebs cycle, tricarboxylic acid cycle). Most of the ATP is generated during this final phase, which begins with the citric acid cycle and ends with oxidative phosphorylation. About two thirds of the total oxidation of carbon compounds in most cells is accomplished during this phase. The major end products are CO2 and two dinucleotides—reduced nicotinamide adenine dinucleotide (NADH) and the reduced form of flavin adenine dinucleotide (FADH2)— both of which transfer their electrons into the electron-transport chain.

Oxidative Phosphorylation Oxidative phosphorylation occurs in the mitochondria and is the mechanism by which the energy produced from carbohydrates, fats, and proteins is transferred to ATP. During the breakdown (catabolism) of foods, many reactions involve the removal of electrons from various intermediates. These reactions generally require a coenzyme (a nonprotein carrier molecule), such as nicotinamide adenine dinucleotide (NAD), to transfer the electrons and thus are called transfer reactions. Molecules of NAD and flavin adenine dinucleotide (FAD) transfer electrons they have gained from the oxidation of substrates to molecular oxygen. The electrons from reduced NAD and FAD, NADH and FADH2, respectively, are transferred to the electron-transport chain on the inner surfaces of the mitochondria with the release of hydrogen ions. Some carrier molecules are brightly coloured, ironcontaining proteins known as cytochromes that accept a pair of electrons. These electrons eventually combine with molecular oxygen. If oxygen is not available to the electron-transport chain, ATP will not be formed by the mitochondria. Instead, an anaerobic (without oxygen) metabolic pathway synthesizes ATP. This process, called substrate phosphorylation or anaerobic glycolysis, is linked to the breakdown (glycolysis) of carbohydrate (see Figure 1-18). Because glycolysis occurs in the cytoplasm of the cell, it provides energy for cells that lack mitochondria. The reactions in anaerobic glycolysis involve the conversion of glucose to pyruvic acid (pyruvate) with the simultaneous production of ATP. With the glycolysis of one molecule of glucose, two ATP molecules and two molecules of pyruvate are liberated. If oxygen is present, the two molecules of pyruvate move into the mitochondria, where they enter the citric acid cycle (Figure 1-19).

FIGURE 1-19 What Happens to Pyruvate, the Product of Glycolysis? In the presence of oxygen, pyruvate is oxidized to acetyl coenzyme A (Acetyl CoA) and enters the citric acid cycle. In the absence of oxygen, pyruvate instead is reduced, accepting the electrons extracted during glycolysis and carried by reduced nicotinamide adenine dinucleotide (NADH). When pyruvate is reduced directly, as it is in muscles, the product is lactic acid. When carbon dioxide (CO2) is first removed from pyruvate and the remainder is reduced, as it is in yeasts, the resulting product is ethanol. NAD+, oxidized nicotinamide adenine dinucleotide.

If oxygen is absent, pyruvate is converted to lactic acid, which is released into the extracellular fluid. The conversion of pyruvic acid to lactic acid is reversible; therefore, once oxygen is restored, lactic acid is quickly converted back to either pyruvic acid or glucose. The anaerobic generation of ATP from glucose through glycolysis is not as efficient as the aerobic generation process. Adding an oxygen-requiring stage to the catabolic process (phase 3; see Figure 1-17) provides cells with a much more powerful method for extracting energy from food molecules.

Membrane Transport: Cellular Intake and Output Cell survival and growth depend on the constant exchange of molecules with their environment. Cells continually import nutrients, fluids, and chemical messengers from the extracellular environment and expel metabolites, or the products of metabolism, and end products of lysosomal digestion. Cells also must regulate ions in their cytosol and organelles. Simple diffusion across the lipid bilayer of the plasma membrane occurs for such important molecules as O2 and CO2. However, the majority of molecular transfer depends on specialized membrane transport proteins that span the lipid bilayer and provide private conduits for select molecules.1 Membrane transport proteins occur in many forms and are present in all cell membranes.1 Transport by membrane transport proteins is sometimes called mediated transport. Most of these transport proteins allow selective passage (e.g., Na+ but not K+ or K+ but not Na+). Each type of cell membrane has its own transport proteins that determine which solute can pass into and out of the cell or organelle.1 The two main classes of membrane transport proteins are transporters and channels. These transport proteins differ in the type of solute—small particles of dissolved substances— they transport. A transporter is specific, allowing only those ions that fit the unique binding sites on the protein (Figure 1-20, A). A transporter undergoes conformational changes to enable membrane transport. A channel, when open, forms a pore across the lipid bilayer that allows ions and selective polar organic molecules to diffuse across the membrane (Figure 1-20, B). Transport by a channel depends on the size and electrical charge of the molecule. Some channels are controlled by a gate mechanism that determines which solute can move into it. Ion channels are responsible for the electrical excitability of nerve and muscle cells and play a critical role in the membrane potential.

FIGURE 1-20

Inorganic Ions and Small, Polar Organic Molecules Can Cross a Cell Membrane Through Either a Transporter or a Channel. (Adapted from Alberts, B. [2014]. Essential cell biology [4th ed.]. New York: Garland.)

The mechanisms of membrane transport depend on the characteristics of the substance to be transported. In passive transport, water and small, electrically uncharged molecules move easily through pores in the plasma membrane's lipid bilayer (Figure 1-20). This process occurs naturally through any semipermeable barrier. Molecules will easily flow “downhill” from a region of high concentration to a region of low concentration; this movement is called passive because it does not require expenditure of energy or a driving force. It is driven by osmosis, hydrostatic pressure, and diffusion, all of which depend on the laws of physics and do not require life. Other molecules are too large to pass through pores or are ligands bound to receptors on the cell's plasma membrane. Some of these molecules are moved into and out of the cell by active transport, which requires life, biological activity, and the cell's expenditure of metabolic energy (Figure 1-21). Unlike passive transport, active transport occurs across only living membranes that have to drive the flow “uphill” by coupling it to an energy source. Movement of a solute against its concentration gradient occurs by special types of transporters called pumps (see Figure 1-21). These transporter pumps must harness an energy source to power the transport process. Energy can come from ATP hydrolysis, a transmembrane ion gradient, or sunlight (see Figure 1-21). The best-known energy source is the Na+–K+dependent adenosine triphosphatase (ATPase) pump (see Figure 1-26). It continuously regulates the cell's

volume by controlling leaks through pores or protein channels and maintaining the ionic concentration gradients needed for cellular excitation and membrane conductivity. Large molecules (macromolecules), along with fluids, are transported by endocytosis (taking in) and exocytosis (expelling). Receptormacromolecule complexes enter the cell by means of receptor-mediated endocytosis.

FIGURE 1-21 Pumps Carry Out Active Transport in Three Ways. 1, Coupled pumps link the uphill transport of one solute to the downhill transport of another solute. 2, ATP-driven pumps drive uphill transport from hydrolysis of ATP. 3, Light-driven pumps are mostly found in bacteria and use energy from sunlight to drive uphill transport. ADP, adenosine diphosphate; ATP, adenosine triphosphate; Pi, inorganic phosphate. (Adapted from Alberts, B. [2014]. Essential cell biology [4th ed.]. New York: Garland.)

Mediated transport systems can move solute molecules singly or two at a time. Two molecules can be moved simultaneously in one direction (a process called symport; e.g., sodium-glucose in the digestive tract) or in opposite directions (called antiport; e.g., the sodium–potassium pump in all cells), or a single molecule can be moved in one direction (called uniport; e.g., glucose) (Figure 1-22).

FIGURE 1-22 Mediated Transport. The illustration shows simultaneous movement of a single solute molecule in one direction (Uniport), of two different solute molecules in one direction (Symport), and of two different solute molecules in opposite directions (Antiport).

Electrolytes as Solutes Body fluids are composed of electrolytes, which are electrically charged and dissociate into constituent ions when placed in solution, and nonelectrolytes, such as glucose, urea, and creatinine, which do not dissociate. Electrolytes account for approximately 95% of the solute molecules in body water. Electrolytes exhibit polarity by orienting themselves toward the positive or negative pole. Ions with a positive charge

are known as cations and migrate toward the negative pole, or cathode, if an electrical current is passed through the electrolyte solution. Anions carry a negative charge and migrate toward the positive pole, or anode, in the presence of electrical current. Anions and cations are located in both the intracellular fluid (ICF) and the extracellular fluid (ECF) compartments, although their concentration depends on their location. (Fluid and electrolyte balance between body compartments is discussed in Chapter 5.) For example, sodium (Na+) is the predominant extracellular cation, and potassium (K+) is the principal intracellular cation. The difference in ICF and ECF concentrations of these ions is important to the transmission of electrical impulses across the plasma membranes of nerve and muscle cells. Electrolytes are measured in milliequivalents per litre (mEq/L) or millimoles per litre (mmol/L). The term milliequivalent indicates the chemical-combining activity of an ion, which depends on the electrical charge, or valence, of its ions. In abbreviations, valence is indicated by the number of plus or minus signs. One milliequivalent of any cation can combine chemically with 1 mEq of any anion: one monovalent anion will combine with one monovalent cation. Divalent ions combine more strongly than monovalent ions. To maintain electrochemical balance, one divalent ion will combine with two monovalent ions (e.g., Ca++ + 2Cl− ⇌ CaCl2).

Passive Transport: Diffusion, Filtration, and Osmosis Diffusion. Diffusion is the movement of a solute molecule from an area of greater solute concentration to an area of lesser solute concentration. This difference in concentration is known as a concentration gradient. Although particles in a solution move randomly in any direction, if the concentration of particles in one part of the solution is greater than that in another part, the particles distribute themselves evenly throughout the solution. According to the same principle, if the concentration of particles is greater on one side of a permeable membrane than on the other side, the particles diffuse spontaneously from the area of greater concentration to the area of lesser concentration until equilibrium is reached. The higher the concentration on one side, the greater the diffusion rate. The diffusion rate is influenced by differences of electrical potential across the membrane. Because the pores in the lipid bilayer are often lined with Ca++, other cations (e.g., Na+ and K+) diffuse slowly because they are repelled by positive charges in the pores. The rate of diffusion of a substance depends also on its size (diffusion coefficient) and its lipid solubility (Figure 1-23). Usually, the smaller the molecule and the more soluble it is in oil, the more hydrophobic or nonpolar it is and the more rapidly it will diffuse across the bilayer. Oxygen, carbon dioxide, and steroid hormones (e.g., androgens and estrogens) are all nonpolar molecules. Water-soluble substances, such as glucose and inorganic ions, diffuse very slowly, whereas uncharged lipophilic (“lipidloving”) molecules, such as fatty acids and steroids, diffuse rapidly. Ions and other polar molecules generally diffuse across cellular membranes more slowly than lipid-soluble substances.

FIGURE 1-23

Passive Diffusion of Solute Molecules Across the Plasma Membrane. Oxygen, nitrogen, water, urea, glycerol, and carbon

dioxide can diffuse readily down the concentration gradient. Macromolecules are too large to diffuse through pores in the plasma membrane. Ions may be repelled if the pores contain substances with identical charges. If the pores are lined with cations, for example, other cations will have difficulty diffusing because the positive charges will repel one another. Diffusion can still occur, but it occurs more slowly.

Water readily diffuses through biological membranes because water molecules are small and uncharged. The dipolar structure of water allows it to rapidly cross the regions of the bilayer containing the lipid head groups. The lipid head groups constitute the two outer regions of the lipid bilayer.

Filtration: hydrostatic pressure. Filtration is the movement of water and solutes through a membrane because of a greater pushing pressure (force) on one side of the membrane than on the other side. Hydrostatic pressure is the mechanical force of water pushing against cellular membranes (Figure 1-24, A). In the vascular system, hydrostatic pressure is the blood pressure generated in vessels when the heart contracts. Blood reaching the capillary bed has a hydrostatic pressure of 25 to 30 mm Hg, which is sufficient force to push water across the thin capillary membranes into the interstitial space. Hydrostatic pressure is partially balanced by osmotic pressure, whereby water moving out of the capillaries is partially balanced by osmotic forces that tend to pull water into the capillaries (Figure 1-24, B). Water that is not osmotically attracted back into the capillaries moves into the lymph system (see the discussion of Starling forces in Chapter 5).

FIGURE 1-24 Hydrostatic Pressure and Oncotic Pressure in Plasma. 1, Hydrostatic pressure in plasma. 2, Oncotic pressure exerted by proteins in the plasma usually tends to pull water into the circulatory system. The proteins are too big to cross the semipermeable membrane, and have a negative charge. 3, Individuals with low protein levels (e.g., starvation) are unable to maintain a normal oncotic pressure; therefore water is not reabsorbed into the circulation and, instead, causes body edema.

Osmosis. Osmosis is the movement of water “down” a concentration gradient—that is, across a semipermeable membrane from a region of higher water concentration to one of lower concentration. For osmosis to occur, (1) the membrane must be more permeable to water than to solutes, and (2) the concentration of solutes on one side of the membrane must be greater than that on the other side so that water moves more easily. Osmosis is directly related to both hydrostatic pressure and solute concentration but not to particle size or weight. For example, particles of the plasma protein albumin are small but are more concentrated in body fluids than the larger and heavier particles of globulin. Therefore albumin exerts a greater osmotic force than does globulin. Osmolality controls the distribution and movement of water between body compartments. The terms osmolality and osmolarity often are used interchangeably in reference to osmotic activity, but they define

different measurements. Osmolality measures the number of milliosmoles per kilogram (mOsm/kg) of water, or the concentration of molecules per weight of water. Osmolarity measures the number of milliosmoles per litre of solution, or the concentration of molecules per volume of solution. In solutions that contain only dissociable substances, such as sodium and chloride, the difference between the two measurements is negligible. When considering all the different solutes in plasma (e.g., proteins, glucose, lipids), however, the difference between osmolality and osmolarity becomes more significant. Osmolarity tends to be less than osmolality because it includes solute content as part of the solution volume. On the other hand, the osmolality of a solution is a measure of weight, and the solvent weight does not include any solutes. Though the distinction between the two measurements is negligible, because of the relatively large proportion of solutes dissolved in plasma compared with the amount of water (or solvent), osmolality is the preferred modality for human clinical assessment. The normal osmolality of body fluids is 280 to 294 mOsm/kg. The osmolalities of intracellular and extracellular fluids tend to equalize, providing a measure of body fluid concentration and thus the body's hydration status. Hydration is affected also by hydrostatic pressure because the movement of water by osmosis can be opposed by an equal amount of hydrostatic pressure. The amount of hydrostatic pressure required to oppose the osmotic movement of water is called the osmotic pressure of the solution. Factors that determine osmotic pressure are the type and thickness of the plasma membrane, the size of the molecules, the concentration of molecules or the concentration gradient, and the solubility of molecules within the membrane. Effective osmolality is sustained osmotic activity and depends on the concentration of solutes remaining on one side of a permeable membrane. If the solutes penetrate the membrane and equilibrate with the solution on the other side of the membrane, the osmotic effect will be diminished or lost. Plasma proteins influence osmolality because they have a negative charge (see Figure 1-24, B). The principle involved is known as Gibbs-Donnan equilibrium; it occurs when the fluid in one compartment contains small, diffusible ions, such as Na+ and chloride (Cl−), together with large, nondiffusible, charged particles, such as plasma proteins. Because the body tends to maintain an electrical equilibrium, the nondiffusible protein molecules cause asymmetry in the distribution of small ions. Anions such as Cl− are thus driven out of the cell or plasma, and cations such as Na+ are attracted to the cell. The proteincontaining compartment maintains a state of electroneutrality, but the osmolality is higher. The overall osmotic effect of colloids, such as plasma proteins, is called oncotic pressure or colloid osmotic pressure. Tonicity describes the effective osmolality of a solution. (The terms osmolality and tonicity may be used interchangeably.) Solutions have relative degrees of tonicity. An isotonic solution (or isosmotic solution) has the same osmolality or concentration of particles (285 mOsm) as the ICF or ECF. A hypotonic solution has a lower concentration and is thus more dilute than body fluids (Figure 1-25). A hypertonic solution has a concentration of more than 285 to 294 mOsm/kg. The concept of tonicity is important when correcting water and solute imbalances by administering different types of replacement solutions (see Figure 1-25) (see Chapter 5).

FIGURE 1-25 Tonicity. Tonicity is important, especially for red blood cell function. A, Isotonic solution. B, Hypotonic solution. C, Hypertonic solution. (From Waugh, A., & Grant, A. [2012]. Ross and Wilson anatomy and physiology in health and illness [12th ed.]. London: Churchill Livingstone.)

Quick Check 1-2 1. What does glycolysis produce? 2. Define membrane transport proteins. 3. What are the differences between passive and active transport? 4. Why do water and small, electrically charged molecules move easily through pores in the plasma membrane?

Active Transport of Na+ and K+ The active transport system for Na+ and K+ is found in virtually all mammalian cells. The Na+–K+-antiport system (i.e., Na+ moving out of the cell and K+ moving into the cell) uses the direct energy of ATP to transport these cations. The transporter protein is ATPase, which requires Na+, K+, and magnesium (Mg++) ions. The concentration of ATPase in plasma membranes is directly related to Na+–K+-transport activity. Approximately 60 to 70% of the ATP synthesized by cells, especially muscle and nerve cells, is used to maintain the Na+–K+-transport system. Excitable tissues have a high concentration of Na+–K+ ATPase, as do other tissues that transport significant amounts of Na+. For every ATP molecule hydrolyzed, three molecules of Na+ are transported out of the cell, whereas only two molecules of K+ move into the cell. The process leads to an electrical potential and is called electrogenic, with the inside of the cell more negative than the outside. Although the exact mechanism for this transport is uncertain, it is possible that ATPase induces the transporter protein to undergo several conformational changes, causing Na+ and K+ to move short distances (Figure 1-26). The conformational change lowers the affinity for Na+ and K+ to the ATPase transporter, resulting in the release of the cations after transport.

FIGURE 1-26 Active Transport and the Sodium–Potassium Pump. 1, Three sodium (Na+) ions bind to sodium-binding sites on the carrier's inner face. 2, At the same time, an energy-containing adenosine triphosphate (ATP) molecule produced by the cell's mitochondria binds to the carrier. The ATP dissociates, transferring its stored energy to the carrier. 3 and 4, The carrier then changes shape, releases the three Na+ ions to the outside of the cell, and attracts two potassium (K+) ions to its potassium-binding sites. 5, The carrier then returns to its original shape, releasing the two K+ ions and the remnant of the ATP molecule to the inside of the cell. The carrier is now ready for another pumping cycle. ADP, adenosine diphosphate; P, protein.

Table 1-4 summarizes the major mechanisms of transport through pores and protein transporters in the plasma membranes. Many disease states are caused or manifested by loss of these membrane transport systems. TABLE 1-4 Major Transport Systems in Mammalian Cells Substance Transported Carbohydrates Glucose Fructose Amino Acids Amino acid specific transporters All amino acids except proline Specific amino acids Other Organic Molecules Cholic acid, deoxycholic acid, and taurocholic acid Organic anions (e.g., malate, α-ketoglutarate, glutamate) ATP–ADP Inorganic Ions Na+ Na+/H+ Na+/K+

Mechanism of Transporta

Tissues

Passive: protein channel Active: symport with Na+ Active: symport with Na+ Passive

Most tissues

Coupled channels Active: symport with Na+ Active: group translocation Passive

Intestines, kidney, and liver Liver Small intestine

Active: symport with Na+ Antiport with counter–organic anion Antiport transport of nucleotides; can be active

Intestines Mitochondria of liver cells Mitochondria of liver cells

Passive Active antiport, proton pump Active: ATP driven, protein channel

Distal renal tubular cells Proximal renal tubular cells and small intestines Plasma membrane of most cells

Small intestines and renal tubular cells Intestines and liver

Ca++ H+/K+

(perhaps other anions) Water

Active: ATP driven, antiport with Na+ Active Mediated: antiport (anion transporter–band 3 protein)

All cells, antiporter in red cells Parietal cells of gastric cells secreting H+ Erythrocytes and many other cells

Osmosis passive

All tissues

a

The known transport systems are listed here; others have been proposed. Most transport systems have been studied in only a few tissues and their sites of activity may be more limited than indicated. ADP, adenosine diphosphate; ATP, adenosine triphosphate, Ca++, calcium; Cl−, chloride; H+, hydrogen; Na+, sodium.

, bicarbonate; K+, potassium;

Data from Alberts, B., Bray, D., Hopkin, K., et al. (2014). Essential cell biology (4th ed.). New York: Garland; Alberts, B., Johnson, A., Lewis, J., et al. (2001). Molecular biology of the cell (4th ed.). New York: Wiley; Devlin, T.M. (Ed.). (1992). Textbook of biochemistry: with clinical correlations (3rd ed.). New York: Wiley; Raven, P.H., & Johnson, G.B. (1995). Understanding biology (3rd ed.). Dubuque, IA: Brown.

Transport by Vesicle Formation Endocytosis and Exocytosis The active transport mechanisms by which the cells move large proteins, polynucleotides, or polysaccharides (macromolecules) across the plasma membrane are very different from those that mediate small solute and ion transport. Transport of macromolecules involves the sequential formation and fusion of membrane-bound vesicles. In endocytosis, a section of the plasma membrane enfolds substances from outside the cell, invaginates (folds inward), and separates from the plasma membrane, forming a vesicle that moves into the cell (Figure 1-27, A). Two types of endocytosis are designated based on the size of the vesicle formed. Pinocytosis (cell drinking) involves the ingestion of fluids, bits of the plasma membrane, and solute molecules through formation of small vesicles; and phagocytosis (cell eating) involves the ingestion of large particles, such as bacteria, through formation of large vesicles (vacuoles).

FIGURE 1-27

Endocytosis and Exocytosis. A, Endocytosis and fusion with lysosome and exocytosis. B, Electron micrograph of exocytosis. (B, from Raven, P.H., & Johnson, G.B. [1999]. Biology [5th ed.]. New York: McGraw-Hill.)

Because most cells continually ingest fluid and solutes by pinocytosis, the terms pinocytosis and endocytosis often are used interchangeably. In pinocytosis, the vesicle containing fluids, solutes, or both fuses with a lysosome, and lysosomal enzymes digest the vesicle's contents for use by the cell. Vesicles that bud from membranes have a particular protein coat on their cytosolic surface and are called coated vesicles. The best studied are those that have an outer coat of bristlelike structures—the protein clathrin.

Pinocytosis occurs mainly by the clathrin-coated pits and vesicles (Figure 1-28). After the coated pits pinch off from the plasma membrane, they quickly shed their coats and fuse with an endosome. An endosome is a vesicle pinched off from the plasma membrane from which its contents can be recycled to the plasma membrane or sent to lysosomes for digestion. In phagocytosis, the large molecular substances are engulfed by the plasma membrane and enter the cell so that they can be isolated and destroyed by lysosomal enzymes (see Chapter 6). Substances that are not degraded by lysosomes are isolated in residual bodies and released by exocytosis. Both pinocytosis and phagocytosis require metabolic energy and often involve binding of the substance with plasma membrane receptors before membrane invagination and fusion with lysosomes in the cell. New data are revealing that endocytosis has an even larger and more important role than previously known (Box 1-3).

FIGURE 1-28 Ligand Internalization by Means of Receptor-Mediated Endocytosis. A, The ligand attaches to its surface receptor (through the bristle coat or clathrin coat) and, through receptor-mediated endocytosis, enters the cell. The ingested material fuses with a lysosome and is processed by hydrolytic lysosomal enzymes. Processed molecules can then be transferred to other cellular components. B, Electron micrograph of a coated pit showing different sizes of filaments of the cytoskeleton (×82 000) receptor-mediated endocytosis with coated pit and vesicle. (B, from Erlandsen, S.L., & Magney, J.E. [1992]. Color atlas of histology. St. Louis: Mosby.)

Box 1-3

The New Endocytic Matrix An explosion of new data is disclosing a much more involved role for endocytosis than just a simple way to internalize nutrients and membrane-associated molecules. These new data show that endocytosis not only is a master organizer of signalling pathways but also has a major role in managing signals in time and space. Endocytosis appears to control signalling; therefore, it determines the net output of biochemical pathways. The control of signalling occurs because endocytosis modulates the presence of receptors and their ligands as well as effectors at the plasma membrane or at intermediate stations of the endocytic route. The overall processes and anatomy of these new functions are sometimes called the endocytic matrix. All of these functions ultimately have a large impact on almost every cellular process, including the nucleus. In eukaryotic cells, secretion of macromolecules almost always occurs by exocytosis (Figure 1-27). Exocytosis has two main functions: (1) replacement of portions of the plasma membrane that have been removed by endocytosis and (2) release of molecules synthesized by the cells into the ECM.

Receptor-Mediated Endocytosis

The internalization process, called receptor-mediated endocytosis (ligand internalization), is rapid and enables the cell to ingest large amounts of receptor-macromolecule complexes in clathrin-coated vesicles without ingesting large volumes of extracellular fluid (see Figure 1-28). The cellular uptake of cholesterol, for example, depends on receptor-mediated endocytosis. Additionally, many essential metabolites (e.g., vitamin B12 and iron) depend on receptor-mediated endocytosis, as does the influenza (flu) virus.

Caveolae The outer surface of the plasma membrane is dimpled with tiny flask-shaped pits (cavelike) called caveolae. Caveolae are thought to form from membrane microdomains or lipid rafts. Caveolae are cholesterol- and glycosphingolipid-rich microdomains where the protein caveolin is thought to be involved in several processes, including clathrin-independent endocytosis, cellular cholesterol regulation and transport, and cellular communication. Many proteins, including a variety of receptors, cluster in these tiny chambers. Caveolae are not only uptake vehicles but also important sites for signal transduction, a tedious process in which extracellular chemical messages or signals are communicated to the cell's interior for execution. For example, in vitro evidence now exists that plasma membrane estrogen receptors can localize in caveolae, and crosstalk with estradiol facilitates several intracellular biological actions.18

Movement of Electrical Impulses: Membrane Potentials All body cells are electrically polarized, with the inside of the cell more negatively charged than the outside. The difference in electrical charge, or voltage, is known as the resting membrane potential and is about −70 to −85 mV. The difference in voltage across the plasma membrane results from the differences in ionic composition of ICF and ECF. Sodium ions are more concentrated in the ECF, and potassium ions are more concentrated in the ICF. The concentration difference is maintained by the active transport of Na+ and K+ (the sodium–potassium pump), which transports sodium outward and potassium inward (Figure 1-29). Because the resting plasma membrane is more permeable to K+ than to Na+, K+ diffuses easily from the ICF to the ECF. Because both Na+ and K+ are cations, the net result is an excess of anions inside the cell, resulting in the resting membrane potential.

FIGURE 1-29 Sodium–Potassium Pump and Propagation of an Action Potential. A, Concentration difference of sodium (Na+) and potassium (K+) intracellularly and extracellularly. The direction of active transport by the sodium–potassium pump is also shown. B, The left diagram represents the polarized state of a neuronal membrane when at rest. The middle and right diagrams represent changes in sodium and potassium membrane permeabilities with depolarization and repolarization. ATP, adenosine triphosphate.

Nerve and muscle cells are excitable and can change their resting membrane potential in response to

electrochemical stimuli. Changes in resting membrane potential convey messages from cell to cell. When a nerve or muscle cell receives a stimulus that exceeds the membrane threshold value, a rapid change occurs in the resting membrane potential, known as the action potential. The action potential carries signals along the nerve or muscle cell and conveys information from one cell to another in a dominolike fashion. Nerve impulses are described in Chapter 13. When a resting cell is stimulated through voltageregulated channels, the cell membranes become more permeable to sodium, so a net movement of sodium into the cell occurs and the membrane potential decreases, or moves forward, from a negative value (in millivolts) to zero. This decrease is known as depolarization. The depolarized cell is more positively charged, and its polarity is neutralized. To generate an action potential and the resulting depolarization, the threshold potential must be reached. Generally this occurs when the cell has depolarized by 15 to 20 mV. When the threshold is reached, the cell will continue to depolarize with no further stimulation. The sodium gates open, and sodium rushes into the cell, causing the membrane potential to drop to zero and then become positive (depolarization). The rapid reversal in polarity results in the action potential. During repolarization, the negative polarity of the resting membrane potential is re-established. As the voltage-gated sodium channels begin to close, voltage-gated potassium channels open. Membrane permeability to sodium decreases and potassium permeability increases, so potassium ions leave the cell. The sodium gates close, and with the loss of potassium the membrane potential becomes more negative. The Na+–K+ pump then returns the membrane to the resting potential by pumping potassium back into the cell and sodium out of the cell. During most of the action potential, the plasma membrane cannot respond to an additional stimulus. This time is known as the absolute refractory period and is related to changes in permeability to sodium. During the latter phase of the action potential, when permeability to potassium increases, a strongerthan-normal stimulus can evoke an action potential; this time is known as the relative refractory period. When the membrane potential is more negative than normal, the cell is in a hyperpolarized state (less excitable: decreased K+ levels within the cell). A stronger-than-normal stimulus is then required to reach the threshold potential and generate an action potential. When the membrane potential is more positive than normal, the cell is in a hypopolarized state (more excitable than normal: increased K+ levels within the cell) and a weaker-than-normal stimulus is required to reach the threshold potential. Changes in the intracellular and extracellular concentrations of ions or a change in membrane permeability can cause these alterations in membrane excitability.

Quick Check 1-3 1. Identify examples of molecules transported in one direction (symport) and opposite directions (antiport). 2. If oxygen is no longer available to make ATP, what happens to the transport of Na+? 3. Describe the differences between pinocytosis, phagocytosis, and receptor-mediated endocytosis.

Cellular Reproduction: The Cell Cycle Human cells are subject to wear and tear, and most do not last for the lifetime of the individual. In most tissues, new cells are created as fast as old cells die. Cellular reproduction is therefore necessary for the maintenance of life. Reproduction of gametes (sperm and egg cells) occurs through a process called meiosis, described in Chapter 2. The reproduction, or division, of other body cells (somatic cells) involves two sequential phases—mitosis, or nuclear division, and cytokinesis, or cytoplasmic division. Before a cell can divide, however, it must double its mass and duplicate all its contents. Separation for division occurs during the growth phase, called interphase. The alternation between mitosis and interphase in all tissues with cellular turnover is known as the cell cycle. The four designated phases of the cell cycle (Figure 1-30) are (1) the S phase (S = synthesis), in which DNA is synthesized in the cell nucleus; (2) the G2 phase (G = gap), in which RNA and protein synthesis occurs, namely, the period between the completion of DNA synthesis and the next phase (M); (3) the M phase (M = mitosis), which includes both nuclear and cytoplasmic division; and (4) the G1 phase, which is the period between the M phase and the start of DNA synthesis. When cells are in the G0 phase, they are neither dividing nor preparing to divide. Rather, they are continuing on with their regular function as part of the tissue or organ to which they belong. Understanding the cell cycle is important when considering the effectiveness of antineoplastic medications and the growth of cancer cells, which will be covered in Chapter 10.

FIGURE 1-30 Interphase and the Phases of Mitosis. A, The G1/S checkpoint is to “check” for cell size, nutrients, growth factors, and DNA damage. See text for resting phases. The G2/M checkpoint checks for cell size and DNA replication. B, The orderly progression through the phases of the cell cycle is regulated by cyclins (so called because levels rise and fall) and cyclin-dependent protein kinases (CDKs) and their inhibitors. When cyclins are complexed with CDKs, cell cycle events are triggered.

Phases of Mitosis and Cytokinesis Interphase (the G1, S, and G2 phases) is the longest phase of the cell cycle. During interphase, the chromatin (the substance that gives the nucleus its granular appearance) consists of very long, slender rods jumbled together in the nucleus. Late in interphase, strands of chromatin begin to coil, causing shortening and thickening. The M phase of the cell cycle, mitosis and cytokinesis, begins with prophase, the first appearance of chromosomes. As the phase proceeds, each chromosome is seen as two identical halves called chromatids, which lie together and are attached by a spindle site called a centromere. (The two chromatids of each chromosome, which are genetically identical, are sometimes called sister chromatids.) The nuclear membrane, which surrounds the nucleus, disappears. Spindle fibres are microtubules

formed in the cytoplasm. They radiate from two centrioles located at opposite poles of the cell and pull the chromosomes to opposite sides of the cell, beginning metaphase. Next, the centromeres become aligned in the middle of the spindle, which is called the equatorial plate (or metaphase plate) of the cell. In this stage, chromosomes are easiest to observe microscopically because they are highly condensed and arranged in a relatively organized fashion. Anaphase begins when the centromeres split and the sister chromatids are pulled apart. The spindle fibres shorten, causing the sister chromatids to be pulled, centromere first, toward opposite sides of the cell. When the sister chromatids are separated, each is considered to be a chromosome. Thus the cell has 92 chromosomes during this stage. By the end of anaphase, there are 46 chromosomes lying at each side of the cell. Barring mitotic errors, each of the two groups of 46 chromosomes is identical to the original 46 chromosomes present at the start of the cell cycle. During telophase, the final stage, a new nuclear membrane is formed around each group of 46 chromosomes, the spindle fibres disappear, and the chromosomes begin to uncoil. Cytokinesis causes the cytoplasm to divide into almost equal parts during this phase. At the end of telophase, two identical diploid cells, called daughter cells, have been formed from the original cell.

Rates of Cellular Division Although the complete cell cycle lasts 12 to 24 hours, about 1 hour is required for the four stages of mitosis and cytokinesis. All types of cells undergo mitosis during formation of the embryo, but many adult cells—such as nerve cells, lens cells of the eye, and muscle cells—lose their ability to replicate and divide. The cells of other tissues, particularly epithelial cells (e.g., cells of the intestine, lung, or skin), divide continuously and rapidly, completing the entire cell cycle in less than 10 hours. The difference between cells that divide slowly and cells that divide rapidly is the length of time spent in the G1 phase of the cell cycle. Once the S phase begins, however, progression through mitosis takes a relatively constant amount of time. The mechanisms that control cell division depend on the integrity of genetic, epigenetic (heritable changes in genome function that occur without alterations in the DNA sequence; see Chapter 3), and protein growth factors. Protein growth factors govern the proliferation of different cell types. Individual cells are members of a complex cellular society in which survival of the entire organism is key—not survival or proliferation of just the individual cells. When a need arises for new cells, as in repair of injured cells, previously nondividing cells must be triggered rapidly to re-enter the cell cycle. With continual wear and tear, the cell birth rate and the cell death rate must be kept in balance.

Growth Factors Growth factors, also called cytokines, are peptides (protein fractions) that transmit signals within and between cells. They have a major role in the regulation of tissue growth and development (Table 1-5). Having nutrients is not enough for a cell to proliferate; it must also receive stimulatory chemical signals (growth factors) from other cells, usually its neighbours or the surrounding supporting tissue called stroma. These signals act to overcome intracellular braking mechanisms that tend to restrain cell growth and block progress through the cell cycle (Figure 1-31). TABLE 1-5 Examples of Growth Factors and Their Actions Growth Factor

Physiological Actions

Platelet-derived growth factor (PDGF) Epidermal growth factor (EGF) Insulinlike growth factor 1 (IGF-1) Vascular endothelial growth factor (VEGF) Insulinlike growth factor 2 (IGF-2)

Stimulates proliferation of connective tissue cells and neuroglial cells Stimulates proliferation of epidermal cells and other cell types Collaborates with PDGF and EGF; stimulates proliferation of fat cells and connective tissue cells Mediates functions of endothelial cells; proliferation, migration, invasion, survival, and permeability Collaborates with PDGF and EGF; stimulates or inhibits response of most cells to other growth factors; regulates differentiation of some cell types (e.g., cartilage) Stimulates or inhibits response of most cells to other growth factors; regulates differentiation of some cell types (e.g., cartilage)

Transforming growth factor-beta (TGF-β; multiple subtypes) Fibroblast growth factor (FGF; multiple subtypes) Interleukin-2 (IL-2) Nerve growth factor (NGF) Hematopoietic cell growth factors (IL-3, GM-CSF, G-CSF,

Stimulates proliferation of fibroblasts, endothelial cells, myoblasts, and other multiple subtypes Stimulates proliferation of T lymphocytes Promotes axon growth and survival of sympathetic and some sensory and central nervous system neurons Promote proliferation of blood cells

erythropoietin)

G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor.

FIGURE 1-31 How Growth Factors Stimulate Cell Proliferation. A, Resting cell. With the absence of growth factors, the retinoblastoma (Rb) protein is not phosphorylated; thus it holds the gene regulatory proteins in an inactive state. The gene regulatory proteins are required to stimulate the transcription of genes needed for cell proliferation. B, Proliferating cell. Growth factors bind to the cell surface receptors and activate intracellular signalling pathways, leading to activation of intracellular proteins. These intracellular proteins phosphorylate and thereby inactivate the Rb protein. The gene regulatory proteins are now free to activate the transcription of genes, leading to cell proliferation.

An example of a brake that regulates cell proliferation is the retinoblastoma (Rb) protein, first identified through studies of a rare childhood eye tumour called retinoblastoma, in which the Rb protein is missing or defective. The Rb protein is abundant in the nucleus of all vertebrate cells. It binds to gene regulatory proteins, preventing them from stimulating the transcription of genes required for cell proliferation (see Figure 1-31). Extracellular signals, such as growth factors, activate intracellular signalling pathways that inactivate the Rb protein, leading to cell proliferation. Different types of cells require different growth factors; for example, platelet-derived growth factor (PDGF) stimulates the production of connective tissue cells. Table 1-5 summarizes the most significant growth factors. Evidence shows that some growth factors also regulate other cellular processes, such as cellular differentiation. In addition to growth factors that stimulate cellular processes, there are factors that inhibit these processes; these factors are not well understood. Cells that are starved of growth factors come to a halt after mitosis and enter the arrested (resting) (G0) state of the cell cycle (see p. 25 for cell cycle).1

Tissues Cells of one or more types are organized into tissues, and different types of tissues compose organs. Finally, organs are integrated to perform complex functions as tracts or systems (Figure 1-32).

FIGURE 1-32 Cells, Tissues, Organs, and Organ Systems. The smallest level of organization shown in this diagram is the cell. Cells working together make up a tissue, which in turn is part of an organ. Organs working together form the different organ systems that make up a whole organism.

All cells are in contact with a network of extracellular macromolecules known as the ECM (see p. 10). This matrix not only holds cells and tissues together but also provides an organized latticework within which cells can migrate and interact with one another.

Tissue Formation To form tissues, cells must exhibit intercellular recognition and communication, adhesion, and memory. Specialized cells sense their environment through signals, such as growth factors, from other cells. This type of communication ensures that new cells are produced only when and where they are required. Different cell types have different adhesion molecules in their plasma membranes, sticking selectively to other cells of the same type. They can also adhere to ECM components. Because cells are tiny and squishy and enclosed by a flimsy membrane, it is remarkable that they form a strong human being. Strength can occur because of the ECM and the strength of the cytoskeleton with cell–cell adhesions to neighbouring cells. Cells have memory because of specialized patterns of gene expression evoked by signals that acted during embryonic development. Memory allows cells to autonomously preserve their distinctive character and pass it on to their progeny.1 Fully specialized or terminally differentiated cells that are lost are regenerated from proliferating precursor cells. These precursor cells have been derived from a smaller number of stem cells.1 Stem cells are cells with the potential to develop into many different cell types during early development and growth. In many tissues, stem cells serve as an internal repair and maintenance system, dividing indefinitely. These cells can maintain themselves over very long periods of time, called self-renewal, and can generate all the differentiated cell types of the tissue or multipotency. This stem cell–driven tissue renewal is very evident in the epithelial lining of the intestine, stomach, blood cells, and skin, which is continuously exposed to environmental factors. A class of extracellular signalling proteins, known as Wnt signals, sustain tissue renewal and enable tissue to be continuously replenished and maintained over a lifetime.19 When a stem cell divides, each daughter cell has a choice: it can remain as a stem cell or it can

follow a pathway that results in terminal differentiation (Figure 1-33).

FIGURE 1-33 Properties of Stem Cell Systems. A, Stem cells have three characteristics: self-renewal, proliferation, and differentiation into mature cells. Stem cells are housed in niches consisting of stromal cells that provide factors for their maintenance. Stem cells of the embryo can give rise to cell precursors that generate all the tissues of the body. This property defines stem cells as multipotent. Stem cells are difficult to identify anatomically. Their identification is based on specific cell surface markers (cell surface antigens recognized by specific monoclonal antibodies) and on the lineage they generate following transplantation. B, Wnt signalling fuels tissue renewal. (A, from Kierszenbaum, A. [2012]. Histology and cell biology: An introduction to pathology [3rd ed.]. St. Louis: Elsevier. B, from Clevers, H., Loh, K.M., & Nusse, R. [2014]. Science, 346[6205], 54.)

Types of Tissues The four basic types of tissues are nerve, epithelial, connective, and muscle tissues. The structure and function of these four types underlie the structure and function of each organ system. Neural tissue is composed of highly specialized cells called neurons, which receive and transmit electrical impulses

rapidly across junctions called synapses (see Figure 13-1). Different types of neurons have special characteristics that depend on their distribution and function within the nervous system. Epithelial, connective, and muscle tissues are summarized in Tables 1-6, 1-7, and 1-8, respectively. TABLE 1-6 Characteristics of Epithelial Tissues Simple Squamous Epithelium Structure Single layer of cells Location and Function Lining of blood vessels leads to diffusion and filtration Lining of pulmonary alveoli (air sacs) leads to separation of blood from fluids in tissues Bowman's capsule (kidney), where it filters substances from blood, forming urine

Simple Squamous Epithelial Cell. Photomicrograph of simple squamous epithelial cell in parietal wall of Bowman's capsule in kidney. (From Erlandsen, S.L., & Magney, J.E. [1992]. Color atlas of histology. St. Louis: Mosby.) Stratified Squamous Epithelium Structure Two or more layers, depending on location, with cells closest to basement membrane tending to be cuboidal Location and Function Epidermis of skin and linings of mouth, pharynx, esophagus, and anus provide protection and secretion

Cornified Stratified Squamous Epithelium. Diagram of stratified squamous epithelium of skin. (Copyright Ed Reschke. Used with permission.) Transitional Epithelium Structure Vary in shape from cuboidal to squamous, depending on whether basal cells of bladder are columnar or are composed of many layers; when bladder is full and stretched, the cells flatten and stretch like squamous cells Location and Function Linings of urinary bladder and other hollow structures stretch, allowing expansion of the hollow organs

Stratified Squamous Transitional Epithelium. Photomicrograph of stratified squamous transitional epithelium of urinary bladder. (Copyright Ed Reschke. Used with permission.) Simple Cuboidal Epithelium Structure Simple cuboidal cells; rarely stratified (layered) Location and Function Glands (e.g., thyroid, sweat, salivary) and parts of the kidney tubules and outer covering of ovary secrete fluids

Simple Cuboidal Epithelium. Photomicrograph of simple cuboidal epithelium of pancreatic duct. (From Erlandsen, S.L., & Magney, J.E. [1992]. Color atlas of histology. St. Louis: Mosby.) Simple Columnar Epithelium Structure Large amounts of cytoplasm and cellular organelles Location and Function Ducts of many glands and lining of digestive tract allow secretion and absorption from stomach to anus

Simple Columnar Epithelium. Photomicrograph of simple columnar epithelium. (Copyright Ed Reschke. Used with permission.) Ciliated Simple Columnar Epithelium Structure Same as simple columnar epithelium but ciliated Location and Function Linings of bronchi of lungs, nasal cavity, and oviducts allow secretion, absorption, and propulsion of fluids and particles Stratified Columnar Epithelium Structure Small and rounded basement membrane (columnar cells do not touch basement membrane) Location and Function Linings of epiglottis, part of pharynx, anus, and male urethra provide protection Pseudostratified Ciliated Columnar Epithelium

Structure All cells in contact with basement membrane Nuclei found at different levels within cell, giving stratified appearance Free surface often ciliated Location and Function Linings of large ducts of some glands (parotid, salivary), male urethra, respiratory passages, and eustachian tubes of ears transport substances

Pseudostratified Ciliated Columnar Epithelium. Photomicrograph of pseudostratified ciliated columnar epithelium of trachea. (Jose Luis Calvo/Shutterstock.com.)

TABLE 1-7 Connective Tissues Loose or Areolar Tissue Structure Unorganized; spaces between fibres Most fibres collagenous, some elastic and reticular Includes many types of cells (fibroblasts and macrophages most common) and large amount of intercellular fluid Location and Function Attaches skin to underlying tissue; holds organs in place by filling spaces between them; supports blood vessels Intercellular fluid transports nutrients and waste products Fluid accumulation causes swelling (edema)

Loose Areolar Connective Tissue. (Copyright Ed Reschke. Used with permission.) Dense Irregular Tissue Structure Dense, compact, and areolar tissue, with fewer cells and greater number of closely woven collagenous fibres than in loose tissue Location and Function Dermis layer of skin; acts as protective barrier

Dense, Irregular Connective Tissue. (Copyright Ed Reschke. Used with permission.) Dense, Regular (White Fibrous) Tissue Structure Collagenous fibres and some elastic fibres, tightly packed into parallel bundles, with only fibroblast cells Location and Function Forms strong tendons of muscle, ligaments of joints, some fibrous membranes, and fascia that surrounds organs and muscles

Dense, Regular (White Fibrous) Connective Tissue. (Copyright Ed Reschke. Used with permission.) Elastic Tissue Structure Elastic fibres, some collagenous fibres, fibroblasts Location and Function Lends strength and elasticity to walls of arteries, trachea, vocal cords, and other structures

Elastic Connective Tissue. (From Erlandsen, S.L., & Magney, J.E. [1992]. Color atlas of histology. St. Louis: Mosby.) Adipose Tissue Structure Fat cells dispersed in loose tissues; each cell containing a large droplet of fat flattens nucleus and forces cytoplasm into a ring around cell's periphery Location and Function Stores fat, which provides padding and protection

Adipose Tissue. A, Fat storage areas—distribution of fat in male and female bodies. B, Photomicrograph of adipose tissue. (A, from Thibodeau, G.A., & Patton, K.T. [2007]. Anatomy & physiology [6th ed.]. St. Louis: Mosby; B, copyright Ed Reschke. Used with permission.) Cartilage (Hyaline, Elastic, Fibrous) Structure Collagenous fibres embedded in a firm matrix (chondrin); no blood supply Location and Function Gives form, support, and flexibility to joints, trachea, nose, ear, vertebral disks, embryonic skeleton, and many internal structures

Cartilage. A, Hyaline cartilage. B, Elastic cartilage. C, Fibrous cartilage. (A, B, and C, copyright Ed Reschke. Used with permission.) Bone Structure Rigid connective tissue consisting of cells, fibres, ground substances, and minerals Location and Function Lends skeleton rigidity and strength

Bone. (Steve Gschmeissner/Science Source.) Special Connective Tissues Plasma Structure Fluid Location and Function Serves as matrix for blood cells Macrophages in Tissue, Reticuloendothelial, or Macrophage System Structure Scattered macrophages (phagocytes) called Kupffer cells (in liver), alveolar macrophages (in lungs), microglia (in central nervous system) Location and Function Facilitate inflammatory response and carry out phagocytosis in loose connective, lymphatic, digestive, medullary (bone marrow), splenic, adrenal, and pituitary tissues

TABLE 1-8 Muscle Tissues Skeletal (Striated) Muscle Structure Characteristics of Cells Long, cylindrical cells that extend throughout length of muscles Striated myofibrils (proteins) Many nuclei on periphery Location and Function Attached to bones directly or by tendons and provide voluntary movement of skeleton and maintenance of posture

Skeletal (Striated) Muscle. (From Thibodeau, G.A., & Patton, K.T. [2007]. Anatomy & physiology [6th ed.]. St. Louis: Mosby.) Cardiac Muscle Structure Characteristics of Cells Branching networks throughout muscle tissue Striated myofibrils Location and Function Cells attached end-to-end at intercalated disks with tissue forming walls of heart (myocardium) to provide involuntary pumping action of heart

Cardiac Muscle. (Copyright Ed Reschke. Used with permission.) Smooth (Visceral) Muscle Structure Characteristics of Cells Long spindles that taper to a point Absence of striated myofibrils Location and Function Walls of hollow internal structures, such as digestive tract and blood vessels (viscera), provide voluntary and involuntary contractions that move substances through hollow structures

Smooth (Visceral) Muscle. (Jose Luis Calvo/Shutterstock.com.)

Quick Check 1-4 1. What is the cell cycle? 2. Describe the five types of intracellular communication. 3. Why is the extracellular matrix important for tissue cells?

Did You Understand? Cellular Functions 1. Cells become specialized through the process of differentiation or maturation. 2. The eight specialized cellular functions are movement, conductivity, metabolic absorption, secretion, excretion, respiration, reproduction, and communication.

Structure and Function of Cellular Components 1. The eukaryotic cell consists of three general components: the plasma membrane, the cytoplasm, and the intracellular organelles. 2. The nucleus is the largest membrane-bound organelle and is found usually in the cell's centre. The chief functions of the nucleus are cell division and control of genetic information. 3. Cytoplasm is an aqueous solution (cytosol) that fills the cytoplasmic matrix—the space between the nuclear envelope and the plasma membrane. 4. The organelles are suspended in the cytoplasm and are enclosed in biological membranes. 5. The endoplasmic reticulum is a network of tubular channels (cisternae) that extend throughout the outer nuclear membrane. It specializes in the synthesis and transport of protein and lipid components of most of the organelles. 6. The Golgi complex is a network of smooth membranes and vesicles located near the nucleus. The Golgi complex is responsible for processing and packaging proteins into secretory vesicles that break away from the Golgi complex and migrate to a variety of intracellular and extracellular destinations, including the plasma membrane. 7. Lysosomes are saclike structures that originate from the Golgi complex and contain digestive enzymes. These enzymes are responsible for digesting most cellular substances to their basic form, such as amino acids, fatty acids, and carbohydrates (sugars). 8. Cellular injury leads to a release of the lysosomal enzymes, causing cellular self-digestion. 9. Peroxisomes are similar to lysosomes but contain several enzymes that either produce or use hydrogen peroxide. 10. Mitochondria contain the metabolic machinery necessary for cellular energy metabolism. The enzymes of the respiratory chain (electron-transport chain), found in the inner membrane of the mitochondria, generate most of the cell's ATP. 11. The cytoskeleton is the “bone and muscle” of the cell. The internal skeleton is composed of a network of protein filaments, including microtubules and actin filaments (microfilaments). 12. The plasma membrane encloses the cell and, by controlling the movement of substances across it, exerts a powerful influence on metabolic pathways. Principles of membrane structure are being overhauled. 13. Proteins are the major workhorses of the cell. Membrane proteins, like other proteins, are synthesized by the ribosome and then make their way, called trafficking, to different locations in the cell. Trafficking places unique demands on membrane proteins for folding, translocation, and stability. Misfolded proteins are emerging as an important cause of disease. 14. Protein regulation in a cell is called protein homeostasis and is defined by the proteostasis network. This network is composed of ribosomes (makers), chaperones (helpers), and protein breakdown or proteolytic systems. Malfunction of these systems is associated with disease. 15. Carbohydrates contained within the plasma membrane are generally bound to membrane proteins (glycoproteins) and lipids (glycolipids). 16. Protein receptors (recognition units) on the plasma membrane enable the cell to interact with other cells and with extracellular substances. 17. Membrane functions are determined largely by proteins. These functions include recognition by protein receptors and transport of substances into and out of the cell.

Cell-to-Cell Adhesions 1. Cell-to-cell adhesions are formed on plasma membranes, thereby allowing the formation of tissues and organs. Cells are held together by three different means: (a) the extracellular membrane, (b) cell adhesion molecules in the cell's plasma membrane, and (c) specialized cell junctions. 2. The extracellular matrix includes three groups of macromolecules: (a) fibrous structural proteins (e.g., collagen and elastin), (b) adhesive glycoproteins, and (c) proteoglycans and hyaluronic acid. The matrix helps regulate cell growth, movement, and differentiation. 3. The basement membrane is a tough layer of extracellular matrix underlying the epithelium of many organs; it is also called the basal lamina. 4. Cell junctions can be classified as symmetrical and asymmetrical. Symmetrical junctions include tight junctions, the belt desmosome, desmosomes, and gap junctions. An asymmetrical junction is the hemidesmosome.

Cellular Communication and Signal Transduction 1. Cells communicate in three main ways: (a) they form protein channels (gap junctions); (b) they display receptors that affect intracellular processes or other cells in direct physical contact; and (c) they use receptor proteins inside the target cell. 2. Primary modes of intercellular signalling include contact-dependent, paracrine, hormonal, neurohormonal, and neurotransmitter. 3. Signal transduction involves signals or instructions from extracellular chemical messengers that are conveyed to the cell's interior for execution. If deprived of appropriate signals, cells undergo a form of cell suicide known as programmed cell death, or apoptosis.

Cellular Metabolism 1. The chemical tasks of maintaining essential cellular functions are referred to as cellular metabolism. Anabolism is the energy-using process of metabolism, whereas catabolism is the energy-releasing process. 2. Adenosine triphosphate (ATP) functions as an energy-transferring molecule. It is fuel for cell survival. Energy is stored by molecules of carbohydrate, lipid, and protein, which, when catabolized, transfers energy to ATP. 3. Oxidative phosphorylation occurs in the mitochondria and is the mechanism by which the energy produced from carbohydrates, fats, and proteins is transferred to ATP.

Membrane Transport: Cellular Intake and Output 1. Cell survival and growth depends on the constant exchange of molecules with their environment. The two main classes of membrane transport proteins are transporters and channels. The majority of molecular transfer depends on specialized membrane transport proteins. 2. Water and small, electrically uncharged molecules move through pores in the plasma membrane's lipid bilayer in the process called passive transport. 3. Passive transport does not require the expenditure of energy; rather, it is driven by the physical effect of osmosis, hydrostatic pressure, and diffusion. 4. Larger molecules and molecular complexes are moved into the cell by active transport, which requires the cell to expend energy (by means of ATP). 5. The largest molecules (macromolecules) and fluids are transported by the processes of endocytosis (ingestion) and exocytosis (expulsion). Endocytosis, or vesicle formation, is when the substance to be transported is engulfed by a segment of the plasma membrane, forming a vesicle that moves into the cell.

6. Pinocytosis is a type of endocytosis in which fluids and solute molecules are ingested through formation of small vesicles. 7. Phagocytosis is a type of endocytosis in which large particles, such as bacteria, are ingested through formation of large vesicles, called vacuoles. 8. In receptor-mediated endocytosis, the plasma membrane receptors are clustered, along with bristlelike structures, in specialized areas called coated pits. 9. Endocytosis occurs when coated pits invaginate, internalizing ligand-receptor complexes in coated vesicles. 10. Inside the cell, lysosomal enzymes process and digest material ingested by endocytosis. 11. Two types of solutes exist in body fluids: electrolytes and nonelectrolytes. Electrolytes are electrically charged and dissociate into constituent ions when placed in solution. Nonelectrolytes do not dissociate when placed in solution. 12. Diffusion is the passive movement of a solute from an area of higher solute concentration to an area of lower solute concentration. 13. Filtration is the measurement of water and solutes through a membrane because of a greater pushing pressure. 14. Hydrostatic pressure is the mechanical force of water pushing against cellular membranes. 15. Osmosis is the movement of water across a semipermeable membrane from a region of lower solute concentration to a region of higher solute concentration. 16. The amount of hydrostatic pressure required to oppose the osmotic movement of water is called the osmotic pressure of the solution. 17. The overall osmotic effect of colloids, such as plasma proteins, is called the oncotic pressure, or colloid osmotic pressure. 18. All body cells are electrically polarized, with the inside of the cell more negatively charged than the outside. The difference in voltage across the plasma membrane is the resting membrane potential. 19. When an excitable (nerve or muscle) cell receives an electrochemical stimulus, cations enter the cell and cause a rapid change in the resting membrane potential, known as the action potential. The action potential “moves” along the cell's plasma membrane and is transmitted to an adjacent cell. This is how electrochemical signals convey information from cell to cell.

Cellular Reproduction: The Cell Cycle 1. Cellular reproduction in body tissues involves mitosis (nuclear division) and cytokinesis (cytoplasmic division). 2. Only mature cells are capable of division. Maturation occurs during a stage of cellular life called interphase (the growth phase). 3. The cell cycle is the reproductive process that begins after interphase in all tissues with cellular turnover. There are four phases of the cell cycle: (a) the S phase, during which DNA synthesis takes place in the cell nucleus; (b) the G2 phase, the period between the completion of DNA synthesis and the next phase (M); (c) the M phase, which involves both nuclear (mitotic) and cytoplasmic (cytokinetic) division; and (d) the G1 phase (growth phase), after which the cycle begins again. 4. The M phase (mitosis) involves four stages: prophase, metaphase, anaphase, and telophase. 5. The mechanisms that control cellular division depend on the integrity of genetic, epigenetic, and protein growth factors.

Tissues 1. Cells of one or more types are organized into tissues, and different types of tissues compose organs. Organs are organized to function as tracts or systems. 2. Three key factors that maintain the cellular organization of tissues are (a) recognition and cell

communication, (b) selective cell-to-cell adhesion, and (c) memory. 3. Fully specialized or terminally differentiated cells that are lost are generated from proliferating precursor cells and they, in turn, have been derived from a smaller number of stem cells. Stem cells are cells with the potential to develop into many different cell types during early development and growth. In many tissues, stem cells serve as an internal repair and maintenance system dividing indefinitely. These cells can maintain themselves over very long periods of time, called self-renewal, and can generate all the differentiated cell types of the tissue or multipotency. 4. Tissue cells are linked at cell junctions, which are specialized regions on their plasma membranes. Cell junctions attach adjacent cells and allow small molecules to pass between them. 5. The four basic types of tissues are epithelial, muscle, nerve, and connective tissues. 6. Neural tissue is composed of highly specialized cells called neurons that receive and transmit electrical impulses rapidly across junctions called synapses. 7. Epithelial tissue covers most internal and external surfaces of the body. The functions of epithelial tissue include protection, absorption, secretion, and excretion. 8. Connective tissue binds various tissues and organs together, supporting them in their locations and serving as storage sites for excess nutrients. 9. Muscle tissue is composed of long, thin, highly contractile cells or fibres called myocytes. Muscle tissue that is attached to bones enables voluntary movement. Muscle tissue in internal organs enables involuntary movement, such as the heartbeat.

Key Terms Absolute refractory period, 24 Action potential, 24 Active transport, 18 Amphipathic, 3 Anabolism, 14 Anaphase, 25 Anion, 19 Antiport, 18 Arrested (resting) (G0) state, 27 Autocrine signalling, 12 Basal lamina, 11 Basement membrane, 10 Binding site, 9 Catabolism, 14 Cation, 19 Caveolae, 23 Cell adhesion molecule (CAM), 7 Cell cortex, 8 Cell cycle, 25 Cell junction, 12 Cell polarity, 2 Cell-to-cell adhesion, 10 Cellular metabolism, 14 Cellular receptor, 9 Centromere, 25 Channel, 17 Chemical synapse, 13 Chromatid, 25 Chromatin, 25 Citric acid cycle (Krebs cycle, tricarboxylic acid cycle), 16 Clathrin, 23 Coated vesicle, 23 Collagen, 10 Concentration gradient, 19 Connective tissue, 11 Connexon, 12 Contact-dependent signalling, 12 Cytokinesis, 25 Cytoplasm, 2 Cytoplasmic matrix, 2 Cytosol, 2 Daughter cell, 26 Depolarization, 24 Desmosome, 12 Differentiation, 2 Diffusion, 19 Digestion, 16 Effective osmolality, 20 Elastin, 10

Electrolyte, 18 Electron-transport chain, 16 Endocytosis, 21 Endosome, 23 Equatorial plate (metaphase plate), 25 ER stress, 8 Eukaryote, 1 Exocytosis, 23 Extracellular matrix (ECM), 10 Fibroblast, 11 Fibronectin, 10 Filtration, 20 G0 phase, 25 G1 phase, 25 G2 phase, 25 Gap junction, 12 Gating, 12 Glycocalyx, 9 Glycolipid, 3 Glycolysis, 16 Glycoprotein, 3 Growth factor (cytokine), 26 Homeostasis, 12 Hormonal signalling, 12 Hydrostatic pressure, 20 Hyperpolarized state, 24 Hypopolarized state, 24 Integral membrane protein, 7 Interphase, 25 Ions, 7 Junctional complex, 12 Ligand, 9 Lipid bilayer, 2 M phase, 25 Macromolecule, 10 Mediated transport, 17 Membrane lipid raft (MLR), 5 Membrane transport protein, 17 Metabolic pathway, 16 Metaphase, 25 Mitosis, 25 Multipotency, 27 Neurohormonal signalling, 12 Neurotransmitter, 13 Nuclear envelope, 2 Nuclear pores, 2 Nucleolus, 2 Nucleus, 2 Oncotic pressure (colloid osmotic pressure), 20 Organelle, 2 Osmolality, 20 Osmolarity, 20 Osmosis, 20

Osmotic pressure, 20 Oxidation, 16 Oxidative phosphorylation, 16 Paracrine signalling, 12 Passive transport, 17 Peripheral membrane protein, 7 Phagocytosis, 21 Phospholipid, 5 Pinocytosis, 21 Plasma membrane (plasmalemma), 2 Plasma membrane receptor, 9 Platelet-derived growth factor (PDGF), 26 Polarity, 19 Polypeptide, 5 Post-translational modification (PTM), 5 Prokaryote, 1 Prophase, 25 Protein, 5 Proteolytic, 8 Proteome, 7 Proteomic, 7 Receptor protein, 14 Receptor-mediated endocytosis (ligand internalization), 23 Relative refractory period, 24 Repolarization, 24 Resting membrane potential, 24 Retinoblastoma (Rb) protein, 26 Self-renewal, 27 Signalling cell, 14 Signal transduction pathway, 14 Solute, 17 S phase, 25 Spindle fibre, 25 Stem cell, 27 Stroma, 26 Substrate, 16 Substrate phosphorylation (anaerobic glycolysis), 17 Symport, 18 Target cell, 14 Telophase, 25 Terminally differentiated, 27 Threshold potential, 24 Tight junction, 12 Tonicity, 20 Transfer reaction, 16 Transmembrane protein, 7 Transporter, 17 Unfolded-protein response (UPR), 8 Uniport, 18 Valence, 19 Wnt signals, 27

References 1. Alberts B. Essential cell biology. 4th ed. Garland: New York; 2014. 2. Simons K, Sampaio JL. Membrane organization and lipid rafts. Cold Spring Harbor Perspectives in Biology. 2011;3(10); 10.1101/cshperspect.a004697 [a004697]. 3. Contreras FX, Ernst AM, Wieland F, et al. Specificity of intramembrane protein-lipid interactions. Cold Spring Harbor Perspectives in Biology. 2011;3(6); 10.1101/cshperspect.a004457 [pii: a004705]. 4. Head BP, Patel HH, Insel PA. Interaction of membrane/lipid rafts with the cytoskeleton: Impact on signaling and function: Membrane/lipid rafts, mediators of cytoskeletal arrangement and cell signaling. Biochimica et Biophysica Acta. 2014;1838(2):532–545; 10.1016/j.bbamem.2013.07.018. 5. Karnovsky MJ, Kleinfeld AM, Hoover RL, et al. The concept of lipid domains in membranes. Journal of Cell Biology. 1982;94(1):1–6. 6. Ribert D, Cossart P. Pathogen-mediated postranslational modification: A re-emerging field. Cell. 2010;143:694–702; 10.1016/j.cell.2010.11.019. 7. Vinothkumar KR, Henderson R. Structure of membrane proteins. Quarterly Review of Biophysics. 2010;43(1):65–158; 10.1017/S0033583510000041. 8. Cogliati S, Frezza C, Soriano ME, et al. Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell. 2013;155(1):160–171; 10.1016/j.cell.2013.08.032. 9. Daum B, Walter A, Horst A, et al. Age-dependent dissociation of ATP synthase dimers and loss of inner-membrane cristae in mitochondria. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(38):15301–15306; 10.1073/pnas.1305462110. 10. Friedman JR, Nunnari J. Mitochondrial form and function. Nature. 2014;505(7483):335–343; 10.1038/nature12985. 11. Amm I, Sommer T, Wolf DH. Protein quality control and elimination of protein waste: The role of the ubiquitin-proteosome system. Biochimica et Biophysica Acta. 2014;1843(1):182–196; 10.1016/j.bbamcr.2013.06.031. 12. Lindquist SL, Kelly JW. Chemical and biological approaches for adapting proteostasis to ameliorate protein misfolding and aggregation diseases: Progress and prognosis. Cold Spring Harbor Perspectives in Biology. 2011;3(12); 10.1101/cshperspect.a004507 [pii: a004507]. 13. Kierszenbaum AL, Tres LT. Histology and cell biology: An introduction to pathology. 3rd ed. Elsevier: St. Louis; 2011. 14. Xu Q, Kopp RF, Chen Y, et al. Gating of connexin 43 gap junctions by a cytoplasmic loop calmodulin binding domain. American Journal of Physiology. Cell Physiology. 2012;302(10):C1548– C1556; 10.1152/ajpcell.00319.2011. 15. Sirnes S, Bruun J, Kolberg M, et al. Connexin43 acts as a colorectal tumor suppressor and predicts disease outcome. International Journal of Cancer. Journal International du Cancer. 2012;131(3):570– 581; 10.1002/ijc.26392. 16. Khan R, Khan AQ, Lateef A, et al. Glycyrrhizic acid suppresses the development of precancerous lesions via regulating the hyperproliferation, inflammation, angiogenesis and apoptosis in the colon of Wistar rats. PLoS ONE. 2013;8(2):e56020; 10.1371/journal.pone.0056020. 17. Zhang MZ, Xu J, Yao B, et al. Inhibition of 11β hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans. Journal of Clinical Investigation. 2009;119(4):876–885; 10.1172/JCI37398. 18. Chaudhri RA, Schwartz N, Elbaradie K, et al. Role of ERα36 in membrane-associated signaling by estrogen. Steroids. 2014;81:74–80; 10.1016/j.steroids.2013.10.020. 19. Clevers H, Loh KM, Nusse R. Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. Science. 2014;346(6205):1248012; 10.1126/science.1248012.

Genes and Genetic Diseases Lynn B. Jorde, Stephanie Zettel

CHAPTER OUTLINE DNA, RNA, and Proteins: Heredity at the Molecular Level, 38 Definitions, 38 From Genes to Proteins, 39 Chromosomes, 42 Chromosome Aberrations and Associated Diseases, 42 Elements of Formal Genetics, 49 Phenotype and Genotype, 49 Dominance and Recessiveness, 49 Transmission of Genetic Diseases, 50 Autosomal Dominant Inheritance, 50 Autosomal Recessive Inheritance, 52 X-Linked Inheritance, 54 Linkage Analysis and Gene Mapping, 56 Classic Pedigree Analysis, 56 Complete Human Gene Map: Prospects and Benefits, 57 Multifactorial Inheritance, 58

Genetics occupies a central position in the entire study of biology. An understanding of genetics is essential to study human, animal, plant, or microbial life. Genetics is the study of biological inheritance. In the nineteenth century, microscopic studies of cells led scientists to suspect the nucleus of the cell contained the important mechanisms of inheritance. Scientists found that chromatin, the substance giving the nucleus a granular appearance, is observable in nondividing cells. Just before the cell divides, the chromatin condenses to form discrete, dark-staining organelles, which are called chromosomes. (Cell division is discussed in Chapter 1.) With the rediscovery of Gregor Mendel's important breeding experiments at the turn of the twentieth century, it soon became apparent the chromosomes contained genes, the basic units of inheritance (Figure 2-1).

FIGURE 2-1 Successive Enlargements from a Human to the Genetic Material.

The primary constituent of chromatin is deoxyribonucleic acid (DNA). Genes are composed of sequences of DNA. By serving as the blueprints of proteins in the body, genes ultimately influence all aspects of body structure and function. Humans have approximately 20 000 protein-coding genes and an additional 9 000 to 10 000 genes that encode various types of RNA (see the following section) that are not translated into proteins. An error in one of these genes often leads to a recognizable genetic disease. To date, more than 20000 genetic traits and diseases have been identified and catalogued. As infectious diseases continue to be more effectively controlled, the proportion of beds in pediatric hospitals occupied by children with genetic diseases has risen. In addition to children, many common diseases primarily affecting adults, such as hypertension, coronary heart disease, diabetes, and cancer, are now known to have important genetic components. Great progress is being made in the diagnosis of genetic diseases and in the understanding of genetic mechanisms underlying them. With the huge strides being made in molecular genetics, “gene therapy”— the utilization of normal genes to correct genetic disease—has begun.

DNA, RNA, and Proteins: Heredity at the Molecular Level Definitions Composition and Structure of DNA Genes are composed of DNA, which has three basic components: the five-carbon monosaccharide deoxyribose; a phosphate molecule; and four types of nitrogenous bases. Two of the bases, cytosine and thymine, are single carbon-nitrogen rings called pyrimidines. The other two bases, adenine and guanine, are double carbon-nitrogen rings called purines. The four bases are commonly represented by their first letters: A (adenine), C (cytosine), T (thymine), and G (guanine). Watson and Crick demonstrated how these molecules are physically assembled as DNA, proposing the double-helix model, in which DNA appears like a twisted ladder with chemical bonds as its rungs (Figure 2-2). The two sides of the ladder consist of deoxyribose and phosphate molecules, united by strong phosphodiester bonds. Projecting from each side of the ladder, at regular intervals, are the nitrogenous bases. The base projecting from one side is bound to the base projecting from the other by a weak hydrogen bond. Therefore the nitrogenous bases form the rungs of the ladder; adenine pairs with thymine, and guanine pairs with cytosine. Each DNA subunit—consisting of one deoxyribose molecule, one phosphate group, and one base—is called a nucleotide.

FIGURE 2-2 Watson–Crick Model of the DNA Molecule. The DNA structure illustrated here is based on that published by James Watson (photograph, left) and Francis Crick (photograph, right) in 1953. Note that each side of the DNA molecule consists of alternating sugar and phosphate groups. Each sugar group is bonded to the opposing sugar group by a pair of nitrogenous bases (adenine-thymine or cytosine-guanine). The sequence of these pairs constitutes a genetic code that determines the structure and function of a cell. (Illustration from Herlihy, B. [2015]. The human body in health and illness [5th ed.]. St. Louis: Saunders. Photo from Barrington Brown/Science Source.)

DNA as the Genetic Code DNA directs the synthesis of all the body's proteins. Proteins are composed of one or more polypeptides (intermediate protein compounds), which in turn consist of sequences of amino acids. The body contains 20 different types of amino acids; they are specified by the 4 nitrogenous bases. To specify (code for) 20 different amino acids with only 4 bases, different combinations of bases, occurring in groups of 3 (triplets), are used. These triplets of bases are known as codons. Each codon specifies a single amino acid in a corresponding protein. Because there are 64 (4 × 4 × 4) possible codons but only 20 amino acids, there are many cases in which several codons correspond to the same amino acid. The genetic code is universal: all living organisms use precisely the same DNA codes to specify proteins except for mitochondria, the cytoplasmic organelles in which cellular respiration takes place (see Chapter 1)—they have their own extranuclear DNA. Several codons of mitochondrial DNA encode different amino acids, as compared with the same nuclear DNA codons.

Replication of DNA DNA replication consists of breaking the weak hydrogen bonds between the bases, leaving a single strand with each base unpaired (Figure 2-3). The consistent pairing of adenine with thymine and of guanine with cytosine, known as complementary base pairing, is the key to accurate replication. The unpaired base attracts a free nucleotide only if the nucleotide has the proper complementary base. When replication is complete, a new double-stranded molecule identical to the original is formed. The single strand is said to be a template, or molecule on which a complementary molecule is built, and is the basis for synthesizing the new double strand.

FIGURE 2-3

Replication of DNA. The two chains of the double helix separate and each chain serves as the template for a new complementary chain. (From Herlihy, B. [2015]. The human body in health and illness [5th ed.]. St. Louis: Saunders.)

Several different proteins are involved in DNA replication. The most important of these proteins is an enzyme known as DNA polymerase. This enzyme travels along the single DNA strand, adding the correct nucleotides to the free end of the new strand and checking to ensure that its base is actually complementary to the template base. This mechanism of DNA proofreading substantially enhances the accuracy of DNA replication.

Mutation A mutation is any inherited alteration of genetic material. One type of mutation is the base pair substitution, in which one base pair replaces another. This replacement can result in a change in the amino acid sequence. However, because of the redundancy of the genetic code, many of these mutations do not change the amino acid sequence and thus have no consequence. Such mutations are called silent mutations. Base pair substitutions altering amino acids consist of two basic types: missense mutations, which produce a change (i.e., the “sense”) in a single amino acid; and nonsense mutations, which produce one of the three stop codons (UAA, UAG, or UGA) in the messenger RNA (mRNA) (Figure 2-4). Missense mutations (Figure 2-4, A) produce a single amino acid change, whereas nonsense mutations (Figure 2-4, B) produce a premature stop codon in the mRNA. Stop codons terminate translation of the polypeptide.

FIGURE 2-4 Base Pair Substitution. Missense mutations (A) produce a single amino acid change, whereas nonsense mutations (B) produce a stop codon in the messenger RNA (mRNA). Stop codons terminate translation of the polypeptide. (From Science, 328(5978), 636–639. doi:10.1126/science.1186802.)

The frameshift mutation involves the insertion or deletion of one or more base pairs of the DNA molecule. As Figure 2-5 shows, these mutations change the entire “reading frame” of the DNA sequence because the deletion or insertion is not a multiple of three base pairs (the number of base pairs in a codon). Frameshift mutations can thus greatly alter the amino acid sequence. (In-frame insertions or deletions, in which a multiple of three bases is inserted or lost, tend to have less severe disease consequences than do frameshift mutations.)

FIGURE 2-5 Frameshift Mutations. Frameshift mutations result from the addition or deletion of a number of bases that is not a multiple of 3. This mutation alters all of the codons downstream from the site of insertion or deletion. mRNA, messenger RNA. (From Jorde, L., L.B., Carey, J.C., & Bamshad, M.J. [2010]. Medical genetics [4th ed.]. St. Louis: Mosby.)

Agents known as mutagens increase the frequency of mutations. Examples include radiation and chemicals such as nitrogen mustard, vinyl chloride, alkylating agents, formaldehyde, and sodium nitrite. Mutations are rare events. The rate of spontaneous mutations (those occurring in the absence of exposure to known mutagens) in humans is about 1.1 × 10−8 per gene per generation.1 This rate varies from one gene to another. Some DNA sequences have particularly high mutation rates and are known as mutational hot spots (Box 2-1).2

Box 2-1

Mutational Hot Spots and Antibiotic Resistance Zhang and colleagues investigated mechanisms of antibiotic resistance (clofazimine [Lamprene]) in Mycobacterium tuberculosis and discovered two nucleotide sequences that accounted for more than 50% of the mutations resulting in resistance to clofazimine. The authors also discovered two new genes responsible for resistant organisms and concluded that this research will assist in more rapidly identifying those who are resistant to this antibiotic and enable the discovery of more effective treatments. From Zhang, S., Chen, J., Cui, P., et al. (2015). J Antimicrob Chemother, 70(9), 2507–2510. doi:10.1093/jac/dkv150.

From Genes to Proteins DNA is formed and replicated in the cell nucleus, but protein synthesis takes place in the cytoplasm. The DNA code is transported from nucleus to cytoplasm, and subsequent protein is formed through two basic processes: transcription and translation. These processes are mediated by ribonucleic acid (RNA), which is chemically similar to DNA except the sugar molecule is ribose rather than deoxyribose, and uracil rather than thymine is one of the four nitrogenous bases. The other three bases of RNA, as in DNA, are adenine, cytosine, and guanine. Uracil is structurally similar to thymine, so it also can pair with adenine. Whereas DNA usually occurs as a double strand, RNA usually occurs as a single strand.

Transcription In transcription, RNA is synthesized from a DNA template, forming messenger RNA (mRNA). RNA

polymerase binds to a promoter site, a sequence of DNA that specifies the beginning of a gene. RNA polymerase then separates a portion of the DNA, exposing unattached DNA bases. One DNA strand then provides the template for the sequence of mRNA nucleotides. The sequence of bases in the mRNA is thus complementary to the template strand, and except for the presence of uracil instead of thymine, the mRNA sequence is identical to that of the other DNA strand. Transcription continues until a termination sequence, codons that act as signals for the termination of protein synthesis, is reached. Then the RNA polymerase detaches from the DNA, and the transcribed mRNA is freed to move out of the nucleus and into the cytoplasm (Figures 2-6 and 2-7).

FIGURE 2-6 General Scheme of RNA Transcription. In transcription of messenger RNA (mRNA), a DNA molecule “unzips” in the region of the gene to be transcribed. RNA nucleotides already present in the nucleus temporarily attach themselves to exposed DNA bases along one strand of the unzipped DNA molecule according to the principle of complementary pairing. As the RNA nucleotides attach to the exposed DNA, they bind to each other and form a chainlike RNA strand called an mRNA molecule. Notice that the new mRNA strand is an exact copy of the base sequence on the opposite side of the DNA molecule. As in all metabolic processes, the formation of mRNA is controlled by an enzyme—in this case, the enzyme is called RNA polymerase. (From Ignatavicius, D.D., & Workman, L.D. [2010]. Medical-surgical nursing [6th ed.]. St. Louis: Saunders.)

FIGURE 2-7

Protein Synthesis. The site of transcription is the nucleus and the site of translation is the cytoplasm. See the text for details. mRNA, messenger RNA; tRNA, transfer RNA.

Gene Splicing When the mRNA is first transcribed from the DNA template, it reflects exactly the base sequence of the DNA. In eukaryotes, many RNA sequences are removed by nuclear enzymes, and the remaining sequences are spliced together to form the functional mRNA that migrates to the cytoplasm. The excised sequences are called introns (intervening sequences), and the sequences that are left to code for proteins are called exons.

Translation In translation, RNA directs the synthesis of a polypeptide (see Figure 2-7), interacting with transfer RNA (tRNA), a cloverleaf-shaped strand of about 80 nucleotides. The tRNA molecule has a site where an amino acid attaches. The three-nucleotide sequence at the opposite side of the cloverleaf is called the anticodon. It undergoes complementary base pairing with an appropriate codon in the mRNA, which specifies the sequence of amino acids through tRNA. The site of actual protein synthesis is in the ribosome, which consists of approximately equal parts of protein and ribosomal RNA (rRNA). During translation, the ribosome first binds to an initiation site on the mRNA sequence and then binds to its surface, so that base pairing can occur between tRNA and mRNA. The ribosome then moves along the mRNA sequence, processing each codon and translating an amino acid by way of the interaction of mRNA and tRNA. The ribosome provides an enzyme that catalyzes the formation of covalent peptide bonds between the adjacent amino acids, resulting in a growing polypeptide. When the ribosome arrives at a termination signal on the mRNA sequence, translation and polypeptide formation cease; the mRNA, ribosome, and polypeptide separate from one another; and the polypeptide is released into the cytoplasm to perform its

required function.

Chromosomes Human cells can be categorized into gametes (sperm and egg cells) and somatic cells, which include all cells other than gametes. Each somatic cell nucleus has 46 chromosomes in 23 pairs (Figure 2-8). These are diploid cells, and the individual's father and mother each donate one chromosome per pair. New somatic cells are formed through mitosis and cytokinesis. Gametes are haploid cells: they have only 1 member of each chromosome pair, for a total of 23 chromosomes. Haploid cells are formed from diploid cells by meiosis (Figure 2-9).

FIGURE 2-8 From Molecular Parts to the Whole Somatic Cell.

FIGURE 2-9

Phases of Meiosis and Comparison to Mitosis. (From Jorde, L.B., Carey, J.C., & Bamshad, M.J. [2010]. Medical genetics [4th ed.]. St. Louis: Mosby.)

In 22 of the 23 chromosome pairs, the 2 members of each pair are virtually identical in microscopic appearance; thus they are homologous (Figure 2-10, B). These 22 chromosome pairs are homologous in both males and females and are termed autosomes. The remaining pair of chromosomes, the sex chromosomes, consists of two homologous X chromosomes in females and a nonhomologous pair, X and Y, in males.

FIGURE 2-10

Karyotype of Chromosomes. A, Human karyotype. B, Homologous chromosomes and sister chromatids. (From Raven, P.H., Johnson, G., Mason, K., et al. [2008]. Biology [8th ed.]. New York: McGraw-Hill.)

Figure 2-10, A, illustrates a metaphase spread, which is a photograph of the chromosomes as they appear in the nucleus of a somatic cell during metaphase. (Chromosomes are easiest to visualize during this stage of mitosis.) In Figure 2-10, A, the chromosomes are arranged according to size, with the homologous chromosomes paired. The 22 autosomes are numbered according to length, with chromosome 1 being the longest and chromosome 22 the shortest. A karyotype, or karyogram, is an ordered display of chromosomes. Some natural variation in relative chromosome length can be expected from person to person, so it is not always possible to distinguish each chromosome by its length. Therefore the position of the centromere (region of DNA responsible for movement of the replicated chromosomes into the two daughter cells during mitosis and meiosis) also is used to classify chromosomes (see Figures 2-10, B and 2-11).

FIGURE 2-11 Structure of Chromosomes. A, Human chromosomes 2, 5, and 13. Each is replicated and consists of two chromatids. Chromosome 2 is a metacentric chromosome because the centromere is close to the middle; chromosome 5 is submetacentric because the centromere is set off from the middle; chromosome 13 is acrocentric because the centromere is at or very near the end. B, During mitosis, the centromere divides and the chromosomes move to opposite poles of the cell. At the time of centromere division, the chromatids are designated as chromosomes.

The chromosomes in Figure 2-10 were stained with Giemsa stain, resulting in distinctive chromosome bands. These bands form various patterns in the different chromosomes so that each chromosome can be distinguished easily. Using banding techniques, researchers can number chromosomes and study individual variations. Missing or duplicated portions of chromosomes, which often result in serious diseases, also are readily identified. More recently, techniques have been devised permitting each chromosome to be visualized with a different colour.

Chromosome Aberrations and Associated Diseases Chromosome abnormalities are the leading known cause of intellectual disability and miscarriage. Estimates indicate that a major chromosome aberration occurs in at least 1 in 12 conceptions. Most of these fetuses do not survive to term; about 50% of all recovered first-trimester spontaneous abortuses have major chromosome aberrations.3 The number of live births affected by these abnormalities is, however, significant; approximately 1 in 150 has a major diagnosable chromosome abnormality.3

Polyploidy Cells with a multiple of the normal number of chromosomes are euploid cells (Greek eu = good or true). Because normal gametes are haploid and most normal somatic cells are diploid, they are both euploid forms. When a euploid cell has more than the diploid number of chromosomes, it is said to be a polyploid cell. Several types of body tissues, including some liver, bronchial, and epithelial tissues, are normally polyploid. A zygote that has three copies of each chromosome, rather than the usual two, has a form of polyploidy called triploidy. Nearly all triploid fetuses are spontaneously aborted or stillborn. The prevalence of triploidy among live births is approximately 1 in 10 000. Tetraploidy, a condition in which euploid cells have 92 chromosomes, has been found primarily in early abortuses, although occasionally affected infants have been born alive. Like triploid infants, however, they do not survive. Triploidy and tetraploidy are relatively common conditions, accounting for approximately 10% of all known miscarriages.4

Aneuploidy A cell that does not contain a multiple of 23 chromosomes is an aneuploid cell. A cell containing three copies of one chromosome is said to be trisomic (a condition termed trisomy) and is aneuploid. Monosomy, the presence of only one copy of a given chromosome in a diploid cell, is the other common form of aneuploidy. Among the autosomes, monosomy of any chromosome is lethal, but newborns with trisomy of chromosomes 13, 18, 21, or X can survive. This difference illustrates an important principle: in general, loss of chromosome material has more serious consequences than duplication of chromosome material. Aneuploidy of the sex chromosomes is less serious than that of the autosomes. Very little genetic material—only about 40 genes—is located on the Y chromosome. For the X chromosome, inactivation of extra chromosomes (see p. 54) largely diminishes their effect. A zygote bearing no X chromosome, however, will not survive. Aneuploidy is usually the result of nondisjunction, an error in which homologous chromosomes or sister chromatids fail to separate normally during meiosis or mitosis (Figure 2-12). Nondisjunction produces some gametes that have two copies of a given chromosome and others that have no copies of the chromosome. When such gametes unite with normal haploid gametes, the resulting zygote is monosomic or trisomic for that chromosome. Occasionally, a cell can be monosomic or trisomic for more than one chromosome.

FIGURE 2-12

Nondisjunction. Nondisjunction causes aneuploidy when chromosomes or sister chromatids fail to divide properly. (From Jorde, L.B., Carey, J.C., & Bamshad, M.J. [2010]. Medical genetics [4th ed.]. St. Louis: Mosby.)

Autosomal aneuploidy. Trisomy can occur for any chromosome, but fetuses with other trisomies of chromosomes (other than 13, 18, 21, or X) do not survive to term. Trisomy 16, for example, is the most common trisomy among abortuses, but it is not seen in live births.5 Partial trisomy, in which only an extra portion of a chromosome is present in each cell, can occur also. The consequences of partial trisomies are not as severe as those of complete trisomies. Trisomies may occur in only some cells of the body. Individuals thus affected are said to be chromosomal mosaics, meaning that the body has two or more different cell lines, each of which has a different karyotype. Mosaics are often formed by early mitotic nondisjunction occurring in one embryonic cell but not in others. The best-known example of aneuploidy in an autosome is trisomy of chromosome 21, which causes Down syndrome (named after J. Langdon Down, who first described the syndrome in 1866). Down syndrome is seen in approximately 1 in 800 live births (from http://www.cdss.ca/positioning/positioning/down-syndrome-defined.html); its principal features are shown and outlined in Figure 2-13 and Table 2-1.

FIGURE 2-13

Child With Down Syndrome. (Dennis Kuvaev/Shutterstock.com.)

TABLE 2-1 Characteristics of Various Chromosome Disorders Disease/Disorder Features Down Syndrome Trisomy of Chromosome 21 IQ It usually ranges from 20 to 70 (intellectual disability). Male/female findings Virtually all males are sterile; some females can reproduce. Face Distinctive features include low nasal bridge, epicanthal folds, protruding tongue, low-set ears. Musculo-skeletal Features include poor muscle tone (hypotonia) and short stature. system Systemic disorders Features include congenital heart disease (one third to half of cases), reduced ability to fight respiratory tract infections, and increased susceptibility to leukemia— overall reduced survival rate; by age 40 years usually develop symptoms similar to those of Alzheimer's disease. Mortality About 75% of fetuses with Down syndrome abort spontaneously or are stillborn; 20% of infants die before age 10 years; those who live beyond 10 years have life expectancy of about 60 years. Causative factors 97% of cases are caused by nondisjunction during formation of one of parent's gametes or during early embryonic development; 3% result from translocations; in 95% of cases, nondisjunction occurs when mother's egg cell is formed; the remainder involve paternal nondisjunction; 1% are mosaics—these have a large number of normal cells, and effects of trisomic cells are attenuated and symptoms are generally less severe. Turner's Syndrome (45,X) Monosomy of X Chromosome IQ Individuals with this syndrome are not considered to be intellectually disabled, although the syndrome is associated with some impairment of spatial and mathematical reasoning ability. Male/female findings It is found only in females. Musculo-skeletal Short stature is common; other features are characteristic webbing of neck, widely spaced nipples, and reduced carrying angle at elbow. system Systemic disorders Features include coarctation (narrowing) of aorta, edema of feet in newborns; females are usually sterile and have gonadal streaks rather than ovaries; streaks are sometimes susceptible to cancer. Mortality About 15–20% of spontaneous abortions with chromosome abnormalities have this karyotype, most common single-chromosome aberration; highly lethal during gestation, only about 0.5% of these conceptions survive to term. Causative factors 75% of cases inherit X chromosome from mother, thus caused by meiotic error in father; frequency is low compared with other sex chromosome aneuploidies (1 : 5 000 newborn females); 50% have simple monosomy of X chromosome; the remainder have more complex abnormalities; combinations of 45,X cells with XX or XY cells common. Klinefelter's Syndrome (47,XXY) XXY Condition IQ A moderate degree of mental impairment may be present. Male/female findings Individuals have a male appearance but are usually sterile; 50% develop femalelike breasts (gynecomastia); occurs in 1 : 1 000 male births. Voice Voice is somewhat high pitched. Systemic disorders Features include sparse body hair, sterility, and small testicles. Causative factors 50% of cases are the result of nondisjunction of X chromosomes in mother, and frequency rises with increasing maternal age; also involves XXY and XXXY karyotypes with degree of physical and mental impairment increasing with each added X chromosome; mosaicism fairly common with most prevalent combination of XXY and XY cells.

The risk of having a child with Down syndrome increases greatly with maternal age. As Figure 2-14 demonstrates, women younger than 30 years have a risk ranging from about 1 in 1 000 births to 1 in 2 000 births. The risk begins to rise substantially after 35 years of age, and reaches 3% to 5% for women older than 45 years. This dramatic increase in risk is caused by the age of maternal egg cells, which are held in an arrested state of prophase I from the time they are formed in the female embryo until they are shed in ovulation. Thus an egg cell formed by a 45-year-old woman is itself 45 years old. This long suspended state may allow defects to accumulate in the cellular proteins responsible for meiosis, leading to nondisjunction. The risk of Down syndrome, as well as other trisomies, does not increase with paternal age.6

FIGURE 2-14

Down Syndrome Increases with Maternal Age. Rate is per 1 000 live births related to maternal age.

Sex chromosome aneuploidy. The incidence of sex chromosome aneuploidies is fairly high. Among live births, about 1 in 500 males and 1 in 900 females have a form of sex chromosome aneuploidy.7 Because these conditions are generally less severe than autosomal aneuploidies, all forms except complete absence of any X chromosome material allow at least some individuals to survive. One of the most common sex chromosome aneuploidies, affecting about 1 in 1 000 newborn females, is trisomy X. Instead of two X chromosomes, these females have three X chromosomes in each cell. Most of these females have no overt physical abnormalities, although sterility, menstrual irregularity, or intellectual disability is sometimes seen. Some females have four X chromosomes, and they are more often intellectually disabled. Those with five or more X chromosomes generally are more severely intellectually disabled and have various physical defects. A condition that leads to somewhat more serious problems is the presence of a single X chromosome and no homologous X or Y chromosome, so that the individual has a total of 45 chromosomes. The karyotype is usually designated 45,X, and it causes a set of symptoms known as Turner's syndrome (Figure 2-15; see Table 2-1). Individuals with at least two X chromosomes and one Y chromosome in each cell (47,XXY karyotype) have a disorder known as Klinefelter's syndrome (Figure 2-16; see Table 2-1).

FIGURE 2-15 Turner's Syndrome. A, A sex chromosome is missing, and the person's chromosomes are 45,X. Characteristic signs are short stature, female genitalia, webbed neck, shieldlike chest with underdeveloped breasts and widely spaced nipples, and imperfectly developed ovaries. B, As this karyotype shows, Turner's syndrome results from monosomy of sex chromosomes (genotype XO). (From Patton, K.T., & Thibodeau, G.A. [2013]. Anatomy & physiology [8th ed.]. St. Louis: Mosby. Courtesy Nancy S. Wexler, PhD, Columbia University.)

FIGURE 2-16 Klinefelter's Syndrome. This young man exhibits many characteristics of Klinefelter's syndrome: small testes, some development of the breasts, sparse body hair, and long limbs. This syndrome results from the presence of two or more X chromosomes with one Y chromosome (e.g., genotypes XXY or XXXY). (From Patton, K.T., & Thibodeau, G.A. [2016]. Anatomy & physiology [9th ed.]. St. Louis: Mosby. Courtesy Nancy S. Wexler, PhD, Columbia University.)

Abnormalities of Chromosome Structure In addition to the loss or gain of whole chromosomes, parts of chromosomes can be lost or duplicated as gametes are formed, and the arrangement of genes on chromosomes can be altered. Unlike aneuploidy and polyploidy, these changes sometimes have no serious consequences for an individual's health. Some of them can even remain entirely unnoticed, especially when very small pieces of chromosomes are involved. Nevertheless, abnormalities of chromosome structure can also produce serious disease in individuals or their offspring. During meiosis and mitosis, chromosomes usually maintain their structural integrity, but chromosome breakage occasionally occurs. Mechanisms exist to “heal” these breaks and usually repair them perfectly with no damage to the daughter cell. However, some breaks remain or heal in a way that alters the chromosome's structure. The risk of chromosome breakage increases with exposure to harmful agents called clastogens (e.g., ionizing radiation, viral infections, and some types of chemicals).

Deletions. Broken chromosomes and lost DNA cause deletions (Figure 2-17). Usually, a gamete with a deletion unites with a normal gamete to form a zygote. The zygote thus has one chromosome with the normal complement of genes and one with some missing genes. Because many genes can be lost in a deletion, serious consequences result even though one normal chromosome is present. The most often cited example of a disease caused by a chromosomal deletion is the cri du chat syndrome. The term literally means “cry of the cat” and describes the characteristic cry of the affected child. Other symptoms include low birth weight, severe intellectual disability, microcephaly (smaller than normal head size), and heart defects. The disease is caused by a deletion of part of the short arm of chromosome 5.

FIGURE 2-17

Abnormalities of Chromosome Structure. A, Deletion occurs when a chromosome segment is lost. B, Normal crossing over. C, The generation of duplication and deletion through unequal crossing over.

Duplications. A deficiency of genetic material is more harmful than an excess, so duplications usually have less serious consequences than deletions. For example, a deletion of a region of chromosome 5 causes cri du chat syndrome, but a duplication of the same region causes intellectual disability but less serious physical defects.

Inversions. An inversion occurs when two breaks take place on a chromosome, followed by the reinsertion of the missing fragment at its original site but in inverted order. Therefore a chromosome symbolized as ABCDEFG might become ABEDCFG after an inversion. Unlike deletions and duplications, no loss or gain of genetic material occurs, so inversions are “balanced” alterations of chromosome structure, and they often have no apparent physical effect. Some genes are influenced by neighbouring genes, however, and this position effect, a change in a gene's expression caused by its position, sometimes results in physical defects in these persons. Inversions can cause serious problems in the offspring of individuals carrying the inversion because the inversion can lead to duplications and deletions in the chromosomes transmitted to the offspring.

Translocations. The interchange of genetic material between nonhomologous chromosomes is called translocation. A reciprocal translocation occurs when breaks take place in two different chromosomes and the material is exchanged (Figure 2-18, A). As with inversions, the carrier of a reciprocal translocation is usually normal, but his or her offspring can have duplications and deletions.

FIGURE 2-18 Normal and Abnormal Chromosome Translocation. A, Normal chromosomes and reciprocal translocation. B, Pairing at meiosis I. C, Consequences of translocation in gametes; unbalanced gametes result in zygotes that are partially trisomic and partially monosomic and consequently develop abnormally.

A second and clinically more important type of translocation is Robertsonian translocation. In this disorder, the long arms of two nonhomologous chromosomes fuse at the centromere, forming a single chromosome. Robertsonian translocations are confined to chromosomes 13, 14, 15, 21, and 22 because the short arms of these chromosomes are very small and contain no essential genetic material. The short arms are usually lost during subsequent cell divisions. Because the carriers of Robertsonian translocations lose no important genetic material, they are unaffected, although they have only 45 chromosomes in each cell. Their offspring, however, may have serious monosomies or trisomies. For example, a common Robertsonian translocation involves the fusion of the long arms of chromosomes 21 and 14. An offspring who inherits a gamete carrying the fused chromosome can receive an extra copy of the long arm of chromosome 21 and develop Down syndrome. Robertsonian translocations are responsible for approximately 3% to 5% of Down syndrome cases. Parents who carry a Robertsonian translocation involving chromosome 21 have an increased risk of producing multiple offspring with Down syndrome.

Fragile sites. A number of areas on chromosomes develop distinctive breaks and gaps (observable microscopically) when the cells are cultured. Most of these fragile sites do not appear to be related to disease. However, one fragile site, located on the long arm of the X chromosome, is associated with fragile X syndrome. The most important feature of this syndrome is intellectual disability. With a relatively high population prevalence (affecting approximately 1 in 4 000 males and 1 in 8 000 females), fragile X syndrome is the second most common genetic cause of intellectual disability (after Down syndrome). In fragile X syndrome, females who inherit the mutation do not necessarily express the disease condition, but they can pass it on to descendants who do express it. Ordinarily, a male who inherits a disease gene on the X chromosome expresses the condition, because he has only one X chromosome. An uncommon feature of this disease is that about one third of carrier females are affected, although less severely than males. Unaffected transmitting males have been shown to have more than about 50 repeated DNA sequences near the beginning of the fragile X gene. These trinucleotide sequences, which consist of CGG sequences duplicated many times, cause fragile X syndrome when the number of copies exceeds 200.8 The number of these repeats can increase from generation to generation. More than 20 other genetic diseases, including Huntington's disease and myotonic dystrophy, also are caused by this mechanism.9

Quick Check 2-1 1. What is the major composition of DNA? 2. Define the terms mutation, autosomes, and sex chromosomes. 3. What is the significance of mRNA? 4. What is the significance of chromosomal translocation?

Elements of Formal Genetics The mechanisms by which an individual's set of paired chromosomes produces traits are the principles of genetic inheritance. Mendel's work with garden peas first defined these principles. Later geneticists have refined Mendel's work to explain patterns of inheritance for traits and diseases that appear in families. Analysis of traits that occur with defined, predictable patterns has helped geneticists to assemble the pieces of the human gene map. Current research focuses on determining the RNA or protein products of each gene and understanding the way they contribute to disease. Eventually, diseases and defects caused by single genes can be traced and therapies to prevent and treat such diseases can be developed. For example, researchers have identified a specific gene sequence which, when mutated, gives rise to sickle cell anemia. By identifying this gene sequence, they have been able to cut out the mutated gene and introduce the correct gene into hematopoietic stem cells, resulting in normal red blood cells.10 Traits caused by single genes are called Mendelian traits (after Gregor Mendel). Each gene occupies a position, or locus, on a chromosome. The genes at a particular locus can have different forms (i.e., they can be composed of different nucleotide sequences) called alleles. A locus that has two or more alleles that each occur with an appreciable frequency in a population is said to be polymorphic (or a polymorphism). Because humans are diploid organisms, each chromosome is represented twice, with one member of the chromosome pair contributed by the father and one by the mother. At a given locus, an individual has one allele whose origin is paternal and one whose origin is maternal. When the two alleles are identical, the individual is homozygous at that locus. When the alleles are not identical, the individual is heterozygous at that locus.

Phenotype and Genotype The composition of genes at a given locus is known as the genotype. The outward appearance of an individual, which is the result of both genotype and environment, is the phenotype. For example, an infant who is born with an inability to metabolize the amino acid phenylalanine has the single-gene disorder known as phenylketonuria (PKU) and thus has the PKU genotype. If the condition is left untreated, abnormal metabolites of phenylalanine will begin to accumulate in the infant's brain and irreversible intellectual disability will occur. Intellectual disability is thus one aspect of the PKU phenotype. By imposing dietary restrictions to exclude food that contains phenylalanine, however, intellectual disability can be prevented. Foods high in phenylalanine include proteins found in milk, dairy products, meat, fish, chicken, eggs, beans, and nuts. Although the child still has the PKU genotype, a modification of the environment (in this case, the child's diet) produces an outwardly normal phenotype.

Dominance and Recessiveness In many loci, the effects of one allele mask those of another when the two are found together in a heterozygote. The allele whose effects are observable is said to be dominant. The allele whose effects are hidden is said to be recessive (from the Latin root for “hiding”). Traditionally, for loci having two alleles, the dominant allele is denoted by an uppercase letter and the recessive allele is denoted by a lowercase letter. When one allele is dominant over another, the heterozygote genotype Aa has the same phenotype as the dominant homozygote AA. For the recessive allele to be expressed, it must exist in the homozygote form, aa. When the heterozygote is distinguishable from both homozygotes, the locus is said to exhibit codominance. A carrier is an individual who has a disease gene but is phenotypically normal. Many genes for a recessive disease occur in heterozygotes who carry one copy of the gene but do not express the disease. When recessive genes are lethal in the homozygous state, they are eliminated from the population when they occur in homozygotes. By “hiding” in carriers, however, recessive genes for diseases are passed on to the next generation.

Transmission of Genetic Diseases The pattern in which a genetic disease is inherited through generations is termed the mode of inheritance. Knowing the mode of inheritance can reveal much about the disease-causing gene itself, and members of families with the disease can be given reliable genetic counselling. Mendel systematically studied modes of inheritance and formulated two basic laws of inheritance. His principle of segregation states that homologous genes separate from one another during reproduction and that each reproductive cell carries only one copy of a homologous gene. Mendel's second law, the principle of independent assortment, states that the hereditary transmission of one gene does not affect the transmission of another. Mendel discovered these laws in the mid-nineteenth century by performing breeding experiments with garden peas, even though he had no knowledge of chromosomes. Early twentieth-century geneticists found that chromosomal behaviour essentially corresponds to Mendel's laws, which now form the basis for the chromosome theory of inheritance. The known single-gene diseases can be classified into four major modes of inheritance: autosomal dominant, autosomal recessive, X-linked dominant, and X-linked recessive. The first two types involve genes known to occur on the 22 pairs of autosomes. The last two types occur on the X chromosome; very few disease-causing genes occur on the Y chromosome. The pedigree chart summarizes family relationships and shows which members of a family are affected by a genetic disease (Figure 2-19). Generally, the pedigree begins with one individual in the family, the proband. This individual is usually the first person in the family diagnosed or seen in a clinic.

FIGURE 2-19

Symbols Commonly Used in Pedigrees. (From Jorde, L.B., Carey, J.C., & Bamshad, M.J. [2010]. Medical genetics [4th ed.]. St. Louis: Mosby.)

Autosomal Dominant Inheritance Characteristics of Pedigrees Diseases caused by autosomal dominant genes are rare, with the most common occurring in fewer than 1 in 500 individuals. Therefore it is uncommon for two individuals who are both affected by the same autosomal dominant disease to produce offspring together. Figure 2-20, A, illustrates this unusual pattern. Affected offspring are usually produced by the union of a normal parent with an affected heterozygous parent. The Punnett square in Figure 2-20, B, illustrates this mating. The affected parent can pass either a disease-causing allele or a normal allele to the next generation. On average, half the children will be heterozygous and will express the disease, and half will be normal.

FIGURE 2-20 Punnett Square and Autosomal Dominant Traits. A, Punnett square for the mating of two individuals with an autosomal dominant gene. Here both parents are affected by the trait. B, Punnett square for the mating of a normal individual with a carrier for an autosomal dominant gene.

The pedigree in Figure 2-21 shows the transmission of an autosomal dominant allele. Several important characteristics of this pedigree support the conclusion that the trait is caused by an autosomal dominant gene:

FIGURE 2-21 Pedigree Illustrating the Inheritance Pattern of Postaxial Polydactyly, an Autosomal Dominant Disorder. Affected individuals are represented by shading. (From Jorde, L.B., Carey, J.C., & Bamshad, M.J. [2010]. Medical genetics [4th ed.]. St. Louis: Mosby.)

• The two sexes exhibit the trait in approximately equal proportions; males and females are equally likely to transmit the trait to their offspring. • No generations are skipped. If an individual has the trait, one parent must also have it. If neither parent has the trait, none of the children have it (with the exception of new mutations, as discussed later). • Affected heterozygous individuals transmit the trait to approximately half their children, and because gamete transmission is subject to chance fluctuations, all or none of the children of an affected parent may have the trait. When large numbers of matings of this type are studied, however, the proportion of affected children closely approaches one half. Skipped generations are not seen in classic autosomal dominant pedigrees.

Recurrence Risks Parents at risk of producing children with a genetic disease nearly always ask the question, “What is the chance that our child will have this disease?” The probability that an individual will develop a genetic disease is termed the recurrence risk. When one parent is affected by an autosomal dominant disease (and is a heterozygote) and the other is unaffected, the recurrence risk for each child is one half. An important principle is that each birth is an independent event, much like a coin toss. Thus, even though parents may have already had a child with the disease, their recurrence risk remains one half. Even if they have produced several children, all affected (or all unaffected) by the disease, the law of independence dictates the probability their next child will have the disease is still one half. Parents' misunderstanding of this principle is a common problem encountered in genetic counselling. If a child is born with an autosomal dominant disease and there is no history of the disease in the family, the child is probably the product of a new mutation. The gene transmitted by one of the parents has thus undergone a mutation from a normal to a disease-causing allele. The alleles at this locus in most of the parent's other germ cells are still normal. In this situation the recurrence risk for the parent's subsequent offspring is not greater than that of the general population. The offspring of the affected child, however, will have a recurrence risk of one half. Because these diseases often reduce the potential for reproduction, many autosomal dominant diseases result from new mutations. Occasionally, two or more offspring have symptoms of an autosomal dominant disease when there is no family history of the disease. Because mutation is a rare event, it is unlikely that this disease would be a result of multiple mutations in the same family. The mechanism most likely responsible is termed germline mosaicism. During the embryonic development of one of the parents, a mutation occurred that affected all or part of the germline. Few or none of the somatic cells of the embryo were affected. Thus the parent carries the mutation in his or her germline but does not actually express the disease. As a result, the unaffected parent can transmit the mutation to multiple offspring. This phenomenon, although relatively rare, can have significant effects on recurrence risks.11

Delayed Age of Onset One of the best-known autosomal dominant diseases is Huntington's disease, a neurological disorder whose main features are progressive dementia and increasingly uncontrollable limb movements (chorea; discussed further in Chapter 15). A key feature of this disease is its delayed age of onset: symptoms usually are not seen until 40 years of age or later. Thus those who develop the disease often have borne children before they are aware they have the disease-causing mutation. If the disease was present at birth, nearly all affected persons would die before reaching reproductive age and the occurrence of the diseasecausing allele in the population would be much lower. An individual whose parent has the disease has a 50% chance of developing it during middle age. He or she is thus confronted with a torturous question: Should I have children, knowing that there is a fifty-fifty chance that I may have this disease-causing gene and will pass it to half of my children? A DNA test can now be used to determine whether an individual has inherited the trinucleotide repeat mutation that causes Huntington's disease.

Penetrance and Expressivity The penetrance of a trait is the percentage of individuals with a specific genotype who also exhibit the expected phenotype. Incomplete penetrance means individuals who have the disease-causing genotype may not exhibit the disease phenotype at all, even though the genotype and the associated disease may be transmitted to the next generation. A pedigree illustrating the transmission of an autosomal dominant mutation with incomplete penetrance is provided in Figure 2-22. Retinoblastoma, the most common malignant eye tumour affecting children, typically exhibits incomplete penetrance. About 10% of the individuals who are obligate carriers of the disease-causing mutation (i.e., those who have an affected parent and affected children and therefore must themselves carry the mutation) do not have the disease. The penetrance of the disease-causing genotype is then said to be 90%.

FIGURE 2-22

Pedigree for Retinoblastoma Showing Incomplete Penetrance. Female with marked arrow in line II must be heterozygous, but she does not express the trait.

The gene responsible for retinoblastoma is a tumour-suppressor gene: the normal function of its protein product is to regulate the cell cycle so cells do not divide uncontrollably. When the protein is altered because of a genetic mutation, its tumour-suppressing capacity is lost and a tumour can form12 (see Chapters 10 and 17). Expressivity is the extent of variation in phenotype associated with a particular genotype. If the expressivity of a disease is variable, penetrance may be complete but the severity of the disease can vary greatly. A good example of variable expressivity in an autosomal dominant disease is neurofibromatosis type 1, or von Recklinghausen disease. As in retinoblastoma, the mutations that cause neurofibromatosis type 1 occur in a tumour-suppressor gene.13 The expression of this disease varies from a few harmless café-au-lait (light brown) spots on the skin to numerous neurofibromas, scoliosis, seizures, gliomas, neuromas, malignant peripheral nerve sheath tumours, hypertension, and learning disorders (Figure 223).

FIGURE 2-23 Neurofibromatosis. Tumours. The most common types are either sessile or pedunculated. Early tumours are soft, domeshaped papules or nodules that have a distinctive violaceous hue. Most are benign. (From Habif, T.P., Campbell, J.L. Jr, Chapman, M.S., et al. [2005]. Skin disease: Diagnosis and treatment [2nd ed.]. St. Louis: Elsevier.)

Several factors cause variable expressivity. Genes at other loci sometimes modify the expression of a disease-causing gene. Environmental factors also can influence expression of a disease-causing gene. Finally, different mutations at a locus can cause variation in severity. For example, a mutation that alters only one amino acid of the factor VIII gene usually produces a mild form of hemophilia A, whereas a “stop” codon (premature termination of translation) usually produces a more severe form of this blood coagulation disorder.

Epigenetics and Genomic Imprinting Although this chapter focuses on DNA sequence variation and its consequence for disease, there is increasing evidence that the same DNA sequence can produce dramatically different phenotypes because

of chemical modifications altering the expression of genes (these modifications are collectively termed epigenetic, Chapter 3). An important example of such a modification is DNA methylation, the attachment of a methyl group to a cytosine base followed by a guanine base in the DNA sequence (Figure 2-24). These sequences, which are common near many genes, are termed CpG islands. When the CpG islands located near a gene become heavily methylated, the gene is less likely to be transcribed into mRNA. In other words, the gene becomes transcriptionally inactive. One study showed that identical (monozygotic) twins accumulate different methylation patterns in the DNA sequences of their somatic cells as they age, causing increasing numbers of phenotypic differences.14 Intriguingly, twins with more differences in their lifestyles (e.g., smoking versus nonsmoking) accumulated larger numbers of differences in their methylation patterns. The twins, despite having identical DNA sequences, become more and more different as a result of epigenetic changes, which in turn affect the expression of genes (see Figure 3-5).

FIGURE 2-24 Epigenetic Modifications. Because DNA is a long molecule, it needs packaging to fit in the tiny nucleus. Packaging involves coiling of the DNA in a “left-handed” spiral around spools, made of four pairs of proteins individually known as histones and collectively termed the histone octamer. The entire spool is called a nucleosome (see also Figure 1-2). Nucleosomes are organized into chromatin, the repeating building blocks of a chromosome. Histone modifications are correlated with methylation, are reversible, and occur at multiple sites. Methylation occurs at the 5 position of cytosine and provides a “footprint” or signature as a unique epigenetic alteration (red). When genes are expressed, chromatin is open or active; however, when chromatin is condensed because of methylation and histone modification, genes are inactivated.

Epigenetic alteration of gene activity can have important disease consequences. For example, a major cause of one form of inherited colon cancer (termed hereditary nonpolyposis colorectal cancer [HNPCC]) is the methylation of a gene whose protein product repairs damaged DNA. When this gene becomes inactive, damaged DNA accumulates, eventually resulting in colon tumours. Epigenetic changes are also discussed in Chapters 3, 10, and 11. Approximately 100 human genes are thought to be methylated differently, depending on which parent transmits the gene. This epigenetic modification, characterized by methylation and other changes, is termed genomic imprinting. For each of these genes, one of the parents imprints the gene (inactivates it) when it is transmitted to the offspring. An example is the insulinlike growth factor 2 (IGF-2) gene on

chromosome 11, which is transmitted by both parents, but the copy inherited from the mother is normally methylated and inactivated (imprinted). Thus only one copy of IGF-2 is active in normal individuals. However, the maternal imprint is occasionally lost, resulting in two active copies of IGF-2. Having two active copies of IGF-2 causes excess fetal growth and contributes to a condition known as BeckwithWeidemann syndrome (see p. 65). A second example of genomic imprinting is a deletion of part of the long arm of chromosome 15 (15q11-q13), which, when inherited from the father, causes the offspring to manifest a disease known as Prader-Willi syndrome (short stature, obesity, hypogonadism). When the same deletion is inherited from the mother, the offspring develop Angelman syndrome (intellectual disability, seizures, ataxic gait). The two different phenotypes reflect the fact that different genes are normally active in the maternally and paternally transmitted copies of this region of chromosome 15 (see pp. 64–65).

Autosomal Recessive Inheritance Characteristics of Pedigrees Like autosomal dominant diseases, diseases caused by autosomal recessive genes are rare in populations, although there can be numerous carriers. The most common lethal recessive disease in White children, cystic fibrosis, occurs in about 1 in 2 500 births. Approximately 1 in 25 White people carries a copy of a mutation that causes cystic fibrosis (see Chapter 28). Carriers are phenotypically unaffected. Some autosomal recessive diseases are characterized by delayed age of onset, incomplete penetrance, and variable expressivity. Figure 2-25 shows a pedigree for cystic fibrosis. The gene responsible for cystic fibrosis encodes a chloride ion channel in some epithelial cells. Defective transport of chloride ions leads to a salt imbalance that results in secretions of abnormally thick, dehydrated mucus. Some digestive organs, particularly the pancreas, become obstructed, causing malnutrition, and the lungs become clogged with mucus, making them highly susceptible to bacterial infections. Death from lung disease or heart failure occurs before 40 years of age in about half of persons with cystic fibrosis.

FIGURE 2-25 Pedigree for Cystic Fibrosis. Cystic fibrosis is an autosomal recessive disorder. The double bar denotes a consanguineous mating. Because cystic fibrosis is relatively common in European populations, most cases do not involve consanguinity.

The clustered regularly interspaced short palindromic repeats (CRISPR) system discovered in the bacterium Streptococcus pyogenes works as a mechanism to defend the bacteria against viruses and foreign DNA. This simple bacterial immune system has provided a revolutionary tool for targeted genome engineering (https://www.systembio.com/crispr-cas9/overview) and has future implications for correcting genetic abnormalities associated with cystic fibrosis. Important criteria for discerning autosomal recessive inheritance include the following:

• Males and females are affected in equal proportions. • Consanguinity (marriage between related individuals) is sometimes present, especially for rare recessive diseases. • The disease may be seen in siblings of affected individuals but usually

not in their parents. • On average, one fourth of the offspring of carrier parents will be affected. Recurrence Risks In most cases of recessive disease, both of the parents of affected individuals are heterozygous carriers. On average, one fourth of their offspring will be normal homozygotes, half will be phenotypically normal carrier heterozygotes, and one fourth will be homozygotes with the disease (Figure 2-26). Thus the recurrence risk for the offspring of carrier parents is 25%. However, in any given family, there are chance fluctuations.

FIGURE 2-26 Punnett Square for the Mating of Heterozygous Carriers Typical of Most Cases of Recessive Disease.

If two parents have a recessive disease, they each must be homozygous for the disease. Therefore all their children also must be affected. Homozygous genes for the disease distinguish recessive from dominant inheritance because two parents both affected by a dominant gene are nearly always both heterozygotes, resulting in only one fourth of their children being unaffected (i.e., having the recessive trait). Because carrier parents usually are unaware that they both carry the same recessive allele, they often produce an affected child before becoming aware of their condition. Carrier detection tests can identify heterozygotes by analyzing the DNA sequence to reveal a mutation. Some recessive diseases for which carrier detection tests are routinely used include phenylketonuria, sickle cell disease, cystic fibrosis, TaySachs disease, hemochromatosis, and galactosemia.

Consanguinity Consanguinity and inbreeding are related concepts. Consanguinity refers to the mating of two related individuals, and the offspring of such matings are said to be inbred. Consanguinity is sometimes an important characteristic of pedigrees for recessive diseases because relatives share a certain proportion of genes received from a common ancestor. The proportion of shared genes depends on the closeness of their biological relationship. Consanguineous matings produce a significant increase in recessive disorders and are seen most often in pedigrees for rare recessive disorders.

X-Linked Inheritance Some genetic conditions are caused by mutations in genes located on the sex chromosomes, and this mode of inheritance is termed sex linked. Only a few diseases are known to be inherited as X-linked dominant or Y chromosome traits, so only the more common X-linked recessive diseases are discussed here. Because females receive two X chromosomes, one from the father and one from the mother, they can be homozygous for a disease allele at a given locus, homozygous for the normal allele at the locus, or heterozygous. Males, having only one X chromosome, are hemizygous for genes on this chromosome. If a male inherits a recessive disease gene on the X chromosome, he will be affected by the disease because the Y chromosome does not carry a normal allele to counteract the effects of the disease gene. Because a

single copy of an X-linked recessive gene will cause disease in a male, whereas two copies are required for disease expression in females, more males are affected by X-linked recessive diseases than are females.

X Inactivation In the late 1950s Mary Lyon proposed that one X chromosome in the somatic cells of females is permanently inactivated, a process termed X inactivation.15,16 This proposal, the Lyon hypothesis, explains why most gene products coded by the X chromosome are present in equal amounts in males and females, even though males have only one X chromosome and females have two X chromosomes. This phenomenon is called dosage compensation. The inactivated X chromosomes are observable in many interphase cells as highly condensed intranuclear chromatin bodies, termed Barr bodies (after Barr and Bertram, who discovered them in the late 1940s). Normal females have one Barr body in each somatic cell, whereas normal males have no Barr bodies. X inactivation occurs very early in embryonic development—approximately 7 to 14 days after fertilization. In each somatic cell, one of the two X chromosomes is inactivated. In some cells, the inactivated X chromosome is the one contributed by the father; in other cells, it is the one contributed by the mother. Once the X chromosome has been inactivated in a cell, all the descendants of that cell have the same chromosome inactivated (Figure 2-27). Thus inactivation is said to be random but fixed.

FIGURE 2-27 The X-Inactivation Process. The maternal (m) and paternal (p) X chromosomes are both active in the zygote and in early embryonic cells. X inactivation then takes place, resulting in cells having either an active paternal X or an active maternal X. Females are thus X chromosome mosaics, as shown in the tissue sample at the bottom of the figure. (From Jorde, L.B., Carey, J.C., & Bamshad, M.J. [2010]. Medical genetics [4th ed.]. St. Louis: Mosby.)

Some individuals do not have the normal number of X chromosomes in their somatic cells. For example, males with Klinefelter's syndrome typically have two X chromosomes and one Y chromosome. These males do have one Barr body in each cell. Females whose cell nuclei have three X chromosomes have two Barr bodies in each cell, and females whose cell nuclei have four X chromosomes have three Barr bodies in each cell. Females with Turner's syndrome have only one X chromosome and no Barr bodies. Thus the number of Barr bodies is always one less than the number of X chromosomes in the cell. All but one X chromosome are always inactivated. Persons with abnormal numbers of X chromosomes, such as those with Turner's syndrome or Klinefelter's syndrome, are not physically normal. This situation presents a puzzle because they presumably have only one active X chromosome, the same as individuals with normal numbers of chromosomes. The difference in the number of X chromosomes is probably because the distal tips of the short and long arms of the X chromosome, as well as several other regions on the chromosome arm, are not inactivated. Thus X inactivation is also known to be incomplete. The inactivated X chromosome DNA is heavily methylated. Inactive X chromosomes can be at least partially reactivated in vitro by administering 5-azacytidine, a demethylating agent.

Sex Determination The process of sexual differentiation, in which the embryonic gonads become either testes or ovaries, begins during the sixth week of gestation. A key principle of mammalian sex determination is that one copy of the Y chromosome is sufficient to initiate the process of gonadal differentiation that produces a male fetus. The number of X chromosomes does not alter this process. For example, an individual with two X chromosomes and one Y chromosome in each cell is still phenotypically a male. Thus the Y chromosome contains a gene that begins the process of male gonadal development. This gene, termed SRY (for “sex-determining region on the Y”), has been located on the short arm of the Y chromosome.17 The SRY gene lies just outside the pseudoautosomal region (Figure 2-28), which pairs with the distal tip of the short arm of the X chromosome during meiosis and exchanges genetic material with it (crossover), just as autosomes do. The DNA sequences of these regions on the X and Y chromosomes are highly similar. The rest of the X and Y chromosomes, however, do not exchange material and are not similar in DNA sequence.

FIGURE 2-28 Distal Short Arms of the X and Y Chromosomes Exchange Material During Meiosis in the Male. The region of the Y chromosome in which this crossover occurs is called the pseudoautosomal region. The SRY gene, which triggers the process leading to male gonadal differentiation, is located just outside the pseudoautosomal region. Occasionally, the crossover occurs on the centromeric side of the SRY gene, causing it to lie on an X chromosome instead of a Y chromosome. An offspring receiving this X chromosome will be an XX male, and an offspring receiving the Y chromosome will be an XY female.

Other genes that contribute to male differentiation are located on other chromosomes. Thus SRY triggers the action of genes on other chromosomes. This concept is supported by the fact that the SRY protein product is similar to other proteins known to regulate gene expression. Occasionally, the crossover between X and Y occurs closer to the centromere than it should, placing the SRY gene on the X chromosome after crossover. This variation can result in offspring with an apparently normal XX karyotype but a male phenotype. Such XX males are seen in about 1 in 20 000 live births and resemble males with Klinefelter's syndrome. Conversely, it is possible to inherit a Y chromosome that has lost the SRY gene (the result of either a crossover error or a deletion of the gene). This situation produces an XY female. Such females have gonadal streaks rather than ovaries and have poorly developed secondary sex characteristics.

Quick Check 2-2

1. Why is the influence of environment significant to phenotype? 2. Describe the differences between a dominant and a recessive allele. 3. Why are the concepts of variable expressivity, incomplete penetrance, and delayed age of onset so important in relation to genetic diseases? 4. What is the recurrence risk for autosomal dominant inheritance and recessive inheritance?

Characteristics of Pedigrees X-linked pedigrees show distinctive modes of inheritance. The most striking characteristic is that females seldom are affected. To express an X-linked recessive trait fully, a female must be homozygous: either both her parents are affected, or her father is affected and her mother is a carrier. Such matings are rare. Four important principles of X-linked recessive inheritance are as follows: 1. The trait is seen much more often in males than in females. 2. Because a father can give a son only a Y chromosome, the trait is never transmitted from father to son. 3. The gene can be transmitted through a series of carrier females, causing the appearance of one or more “skipped generations.” 4. The gene is passed from an affected father to all his daughters, who, as phenotypically normal carriers, transmit it to approximately half their sons, who are affected. A relatively common X-linked recessive disorder is Duchenne muscular dystrophy (DMD), which affects approximately 1 in 3 500 males. As its name suggests, this disorder is characterized by progressive muscle degeneration. Affected individuals usually are unable to walk by age 10 or 12 years. The disease affects the heart and respiratory muscles, and death caused by respiratory or cardiac failure usually occurs before 20 years of age. Identification of the disease-causing gene (on the short arm of the X chromosome) has greatly increased our understanding of the disorder.18 The DMD gene is the largest gene ever found in humans, spanning more than 2 million DNA bases. It encodes a previously undiscovered muscle protein, termed dystrophin. Extensive study of dystrophin indicates that it plays an essential role in maintaining the structural integrity of muscle cells: it may also help to regulate the activity of membrane proteins. When dystrophin is absent, as in DMD, the cell cannot survive, and muscle deterioration ensues. Most cases of DMD are caused by frameshift deletions of portions of the DMD gene and thus involve alterations of the amino acids encoded by the DNA following the deletion.

Recurrence Risks The most common mating type involving X-linked recessive genes is the combination of a carrier female and a normal male (Figure 2-29, A). On average, the carrier mother will transmit the disease-causing allele to half her sons (who are affected) and half her daughters (who are carriers).

FIGURE 2-29 Punnett Square and X-Linked Recessive Traits. A, Punnett square for the mating of a normal male (XHY) and a female carrier of an X-linked recessive gene (XHXh). B, Punnett square for the mating of a normal female (XHXH) with a male affected by an Xlinked recessive disease (XhY). C, Punnett square for the mating of a female who carries an X-linked recessive gene (XHXh) with a male who is affected with the disease caused by the gene (XhY).

The other common mating type is an affected father and a normal mother (Figure 2-29, B). In this situation, all the sons will be normal because the father can transmit only his Y chromosome to them. Because all the daughters must receive the father's X chromosome, they will all be heterozygous carriers. Because the sons must receive the Y chromosome and the daughters must receive the X chromosome with the disease gene, these are precise outcomes and not probabilities. None of the children will be affected. The final mating pattern, less common than the other two, involves an affected father and a carrier mother (Figure 2-29, C). With this pattern, on average, half the daughters will be heterozygous carriers, and half will be homozygous for the disease allele and thus affected. Half the sons will be normal, and half will be affected. Some X-linked recessive diseases, such as DMD, are fatal or incapacitating before the affected individual reaches reproductive age, and therefore affected fathers are rare.

Sex-Limited and Sex-Influenced Traits A sex-limited trait can occur in only one sex, often because of anatomical differences. Inherited uterine and testicular defects are two obvious examples. A sex-influenced trait occurs much more often in one sex than the other. For example, male-pattern baldness occurs in both males and females but is much more common in males. Autosomal dominant breast cancer, which is much more commonly expressed in females than males, is another example of a sex-influenced trait.

Linkage Analysis and Gene Mapping Locating genes on specific regions of chromosomes has been one of the most important goals of human genetics. The location and identification of a gene can tell much about the function of the gene, the interaction of the gene with other genes, and the likelihood that certain individuals will develop a genetic disease.

Classic Pedigree Analysis Mendel's second law, the principle of independent assortment, states that an individual's genes will be transmitted to the next generation independently of one another. This law is only partly true, however, because genes located close together on the same chromosome do tend to be transmitted together to the offspring. Thus Mendel's principle of independent assortment holds true for most pairs of genes but not those that occupy the same region of a chromosome. Such loci demonstrate linkage and are said to be linked. During the first meiotic stage, the arms of homologous chromosome pairs intertwine and sometimes exchange portions of their DNA (Figure 2-30) in a process known as crossover. During crossover, new combinations of alleles can be formed. For example, two loci on a chromosome have alleles A1 and A2 and alleles B1 and B2. Alleles A1 and B1 are located together on one member of a chromosome pair, and alleles A2 and B2 are located on the other member. The genotype of this individual is denoted as A1B1/A2B2.

FIGURE 2-30

Genetic Results of Crossing Over. A, No crossing over. B, Crossing over with recombination. C, Double crossing over, resulting in no recombination.

As Figure 2-30, A, shows, the allele pairs A1B1 and A2B2 would be transmitted together when no crossover occurs. However, when crossover occurs (Figure 2-30, B), all four possible pairs of alleles can be transmitted to the offspring: A1B1, A2B1, A1B2, and A2B2. The process of forming such new arrangements of alleles is called recombination. Crossover does not necessarily lead to recombination, however, because double crossover between two loci can result in no actual recombination of the alleles at the loci (Figure 230, C). Once a close linkage has been established between a disease-gene locus and a “marker” locus (a DNA sequence that varies among individuals) and once the alleles of the two loci that are inherited together within a family have been determined, reliable predictions can be made as to whether a member of a family will develop the disease. This type of analysis is called linkage analysis. Linkage has been

established between several DNA polymorphisms and each of the two major genes that can cause autosomal dominant breast cancer (about 5% of breast cancer cases are caused by these autosomal dominant genes). Determining this kind of linkage means that it is possible for offspring of an individual with autosomal dominant breast cancer to know whether they also carry the gene and thus could pass it on to their own children. In most cases, specific disease-causing mutations can be identified, allowing direct detection and diagnosis. For some genetic diseases, prophylactic treatment is available if the condition can be diagnosed in time. An example of this is hemochromatosis, a recessive genetic disease in which excess iron is absorbed, causing degeneration of the heart, liver, brain, and other vital organs. Individuals at risk of developing the disease can be determined by testing for a mutation in the hemochromatosis gene and through clinical tests, and preventive therapy (periodic phlebotomy) can be initiated to deplete iron stores and ensure a normal lifespan.

Complete Human Gene Map: Prospects and Benefits The major goals of the Human Genome Project were to find the locations of all human genes (the “gene map”) and to determine the entire human DNA sequence. These goals have now been accomplished, and the genes responsible for more than 4 000 Mendelian conditions have been identified (Figure 2-31).3,19,20 The project has greatly increased our understanding of the mechanisms that underlie many diseases, such as retinoblastoma, cystic fibrosis, neurofibromatosis, and Huntington's disease. The project also has led to more accurate diagnosis of these conditions and, in some cases, more effective treatment.

FIGURE 2-31

Example of Diseases: A Gene Map. ADA, adenosine deaminase; ALD, adrenoleukodystrophy; PKU, phenylketonuria.

DNA sequencing has become much less expensive and more efficient in recent years. Consequently, many thousands of individuals have now been completely sequenced, leading in some cases to the identification of disease-causing genes (see Health Promotion: Gene Therapy).21

Health Promotion: Gene Therapy Thousands of subjects are currently enrolled in more than 1 000 gene therapy protocols. Most of these

protocols involve the genetic alteration of cells to combat various types of cancer. Others involve the treatment of inherited diseases, such as β-thalassemia, hemophilia B, severe combined immunodeficiency, and retinitis pigmentosa.

Multifactorial Inheritance Not all traits are produced by single genes; some traits result from several genes acting together. They are called polygenic traits. When environmental factors also influence the expression of the trait (as is usually the case), the term multifactorial inheritance is used. Many multifactorial and polygenic traits tend to follow a normal distribution in populations (the familiar bell-shaped curve). Figure 2-32 shows how three loci acting together can cause grain colour in wheat to vary in a gradual way from white to red, exemplifying multifactorial inheritance. If both alleles at each of the three loci are white alleles, the colour is pure white. If most alleles are white but a few are red, the colour is somewhat darker; if all are red, the colour is dark red.

FIGURE 2-32

Multifactorial Inheritance. Analysis of mode of inheritance for grain colour in wheat. The trait is controlled by three independently assorted gene loci.

Other examples of multifactorial traits include height and IQ. Although both height and IQ are determined in part by genes, they are influenced also by environment. For example, the average height of many human populations has increased by 5 to 10 cm in the past 100 years because of improvements in nutrition and health care. Also, IQ scores can be improved by exposing individuals (especially children) to enriched learning environments. Thus both genes and environment contribute to variation in these traits. A number of diseases do not follow the bell-shaped distribution. Instead they appear to be either present in or absent from an individual. Yet they do not follow the patterns expected of single-gene diseases. Many of them are probably polygenic or multifactorial, but a certain threshold of liability must be crossed before the disease is expressed. Below the threshold, the individual appears normal; above it, the individual is affected by the disease (Figure 2-33).

FIGURE 2-33 Threshold of Liability for Pyloric Stenosis in Males and Females.

A good example of such a threshold trait is pyloric stenosis, a disorder characterized by a narrowing or obstruction of the pylorus, the area between the stomach and small intestine. Chronic vomiting, constipation, weight loss, and electrolyte imbalance can result from the condition, but it is easily corrected by surgery. The prevalence of pyloric stenosis is about 3 in 1 000 live births in White people. This disorder is much more common in males than females, affecting 1 in 200 males and 1 in 1 000 females. The apparent reason for this difference is that the threshold of liability is much lower in males than females, as shown in Figure 2-33. Thus fewer defective alleles are required to generate the disorder in males. This situation also means the offspring of affected females are more likely to have pyloric stenosis because affected females necessarily carry more disease-causing alleles than do most affected males. A number of other common diseases are thought to correspond to a threshold model. They include cleft lip and cleft palate, neural tube defects (anencephaly, spina bifida), clubfoot (talipes), and some forms of congenital heart disease. Although recurrence risks can be given with confidence for single-gene diseases (e.g., 50% for autosomal dominants, 25% for autosomal recessives), it is considerably more difficult to do so for multifactorial diseases. The number of genes contributing to the disease is not known, the precise allelic constitution of the biological parents is not known, and the extent of environmental effects can vary from one population to another. For most multifactorial diseases, empirical risks (i.e., those based on direct observation) have been derived. To determine empirical risks, a large sample of biological families in which one child has developed the disease is examined. The siblings of each child are then surveyed to calculate the percentage who also develop the disease. Another difficulty is distinguishing polygenic or multifactorial diseases from single-gene diseases having incomplete penetrance or variable expressivity. Large data sets and good epidemiological data often are necessary to make the distinction. Box 2-2 lists criteria commonly used to define multifactorial diseases.

Box 2-2

Criteria Used to Define Multifactorial Diseases 1. The recurrence risk becomes higher if more than one family member is affected. For example, the recurrence risk for neural tube defects in a British family increases to 10% if two siblings have been born with the disease. By contrast, the recurrence risk for single-gene diseases remains the same

regardless of the number of siblings affected. 2. If the expression of the disease is more severe, the recurrence risk is higher. This finding is consistent with the liability model; a more severe expression indicates that the individual is at the extreme end of the liability distribution. Relatives of the affected individual are thus at a higher risk of inheriting disease genes. Cleft lip or cleft palate is a condition in which relatives are at a higher risk of inheriting disease genes. 3. Relatives of probands of the less commonly affected are more likely to develop the disease. As with pyloric stenosis, development of the disease occurs because an affected individual of the less susceptible sex is usually at a more extreme position on the liability distribution. 4. Generally, if the population frequency of the disease is f, the risk for offspring and siblings of probands is approximately . The same principle does not usually hold true for single-gene traits. 5. The recurrence risk for the disease decreases rapidly in more remotely related relatives. Although the recurrence risk for single-gene diseases decreases by 50% with each degree of relationship (e.g., an autosomal dominant disease has a 50% recurrence risk for siblings, 25% for uncle-nephew relationship, 12.5% for first cousins), the risk for multifactorial inheritance decreases much more quickly. The genetics of common disorders such as hypertension, heart disease, and diabetes is complex and often confusing. Nevertheless, the public health impact of these diseases, together with the evidence for hereditary factors in their etiology, demands that genetic studies be pursued. Hundreds of genes contributing to susceptibility for these diseases have been discovered, and the next decade will undoubtedly witness substantial advancements in our understanding of these disorders.

Quick Check 2-3 1. Define linkage analysis; cite an example. 2. Why is “threshold of liability” an important consideration in multifactorial inheritance? 3. Describe the concept of multifactorial inheritance, and include two examples.

Did You Understand? DNA, RNA, and Proteins: Heredity at the Molecular Level 1. Genes, the basic units of inheritance, are composed of deoxyribonucleic acid (DNA) and are located on chromosomes. 2. DNA is composed of deoxyribose, a phosphate molecule, and four types of nitrogenous bases. The physical structure of DNA is a double helix. 3. The DNA bases code for amino acids, which in turn make up proteins. The amino acids are specified by triplet codons of nitrogenous bases. 4. DNA replication is based on complementary base pairing, in which a single strand of DNA serves as the template for attracting bases that form a new strand of DNA. 5. DNA polymerase is the primary enzyme involved in replication. It adds bases to the new DNA strand and performs “proofreading” functions. 6. A mutation is an inherited alteration of genetic material (i.e., DNA). 7. Substances that cause mutations are called mutagens. 8. The mutation rate in humans varies from locus to locus and is about 1.1 x 10-8 per gene per generation. 9. Transcription and translation, the two basic processes in which proteins are specified by DNA, both involve ribonucleic acid (RNA). RNA is chemically similar to DNA, but it is single stranded, has a ribose sugar molecule, and has uracil rather than thymine as one of its four nitrogenous bases. 10. Transcription is the process by which DNA specifies a sequence of messenger RNA (mRNA). 11. Much of the RNA sequence is spliced from the mRNA before the mRNA leaves the nucleus. The excised sequences are called introns, and those that remain to code for proteins are called exons. 12. Translation is the process by which RNA directs the synthesis of polypeptides. This process takes place in the ribosomes, which consist of proteins and ribosomal RNA (rRNA). 13. During translation, mRNA interacts with transfer RNA (tRNA), a molecule that has an attachment site for a specific amino acid.

Chromosomes 1. Human cells consist of diploid somatic cells (body cells) and haploid gametes (sperm and egg cells). 2. Humans have 23 pairs of chromosomes. Twenty-two of these pairs are autosomes. The remaining pair consists of the sex chromosomes. Females have two homologous X chromosomes as their sex chromosomes; males have an X and a Y chromosome. 3. A karyotype is an ordered display of chromosomes arranged according to length and the location of the centromere. 4. Various types of stains can be used to make chromosome bands more visible. 5. About 1 in 150 live births has a major diagnosable chromosome abnormality. Chromosome abnormalities are the leading known cause of intellectual disability and miscarriage. 6. Polyploidy is a condition in which a euploid cell has some multiple of the normal number of chromosomes. Humans have been observed to have triploidy (three copies of each chromosome) and tetraploidy (four copies of each chromosome); both conditions are lethal. 7. Somatic cells that do not have a multiple of 23 chromosomes are aneuploid. Aneuploidy is usually the result of nondisjunction. 8. Trisomy is a type of aneuploidy in which one chromosome is present in three copies in somatic cells. A partial trisomy is one in which only part of a chromosome is present in three copies. 9. Monosomy is a type of aneuploidy in which one chromosome is present in only one copy in somatic cells.

10. In general, monosomies cause more severe physical defects than do trisomies, illustrating the principle that the loss of chromosome material has more severe consequences than the duplication of chromosome material. 11. Down syndrome, a trisomy of chromosome 21, is the best-known disease caused by a chromosome aberration. It affects 1 in 800 live births and is much more likely to occur in the offspring of women older than 35 years. 12. Most aneuploidies of the sex chromosomes have less severe consequences than those of the autosomes. 13. The most commonly observed sex chromosome aneuploidies involve alterations in the number of X chromosomes, namely the 47,XXX karyotype, 45,X karyotype (Turner's syndrome), and 47,XXY karyotype (Klinefelter's syndrome). 14. Abnormalities of chromosome structure include deletions, duplications, inversions, and translocations.

Elements of Formal Genetics 1. Mendelian traits are caused by single genes, each of which occupies a position, or locus, on a chromosome. 2. Alleles are different forms of genes located at the same locus on a chromosome. 3. At any given locus in a somatic cell, an individual has two genes, one from each parent. An individual may be homozygous or heterozygous at a locus. 4. An individual's genotype is his or her genetic makeup, and the phenotype reflects the interaction of genotype and environment. 5. In a heterozygote, a dominant gene's effects mask those of a recessive gene. The recessive gene is expressed only when it is present in two copies.

Transmission of Genetic Diseases 1. Genetic diseases caused by single genes usually follow autosomal dominant, autosomal recessive, or X-linked recessive modes of inheritance. 2. Pedigree charts are important tools in the analysis of modes of inheritance. 3. Skipped generations are not seen in classic autosomal dominant pedigrees. 4. Recurrence risks specify the probability that future offspring will inherit a genetic disease. For single-gene diseases, recurrence risks remain the same for each offspring, regardless of the number of affected or unaffected offspring. 5. The recurrence risk for autosomal dominant diseases is usually 50%. 6. Germline mosaicism can alter recurrence risks for genetic diseases because unaffected parents can produce multiple affected offspring. This situation occurs because the germline of one parent is affected by a mutation but the parent's somatic cells are unaffected. 7. Males and females are equally likely to exhibit autosomal dominant diseases and to pass them on to their offspring. 8. Many genetic diseases have a delayed age of onset. 9. A gene that is not always expressed phenotypically is said to have incomplete penetrance. 10. Variable expressivity is a characteristic of many genetic diseases. 11. Genomic imprinting, which is associated with methylation, results in differing expression of a disease gene, depending on which parent transmitted the gene. 12. Epigenetics involves changes, such as the methylation of DNA bases, that do not alter the DNA sequence but can alter the expression of genes. 13. Most commonly, biological parents of children with autosomal recessive diseases are both heterozygous carriers of the disease gene. 14. The recurrence risk for autosomal recessive diseases is 25%. 15. Males and females are equally likely to be affected by autosomal recessive diseases.

16. Consanguinity is sometimes present in families with autosomal recessive diseases, and it becomes more prevalent with rarer recessive diseases. 17. Carrier detection tests for an increasing number of autosomal recessive diseases are available. 18. In each normal female somatic cell, one of the two X chromosomes is inactivated early in embryogenesis. 19. X inactivation is random, fixed, and incomplete (i.e., only part of the chromosome is actually inactivated). It may involve methylation. 20. Gender is determined embryonically by the presence of the SRY gene on the Y chromosome. Embryos that have a Y chromosome (and thus the SRY gene) become males, whereas those lacking the Y chromosome become females. When the Y chromosome lacks the SRY gene, an XY female can be produced. Similarly, an X chromosome that contains the SRY gene can produce an XX male. 21. X-linked genes are those that are located on the X chromosome. Nearly all known X-linked diseases are caused by X-linked recessive genes. 22. Males are hemizygous for genes on the X chromosome. 23. X-linked recessive diseases are seen much more often in males than in females because males need only one copy of the gene to express the disease. 24. Biological fathers cannot pass X-linked genes to their sons. 25. Skipped generations often are seen in X-linked recessive disease pedigrees because the gene can be transmitted through carrier females. 26. Recurrence risks for X-linked recessive diseases depend on the carrier and affected status of the mother and father. 27. A sex-limited trait is one that occurs only in one sex (gender). 28. A sex-influenced trait is one that occurs more often in one sex than the other.

Linkage Analysis and Gene Mapping 1. During meiosis I, crossover occurs and can cause recombinations of alleles located on the same chromosome. 2. The frequency of recombinations can be used to infer the map distance between loci on the same chromosome. 3. A marker locus, when closely linked to a disease-gene locus, can be used to predict whether an individual will develop a genetic disease. 4. The major goals of the Human Genome Project were to find the locations of all human genes (the “gene map”) and to determine the entire human DNA sequence. These goals have now been accomplished, and the genes responsible for more than 4 000 Mendelian conditions have been identified.

Multifactorial Inheritance 1. Traits that result from the combined effects of several loci are polygenic. When environmental factors also influence the expression of the trait, the term multifactorial inheritance is used. 2. Many multifactorial traits have a threshold of liability. Once the threshold of liability has been crossed, the disease may be expressed. 3. Empirical risks, based on direct observation of large numbers of families, are used to estimate recurrence risks for multifactorial diseases. 4. Recurrence risks for multifactorial diseases become higher if more than one biological family member is affected or if the expression of the disease in the proband is more severe. 5. Recurrence risks for multifactorial diseases decrease rapidly for more remote relatives.

Key Terms Adenine, 38 Allele, 49 Amino acid, 39 Aneuploid cell, 43 Anticodon, 42 Autosome, 42 Barr body, 54 Base pair substitution, 39 Carrier, 49 Carrier detection test, 54 Chromosomal mosaic, 46 Chromosome, 38 Chromosome band, 42 Chromosome breakage, 46 Chromosome theory of inheritance, 50 Clastogen, 46 Codominance, 49 Codon, 39 Complementary base pairing, 39 Consanguinity, 54 CpG islands, 52 Cri du chat syndrome, 47 Crossover, 56 Cytokinesis, 42 Cytosine, 38 Delayed age of onset, 51 Deletion, 46 Deoxyribonucleic acid (DNA), 38 Diploid cell, 42 DNA methylation, 52 DNA polymerase, 39 Dominant, 49 Dosage compensation, 54 Double-helix model, 38 Down syndrome, 46 Duplication, 47 Dystrophin, 55 Empirical risk, 58 Epigenetic, 52 Euploid cell, 42 Exon, 41 Expressivity, 51 Fragile site, 49 Frameshift mutation, 39 Gamete, 42 Gene, 38 Genomic imprinting, 52 Genotype, 49 Germline mosaicism, 51

Guanine, 38 Haploid cell, 42 Hemizygous, 54 Heterozygote, 49 Heterozygous, 49 Homologous, 42 Homozygote, 49 Homozygous, 49 Inbreeding, 54 Intron, 41 Inversion, 47 Karyotype (karyogram), 42 Klinefelter's syndrome, 46 Linkage, 56 Linkage analysis, 57 Locus, 49 Meiosis, 42 Messenger RNA (mRNA), 41 Metaphase spread, 42 Methylation, 52 Missense, 39 Mitosis, 42 Mode of inheritance, 50 Multifactorial inheritance, 58 Mutagen, 39 Mutation, 39 Mutational hot spot, 39 Nondisjunction, 45 Nonsense, 39 Nucleotide, 39 Obligate carrier, 51 Partial trisomy, 46 Pedigree, 50 Penetrance, 51 Phenotype, 49 Polygenic trait, 58 Polymorphic (polymorphism), 49 Polypeptide, 39 Polyploid cell, 42 Position effect, 47 Principle of independent assortment, 50 Principle of segregation, 50 Proband, 50 Promoter site, 41 Pseudoautosomal, 55 Purine, 38 Pyrimidine, 38 Recessive, 49 Reciprocal translocation, 47 Recombination, 57 Recurrence risk, 50 Ribonucleic acid (RNA), 39 Ribosomal RNA (rRNA), 42

Ribosome, 42 RNA polymerase, 41 Robertsonian translocation, 48 Sex-influenced trait, 56 Sex-limited trait, 56 Sex linked (inheritance), 54 Silent mutation, 39 Somatic cell, 42 Spontaneous mutation, 39 Template, 39 Termination sequence, 41 Tetraploidy, 42 Threshold of liability, 58 Thymine, 38 Transcription, 41 Transfer RNA (tRNA), 42 Translation, 42 Translocation, 47 Triploidy, 42 Trisomy, 43 Tumour-suppressor gene, 51 Turner's syndrome, 46 X inactivation, 54

References 1. Roach JC, Glusman G, Smit AF, et al. Analysis of genetic inheritance in a family quartet by wholegenome sequencing. Science. 2010;328(5978):636–639; 10.1126/science.1186802. 2. Zhang S, Chen J, Cui P, et al. Identification of novel mutations associated with clofazimine resistance in Mycobacterium tuberculosis. Journal of Antimicrobial Chemotherapy. 2015;70(9):2507– 2510; 10.1093/jac/dkv150. 3. Jorde LB, Carey JC, Bamshad MJ. Medical genetics. 4th ed. Mosby: St. Louis; 2010. 4. Gardner RJM, Sutherland GR, Schaffer LG. Chromosome abnormalities and genetic counseling. Oxford University Press: Oxford; 2012. 5. Nagaoka SI, Hassold TJ, Hunt PA. Human aneuploidy: Mechanisms and new insights into an age-old problem. Nature Reviews. Genetics. 2012;13(7):493–504; 10.1038/nrg3245. 6. Antonarakis SE, Epstein CJ. The challenge of Down syndrome. Trends in Molecular Medicine. 2006;12(10):473–479; 10.1016/j.molmed.2006.08.005. 7. Gravholt CH. Sex chromosome abnormalities. Rimoin DL, Pyeritz RE, Korf BR. Emery and Rimoin's principles and practice of medical genetics. 6th ed. Elsevier: Philadelphia; 2013. 8. Rooms L, Kooy RF. Advances in understanding fragile X syndrome and related disorders. Current Opinion in Pediatrics. 2011;23(6):601–606; 10.1097/MOP.0b013e32834c7f1a. 9. Nelson DL, Orr HT, Warren ST. The unstable repeats—three evolving faces of neurological disease. Neuron. 2013;77(5):825–843; 10.1016/j.neuron.2013.02.022. 10. Hoban MD, Gregory JC, Mendel MC, et al. Correction of the sickle-cell disease mutation in human hematopoietic stem/progenitor cells. Blood. 2015;125(17):2597–2604; 10.1182/blood-2014-12-615948. 11. Biesecker LG, Spinner NB. A genomic view of mosaicism and human disease. Nature Reviews. Genetics. 2013;14(5):307–320; 10.1038/nrg3424. 12. Tomlinson I. The Mendelian colorectal cancer syndromes. Annals of Clinical Biochemistry. 2015;52(6):690–692; 10.1177/0004563215597944. 13. Pasmant E, Vidaud M, Vidaud D, et al. Neurofibromatosis type 1: From genotype to phenotype. Journal of Medical Genetics. 2012;49(8):483–489; 10.1136/jmedgenet-2012-100978. 14. Livshits G, Gao F, Malkin I, et al. Contribution of heritability and epigenetic factors to skeletal muscle mass variation in United Kingdom twins. Journal of Clinical Endocrinology and Metabolism. 2016;101(6):2450–2459; 10.1210/jc.2016-1219. 15. Lyon MF. X-chromosome inactivation. Current Biology. 1999;9(7):R235–R237. 16. Lee JT, Bartolomei MS. X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell. 2013;152(6):1308–1323; 10.1016/j.cell.2013.02.016. 17. Larney C, Bailey TL, Koopman P. Switching on sex: Transcriptional regulation of the testisdetermining gene SRY. Development (Cambridge, England). 2014;141(11):2195–2205; 10.1242/dev.107052. 18. Flanigan KM. The muscular dystrophies. Seminars in Neurology. 2012;32(3):255–263; 10.1055/s-00321329199. 19. Lander ES. Initial impact of the sequencing of the human genome. Nature. 2011;470(7333):187–197; 10.1038/nature09792. 20. Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome sequencing for the diagnosis of Mendelian disorders. The New England Journal of Medicine. 2013;369(16):1502–1511; 10.1056/NEJMoa1306555. 21. Koboldt DC, Steinberg KM, Larson DE, et al. The next-generation sequencing revolution and its impact on genomics. Cell. 2013;155(1):27–38; 10.1016/j.cell.2013.09.006.

Epigenetics and Disease Diane P. Genereux, Lynn B. Jorde, Stephanie Zettel

CHAPTER OUTLINE Epigenetic Mechanisms, 62 DNA Methylation, 62 Histone Modifications, 63 RNA-Based Mechanisms, 64 Epigenetics and Human Development, 64 Genomic Imprinting, 64 Prader-Willi and Angelman Syndromes, 64 Beckwith-Wiedemann Syndrome, 65 Russell-Silver Syndrome, 66 Inheritance of Epigenetic States, 66 Epigenetics and Nutrition, 66 Epigenetics and Maternal Care, 66 Epigenetics and Mental Illness, 67 Epigenetic Disease in the Context of Genetic Abnormalities, 67 Twin Studies Provide Insights on Epigenetic Modification, 68 Molecular Approaches to Understand Epigenetic Disease, 68 Epigenetics and Cancer, 68 DNA Methylation and Cancer, 68 microRNAs and Cancer, 69 Epigenetic Screening for Cancer, 69 Emerging Strategies for the Treatment of Epigenetic Disease, 69 Future Directions, 71

Human beings exhibit an impressive diversity of physical and behavioural features. Some of this

diversity is attributable to genetic variation. Another contributor to human diversity is epigenetic (“upon genetic”) modification (a change in phenotype or gene expression that does not involve DNA mutation or changes in nucleotide sequence). Basically, epigenetics is the study of mechanisms that will switch genes “on,” such that they are expressed, and “off,” such that they are silenced. Epigenetic mechanisms include chemical modifications to DNA and associated histones, and the production of small RNA molecules. Gene regulation by epigenetic processes can occur at the level of either transcription or translation. Epigenetic modification is critical for fundamental processes of human development, including the differentiation of embryonic stem cells into specific cell types, and the inactivation of one of the two X chromosomes in each cell of a genetic female. Some genes are noted to be imprinted, a form of epigenetic regulation where the expression of a gene depends on whether it is inherited from the mother or the father.

Epigenetic Mechanisms A variety of diseases can result from abnormal epigenetic states. Metabolic disease can occur when there is aberrant expression of both copies of a locus that is typically imprinted. Environmental stressors can markedly increase the risk of aberrant epigenetic modification and are strongly associated with some cancers. It is because of their increasing clear role in a wide range of pathologies that abnormal epigenetic states are currently a focus of both preventive efforts and pharmaceutical intervention. Currently known epigenetic mechanisms include DNA methylation, histone modifications, and RNA-based mechanisms (Figure 3-1).

FIGURE 3-1

Three Types of Epigenetic Mechanisms. Investigators are studying three epigenetic mechanisms: (1) DNA methylation, (2) histone modifications, and (3) RNA-based mechanisms. See text for discussion.

DNA Methylation DNA methylation (see Figure 3-1) occurs through the attachment of a methyl group (CH3) to a cytosine. Dense DNA methylation can be thought of as “insulation” that renders genes silent by blocking access by transcription factors. Dense methylation is typically coincident with hypoacetylation (decrease of the functional group acetyl) of the histone proteins around which the DNA is wound (see “Histone Modifications”). Together, DNA methylation and histone hypoacetylation can render a gene transcriptionally silent, preventing production of the encoded protein. Methylated cytosines have been found to occur principally at cytosines that are followed by a guanine base (sometimes known as cytosines in “CpG dinucleotides”). In human embryonic stem cells, methylation also can occur at cytosines outside of the CpG context (see Figure 2-24).

DNA methylation plays a prominent role in both human health and disease. For example, in each cell of a normal human female, one of the two X chromosomes is silenced by dense methylation and associated molecular marks, whereas the other X chromosome is transcriptionally active and largely devoid of methylation. During early embryonic development, there is epigenetic inactivation of one of the two X chromosomes in each cell of a human female—either the X chromosome inherited from her mother or the X chromosome inherited from her father. The determination of which chromosome is to be silenced occurs at random and independently in each of the cells present at this stage of development; the silent state of that chromosome is inherited by all subsequent copies. If a woman's two X chromosomes carry different alleles at a given locus, random X inactivation can lead to somatic mosaicism, wherein the alleles active in two different cells can confer two very different traits. Striking examples include the patchy coloration of calico cats and anhidrotic ectodermal dysplasia, a condition characterized by patchy presence and absence of sweat glands in the skin of human females who have one X chromosome bearing a normal allele and one X chromosome bearing a mutant allele at the X-encoded locus. Because of the somatic mosaicism that arises through random inactivation of the X chromosome, females tend to have less severe phenotypes than do males for a variety of X-linked disorders, including colour blindness and fragile X syndrome. Aberrant DNA methylation, either the presence of dense methylation where it is typically absent or the absence of methylation where it is typically present, can lead to misregulation of tumour-suppressor genes and oncogenes. Abnormal DNA methylation states are a common feature of several human cancers, including those of the colon1-3 (see Figures 3-1 and 3-6 [p. 69]; see also Chapter 10).

Histone Modifications Histone modifications (see Figure 3-1) include histone acetylation (adding an acetyl group) and deacetylation (deletion of an acetyl group) to the end of a histone protein. Like DNA methylation, these changes can alter the expression state of chromatin. Histones are proteins that facilitate compaction of genomic DNA into the nucleus of a cell, much as a spool helps to organize a long piece of thread for storage in a small space. When the DNA of the human genome is wound around histones, it is only ≈1/40 000 as long as it would be in its uncondensed state. Chemical modification of histones in a region of DNA can either upregulate or downregulate nearby gene expression by increasing or decreasing the tightness of the interaction between DNA and histones, thus modulating the extent to which DNA is accessible to transcription factors. DNA in association with histones is referred to as chromatin. At any given time, various regions of chromatin are typically in one of two forms: euchromatin, an open state in which most or all nearby genes are transcriptionally active; or heterochromatin, a closed state in which most or all nearby genes are transcriptionally inactive. Chromatin structure plays a critical role in determining the developmental potential of a given cell lineage, and can undergo dramatic changes during organismal development. For example, chromatin states differ substantially between embryonic stem cells, which are poised to give rise to all of the different cell types that make up an individual, and terminally differentiated cells, which are committed to a specific developmental path. The fraction of DNA that is in the heterochromatic state increases as cells differentiate, consistent with the reduction in the number of genes that are active as a cell lineage transitions from pluripotency to terminal differentiation.4 Mutations in genes that encode histonemodifying proteins have been implicated in congenital heart disease,5 for example, highlighting histone modification states as critical for normal development. In contrast to the vast majority of other cell types, including oocytes, sperm cells express not histones but protamines, which are evolutionarily derived from histones.6 Protamines enable sperm DNA to wind into an even more compact state than does the histone-bound DNA in somatic cells. This tight compaction improves the hydrodynamic features of the sperm head, facilitating its movement toward the egg.

RNA-Based Mechanisms Noncoding RNAs (ncRNAs) and other RNA-based mechanisms (see Figure 3-1) play an important role in regulating a wide variety of cellular processes, including RNA splicing and DNA replication. These

ncRNAs have been likened to “sponges” in so far as they can “sop up” complementary RNAs, thus inhibiting their function (see, e.g., http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2957044/). Of particular relevance to gene regulation are the hairpin-shaped microRNAs (miRNAs), which are encoded by DNA sequences of approximately 22 nucleotides, typically within the introns (a segment of a DNA molecule that does not code for proteins) of genes or in noncoding DNA located between genes (see Chapter 2). In contrast to DNA methylation and histone modification, both of which principally affect gene expression at the level of transcription, miRNAs typically modulate the stability and translational efficiency of existing messenger RNAs (mRNAs) encoded at other loci. Interaction between miRNAs and mRNAs target for degradation is typically mediated by regions of partial sequence complementarity. As a result, miRNAs can at once be specific enough so that they do not bind to all of the mRNAs in a cell and general enough to regulate a large number of different mRNA sequences. miRNAs also directly modulate translation by impairing ribosomal function. miRNAs regulate diverse signalling pathways; those that stimulate cancer development and progression are called oncomirs. For example, miRNAs have been linked to carcinogenesis because they alter the activity of oncogenes and tumour-suppressor genes (see Chapter 10).

Epigenetics and Human Development Each of the cells in the very early embryo has the potential to give rise to a somatic cell of any type. These embryonic stem cells are therefore said to be totipotent (“possessing all powers”). A key process in early development then is the differential epigenetic modification of specific DNA nucleotide sequences in these embryonic stem cells, ultimately leading to the differential gene-expression profiles that characterize the various differentiated somatic cell types. These early modifications ensure that specific genes are expressed only in the cells and tissue types in which their gene products typically function (e.g., factor VIII expression primarily in hepatocytes, or dopamine receptor expression in neurons). Epigenetic modifications early in development also highlight a fundamental feature of genetics as compared with epigenetic information: all of the cells in a given individual contain almost exactly the same genetic information. It is the epigenetic information eventually placed on top of these sequences that enables them to achieve the diverse functions of differentiated somatic cells. A small percentage of genes, termed housekeeping genes, are necessary for the function and maintenance of all cells. These genes escape epigenetic silencing and remain transcriptionally active in all or nearly all cells. Housekeeping genes include encoding histones, DNA and RNA polymerases, and ribosomal RNA genes. How do embryonic stem cells achieve epigenetic states typical of totipotency, whereby they can give rise to all of the diverse cell types that make up a fully developed organism? One explanation is that early embryogenesis (approximately the 10 days just after fertilization) is characterized by rapid fluctuation in genome-wide DNA methylation densities. Fertilization triggers a global loss of DNA methylation at most loci in both the oocyte-contributed and the sperm-contributed genomes. This loss of methylation is accomplished in part by suppression of the DNA methyltransferases, the enzymes that add methyl groups to DNA. Methylation is not directly copied by the DNA replication process. Instead, immediately following replication, the methyltransferases read the pattern of methylation on the parent DNA strand and use that information to determine which daughter-strand cytosines should be methylated. As embryonic cell division proceeds in the absence of DNA methyltransferases, cell division continues, eventually yielding cells that have nearly all of their loci in unmethylated, transcriptionally active states. Around the time of implantation in the uterus, the DNA methyltransferases become active again, permitting establishment of the cell-lineage–specific marks required for the establishment of organ systems.

Genomic Imprinting A baby inherits two copies of each autosomal gene: one from its mother and one from its father. For a large subset of these genes, expression is biallelic, meaning that both the maternally and the paternally inherited copies contribute to offspring phenotype. For another, smaller subset of these genes, expression is stochastically monoallelic,7 meaning that the maternal copy is randomly chosen for inactivation in some somatic cells and the paternal copy is randomly chosen for inactivation in other somatic cells. For a third and smaller subset of autosomes (about 1%) either the maternal copy or the paternal copy is imprinted, meaning that either the copy inherited through the sperm or the copy inherited through the egg is inactivated and remains in this inactive state in all of the somatic cells of the individual. The subset of genes that are subject to imprinting is highly enriched for loci relevant to organismal growth. The genetic conflict hypothesis7 was developed as a potential explanation for this pattern. Although both the mother and the father benefit genetically from the birth and survival of offspring, their interests are not entirely aligned. Because a mother makes a large physiological investment in each child, it is in her evolutionary best interest to limit the flow of energetic resources to any given offspring so as to maintain her physiological capacity to bear subsequent children. By contrast, except in cases of certain permanent and monogamous relationships, it is in the best interest of the father for his child to extract maximal resources from its mother, as his own future fecundity, or fertility, is not contingent on the sustained fecundity of the mother. In general, imprinting of maternally inherited genes tends to reduce offspring size; imprinting of paternally inherited genes tends to increase offspring size. One hallmark of imprinting-associated disease is that the phenotype of affected individuals is critically dependent on whether the mutation is inherited from the mother or from the father. Some examples are included in the following syndromes.

Prader-Willi and Angelman Syndromes A well-known disease example of imprinting is associated with a deletion of about 4 million base pairs (Mb) of the long arm of chromosome 15. When this deletion is inherited from the father, the child manifests Prader-Willi syndrome, with features including short stature, hypotonia, small hands and feet, obesity, mild to moderate intellectual disability, and hypogonadism8 (Figure 3-2, A). The same 4-Mb deletion, when inherited from the mother, causes Angelman syndrome, which is characterized by severe intellectual disability, seizures, and an ataxic gait (Figure 3-2, B).9 These diseases are each observed in about 1 of every 15 000 live births; chromosome deletions are responsible for about 70% of cases of both diseases. The deletions that cause Prader-Willi and Angelman syndromes are indistinguishable at the DNA sequence level and affect the same group of genes.

FIGURE 3-2 Prader-Willi and Angelman Syndromes. A, A child with Prader-Willi syndrome (truncal obesity, small hands and feet, inverted V-shaped upper lip). B, A child with Angelman syndrome (characteristic posture, ataxic gait, bouts of uncontrolled laughter). (From Jorde, L.B., Carey, J.C., & Bamshad, M.J. [2010]. Medical genetics [4th ed.]. Philadelphia: Mosby.)

For several decades, it was unclear how the same deletion could produce such disparate results in different individuals. Further analysis showed that the 4-Mb deletion (the critical region) contains several genes that are normally transcribed only on the copy of chromosome 15 that is inherited from the father.10 These genes are transcriptionally inactive (imprinted) on the copy of chromosome 15 inherited from the mother. Similarly, other genes in the critical region are transcriptionally active only on the chromosome copy inherited from the mother and are inactive on the chromosome inherited from the father. Thus, several genes in this region are normally active on only one chromosome copy (Figure 3-3). If the single active copy of one of these genes is lost because of a chromosome deletion, then no gene product is produced, resulting in disease.

FIGURE 3-3 Prader-Willi Syndrome Pedigrees. These pedigrees illustrate the inheritance patterns of Prader-Willi syndrome (PWS), which can be caused by a deletion of about 4 million base pairs (Mb) of chromosome 15q when inherited from the father. In contrast, Angelman syndrome (AS) can be caused by the same deletion but only when it is inherited from the mother. The reason for this difference is that different genes in this region are normally imprinted (inactivated) in the copies of 15q transmitted by the mother and the father. (From Jorde, L.B., Carey, J.C., & Bamshad, M.J. [2010]. Medical genetics [4th ed.]. Philadelphia: Mosby.)

Molecular analysis has revealed much about genes in this critical region of chromosome 15.10 The gene responsible for Angelman syndrome encodes a ligase involved in protein degradation during brain

development (consistent with the intellectual disability and ataxia observed in this disorder). In brain tissue, this gene is active only on the chromosome copy inherited from the mother. Consequently, a maternally transmitted deletion removes the single active copy of this gene. Several genes in the critical region are associated with Prader-Willi syndrome, and they are transcribed only on the chromosome transmitted by the father. A paternally transmitted deletion removes the only active copies of these genes producing the features of Prader-Willi syndrome.

Beckwith-Wiedemann Syndrome Another well-known example of imprinting is Beckwith-Wiedemann syndrome, an overgrowth condition accompanied by an increased predisposition to cancer. Beckwith-Wiedemann syndrome is usually identifiable at birth because of the presence of large size for gestational age, neonatal hypoglycemia, a large tongue, creases on the earlobe, and omphalocele (birth defect of infant intestines).11 Children with Beckwith-Wiedemann syndrome have an increased risk of developing Wilms tumour or hepatoblastoma. Both of these tumours can be treated effectively if they are detected early; thus screening at regular intervals is an important part of management. Some children with Beckwith-Wiedemann syndrome also develop asymmetrical overgrowth of a limb or one side of the face or trunk (hemihyperplasia). As with Angelman syndrome, a minority of Beckwith-Wiedemann syndrome cases (about 20 to 30%) are caused by the inheritance of two copies of a chromosome from the father and no copy of the chromosome from the mother (uniparental disomy, in this case affecting chromosome 11). Several genes on the short arm of chromosome 11 are imprinted on either the paternally or the maternally transmitted chromosome. These genes are found in two separate, differentially methylated regions (DMRs). In DMR1, the gene that encodes insulinlike growth factor 2 (IGF-2) is inactive on the maternally transmitted chromosome but active on the paternally transmitted chromosome. Thus, a normal individual has only one active copy of IGF-2. When two copies of the paternal chromosome are inherited (i.e., paternal uniparental disomy) or there is loss of imprinting on the maternal copy of IGF-2, an active IGF-2 gene is present in double dose. These changes produce increased levels of IGF-2 during fetal development, contributing to the overgrowth features of Beckwith-Wiedemann syndrome. Note that, in contrast to Prader-Willi and Angelman syndromes, which are produced by a missing gene product, BeckwithWiedemann syndrome is caused, in part, by overexpression of a gene product.

Russell-Silver Syndrome Russell-Silver syndrome is characterized by delayed growth, proportionate short stature, leg length discrepancy, and a small, triangular face. About one third of Russell-Silver syndrome cases are caused by imprinting abnormalities of chromosome 11p15.5 that lead to downregulation of IGF-2 and therefore diminished growth. Another 10% of cases of Russell-Silver syndrome are caused by maternal uniparental disomy. Thus, whereas upregulation, or extra copies, of active IGF-2 causes overgrowth in BeckwithWiedemann syndrome, downregulation of IGF-2 causes the diminished growth seen in Russell-Silver syndrome.

Quick Check 3-1 1. Define epigenetics. 2. What are the three types of epigenetic mechanisms? 3. What is meant by the genetic conflict hypothesis? 4. Compare and contrast the molecular and phenotypic features of Prader-Willi and Angelman syndromes.

Inheritance of Epigenetic States It is increasingly clear that imprinted genes are not the only loci for which epigenetic modifications persist over time. Conditions encountered in utero, during childhood, and even during adolescence or later can have long-term impacts on epigenetic states, sometimes with impacts that can be transmitted across generations.12 A few such examples are discussed next.

Epigenetics and Nutrition During the winter of 1943, millions of people in urban areas of the Netherlands suffered starvation conditions as a result of a Nazi blockade that prevented shipments of food from agricultural areas. When researchers sought to investigate how exposure to famine in utero had affected individuals born in a historically prosperous country, they found individuals who suffered nutritional deprivation in utero were more likely to suffer from obesity and diabetes as adults than individuals in the Netherlands who had not experienced nutritional deprivation during gestation. There also seemed to be a transgenerational impact, in that the children of individuals who were in utero during the Dutch Hunger Winter were found to be significantly smaller than the children of those not affected by the blockade. Other data sets reveal an elevated risk for cardiovascular and metabolic disease for offspring of individuals exposed during early development to fluctuations in agricultural yields.13 The specific molecular mechanisms that may mediate these apparent relationships between nutritional deprivation and disease risk on one or more generations are largely unknown. From some animal models, it seems that the IGF-2 gene is a possible target of epigenetic modifications arising through nutritional deprivation. Exposure in utero and through lactation to some chemicals (including bisphenol A, a constituent of plastics sometimes used in food preparation and storage) seems to lead to epigenetic modifications similar to those that arise through nutritional deprivation in early life.14

Epigenetics and Maternal Care It is increasingly clear that parenting style can affect epigenetic states, and that this information can be transmitted from one generation to the next. Mice and other rodents can exhibit two alternate styles of nursing behaviour: frequent arched-back nursing with a high level of licking and grooming behaviour, and an alternate style with infrequent arched-back nursing and much reduced licking and grooming behaviour. In one especially compelling study,15 pups of mothers that engaged in frequent arched-backed nursing were found to have significantly lower methylation levels and higher transcription activity of a glucocorticoid receptor–encoding locus. Similarly, Anacker, O'Donnell, and Meaney investigated how parent–offspring interactions affect the epigenetic state and expression of genes, both in humans and nonhumans. Most of the products of these genes influence hypothalamic-pituitary-adrenal function.16 Because the glucocorticoid receptor is involved in a pathway that intensifies fearfulness and response to stress, these findings suggest that alteration to methylation states could help explain the finding that exposure to stress early in life can modulate behaviour in adulthood. These findings also highlight the concept that epigenetic processes can help store information about the environment, and that the relevant epigenetic modifications can modulate behaviour later in life.

Epigenetics and Ethanol Exposure During Gestation The impact of ethanol exposure in utero on skeletal and neural development was first reported in 197317 and led to broad awareness of fetal alcohol spectrum disorder. It was not until recently, however, that population-based and molecular-level studies began to clarify the epigenetic signals that mediate these impacts. At first, researchers found alcohol exposure in utero can affect the DNA methylation states of various genomic elements, but without specific emphasis on loci directly relevant to skeletal and neural development.11 More recently, it was found that treating cultured neural stem cells with ethanol impairs their ability to differentiate to functional neurons; this impairment seems to be correlated with aberrant, dense methylation at loci that are active in normal neuronal tissue.18 One possible explanation for these

effects is that ethanol exposure in utero modulates fetal expression of the DNA methyltransferases.19

Epigenetics and Mental Illness Researchers suggest that epigenetics also plays a role in psychiatric illness, resulting in many different phenotypes.12 Schizophrenia, major depressive disorder, and bipolar disorder are just a few examples of how epigenetic influences can alter the course of an illness. These disorders are associated with alternating remissions and relapses, and the epigenetic changes that occur demonstrate how genetic activity is altered by the interactions of the organism with its environment. These epigenetic influences are reversible and can change over time. Further research in this area is considering how the environment impacts the expression of psychiatric conditions and the possibility of understanding the effect of environmental stimuli on the course of the illness with the intention to better treat and support individuals with these conditions.

Epigenetic Disease in the Context of Genetic Abnormalities In some diseases, both genetic and epigenetic factors contribute to the origin of abnormal phenotypes. For example, several abnormal phenotypes can arise in individuals with mutations at the fragile X locus FMR1 (Figure 3-4, A). Some of these phenotypes arise in individuals for whom epigenetic changes are coincident with genetic changes. The most common genetic abnormality at FMR1 involves expansion in the number of cytosine-guanine (CG) dinucleotide repeats in the gene promoter. Females who have CG repeats in excess of the approximately 35 that are typical at this locus are at risk for fragile X–associated primary ovarian insufficiency, characterized by an elevated risk for early menopause.20 Males with moderate expansions are at risk for fragile X tremor ataxia syndrome (FXTAS), characterized by a lateonset intention tremor.21 Both of these conditions seem to arise through accumulation of excess levels of FMR1 mRNAs in nuclear inclusion bodies.20,22 Individuals with 200 repeats are at risk for fragile X syndrome, characterized by reduced IQ and a set of behavioural abnormalities. Remarkably, although possession of a large CG repeat in the FMR1 promoter dramatically increases the probability that an individual will have fragile X syndrome, the disease can be present in males who have the large repeat but be absent in their brothers who have inherited an allele of very similar size.23 This difference can be explained, at least in part, by the observation that acquisition of methylation-based silencing at FMR1 is stochastic, meaning that the presence of a large repeat increases the probability of the dense promoter methylation that could lead to gene silencing, but does not guarantee it. It remains to be seen whether dietary or environmental features can modulate the probability that dense methylation at FMR1 will accrue in individuals with the full-mutation allele.

FIGURE 3-4 Comparing the Molecular Mechanisms of Fragile X and FSHD. A, FMR1 in normal, expanded permutation, and full-mutation states. B, DUX4 in normal and contracted states. FSHD, facioscapulohumeral muscular dystrophy; mRNA, messenger RNA.

In another genetic-epigenetic disease, facioscapulohumeral muscular dystrophy (FSHD) (Figure 3-4, B), the disease phenotype arises through loss of normal methylation rather than gain of abnormal methylation. Symptoms of the disease include adverse impacts on skeletal musculature. Though lifespan is not typically reduced by the disease, wheelchair use becomes necessary late in life for a subset of individuals. The primary genetic event in FSHD is deletion of a nucleotide repeat in the DUX4 gene (see Figure 3-4, B). In normal individuals, the D4Z4 gene promoter has between 11 and 150 copies. This number is typically found to have been reduced by mutation in individuals with FSHD, who usually have only 1 to 10 such repeats. In healthy individuals with a normal-sized allele, the D4Z4 promoter typically has dense methylation. In individuals with reduced copy-counts, the normally dense methylation is lost (see Figure 3-4, B).24 The disease allele typically also has fewer repressive histone marks than does the normal allele.25 Together, fragile X syndrome and FSHD highlight that both abnormal gain and abnormal loss of epigenetic modifications can result in disease.

Twin Studies Provide Insights on Epigenetic Modification Identical (monozygotic) twin pairs, whose DNA sequences are essentially the same, offer a unique opportunity to isolate and examine the impacts of epigenetic modifications. A recent study found that as twins age, they exhibit increasingly substantial differences in methylation patterns of the DNA sequences of their somatic cells; these changes are often reflected in increasing numbers of phenotypic differences. Twins with significant lifestyle differences (e.g., smoking versus nonsmoking) tend to accumulate larger numbers of differences in their methylation patterns. These results, along with findings generated in animal studies, suggest that changes in epigenetic patterns may be an important part of the aging process26 (Figure 3-5).

FIGURE 3-5

Twins and Aging. A, Twins as babies look very much alike but, B, as adults, twins have slight differences in appearance, possibly because of epigenetics. (A, leungchophan/Shutterstock.com. B, Stacey Bates/Shutterstock.com.)

Molecular Approaches to Understand Epigenetic Disease Because epigenetic information is not encoded by DNA molecules but instead by chemical modifications to those molecules, conventional sequencing approaches are not sufficient to reveal epigenetic differences between normal individuals and those who have epigenetic modifications associated with disease. To collect information on DNA methylation states of individual nucleotides, DNA is typically subjected to bisulfite conversion before sequencing. Bisulfite treatment does not alter most nucleotides, including methylated cytosines, but deaminates unmethylated cytosines to uracil.27 Because uracil complements adenine, not guanine, methylated and unmethylated cytosines can be distinguished in resulting sequence data, so long as the genetic sequence is known. Histone modification states can be assayed through the use of antibodies specific for histones with various modifications.28

Quick Check 3-2 1. Evaluate the statement: “Epigenetic information is highly dynamic in early development.” 2. How does the epigenetic regulation of imprinted genes compare with that of the rest of the genome? 3. Compare and contrast the molecular mechanisms leading to fragile X syndrome and to FSHD. 4. Why are pairs of identical twins especially useful in the study of epigenetic phenomena?

Epigenetics and Cancer DNA Methylation and Cancer Some of the most extensive evidence for the role of epigenetic modification in human disease comes from studies of cancer (Figure 3-6).29,30 Tumour cells typically exhibit genome-wide hypomethylation (decreased methylation), which can increase the activity of oncogenes (see Chapter 10). Hypomethylation increases as tumours progress from benign neoplasms to malignancy. In addition, the promoter regions of tumour-suppressor genes are often hypermethylated, which decreases their rate of transcription and their ability to inhibit tumour formation. Hypermethylation of the promoter region of the RB1 gene is often seen in retinoblastoma31; hypermethylation of the BRCA1 gene is seen in some cases of inherited breast cancer (Chapter 33).32

FIGURE 3-6 Global Epigenomic Alterations and Cancer. Oncogenesis often occurs through a combination of genetic mutations and epigenetic change. In cancer cells, the promoters of tumour-suppressor genes typically become hypermethylated, leading, in combination with histone modifications, to abnormal gene silencing. Because tumour-suppressor genes typically help to control cell division, their silencing can result in tumour progression. Global hypomethylation leads to chromosomal instability and fragility, and increases the risk of additional genetic mutations. As well, these modifications create abnormal messenger RNA and microRNA (miRNA) expression, which leads to activation of oncogenes and silencing of tumour-suppressor genes. (Reprinted from Current Opinion in Genetics & Development, 22(1), Sandoval, J., & Esteller, M., “Cancer epigenomics: beyond genomics,” Pages 50–55, Copyright 2012, with permission from Elsevier.)

A major cause of one form of inherited colon cancer (hereditary nonpolyposis colorectal cancer [HNPCC]) is the methylation of the promoter region of a gene, MLH1, whose protein product repairs damaged DNA. When MLH1 becomes inactive, DNA damage accumulates, eventually resulting in colon tumours.33,34 Abnormal methylation of tumour-suppressor genes also is common in the progression of Barrett esophagus, a condition in which the lining of the esophagus is replaced by cells that have features associated with the lower intestinal tract, and to adenocarcinoma possibly through upregulation of one of the enzymes that adds methyl groups to DNA.35

microRNAs and Cancer Hypermethylation also is seen in miRNA genes, which encode small (22 base pair) RNA molecules that bind to the ends of mRNAs, degrading them and preventing their translation. More than 1 000 miRNA

sequences have been identified in humans, and hypermethylation of specific subgroups of miRNAs is associated with tumourigenesis. When miRNA genes are methylated, their mRNA targets are overexpressed, and this overexpression has been associated with metastasis.29

Epigenetic Screening for Cancer The common finding of epigenetic alteration in cancerous tissue raises the possibility that epigenetic screening approaches could complement or even replace existing early-detection methods. In some cases, epigenetic screening could be done using bodily fluids, such as urine or sputum, eliminating the need for the more invasive, costly, and risky strategies currently in place. Monitoring for misregulation of miRNAs has shown promise as a tool for early diagnosis of cancers of the colon,36 breast,37 and prostate.38 Other epigenetics-based screening approaches have shown promise for detection of cancers of the bladder,39 lung,40 and prostate.41

Emerging Strategies for the Treatment of Epigenetic Disease Epigenetic modifications are potentially reversible: DNA can be demethylated, histones can be modified to change the transcriptional state of nearby DNA, and miRNA-encoding loci can be upregulated or downregulated. This possibility raises the prospect for treating epigenetic disease with pharmaceutical agents that directly reverse the changes associated with the disease phenotype. In recent years, interventions involving all three types of epigenetic modulators (DNA methylation, histone modification, and miRNAs) have shown considerable promise for the treatment of disease.

DNA Demethylating Agents 5-Azacytidine has been used as a therapeutic drug in the treatment of leukemia and myelodysplastic syndrome (5-azacytosine, the active component of 5-azacytidine, is shown in Figure 3-7).42 A cytosine analogue, 5-azacytidine, is incorporated into DNA opposite its complementary nucleotide, guanine. 5Azacytidine differs from cytosine in that it has a nitrogen, rather than a carbon, in the fifth position of its cytidine ring. As a result, the DNA methyltransferases cannot add methyl groups to 5-azacytidine, and DNA that contains 5-azacytidine declines in its methylation density over successive rounds of DNA replication.43 Administration of 5-azacytidine is associated with various adverse effects, including digestive disturbance, but has shown promise in the treatment of diseases, including pancreatic cancer44 and myelodysplastic syndromes.45,46

FIGURE 3-7 5-Azacytosine as Demethylating Agent. A, Unmethylated cytosines in DNA are typically subject to the addition of methyl groups by DNMT1, a DNA methyltransferase, using methyl groups supplied by the methyl donor S-adenosylmethionine. B, In 5azacytosine, the 5′ carbon of cytosine is replaced with a nitrogen. This chemical difference is sufficient both to block the addition of a methyl group and to confer irreversible binding to DNMT1. Incorporation of 5-azacytosine into DNA is therefore sufficient to drive passive loss of methylation from replicating DNA, and thus to reactivate hypermethylated loci. 5-Azacytosine, bound to a sugar, can be integrated into DNA, and has been administered with some success in treating epigenetic diseases that arise through hypermethylation of individual loci.

Histone Deacetylase Inhibitors The activity of the histone deacetylases (HDACs) increases chromatin compaction, decreasing transcriptional activity (Figure 3-8). In many cases, excessive activity of HDACs results in transcriptional inactivation of tumour-suppressor genes, leading ultimately to the development of tumours. Treatment with HDAC inhibitors, either alone or in combination with other medications, has shown promise in the treatment of cancers of the breast47 and prostate,48 but only very limited success in the treatment of pancreatic cancer.49

FIGURE 3-8 Effect of HDAC Inhibitors on Chromatin Remodelling and Transcription. A, Levels of histone acetylation at specific lysine (K) residues are determined by concurrent reactions of acetylation (Ac) and deacetylation, which are mediated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). This histone acetylation is vital for establishing the conformational structure of DNA–chromatin complexes, and, subsequently, transcriptional gene expression. B, By blocking the deacetylation reaction, HDAC inhibitors change the equilibrium of histone acetylation levels, leading to increased acetylation, chromatin modification to relax conformation, and transcription upregulation. (Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Drug Discovery 7, 854–868 (2008).)

microRNA Coding A major challenge in developing medications that modify epigenetic alterations is to target only the genes responsible for a specific cancer. Therapeutic approaches that use miRNA offer a potential solution to this problem as treatment can be targeted to individual loci using sequence characteristics of relevant RNA molecules.

Quick Check 3-3 1. Evaluate the statement: “Cancer is, in many cases, an epigenetic disease.” 2. Describe the role of miRNAs in cancer. 3. Describe a potential strategy for the treatment of epigenetic disease. 4. Describe some of the challenges of developing pharmaceutical approaches to remedy abnormal epigenetic states.

Future Directions Robust experimental observations are clarifying the roles of epigenetic states in determining cell fates and disease phenotypes. The well-documented involvement of epigenetic abnormalities in carcinogenesis and the mounting evidence for these epigenetic changes in other common diseases (discussed in other chapters) will likely elucidate possibilities for reversing the epigenetic abnormalities and possibly preventing their establishment in utero.

Did You Understand? Epigenetic Mechanisms 1. Investigators are studying three major types of epigenetic mechanisms: (a) DNA methylation, which results from attachment of a methyl group to a cytosine; in the somatic cells, all or nearly all methylation occurs at cytosines that are followed by guanines (“CpG dinucleotides”); (b) histone modifications, through the addition of various chemical groups, including methyl and acetyl; and (c) noncoding RNAs (ncRNAs) or microRNAs (miRNAs), short nucleotides derived from introns of protein coding genes or transcribed as independent genes from regions of the genome whose functions, if any, remain poorly understood. miRNAs regulate diverse signalling pathways. 2. DNA methylation is, at present, the best-studied epigenetic process. When a gene becomes heavily methylated, the DNA is less likely to be transcribed into mRNA. 3. Methylation, along with histone hypoacetylation and condensation of chromatin, inhibits the binding of proteins that promote transcription, such that the gene becomes transcriptionally inactive. 4. Environmental factors, such as diet and exposure to certain chemicals, may cause epigenetic modification. 5. The heritable transmission to future generations of epigenetic modifications is called transgenerational inheritance.

Epigenetics and Human Development 1. Epigenetic modification alters gene expression without changes to DNA sequence. 2. Housekeeping genes are necessary for the function and maintenance of all cells, and they escape epigenetic silencing, remaining transcriptionally active in all (or nearly all) cells. 3. Fertilization triggers loss of DNA methylation and suppression of DNA methyltransferases (enzymes that add methyl groups to DNA), yielding cells that have nearly all of their loci in unmethylated and transcriptionally active states. 4. Implantation in the uterus activates the DNA methyltransferases and allows for cell-lineage– specific marks required for the development of organ systems.

Genomic Imprinting 1. Gregor Mendel's experiments with garden peas demonstrated that the phenotype is the same whether a given allele is inherited from the mother or the father. This principle, which has long been part of the central dogma of genetics, does not always hold. For some human genes, a given gene is transcriptionally active on only one copy of a chromosome (e.g., the copy inherited from the father). On the other copy of the chromosome (the one inherited from the mother) the gene is transcriptionally inactive. This process of gene silencing, in which genes are silenced depending on which parent transmits them, is known as imprinting; the transcriptionally silenced genes are said to be “imprinted.” 2. When an allele is imprinted, it typically has heavy methylation. By contrast, the nonimprinted allele is typically not methylated. 3. A well-known disease example of imprinting is associated with a deletion of about 4 million base pairs (Mb) of the long arm of chromosome 15. When this deletion is inherited from the father, the child manifests Prader-Willi syndrome. 4. The same 4-Mb deletion, when inherited from the mother, causes Angelman syndrome. 5. Another well-known example of imprinting is Beckwith-Wiedemann syndrome, an overgrowth condition accompanied by an increased predisposition to cancer.

6. Whereas upregulation, or extra copies, of active IGF-2 causes overgrowth in Beckwith-Wiedemann syndrome, downregulation of IGF-2 causes the diminished growth seen in Russell-Silver syndrome.

Inheritance of Epigenetic States 1. Events encountered in utero, in childhood, and in adolescence can result in specific epigenetic changes that yield a wide range of phenotypic abnormalities, including metabolic syndromes. 2. Fetal alcohol spectrum disorder, which results from ethanol exposure in utero, may be mediated by the repressive impact of ethanol on the DNA methyltransferases. 3. Both abnormal gain of methylation, as in the case of fragile X syndrome, and abnormal loss of methylation, as in the case of facioscapulohumeral muscular dystrophy, can produce disease phenotypes. 4. As twins age, they demonstrate increasing differences in methylation patterns of their DNA sequences, causing increasing numbers of phenotypic differences. 5. In studies of twins with significant lifestyle differences (e.g., smoking versus nonsmoking) large numbers of differences in their methylation patterns are observed to accrue over time.

Epigenetics and Cancer 1. The best evidence for epigenetic effects on human disease risk comes from studies of cancer. 2. Methylation densities decline as tumours progress, which can increase the activity of oncogenes, causing tumours to progress from benign neoplasms to malignancy. Additionally, the promoter regions of tumour-suppressor genes are often hypermethylated. These elevated methylation levels decreases their rate of transcription at these critical genes, thus reducing the ability to inhibit tumour formation. 3. Hypermethylation also is seen in miRNA genes and is associated with tumourigenesis. 4. Unlike DNA sequence mutations, epigenetic modifications can be reversed through pharmaceutical intervention. For example, 5-azacytidine, a demethylating agent, has been used as a therapeutic drug in the treatment of leukemia and myelodysplastic syndrome.

Future Directions 1. Robust experimental observations are defining the roles of epigenetic states in shaping cell fates. 2. The well-documented involvement of epigenetic abnormalities in carcinogenesis and the mounting evidence for these epigenetic changes in other common diseases (discussed throughout the text) will likely elucidate new therapies with the possibilities of reversing the epigenetic abnormalities.

Key Terms 5-Azacytidine, 70 Angelman syndrome, 65 Beckwith-Wiedemann syndrome, 65 Biallelic, 64 DNA methylation, 62 Embryonic stem cell, 64 Epigenetics, 62 Facioscapulohumeral muscular dystrophy (FHMD), 68 Fragile X, 67 Histone, 63 Histone modification, 63 Housekeeping genes, 64 Imprinted, 64 MicroRNA (miRNA), 64 Monoallelic, 64 Noncoding RNA (ncRNA), 64 Prader-Willi syndrome, 64 Russell-Silver syndrome, 66

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Altered Cellular and Tissue Biology Kathryn L. McCance, Todd Cameron Grey, Stephanie Zettel

CHAPTER OUTLINE Cellular Adaptation, 75 Atrophy, 75 Hypertrophy, 76 Hyperplasia, 77 Dysplasia: Not a True Adaptive Change, 77 Metaplasia, 78 Cellular Injury, 78 General Mechanisms of Cellular Injury, 79 Hypoxic Injury, 80 Free Radicals and Reactive Oxygen Species Injury: Oxidative Stress, 82 Chemical or Toxic Injury, 83 Unintentional and Intentional Injuries, 93 Infectious Injury, 96 Immunological and Inflammatory Injury, 96 Manifestations of Cellular Injury: Accumulations, 96 Water, 97 Lipids and Carbohydrates, 97 Glycogen, 98 Proteins, 99 Pigments, 99 Calcium, 100 Urate, 100 Systemic Manifestations, 101 Cellular Death, 101 Necrosis, 101 Apoptosis, 105 Autophagy, 106 Aging and Altered Cellular and Tissue Biology, 107 Normal Lifespan, Life Expectancy, and Quality-Adjusted Life Year, 108 Degenerative Extracellular Changes, 108 Cellular Aging, 108 Tissue and Systemic Aging, 109 Frailty, 109 Somatic Death, 109

The majority of diseases are caused by many factors acting together (i.e., multifactorial) or interacting with a genetically susceptible person. Injury to cells and their surrounding environment, called the extracellular matrix (ECM), leads to tissue and organ injury. Although the normal cell is restricted by a narrow range of structure and functions, including metabolism and specialization, it can adapt to physiological demands or stress to maintain a steady state called homeostasis. Adaptation is a reversible, structural, or functional response both to normal or physiological conditions and to adverse or pathological conditions. For example, the uterus adapts to pregnancy—a normal physiological state—by enlarging. Enlargement occurs because of an increase in the size and number of uterine cells. In an adverse condition, such as high blood pressure, myocardial cells are stimulated to enlarge by the increased work of pumping. Like most of the body's adaptive mechanisms, however, cellular adaptations to adverse conditions are usually only temporarily successful. Severe or long-term stressors overwhelm adaptive processes and cellular injury or death ensues. Altered cellular and tissue biology can result from adaptation, injury, neoplasia, accumulations, aging, or death. (Neoplasia is discussed in Chapters 10 and 11.) Knowledge of the structural and functional reactions of cells and tissues to injurious agents, including genetic defects, is vital to understanding disease processes. Cellular injury can be caused by any factor that disrupts cellular structures or deprives the cell of oxygen and nutrients required for survival. Injury may be reversible (sublethal) or irreversible (lethal) and is classified broadly as chemical, hypoxic (lack of sufficient oxygen), free radical, intentional, unintentional, immunological, infection, and inflammatory. Cellular injuries from various causes have different clinical and pathophysiological manifestations. Stresses from metabolic derangements may be associated with intracellular accumulations and include carbohydrates, proteins, and lipids. Sites of cellular death can cause accumulations of calcium resulting in pathological calcification. Cellular death is confirmed by structural changes seen when cells are stained and examined under a microscope. The two main types of cellular death are necrosis and apoptosis, and nutrient deprivation can initiate autophagy that results in cellular death. All of these pathways of cellular death are discussed later in this chapter. Cellular aging causes structural and functional changes that eventually may lead to cellular death or a decreased capacity to recover from injury. Mechanisms explaining how and why cells age are not known, and distinguishing between pathological changes and physiological changes that occur with aging is often difficult. Aging clearly causes alterations in cellular structure and function, yet senescence, growing old, is both inevitable and normal.

Cellular Adaptation Cells adapt to their environment to escape and protect themselves from injury. An adapted cell is neither normal nor injured—its condition lies somewhere between these two states. Adaptations are reversible changes in cell size, number, phenotype, metabolic activity, or functions of cells.1 Adaptive responses have limits, however, and additional cell stresses can affect essential cell function leading to cellular injury. Cellular adaptations also can be a common and central part of many disease states. In the early stages of a successful adaptive response, cells may have enhanced function; thus, it is hard to distinguish a pathological response from an extreme adaptation to an excessive functional demand. The most significant adaptive changes in cells include atrophy (decrease in cell size), hypertrophy (increase in cell size), hyperplasia (increase in cell number), and metaplasia (reversible replacement of one mature cell type by another less mature cell type or a change in the phenotype). Dysplasia (deranged cellular growth) is not considered a true cellular adaptation but rather an atypical hyperplasia. These changes are shown in Figure 4-1.

FIGURE 4-1

Adaptive and Dysplastic Alterations in Simple Cuboidal Epithelial Cells.

Atrophy Atrophy is a decrease or shrinkage in cellular size. If atrophy occurs in a sufficient number of an organ's cells, the entire organ shrinks or becomes atrophic. Atrophy can affect any organ, but it is most common in skeletal muscle, the heart, secondary sex organs, and the brain. Atrophy can be classified as physiological or pathological. Physiological atrophy occurs with early development. For example, the thymus gland undergoes physiological atrophy during childhood. Pathological atrophy occurs as a result of decreases in workload, pressure, use, blood supply, nutrition, hormonal stimulation, and nervous system stimulation (Figure 4-2). Individuals immobilized in bed for a prolonged period of time exhibit a type of skeletal muscle atrophy called disuse atrophy. Aging causes brain cells to become atrophic and endocrine-dependent organs, such as the gonads, to shrink as hormonal stimulation decreases. Whether

atrophy is caused by normal physiological conditions or by pathological conditions, atrophic cells exhibit the same basic changes.

FIGURE 4-2 Atrophy. A, Normal brain of a young adult. B, Atrophy of the brain in an 82-year-old male with atherosclerotic cerebrovascular disease, resulting in reduced blood supply. Note that loss of brain substance narrows the gyri and widens the sulci. The meninges have been stripped from the right half of each specimen to reveal the surface of the brain. (From Kumar, V., Abbas, A.K., & Aster, J.C. [Eds.]. [2015]. Robbins and Cotran pathologic basis of disease [9th ed.]. Philadelphia: Saunders.)

The atrophic muscle cell contains less endoplasmic reticulum (ER) and fewer mitochondria and myofilaments (part of the muscle fibre that controls contraction) than found in the normal cell. In muscular atrophy caused by nerve loss, oxygen consumption and amino acid uptake are immediately reduced. The mechanisms of atrophy include decreased protein synthesis, increased protein catabolism, or both. A new hypothesis includes ribosome function and its role as translation machinery or the conversion of messenger RNA (mRNA) into protein called ribosome biogenesis. Ribosome biogenesis has an important role in the regulation of skeletal muscle mass.2 The primary pathway of protein catabolism is the ubiquitin–proteasome pathway, and catabolism involves proteasomes (protein-degrading complexes). Proteins degraded in this pathway are first conjugated to ubiquitin (another small protein) and then degraded by proteasomes. An increase in proteasome activity is characteristic of atrophic muscle changes. Deregulation of this pathway often leads to abnormal cell growth and is associated with cancer and other diseases (see Chapters 3 and 10). Atrophy as a result of chronic malnutrition is often accompanied by a “self-eating” process called autophagy that creates autophagic vacuoles (see p. 75). These vacuoles are membrane-bound vesicles within the cell that contain cellular debris and hydrolytic enzymes, which function to break down substances to the simplest units of fat, carbohydrate, or protein. The levels of hydrolytic enzymes rise rapidly in atrophy. The enzymes are isolated in autophagic vacuoles to prevent uncontrolled cellular destruction. Thus the vacuoles form as needed to protect uninjured organelles from the injured organelles and are eventually engulfed and destroyed by lysosomes. Certain contents of the autophagic vacuole may resist destruction by lysosomal enzymes and persist in membrane-bound residual bodies. An example of granules that can persist and resist breakdown is granules containing lipofuscin, the yellow-brown age pigment. Lipofuscin accumulates primarily in liver cells, myocardial cells, and atrophic cells.

Hypertrophy Hypertrophy is a compensatory increase in the size of cells in response to mechanical stimuli (also called mechanical load or stress, such as from repetitive stretching, chronic pressure, or volume overload) and consequently increases the size of the affected organ (Figures 4-3 and 4-4). The cells of the heart and kidneys are particularly prone to enlargement. Hypertrophy, as an adaptive response (muscular enlargement), occurs in the striated muscle cells of both the heart and skeletal muscles. Initial cardiac enlargement is caused by dilation of the cardiac chambers, is short lived, and is followed by increased synthesis of cardiac muscle proteins, allowing muscle fibres to do more work. The increase in cellular size is associated with an increased accumulation of protein in the cellular components (plasma membrane, ER, myofilaments, mitochondria) and not with an increase in cellular fluid. Yet, individual protein pools

may expand or shrink.3 Cardiac hypertrophy involves changes in signalling and transcription factor pathways resulting in increased protein synthesis, leading to left ventricular hypertrophy (LVH). Emerging evidence suggests that the ubiquitin–proteasome system (UPS) not only attends to damaged, misfolded, or mutant proteins by protein breakdown but also may attend to cell growth eventually leading to LVH.4 With time, cardiac hypertrophy is characterized by ECM remodelling and increased growth of adult myocytes. The myocytes progressively increase in size and reach a limit beyond which no further hypertrophy can occur (see Chapter 24).5,6

FIGURE 4-3 Hypertrophy of Cardiac Muscle in Response to Valve Disease. A, Transverse slices of a normal heart and a heart with hypertrophy of the left ventricle (L, normal thickness of left ventricular wall; T, thickened wall from heart in which severe narrowing of aortic valve caused resistance to systolic ventricular emptying). B, Histology of cardiac muscle from the normal heart. C, Histology of cardiac muscle from a hypertrophied heart. (From Stevens, A., & Lowe, J. [2000]. Pathology: Illustrated review in color [2nd ed.]. Edinburgh: Mosby.)

FIGURE 4-4 Mechanisms of Myocardial Hypertrophy. Mechanical sensors appear to be the main stimulators for physiological hypertrophy. Other stimuli possibly more important for pathological hypertrophy include agonists (initiators) and growth factors. These factors then signal transcription pathways whereby transcription factors then bind to DNA sequences, activating muscle proteins that are responsible for hypertrophy. These pathways include induction of embryonic/fetal genes, increased synthesis of contractile proteins, and production of growth factors. ANF, atrial natriuretic factor; IGF-1, insulinlike growth factor 1; NFAT, nuclear factor of activated T-cells; MEF2, myocyte enhancer factor-2. (Adapted from Kumar, V., Abbas, A.K., & Aster, J.C. [Eds.]. [2015]. Robbins and Cotran pathologic basis of disease [9th ed.]. Philadelphia: Saunders.)

Although hypertrophy can be classified as physiological or pathological, time may be the critical factor or determinant of the transition from physiological to pathological cardiac hypertrophy. With physiological hypertrophy, preservation of myocardial structure characterizes postnatal development, moderate endurance exercise training, pregnancy, and the early phases of increased pressure and volume loading on the adult human heart. This physiological response is temporary; however, aging, strenuous exercise, and sustained workload or stress lead to pathological hypertrophy with structural and functional

manifestations. Pathological hypertrophy in the heart is secondary to hypertension, coronary heart disease, or problem valves and is presumably a key risk factor for heart failure. Additionally, it is associated with increased interstitial fibrosis, cellular death, and abnormal cardiac function (see Figure 4-3). Historically, the progression of pathological cardiac hypertrophy has been considered irreversible. However, emerging data from experimental studies and clinical observations show reversal of pathological cardiac hypertrophy in certain cases. Cardiac hypertrophy can be reversed when the increased wall stress is normalized, a process termed regression.7 For example, unloading of hemodynamic stress by a left ventricular assist device (used in individuals with heart failure for bridging to heart transplantation) induces regression of cardiac hypertrophy and improvement of left ventricular function in those with end-stage heart failure.8 Regression of cardiac hypertrophy is accompanied by activation of unique sets of genes, including fetal-type genes and those involved in protein degradation.9,10 However, the signalling mechanisms mediating regression of cardiac hypertrophy have been poorly understood. Improvement in new blood vessel development (angiogenesis) in the hypertrophic heart can lead to regression of the hypertrophy and prevention of heart failure.11,12 In mice, dietary supplementation of physiologically relevant levels of copper can reverse pathological cardiac hypertrophy.12,13 When a diseased kidney is removed, the remaining kidney adapts to the increased workload with an increase in both the size and the number of cells. The major contributing factor to this renal enlargement is hypertrophy. Another example of normal or physiological hypertrophy is the increased growth of the uterus and mammary glands in response to pregnancy.

Hyperplasia Hyperplasia is an increase in the number of cells, resulting from an increased rate of cellular division. Hyperplasia, as a response to injury, occurs when the injury has been severe and prolonged enough to have caused cellular death. Loss of epithelial cells and cells of the liver and kidney triggers deoxyribonucleic acid (DNA) synthesis and mitotic division. Increased cell growth is a multistep process involving the production of growth factors, which stimulate the remaining cells to synthesize new cell components and, ultimately, to divide. Hyperplasia and hypertrophy often occur together, and both take place if the cells can synthesize DNA. Two types of normal, or physiological, hyperplasia are compensatory hyperplasia and hormonal hyperplasia. Compensatory hyperplasia is an adaptive mechanism that enables certain organs to regenerate. For example, removal of part of the liver leads to hyperplasia of the remaining liver cells (hepatocytes) to compensate for the loss. Even with removal of 70% of the liver, regeneration is complete in about 2 weeks. Several growth factors and cytokines (chemical messengers) are induced and play critical roles in liver regeneration. Not all types of mature cells have the same capacity for compensatory hyperplastic growth. Nondividing tissues contain cells that can no longer (i.e., postnatally) go through the cell cycle and undergo mitotic division. These highly specialized cells, for example, neurons and skeletal muscle cells, never divide again once they have differentiated—that is, they are terminally differentiated.14 In human cells, cell growth and cell division depend on signals from other cells; but cell growth, unlike cell division, does not depend on the cell-cycle control system.14 Nerve cells and most muscle cells do most of their growing after they have terminally differentiated and permanently ceased dividing.14 Significant compensatory hyperplasia occurs in epidermal and intestinal epithelia, hepatocytes, bone marrow cells, and fibroblasts; and some hyperplasia is noted in bone, cartilage, and smooth muscle cells. Another example of compensatory hyperplasia is the callus, or thickening, of the skin as a result of hyperplasia of epidermal cells in response to a mechanical stimulus. Hormonal hyperplasia occurs chiefly in estrogen-dependent organs, such as the uterus and breast. After ovulation, for example, estrogen stimulates the endometrium to grow and thicken in preparation for receiving the fertilized ovum. If pregnancy occurs, hormonal hyperplasia, as well as hypertrophy, enables the uterus to enlarge. (Hormone function is described in Chapters 19 and 33.) Pathological hyperplasia is the abnormal proliferation of normal cells, usually in response to excessive hormonal stimulation or growth factors on target cells (Figure 4-5). The most common example is pathological hyperplasia of the endometrium (caused by an imbalance between estrogen and progesterone secretion, with oversecretion of estrogen) (see Chapter 33). Pathological endometrial

hyperplasia, which causes excessive menstrual bleeding, is under the influence of regular growthinhibition controls. If these controls fail, hyperplastic endometrial cells can undergo malignant transformation. Benign prostatic hyperplasia is another example of pathological hyperplasia and results from changes in hormone balance. In both of these examples, if the hormonal imbalance is corrected, hyperplasia regresses.1

FIGURE 4-5 Hyperplasia of the Prostate with Secondary Thickening of the Obstructed Urinary Bladder (Bladder Cross-Section). The enlarged prostate is seen protruding into the lumen of the bladder, which appears trabeculated. These “trabeculae” result from hypertrophy and hyperplasia of smooth muscle cells that occur in response to increased intravesical pressure caused by urinary obstruction. (From Damjanov, I. [2012]. Pathology for the health professions [4th ed.]. St. Louis: Saunders.)

Dysplasia: Not a True Adaptive Change Dysplasia refers to abnormal changes in the size, shape, and organization of mature cells (Figure 4-6). Dysplasia is not considered a true adaptive process but is related to hyperplasia and is often called atypical hyperplasia. Dysplastic changes often are encountered in epithelial tissue of the cervix and respiratory tract, where they are strongly associated with common neoplastic growths and often are found adjacent to cancerous cells. Importantly, however, the term dysplasia does not indicate cancer and may not progress to cancer. Dysplasia is often classified as mild, moderate, or severe; yet, because this classification scheme is somewhat subjective, it has prompted some to recommend the use of either “low grade” or “high grade” instead. If the inciting stimulus is removed, dysplastic changes often are reversible. (Dysplasia is discussed further in Chapter 10.)

FIGURE 4-6

Dysplasia of the Uterine Cervix. A, Mild dysplasia. B, Severe dysplasia. (From Damjanov, I., & Linder, J. [1996]. Anderson's pathology [10th ed.]. St. Louis: Mosby.)

Metaplasia Metaplasia is the reversible replacement of one mature cell type (epithelial or mesenchymal) by another, sometimes less differentiated, cell type. It is thought to develop (as an adaptive response better suited to withstand the adverse environment) from a reprogramming of stem cells that exist on most epithelia or of undifferentiated mesenchymal (tissue from embryonic mesoderm) cells present in connective tissue. These precursor cells mature along a new pathway because of signals generated by growth factors in the cell's environment. The best example of metaplasia is replacement of normal columnar ciliated epithelial cells of the bronchial (airway) lining by stratified squamous epithelial cells (Figure 4-7). The newly formed cells do not secrete mucus or have cilia, causing loss of a vital protective mechanism. Bronchial metaplasia can be reversed if the inducing stimulus, usually cigarette smoking, is removed. With prolonged exposure to the inducing stimulus, however, dysplasia and cancerous transformation can occur.

FIGURE 4-7

Reversible Changes in Cells Lining the Bronchi.

Cellular Injury Injury to cells and to the ECM leads to injury of tissues and organs, ultimately determining the structural patterns of disease. Loss of function is derived from cell and ECM injury and cellular death. Cellular injury occurs if the cell is unable to maintain homeostasis—a normal or adaptive steady state—in the face of injurious stimuli or stress. Injured cells may recover (reversible injury) or die (irreversible injury). Injurious stimuli include chemical agents, lack of sufficient oxygen (hypoxia), free radicals, infectious agents, physical and mechanical factors, immunological reactions, genetic factors, and nutritional imbalances. Types of injuries and their responses are summarized in Table 4-1 and Figure 4-8. TABLE 4-1 Types of Progressive Cellular Injury and Responses Type

Responses

Adaptation Active cellular injury Reversible Irreversible Necrosis Apoptosis, or programmed cellular death Autophagy Chronic cellular injury (subcellular alterations) Accumulations or infiltrations Pathological calcification

Atrophy, hypertrophy, hyperplasia, metaplasia Immediate response of “entire” cell Loss of ATP, cellular swelling, detachment of ribosomes, autophagy of lysosomes “Point of no return” structurally when severe vacuolization of mitochondria occurs and Ca++ moves into cell Common type of cellular death with severe cell swelling and breakdown of organelles Cellular self-destruction for elimination of unwanted cell populations Eating of self, cytoplasmic vesicles engulf cytoplasm and organelles, recycling factory Persistent stimuli response may involve only specific organelles or cytoskeleton (e.g., phagocytosis of bacteria) Water, pigments, lipids, glycogen, proteins Dystrophic and metastatic calcification

ATP, adenosine triphosphate; Ca++, calcium.

FIGURE 4-8 Stages of Cellular Adaptation, Injury, and Death. The normal cell responds to physiological and pathological stresses by adapting (atrophy, hypertrophy, hyperplasia, metaplasia). Cellular injury occurs if the adaptive responses are exceeded or compromised by injurious agents, stress, and mutations. The injury is reversible if it is mild or transient, but if the stimulus persists, the cell suffers irreversible injury and eventually death.

The extent of cellular injury depends on the type, state (including level of cell differentiation and increased susceptibility to fully differentiated cells), and adaptive processes of the cell, as well as the type, severity, and duration of the injurious stimulus. Two individuals exposed to an identical stimulus may incur varying degrees of cellular injury. Modifying factors, such as nutritional status, can profoundly influence the extent of injury. The precise “point of no return” that leads to cellular death is a biochemical puzzle, but once changes to the nucleus occur and cell membranes are disrupted, the cell moves to irreversible injury and death.

General Mechanisms of Cellular Injury

Common biochemical themes are important to understanding cellular injury and cellular death, regardless of the injuring agent. These include adenosine triphosphate (ATP) depletion, mitochondrial damage, oxygen and oxygen-derived free radical membrane damage (depletion of ATP), protein folding defects, DNA damage defects, and calcium-level alterations (Table 4-2). Examples of common forms of cellular injury are (1) hypoxic injury, (2) free radicals and reactive oxygen species injury, and (3) chemical injury. TABLE 4-2 Common Themes in Cellular Injury and Cellular Death Theme

Comments

ATP depletion

Loss of mitochondrial ATP and decreased ATP synthesis; results include cellular swelling, decreased protein synthesis, decreased membrane transport, and lipogenesis, all changes that contribute to loss of integrity of plasma membrane Lack of oxygen is key in progression of cellular injury in ischemia (reduced blood supply); activated oxygen species (ROS, , H O , •OH) cause destruction of cell

Reactive oxygen species (↑ROS) Ca++ entry Mitochondrial damage Membrane damage Protein misfolding, DNA damage

2

2

membranes and cell structure Normally intracellular cytosolic calcium concentrations are very low; ischemia and certain chemicals cause an increase in cytosolic Ca++ concentrations; sustained levels of Ca++ continue to increase with damage to plasma membrane; Ca++ causes intracellular damage by activating a number of enzymes Can be damaged by increases in cytosolic Ca++, ROS; two outcomes of mitochondrial damage are loss of membrane potential, which causes depletion of ATP and eventual death or necrosis of cell, and activation of another type of cellular death (apoptosis) (see p. 105) Early loss of selective membrane permeability found in all forms of cellular injury, lysosomal membrane damage with release of enzymes causing cellular digestion Proteins may misfold, triggering unfolded protein response that activates corrective responses; if overwhelmed, response activates cell suicide program or apoptosis; DNA damage (genotoxic stress) also can activate apoptosis (see p. 105)

ATP, adenosine triphosphate; Ca++, calcium.

Hypoxic Injury Hypoxia, or lack of sufficient oxygen within cells, is the single most common cause of cellular injury (Figure 4-9). Hypoxia can result from a reduced amount of oxygen in the air, loss of hemoglobin or decreased efficacy of hemoglobin, decreased production of red blood cells, diseases of the respiratory and cardiovascular systems, and poisoning of the oxidative enzymes (cytochromes) within the cells. Hypoxia plays a role in physiological processes including cell differentiation, angiogenesis, proliferation, erythropoiesis, and overall cell viability.15 The main consumers of oxygen are mitochondria, and the cellular responses to hypoxia are reported to be mediated by the production of reactive oxygen species (ROS) at the mitochondrial complex III.15 Investigators are studying the role of ROS as hypoxia signalling molecules. More commonly, hypoxia is associated with the pathophysiological conditions such as inflammation, ischemia, and cancer. Hypoxia can induce inflammation, and inflamed lesions can become hypoxic (Figure 4-10).16 The cellular mechanisms involved in hypoxia and inflammation are emerging and include activation of immune responses and oxygen-sensing compounds called prolyl hydroxylases (PHDs) and hypoxia-inducible transcription factor (HIF). HIF is a family of transcription regulators that coordinate the expression of many genes in response to oxygen deprivation. Mammalian development occurs in a hypoxic environment.17 Hypoxia-induced signalling involves complicated crosstalk between hypoxia and inflammation, linking hypoxia and inflammation to inflammatory bowel disease, certain cancers, and infections.16 Research is ongoing to understand the mechanisms of how tumours adapt to low oxygen levels by inducing angiogenesis, increasing glucose consumption, and promoting the metabolic state of glycolysis (see Chapter 10).18

FIGURE 4-9 Hypoxic Injury Induced by Ischemia. A, Consequences of decreased oxygen delivery or ischemia with decreased adenosine triphosphate (ATP). The structural and physiological changes are reversible if oxygen (H2O) is delivered quickly. Significant decreases in ATP result in cellular death, mostly by necrosis. B, Mitochondrial damage can result in changes in membrane permeability, loss of membrane potential, and decrease in ATP concentration. Between the outer and inner membranes of the mitochondria are proteins that can activate the cell's suicide pathways, called apoptosis. C, Calcium ions (Ca++) are critical mediators of cellular injury. Ca++ are usually maintained at low concentrations in the cell's cytoplasm; thus ischemia and certain toxins can initially cause an increase in the release of Ca++ from intracellular stores and later an increased movement (influx) across the plasma membrane. (Adapted from Kumar, V., Abbas, A.K., & Aster, J.C. [Eds.]. [2015]. Robbins and Cotran pathologic basis of disease [9th ed.]. Philadelphia: Saunders.)

FIGURE 4-10 Hypoxia and Inflammation. Shown is a simplified drawing of clinical conditions characterized by tissue hypoxia that causes inflammatory changes (left) and inflammatory diseases that ultimately lead to hypoxia (right). These diseases and conditions are discussed in more detail in their respective chapters. (From The New England Journal of Medicine, Holger K. Eltzschig, Peter Carmeliet, “Hypoxia and Inflammation,” 364:656–665. Copyright © 2011 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)

The most common cause of hypoxia is ischemia (reduced blood supply). Ischemic injury often is caused by the gradual narrowing of arteries (arteriosclerosis) or complete blockage by blood clots (thrombosis) or both. Progressive hypoxia caused by gradual arterial obstruction is better tolerated than the acute anoxia (total lack of oxygen) caused by a sudden obstruction, as with an embolus (a blood clot or other blockage in the circulation). An acute obstruction in a coronary artery can cause myocardial cellular death (infarction) within minutes if the blood supply is not restored, whereas the gradual onset of ischemia usually results in myocardial adaptation. Myocardial infarction and stroke, which are common causes of death in North America, generally result from atherosclerosis (a type of arteriosclerosis) and consequent ischemic injury. (Vascular obstruction is discussed in Chapter 24.) Cellular responses to hypoxic injury caused by ischemia have been demonstrated in studies of the heart muscle. Within 1 minute after blood supply to the myocardium is interrupted, the heart becomes pale and has difficulty contracting normally. Within 3 to 5 minutes, the ischemic portion of the myocardium ceases to contract because of a rapid decrease in mitochondrial phosphorylation, causing insufficient ATP production. Lack of ATP leads to increased anaerobic metabolism, which generates ATP from glycogen when there is insufficient oxygen. When glycogen stores are depleted, even anaerobic metabolism ceases. A reduction in ATP levels causes the plasma membrane's sodium–potassium (Na+–K+) pump and sodium–calcium exchange mechanism to fail, which leads to an intracellular accumulation of sodium and calcium and diffusion of potassium out of the cell. Sodium and water then can enter the cell freely, and cellular swelling, as well as early dilation of the ER, results. Dilation causes the ribosomes to detach from the rough ER, reducing protein synthesis. With continued hypoxia, the entire cell becomes markedly swollen, with increased concentrations of sodium, water, and chloride and decreased concentrations of

potassium. These disruptions are reversible if oxygen is restored. If oxygen is not restored, however, vacuolation (formation of vacuoles) occurs within the cytoplasm, and swelling of lysosomes and marked mitochondrial swelling result from damage to the outer membrane. Continued hypoxic injury with accumulation of calcium subsequently activates multiple enzyme systems, resulting in membrane damage, cytoskeleton disruption, DNA and chromatin degradation, ATP depletion, and eventual cellular death (Figure 4-9, C). Structurally, with plasma membrane damage, extracellular calcium readily moves into the cell and intracellular calcium stores are released. Increased intracellular calcium levels activate cell enzymes (caspases) that promote cellular death by apoptosis. Persistent ischemia is associated with irreversible injury and necrosis. Irreversible injury is associated structurally with severe swelling of the mitochondria, severe damage to plasma membranes, and swelling of lysosomes. Overall, death is mainly by necrosis but apoptosis also contributes.1 Restoration of blood flow and oxygen, however, can cause additional injury called ischemiareperfusion injury (Figure 4-11). Ischemia-reperfusion injury is very important clinically because it is associated with tissue damage during myocardial and cerebral infarction. Several mechanisms are now proposed for ischemia-reperfusion injury and include the following:

FIGURE 4-11 Reperfusion Injury. Without oxygen, or anoxia, the cells display hypoxic injury and become swollen. With reoxygenation, reperfusion injury increases because of the formation of reactive oxygen radicals that can cause cell necrosis. (JOURNAL OF CLINICAL INVESTIGATION. ONLINE by AMERICAN SOCIETY FOR CLINICAL INVESTIGATION. Reproduced with permission of AMERICAN SOCIETY FOR CLINICAL INVESTIGATION in the format Republish in a book via Copyright Clearance Center.)

• Oxidative stress—Reoxygenation causes the increased generation of ROS and nitrogen species.1 Highly reactive oxygen intermediates (oxidative stress) generated include hydroxyl radical (OH−), superoxide radical ( ), and hydrogen peroxide (H2O2). The nitrogen species include nitric oxide (NO) generated by endothelial cells, macrophages, neurons, and other cells. These radicals can all cause further membrane damage and mitochondrial calcium overload. The white blood cells (neutrophils) are especially affected with reperfusion injury, including neutrophil adhesion to the endothelium. Antioxidant treatment not only

reverses neutrophil adhesion but also can reverse neutrophil-mediated heart injury. In one study of individuals undergoing elective percutaneous coronary intervention (PCI), pretreatment with vitamin C was associated with less myocardial injury.19 The PREVEC Trial (prevention of reperfusion damage associated with percutaneous coronary angioplasty following acute myocardial infarction) seeks to evaluate whether vitamins C and E reduce infarct size in patients subjected to percutaneous coronary angioplasty after acute myocardial infarction.20 • Increased intracellular calcium concentration—Intracellular and mitochondrial calcium overload the cell; this process begins during acute ischemia. Reperfusion causes even more calcium influx because of cell membrane damage and ROS-induced injury to the sarcoplasmic reticulum. The increased calcium increases mitochondrial permeability, eventually leading to depletion of ATP and further cellular injury. • Inflammation—Ischemic injury increases inflammation because danger signals (from cytokines) are released by resident immune cells when cells die and this signalling initiates inflammation. • Complement activation—The activation of complement may increase the tissue damage from reperfusion-ischemia injury.1 Quick Check 4-1 1. When does a cell become irreversibly injured? 2. Describe the pathogenesis of hypoxic injury. 3. What are the mechanisms of ischemia-reperfusion injury?

Free Radicals and Reactive Oxygen Species Injury: Oxidative Stress An important mechanism of cellular injury is injury induced by free radicals, especially by ROS; this form of injury is called oxidative stress. Oxidative stress occurs when excess ROS overwhelm endogenous antioxidant systems. A free radical is an electrically uncharged atom or group of atoms that has an unpaired electron. Having one unpaired electron makes the molecule unstable; the molecule becomes stabilized by either donating or accepting an electron from another molecule. When the attacked molecule loses its electron, it becomes a free radical. Therefore it is capable of injurious chemical bond formation with proteins, lipids, and carbohydrates—key molecules in membranes and nucleic acids. Free radicals are difficult to control and initiate chain reactions. They are highly reactive because they have low chemical specificity, meaning that they can react with most molecules in their proximity. Oxidative stress can activate several intracellular signalling pathways because ROS can modulate enzymes and transcription factors. Oxidative stress is an important mechanism of cell damage in many conditions, including chemical and radiation injury, ischemia-reperfusion injury, cellular aging, and microbial killing by phagocytes, particularly neutrophils and macrophages.1 Free radicals may be generated within cells, first by the reduction–oxidation reactions (redox reactions) in normal metabolic processes such as respiration. Under normal physiological conditions, ROS serve as

“redox messengers” in the regulation of intracellular signalling; however, excess ROS may produce irreversible damage to cellular components. All biological membranes contain redox systems, which also are important for cell defence (e.g., inflammation, iron uptake, growth and proliferation, and signal transduction). Second, absorption of extreme energy sources (e.g., ultraviolet light, radiation) produces free radicals. Third, enzymatic metabolism of exogenous chemicals or medications (e.g., , a product of carbon tetrachloride [CCl4]) results in the formation of free radicals. Fourth, transition metals (i.e., iron and copper) donate or accept free electrons during intracellular reactions and activate the formation of free radicals such as in the Fenton reaction (i.e., when they react with H2O2 to create hydroxyl ions and water). Finally, NO is an important colourless gas that is an intermediate in many reactions generated by endothelial cells, neurons, macrophages, and other cell types. NO can act as a free radical and can be converted to highly reactive peroxynitrite anion (ONOO−), nitrogen dioxide (NO2), and nitrate ( ). Table 4-3 describes the most significant free radicals. TABLE 4-3 Free Radicals as Contributors to Oxidative Stress Name

Formula

Characteristics

Hyperoxide/superoxide

•O − 2

Highly unstable, signalling function, synaptic plasticity

Hydrogen peroxide

H2O2

Cell toxicity, signalling function, generation of other reactive oxygen species

Hydroxyl radical Alkoxyl radical Peroxyl radical Hypochlorite anion Singlet oxygen

•OH

OCl− 1O 2

Free radical, highly unstable, very reactive agent Free radical, reaction product of lipids Free radical, reaction product of lipids Reactive oxygen species, reactive chlorine species, enzymatically generated by myeloperoxidase Induced/excited oxygen molecule, radical and nonradical form

Ozone

O3

Environmental toxin

Nitric oxide Peroxynitrite anion

•NO

ONOO−

Environmental toxin, endogenous signal molecule Highly reactive reaction intermediate of •O2 and •NO

Nitrogen dioxide

•NO 2

Highly reactive radical, environmental toxin

Nitrogen oxides

NOx

Environmental toxins, including NO and •NO2, derived from the combustion process

RO• ROO•

From Domej, W., Oettl, K., & Renner, W. (2014). Int J Chron Obstruct Pulmon Dis, 9(1), 1207–1224, Table 1. International Journal of Chronic Obstructive Pulmonary Disease by DOVE Medical Press. Reproduced with permission of DOVE Medical Press in the format Republish in a book via Copyright Clearance Center.

Free radicals cause several damaging effects by (1) lipid peroxidation, which is the destruction of polyunsaturated lipids (the same process by which fats become rancid), leading to membrane damage and increased permeability; (2) protein alterations, causing fragmentation of polypeptide chains that can lead to loss and protein misfolding; and (3) DNA damage, causing mutations (Figure 4-12). Because of the increased understanding of free radicals, a growing number of diseases and disorders have been linked either directly or indirectly to these reactive species (Box 4-1).

FIGURE 4-12

The Role of Reactive Oxygen Species in Cellular Injury. The production of reactive oxygen species (ROS) can be initiated

by many cell stressors, such as radiation, toxins, and reperfusion of oxygen. Free radicals are removed by normal decay and enzymatic systems. ROS accumulates in cells because of insufficient removal or excess production leading to cellular injury, including lipid peroxidation, protein modifications, and DNA damage or mutations. SOD, superoxide dismutase. (Adapted from Kumar, V., Abbas, A.K., & Aster, J.C. [Eds.]. [2015]. Robbins and Cotran pathologic basis of disease [9th ed.]. Philadelphia: Saunders.)

Box 4-1

Diseases and Disorders Linked to Oxygen-Derived Free Radicals Deterioration noted in aging Atherosclerosis Ischemic brain injury Alzheimer's disease Neurotoxins Cancer Cardiac myopathy Chronic granulomatous disease Diabetes mellitus Eye disorders Macular degeneration Cataracts Inflammatory disorders Iron overload Lung disorders Asbestosis Oxygen toxicity Emphysema Nutritional deficiencies Radiation injury Reperfusion injury Rheumatoid arthritis Skin disorders Toxic states Xenobiotics (CCl4, paraquat, cigarette smoke, etc.) Metal irons (Ni, Cu, Fe, etc.) The body can eliminate free radicals. The oxygen free radical superoxide may spontaneously decay into oxygen and hydrogen peroxide. Table 4-4 summarizes other methods that contribute to inactivation or termination of free radicals. The toxicity of certain medications and chemicals can be attributed either to conversion of these chemicals to free radicals or to the formation of oxygen-derived metabolites (see the following discussion). TABLE 4-4 Methods Contributing to Inactivation or Termination of Free Radicals Method Process Antioxidants Endogenous or exogenous; either blocks synthesis or inactivates (e.g., scavenges) free radicals; includes vitamin E, vitamin C, cysteine, glutathione, albumin, ceruloplasmin, transferrin, γ-lipoacid, others Enzymes Superoxide dismutase,a which converts superoxide to hydrogen peroxide (H2O2); catalasea (in peroxisomes) decomposes H2O2; glutathione peroxidasea decomposes hydroxyl radical (OH-) and H2O2 a

These enzymes are important in modulating the cellular destructive effects of free radicals, also released in inflammation.

Mitochondrial Effects Mitochondria are key players in cellular injury and cellular death because they produce ATP, or lifesustaining energy. Mitochondria can be damaged by ROS and by increases of cytosolic calcium ion (Ca++) concentration (see Figure 4-9). Box 4-2 summarizes the three major types and consequences of mitochondrial damage. Currently, investigators are trying to identify the polypeptides (i.e., proteomes) directly involved in diseases associated with mitochondrial dysfunction. ROS not only damage proteins and mitochondria but also can promote damage in neighbouring cells. An important area of research emphasis is that protein aggregates can increase mitochondrial damage and damaged mitochondria can further induce protein damage, thus resulting in neuro-degeneration. An emerging area of research concerns mitochondrial DNA that escapes from autophagy, which may be a mechanism of tissue inflammation.21

Box 4-2

Three Major Types and Consequences of Mitochondrial Damage 1. Damage to the mitochondria results in the formation of the mitochondrial permeability transition pore, a high-conductance channel or pore. The opening of this channel results in the loss of mitochondrial membrane potential, causing failure of oxidative phosphorylation, depletion of adenosine triphosphate, and damage to mitochondrial DNA, leading to necrosis of the cell. 2. Altered oxidative phosphorylation leads to the formation of reactive oxygen species that can damage cellular components. 3. Because mitochondria store several proteins between their membranes, increased permeability of the outer membrane may result in leakage of pro-apoptotic proteins and cause cellular death by apoptosis. Data from Kumar, V., Abbas, A.K., & Aster, J.C. (Eds.). (2015). Robbins and Cotran pathologic basis of disease (9th ed.). Philadelphia: Saunders.

Chemical or Toxic Injury Mechanisms Humans are constantly exposed to a variety of compounds termed xenobiotics (Greek xenos, “foreign”; bios, “life”) that include toxic, mutagenic, and carcinogenic chemicals (Figure 4-13). Some of these chemicals are found in the human diet, for example, fungal mycotoxins such as aflatoxin B1. Many xenobiotics are toxic to the liver (hepatotoxic). The liver is the initial site of contact for many ingested xenobiotics, medications, and alcohol, making this organ most susceptible to chemically induced injury. The toxicity of many chemicals results from absorption through the gastro-intestinal tract after oral ingestion. A main cause for withdrawing medications from the market is hepatotoxicity. Certain dietary supplements (e.g., chaparral and ma huang) are potent hepatotoxins.22 Other common routes of exposure for xenobiotics are absorption through the skin and inhalation. The severity of chemically induced liver injury varies from minor liver injury to acute liver failure, cirrhosis, and liver cancer.23

FIGURE 4-13 Human Exposure to Pollutants. Pollutants contained in air, water, and soil are absorbed through the lungs, gastrointestinal (GI) tract, and skin. In the body, the pollutants may act at the site of absorption but are generally transported through the bloodstream to various organs where they can be stored or metabolized. Metabolism of xenobiotics may result in the formation of watersoluble compounds that are excreted, or a toxic metabolite may be created by activation of the agent. (From Kumar, V., Abbas, A.K., & Aster, J.C. [Eds.]. [2015]. Robbins and Cotran pathologic basis of disease [9th ed.]. Philadelphia: Saunders.)

The use of a systems biology approach includes delineation of toxicity pathways that may be defined as cellular response pathways, which when disturbed are expected to result in adverse health effects. Using this model of testing, investigators proposed screening and classifying compounds using a “cellular stress response pathway.” Components or mechanisms of these pathways include oxidative stress, heat shock response, DNA damage response, hypoxia, ER stress (see Chapter 1), mental stress, inflammation, and osmotic stress. Many chemicals have already been classified under these mechanisms. The liver as the principal site for xenobiotic metabolism, called biotransformation, converts the lipophilic xenobiotics to more hydrophilic forms for efficient excretion. Biotransformation, however, also can produce short-lived unstable highly reactive chemical intermediates that can lead to adverse effects.24 These harmful intermediates, classified and catalogued, are called toxicophores. The intermediates include electrophiles, nucleophiles, free radicals, and redox-active reactants. Electrophiles (electron lovers) are atoms or molecules attracted to electrons and accept a pair of electrons to make a covalent bond. This process creates a partially or fully charged centre in electrophilic molecules.24 A nucleophile is an atom or molecule that donates an electron pair to an electrophile to make a chemical bond. All chemical species with a free pair of electrons can act as nucleophiles. Nucleophiles are strongly attracted to positively charged regions in other chemicals and can be oxidized to free radicals and electrophiles.24 In general, the majority of all reactive chemical species are electrophilic because the formation of nucleophiles is rare24. The generation of these excess reactive chemical species leads to molecular damage in liver cells. These reactive intermediates can interact with cellular macromolecules (such as proteins and DNA), can covalently bind to proteins and form protein adducts (chemical bound to protein) and DNA adducts, or can react directly with cell structures to cause cell damage.25 Adduct formation can lead to adverse conditions including disruption in protein function, excess formation of fibrous connective tissue

(fibrogenesis), and activation of immune responses.24 The identity of proteins modified by xenobiotics can be found in the resource known as the reactive metabolite target protein database.26 The body has two major defence systems for counteracting these effects: (1) detoxification enzymes and their cofactors and (2) antioxidant systems. Phases of detoxification include phase I enzymes, such as cytochrome P-450 (CYP) oxidases, which are the most important oxidative reactions. Other phase I detoxification enzymes include those for reduction and hydrolysis. In phase II detoxification, conjugation enzymes, such as glutathione (GSH), detoxify reactive electrophiles and produce polar metabolites that cannot diffuse across membranes. Most conjugation enzymes are located in the cytosol. Phase III detoxification is often called the efflux transporter system because enzymes remove the parent medications, metabolites, and xenobiotics from cells. The liver has the highest supply of biotransformation enzymes of all organs and, therefore, has the key role in protection from chemical toxicity.24 Figure 4-14 is a summary of chemically induced liver injury.

FIGURE 4-14 Chemical Liver Injury. Liver injury is a result of genetic, environmental, biological, and dietary factors. Certain chemicals can form toxic or chemically reactive metabolites. The risk of liver injury also can increase with increasing doses of a toxicant. Xenobiotic enzyme induction can lead to altered metabolism of chemicals, and medications can either inhibit or induce medication-metabolizing enzymes. These changes can lead to greater toxicity. The dose at the site of action is controlled by the Phase I to III xenobiotic metabolites, and metabolizing enzymes are encoded by numerous different genes. Therefore, the metabolism and toxicity outcomes can vary greatly among individuals. Additionally, all aspects of xenobiotic metabolism are regulated by certain transcription factors (cellular mediators of gene regulation). Overall, the extent of cell damage depends on the balance between reactive chemical species and protective responses aimed at decreasing oxidative stress, repairing macromolecular damage, or preserving cell health by inducing apoptosis or cellular death. Significant clinical outcomes of chemical-induced liver injury occur with necrosis and the immune response. Covalent binding of reactive metabolites to cellular proteins can produce new antigens (haptens) that initiate autoantibody production and T-cytotoxic cell responses. Necrosis, a form of cellular death, can result from extensive damage to the plasma membrane with altered ion transport, changes of membrane potential, cell swelling, and eventual dissolution. Altogether the pathogenesis of chemically induced liver injury is determined by genetics, environmental factors, and other underlying pathological conditions. Green arrows are pathways leading to cell recovery; red arrows indicate pathways to cell damage or death; black arrows are pathways leading to chemically induced liver injury. mRNA, messenger RNA. (Adapted from Gu, X., & Manautou, J.E. [2013]. Exp Rev Mol Med, 14, e4.)

The consequence of self-propagating chain reactions of free radicals is lipid peroxidation. Free radicals react mainly with polyunsaturated fatty acids in membranes and can initiate lipid peroxidation. The breakdown of membrane lipids results in altered function of the mitochondria, ER, plasma membranes, and Golgi apparatus, and therefore has a role in acute liver cellular death (necrosis) and progression of liver injury (Figure 4-15).24

FIGURE 4-15 Chemical Injury of Liver Cells Induced by Carbon Tetrachloride Poisoning. Light blue boxes are mechanisms unique to chemical injury, purple boxes involve hypoxic injury, and green boxes are clinical manifestations. CCl4, carbon tetrachloride; CCl3̇, trichloromethyl free radical; O2, oxygen; Na+, sodium, H2O, water; Ca++, calcium ion; ATP, adenosine triphosphate.

Chemical Agents, Including Medications Numerous chemical agents cause cellular injury. Because chemical injury remains a constant problem in clinical settings, it is a major limitation to medication therapy. Over-the-counter and prescribed medications can cause cellular injury, sometimes leading to death. The leading cause of child poisoning is medications (see Health Promotion: The Percentage of Child Medication–Related Poisoning Deaths Is Increasing). The site of injury is frequently the liver, where many chemicals and medications are metabolized (see Figure 4-15). Long-term exposure to air pollutants, insecticides, and herbicides can cause cellular injury (see Health Promotion: Air Pollution Reported as Largest Single Environmental Health Risk).

Health Promotion The Percentage of Child Medication–Related Poisoning Deaths Is Increasing

Today, the second leading cause of childhood hospitalizations in Ontario is unintentional poisoning with prescription and over-the-counter medications. Children under 5 years of age account for 86% of all deaths and unintentional poisonings. How can we increase the safety of children exposed to so many medications? Safe storage is the most important solution, and safe dosing from clinicians will reduce dosing errors. Medications should be locked away where children cannot reach them. Additionally, improvements are continuing through improved packaging and labelling of medications as well as education of parents and consumers on dosing information. See the following online resource for further information: https://members.oma.org/HEALTHPROMOTION/Pages/ChildPoisoning.aspx. From Ontario Medical Association. (2016). Preventing child poisoning. Retrieved from https://www.oma.org/HEALTHPROMOTION/Pages/ChildPoisoning.aspx.

Health Promotion Air Pollution Reported as Largest Single Environmental Health Risk The World Health Organization (WHO) reports that about 7 million people died in 2012 as a result of air pollution exposure. Improved measurements and better technology have enabled scientists to make more detailed analyses of health risks. These findings confirm that air pollution is now the world's largest single environmental health risk and reducing air pollution could save millions of lives. New data show a stronger link between indoor and outdoor air pollution exposure and cardiovascular diseases (e.g., strokes and ischemic heart disease) as well as the link between air pollution and cancer. These data are in addition to the role of air pollution and the development of respiratory diseases, including infections and chronic obstructive pulmonary diseases. Using these 2012 data for low- and middleincome countries, Southeast Asia and Western Pacific regions had the largest air pollution burden. Included in the analysis is a breakdown of deaths for adults and children attributed to specific diseases:

Outdoor Air Pollution–Caused Deaths—Breakdown by Disease: • 40% ischemic heart disease • 40% stroke • 11% chronic obstructive pulmonary disease (COPD) • 6% lung cancer • 3% acute lower respiratory tract infections in children

Indoor Air Pollution–Caused Deaths—Breakdown by Disease: • 34% stroke • 26% ischemic heart disease • 22% COPD • 12% acute lower respiratory tract infections in children • 6% lung cancer WHO estimates that indoor air pollution was linked to 4.3 million deaths in 2012 from cooking over coal, wood, dung, and biomass stoves. Outdoor air pollution estimates were 3.7 million deaths in 2012 from urban and rural sources. WHO has suggested some recommendations for controlling air pollution in its WHO Guideline for Indoor Air Quality: Household Fuel Combustion (http://www.who.int/indoorair/guidelines/hhfc/en/). Data from World Health Organization. (2014). 7 million premature deaths annually linked to air pollution [Press release]. Retrieved from http://www.who.int/mediacentre/news/releases/2014/air-pollution/en/#.

Another way to classify mechanisms by which medication actions, chemicals, and toxins produce injury includes (1) direct damage, also called on-target toxicity; (2) exaggerated response at the target, including overdose; (3) biological activation to toxic metabolites, including free radicals; (4) hypersensitivity and related immunological reactions; and (5) rare toxicities.27 These mechanisms are not mutually exclusive; thus several may be operating concurrently. Direct damage is when chemicals and medications injure cells by combining directly with critical molecular substances. For example, cyanide is highly toxic (e.g., poisonous) because it inhibits mitochondrial cytochrome oxidase and hence blocks electron transport. Many chemotherapeutic medications, known as antineoplastic agents, induce cell damage by direct cytotoxic effects. Exaggerated pharmacological responses at the target include tumours caused by industrial chemicals and the birth defects attributed to thalidomide.27 Importantly, another example includes common drugs of abuse (Table 4-5). Drug abuse can involve mind-altering substances beyond therapeutic or social norms (Table 4-6). Drug addiction and overdose are serious public health issues. TABLE 4-5 Common Drugs of Abuse Class

Molecular Target

Opioid narcotics

Mu opioid receptor (agonist)

Sedative-hypnotics

GABAA receptor (agonist)

Psychomotor stimulants

Dopamine transporter (antagonist) Serotonin receptors (toxicity)

Phencyclidinelike medications

NMDA glutamate receptor channel (antagonist)

Cannabinoids

CB1 cannabinoid receptors (agonist)

Hallucinogens

Serotonin 5-HT2 receptors (agonist)

Example Heroin, hydromorphone (Dilaudid) Oxycodone (Percodan, Percocet, OxyContin) Methadone (Metadol) Meperidine (Demerol) Barbiturates Ethanol Methaqualone (Quaalude) Glutethimide (Doriden) Ethchlorvynol (Placidyl) Cocaine Amphetamines 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) Phencyclidine (PCP, angel dust) Ketamine Marihuana Hashish Lysergic acid diethylamide (LSD) Mescaline Psilocybin

5-HT2, 5-hydroxytryptamine; CB1, cannabinoid receptor type 1; GABA, gamma-aminobutyric acid; NMDA, N-methyl-D-aspartate. From Hyman, S.E. (2001). JAMA, 286, 2586; Kumar, V., Abbas, A.K., & Aster, J.C. (2015). Cellular responses to stress and toxic insults: Adaptation, injury, and death. In V. Kumar, A.K. Abbas, & J.C. Aster (Eds.), Robbins and Cotran pathologic basis of disease (9th ed., 31–68). Philadelphia: Saunders.

TABLE 4-6 Social or Street Drugs and Their Effects Type of Drug Description and Effects Marihuana (pot)

Methamphetamine (meth)

Cocaine and crack

Heroin

Active substance: Δ9-tetrahydrocannabinol (THC), found in resin of Cannabis sativa plant With smoking (e.g., “joints”), about 5–10% is absorbed through lungs; with heavy use the following adverse effects have been reported: alterations of sensory perception; cognitive and psychomotor impairment (e.g., inability to judge time, speed, distance); an increase in heart rate and blood pressure; an increase in susceptibility to laryngitis, pharyngitis, bronchitis; coughing and hoarseness; possible contribution to lung cancer (different dosages need study; it contains large number of carcinogens); based on data from animal studies, reproductive changes, including reduced fertility, decreased sperm motility, and decreased levels of circulatory testosterone; fetal abnormalities, including low birth weight; increased frequency of infectious illness, which is thought to be result of depressed cellmediated and humoral immunity; beneficial effects include decreased nausea secondary to cancer chemotherapy and decreased pain in certain chronic conditions An amine derivation of amphetamine (C10H15N) used as crystalline hydrochloride CNS stimulant; in large doses causes irritability, aggressive (violent) behaviour, anxiety, excitement, auditory hallucinations, and paranoia (delusions and psychosis); mood changes are common and abuser can swiftly change from friendly to hostile; paranoiac swings can result in suspiciousness, hyperactive behaviour, and dramatic mood swings Appeals to abusers because body's metabolism is increased and produces euphoria, alertness, and perception of increased energy Stages: Low intensity: User is not psychologically addicted and uses methamphetamine by swallowing or snorting Binge and high intensity: User has psychological addiction and smokes or injects to achieve a faster, stronger high Tweaking: Most dangerous stage; user is continually under the influence, not sleeping for 3–15 days, extremely irritated, and paranoid Extracted from leaves of cocoa plant and sold as a water-soluble powder (cocaine hydrochloride) liberally diluted with talcum powder or other white powders; extraction of pure alkaloid from cocaine hydrochloride is “free-base” called crack because it “cracks” when heated Crack is more potent than cocaine; cocaine is widely used as an anaesthetic, usually in procedures involving oral cavity; it is a potent CNS stimulant, blocking reuptake of neurotransmitters norepinephrine, dopamine, and serotonin; also increases synthesis of norepinephrine and dopamine; dopamine induces sense of euphoria, and norepinephrine causes adrenergic potentiation, including hypertension, tachycardia, and vasoconstriction; cocaine can therefore cause severe coronary artery narrowing and ischemia; the reason cocaine increases thrombus formation is unclear; other cardiovascular effects include dysrhythmias, sudden death, dilated cardiomyopathy, rupture of descending aorta (i.e., secondary to hypertension); effects on fetus include premature labour, delayed fetal development, stillbirth, hyperirritability Opiate closely related to morphine, methadone, and codeine Highly addictive, and withdrawal causes intense fear (“I'll die without it”); sold “cut” with similar-looking white powder; dissolved in water it is often highly contaminated; feeling of tranquility and sedation lasts only a few hours and thus encourages repeated intravenous or subcutaneous injections; acts on the receptors enkephalins, endorphins, and dynorphins, which are widely distributed throughout body with high affinity to CNS; effects can include infectious complications, especially Staphylococcus aureus, granulomas of lung, septic embolism, and pulmonary edema—in addition, viral infections, including from HIV, from casual exchange

of needles; sudden death is related to overdosage secondary to respiratory depression, decreased cardiac output, and severe pulmonary edema

CNS, central nervous system; HIV, human immunodeficiency virus. Data from Kumar, V., Abbas, A.K., & Aster, J.C. (Eds.). (2015). Robbins and Cotran pathologic basis of disease (9th ed.). Philadelphia: Saunders; Nahas, G., Sutin, K., & Bennett, W.M. (2000). N Engl J Med, 343(7), 514–515.

Most toxic chemicals are not biologically active in their parent (native) form but must be converted to reactive metabolites, which then act on target molecules. This conversion is usually performed by the cytochrome P-450 oxidase enzymes in the smooth ER of the liver and other organs. These toxic metabolites cause membrane damage and cellular injury mostly from formation of free radicals and subsequent membrane damage from lipid peroxidation (see Figure 4-15). For example, acetaminophen (Paracetamol) is converted to a toxic metabolite in the liver, causing cellular injury (Figure 4-16). Acetaminophen is one of the most common causes of poisoning worldwide.28 Many investigators are studying hepatoprotective strategies.29

FIGURE 4-16

Acetaminophen Metabolism and Toxicity. CYP2E1, a cytochrome; GSH, glutathione; NAPQI, toxic byproduct.

Hypersensitivity reactions are a common medication toxicity and range from mild skin rashes to immune-mediated organ failure.27 One type of hypersensitivity reaction is the delayed-onset reaction, which occurs after multiple doses of a medication are administered. Some protein medications and large polypeptide medications (e.g., insulin) can directly stimulate antibody production (see Chapter 8). Most medications, however, act as haptens and bind covalently to serum or cell-bound proteins. The binding makes the protein immunogenic, stimulating antidrug antibody production, T-cell responses against the medication, or both. For example, penicillin itself is not antigenic but its metabolic degradation products can become antigenic and cause an allergic reaction. Rare toxicities simply mean infrequent occurrences as described previously by the other four mechanisms. These toxicities reflect individual genetic predispositions that affect medication or chemical metabolism, disposition, and immune responses. Carbon monoxide, carbon tetrachloride, and social drugs, such as alcohol, can significantly alter cellular function and injure cellular structures. Accidental or suicidal poisonings by chemical agents cause numerous deaths. The injurious effects on cells of some agents—lead, carbon monoxide, ethyl alcohol, mercury—are common.

Lead. Lead (Pb) is a heavy toxic metal that persists in older homes, the environment, and the workplace. Lead may be found in hazardous concentrations in food, water, and air, and it is one of the most common overexposures found in industry.30 Despite efforts to reduce exposure through government regulation, exposure still persists for many people, and toxicity is still a primary hazard for children31 (see Health

Promotion: Low-Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention). Although Pb was removed from paint in Europe in 1922 and regulations to reduce the amount of Pb in paint were created in Canada in 2002, many homes in Canada still contain leaded paint, and chipped and peeling leaded paint constitutes a major source of current childhood exposure.32-35 The chipped paint can disintegrate at friction surfaces to form Pb dust.35 Another source of contamination is Pb dust dispersed along roadways from previous leaded gasoline emissions.35 When Pb was removed from gasoline, blood lead levels (BLLs) dropped significantly.36-38 Previous emissions of leaded fuel created large dispersions of Pb dust in the environment. Particulate Pb (2 to 10 µm) does not degrade and persists in the environment, making it a notable source of human exposure.39 Other airborne sources include smelters and pistonengine airplanes.40 Drinking water exposed to Pb occurs from outdated fixtures, plumbing without corrosion control, and solders.35 Well water may not be tested for Pb.35 Although the average blood levels of Pb in children in Canada have dropped since the 1970s, there are at-risk populations with higher than average BLLs.35 Children of lower social economic status or racial minority status are still at higher risk of Pb poisoning, and some regions in Canada have an increased prevalence of higher BLLs in children.35 More importantly, the American Centers for Disease Control and Prevention (CDC) reports that “no safe blood lead level in children has been identified.”41 Common sources of Pb are included in Table 4-7. TABLE 4-7 Common Sources of Lead Exposure Exposure

Source

Environmental Lead paint, soil, or dust near roadways or lead-painted homes; plastic window blinds; plumbing materials (from pipes or solder); pottery glazes and ceramic ware; lead-core candle wicks; leaded gasoline; water (pipes) Occupational Lead mining and refining, plumbing and pipe fitting, auto repair, glass manufacturing, battery manufacturing and recycling, printing shop, construction work, plastic manufacturing, gas station attendant, firing-range attendant Hobbies Glazed pottery making, target shooting at firing ranges, lead soldering, preparing fishing sinkers, stained-glass making, painting, car or boat repair Other Gasoline sniffing, costume jewelry, cosmetics, contaminated herbal products

Data from Sanborn, M.D., Abelsohn, A., Campbell, M., et al. (2002). CMAJ, 166(10), 1287–1292.

Health Promotion Low-Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention Lead exposure is relatively low in Canada, and levels are often difficult to determine. Notable symptoms include headaches, irritability, abdominal pain, vomiting, anemia (general weakness, paleness), weight loss, poor attention span, noticeable learning difficulty, slowed speech development, and hyperactivity. Low levels of lead exposure tend to create vague symptoms, and the cause often cannot be determined very easily. Exposure to lead is mainly through oral ingestion or absorption by the skin. Because children tend to touch everything and put things into their mouths, they are at greater risk of exposure, although blood lead levels of Canadian children are generally low (at less than 0.483 mcmol/L). Routine blood lead testing may be necessary in communities with a history of soil contamination (from nearby industrial activity). Further information on lead screening is available through Health Canada at http://www.hcsc.gc.ca/ewh-semt/contaminants/lead-plomb/asked_questions-questions_posees-eng.php. From Health Canada. (2009). Lead information package—Some commonly asked questions about lead and human health. Retrieved from http://www.hc-sc.gc.ca/ewh-semt/contaminants/lead-plomb/asked_questions-questions_posees-eng.php.

Children are more susceptible to the effects of Pb than adults for several reasons, including (1) children have increased hand-to-mouth behaviour and exposure from the ingestion of Pb dust; (2) the blood–brain barrier in children is immature during fetal development, contributing to greater Pb accumulation in the developing brain; and (3) infant absorption of Pb is greater than that in adults, and bone turnover (in adults the body burden of Pb is found in bone) in children from skeletal growth results in continuous leaching of Pb into blood, causing constant body exposure.35,41 If nutrition is compromised, especially if dietary intake of iron and calcium is insufficient, children are more likely to have elevated BLLs.35 Particularly worrisome is Pb exposure during pregnancy because the developing fetal nervous system is

especially vulnerable; Pb exposure can result in lower IQ, learning disorders, hyperactivity, and attention problems.31 The organ systems primarily affected by Pb ingestion include the nervous system, the hematopoietic system (tissues that produce blood cells), and the kidneys of the urological system. The neurological effect of Pb in exposed children is the driving factor for reducing Pb levels in the environment.35 Elevated BLLs not only are linked to cognitive deficits but also are associated with behavioural changes including antisocial behaviour, acting out in school, and difficulty paying attention.35 The cognitive and behavioural changes of Pb-exposed children persist after complete cessation of Pb exposure.35 In 1991 the CDC lowered the definition of Pb intoxication to 0.483 mcmol/L BLL because several studies reported that children with BLLs of at least 10 µm/dL had impaired intellectual functioning35 (Figure 4-17). Studies in animals have led to the hypothesis that Pb targets the learning and memory processes by inhibiting the N-methyl-D-aspartate receptor (NMDAR), which is necessary for hippocampus-mediated learning and memory.35,42 Similar changes also have been found in cultured neuron systems.35 Inhibition of either voltage-gated calcium channels or NMDARs by Pb results in reduction of Ca++ entry into the cell, thereby disrupting the necessary Ca++ signalling for neurotransmission.43,44 Pb induces cellular damage by increasing oxidative stress.45 Lead toxicity involves the direct formation of ROS (singlet oxygen, hydrogen peroxides, hydroperoxides) and depletion of antioxidants.45 Pb exposure leads to lowered levels of glutathione; and because glutathione is important for the metabolism of specific medications and other toxins, low Pb levels can increase their toxicity, as well as the levels of other metals.45 From animal studies and human population studies, low-level Pb exposure may cause hypertension.46 Pb interferes with the normal remodelling of cartilage and bone in children. From radiological studies of bone, “lead lines” are detectable and Pb also can be found in the gums as a result of hyperpigmentation. Pb inhibits several enzymes involved in hemoglobin synthesis and causes anemia (most obvious is a microcytic hypochromic anemia). Renal lesions can cause tubular dysfunction, resulting in glycosuria (glucose in the urine), aminoaciduria (amino acids in the urine), and hyperphosphaturia (excess phosphate in the urine). Gastro-intestinal symptoms are less severe and include nausea, loss of appetite, weight loss, and abdominal cramping.

FIGURE 4-17

Lead Poisoning in Children Related to Blood Levels. (From Kumar, V., Abbas, A.K., & Aster, J.C. [Eds.]. [2015]. Robbins and Cotran pathologic basis of disease [9th ed.]. Philadelphia: Saunders.)

Carbon monoxide. Gaseous substances can be classified according to their ability to asphyxiate (interrupt respiration) or irritate. Toxic asphyxiants, such as carbon monoxide, hydrogen cyanide, and hydrogen sulphide, directly interfere with cellular respiration. Carbon monoxide (CO) is an odourless, colourless, nonirritating, and undetectable gas unless it is mixed with a visible or odorous pollutant. CO is produced by the incomplete combustion of fuels such as gasoline. Although CO is a chemical agent, the ultimate injury it produces is a hypoxic injury—namely, oxygen deprivation. As a systemic asphyxiant, CO causes death by inducing central nervous system (CNS) depression. Normally, oxygen molecules are carried to tissues bound to hemoglobin in red blood cells (see Chapter 27). Because CO's affinity for hemoglobin is 300 times greater than that of oxygen, CO quickly binds with the hemoglobin, preventing the oxygen molecules' ability to bind to the hemoglobin. Minute amounts of CO can produce a significant percentage of carboxyhemoglobin (carbon monoxide bound with hemoglobin). With increasing levels of carboxyhemoglobin, hypoxia occurs insidiously, evoking widespread ischemic changes in the CNS, and individuals are often unaware of their plight. The diagnosis is made from measurement of carboxyhemoglobin levels in the blood. Symptoms related to CO poisoning include headache, giddiness, tinnitus (ringing in the ears), chest pain, confusion, nausea, weakness, and vomiting. CO is an air pollutant found in combustion fumes produced by cars and trucks, small gasoline engines, stoves, gas ranges, gas refrigerators, heating systems, lanterns, burning charcoal or wood, and cigarette smoke. Chronic exposure can occur in people working in confined spaces, such as underground garages and tunnels. Fumes can accumulate in enclosed or semienclosed spaces, and poisoning from breathing CO can occur in humans and animals. High levels of CO can cause loss of consciousness and death. Death can occur in individuals sleeping or intoxicated before experiencing any symptoms. Although all people and animals are at risk, those most susceptible to poisoning include unborn babies, infants, and people with chronic heart disease, respiratory problems, and anemia. For information on preventing CO poisoning from home appliances and on proper venting, see the following Government of Canada website: http://www.healthycanadians.gc.ca.

Ethanol. Alcohol (ethanol) is the most abused drug in Canada. In 2002, alcohol contributed to 2 000 deaths annually from alcoholic liver disease. A blood concentration of 17 mmol/L is the legal definition for drunk driving in Canada. This level of alcohol in an average person may be reached after consumption of three drinks (three 12-ounce bottles of beer, 15 ounces of wine, and 4 to 5 ounces of distilled liquor). The effects of alcohol vary by age, gender, and percentage of body fat; the rate of metabolism affects the blood alcohol level. Because alcohol is not only a psychoactive drug but also a food, it is considered part of the basic food supply in many societies. A large intake of alcohol has enormous effects on nutritional status. Liver and nutritional disorders are the most serious consequences of alcohol abuse. Major nutritional deficiencies include magnesium, vitamin B6, thiamine, and phosphorus. Folic acid deficiency is a common problem in chronic alcoholic populations. Ethanol alters folic acid (folate) homeostasis by decreasing intestinal absorption of folate, increasing liver retention of folate, and increasing the loss of folate through urinary and fecal excretion.47 Folic acid deficiency becomes especially serious in pregnant women who consume alcohol and may contribute to fetal alcohol spectrum disorder (see p. 92). Most of the alcohol in blood is metabolized to acetaldehyde in the liver by three enzyme systems: alcohol dehydrogenase (ADH), the microsomal ethanol-oxidizing system (MEOS; CYP2E1), and catalase (Figure 4-18). The major pathway involves ADH, an enzyme located in the cytosol of hepatocytes. The MEOS depends on cytochrome P-450 (CYP2E1), an enzyme needed for cellular oxidation. Activation of CYP2E1 requires a high ethanol concentration and thus is thought to be important in the accelerated ethanol metabolism (i.e., tolerance) noted in persons with chronic alcoholism. Acetaldehyde has many toxic tissue effects and is responsible for some of the acute effects of alcohol and for development of head and neck cancer (HNC).1 A recent and first study showed that HNC risk may be influenced by alcoholmetabolizing genes (ADH1B and ALDH2) and oral hygiene.48

FIGURE 4-18 Ethanol Metabolism Pathway. Ethanol is metabolized into acetaldehyde through the cytosolic enzyme alcohol dehydrogenase (ADH), the microsomal enzyme cytochrome P-450 2E1 (CYP2E1), and the peroxisomal enzyme catalase. The ADH enzyme reaction is the main ethanol metabolic pathway involving an intermediate carrier of electrons, namely, nicotinamide adenine dinucleotide (NAD+), which is reduced by two electrons to form NADH. Acetaldehyde is metabolized mainly by aldehyde dehydrogenase 2 (ALDH2) in the mitochondria to acetate and NADH before being cleared into the systemic circulation. CO2, carbon dioxide; H2O2, hydrogen peroxide; H2O, water; NADP+, oxidized form of nicotinamide adenine dinucleotide phosphate; NADPH, dihydronicotinamide-adenine dinucleotide phosphate. (Reprinted from Pharmacology & Therapeutics, 132(1), Yingmei Zhang, Jun Ren, “ALDH2 in alcoholic heart diseases: Molecular mechanism and clinical implications,” Pages 86–95, Copyright 2011, with permission from Elsevier.)

The major effects of acute alcoholism involve the CNS. After alcohol is ingested, it is absorbed, unaltered, in the stomach and small intestine. Fatty foods and milk slow absorption. Alcohol then is distributed to all tissues and fluids of the body in direct proportion to the blood concentration. Individuals differ in their capability to metabolize alcohol. Genetic differences in the metabolism of liver alcohol, including levels of aldehyde dehydrogenases, have been identified.49 These genetic polymorphisms may account for ethnic and gender differences in ethanol metabolism. Persons with chronic alcoholism develop tolerance because of production of enzymes, leading to an increased rate of metabolism (e.g., P-450).

Health Promotion Low-Risk Alcohol Drinking Guidelines Canada's Low-Risk Alcohol Drinking Guidelines recommend no more than 10 drinks per week for women (15 drinks/week for men) with no more than 3 drinks at one time (4 drinks/one time for men). The annual national consumption of alcohol is 470 standard servings per person (or 9 servings/week) for individuals 15 years and over. Risky alcohol consumption is common in underage drinkers (30% at least monthly in 2010) and peaks between 19 and 24 years, with more than 50% of males and 45% of females drinking more than the recommended levels monthly, or more often. The guidelines recommend not drinking when you are: • operating a motor vehicle • using machinery or tools • pregnant or planning to be pregnant • responsible for the safety of others • taking medicine or other drugs that interact with alcohol • doing any kind of dangerous physical activity • living with mental or physical health problems

• living with alcohol dependence • making important decisions The guidelines suggest the following safer drinking tips to prevent injury and illness: • Set limits for yourself when you drink, and stick to them. • Eat before and while you are drinking. • Drink slowly: consume no more than 2 drinks in any 3 hours. • Have one non-alcoholic drink for every drink of alcohol. • Consider your age, body weight and health problems that might suggest lower limits. • Do not start to drink or increase your drinking for perceived health benefits. From Canadian Centre on Substance Abuse. (2013). Drinking guidelines. Retrieved from http://www.ccsa.ca/Eng/topics/alcohol/drinkingguidelines/Pages/default.aspx (accessed October 14, 2016); Statistics Canada. (2012). Table 183-0019: Volume of sales of alcoholic beverages in litres of absolute alcohol and per capita 15 years and over, fiscal years ended March 31, annual. Retrieved March 5, 2012, from http://www5.statcan.gc.ca/cansim/a26? lang=eng&retrLang=eng&id=1830019&paSer=&pattern=&stByVal=2&p1=-1&p2=-1&tabMode=dataTable&csid=; Canadian Centre on Substance Abuse. (2012). Levels and Patterns of Alcohol Use in Canada. Alcohol Price Policy Series, Report 1 of 3. Ottawa: CCSA. Retrieved from http://www.ccsa.ca/Resource%20Library/CCSA-Patterns-Alcohol-Use-Policy-Canada-2012-en.pdf.

Numerous studies have validated the so-called J- or U-shaped inverse association between alcohol and overall or cardiovascular mortality, such as from myocardial infarction and ischemic stroke. These studies have found that light to moderate (nonbinge) drinkers tend to have lower mortality than nondrinkers, and heavy drinkers have higher mortality.50 (See Health Promotion: Low-Risk Alcohol Drinking Guidelines.) The suggested mechanisms for cardioprotection for light to moderate drinkers include increase in levels of high-density lipoprotein–cholesterol (HDL-C), decrease in levels of low-density lipoprotein (LDL), prevention of clot formation, reduction in platelet aggregation, decrease in blood pressure, increase in coronary vessel vasodilation, increase in coronary blood flow, decrease in coronary inflammation, decrease in atherosclerosis, limited ischemia-reperfusion injury (I/R injury), and a decrease in diabetic vessel pathology.51 The Canadian Heart and Stroke Association recommends no more than 15 drinks per week for men and 10 drinks per week for women (one 341-mL beer, 118 mL of wine, 44 mL of 80-proof spirits, or 29 mL of 100-proof spirits). Drinking more alcohol can increase the risks of alcoholism, high blood pressure, obesity, stroke, breast cancer, suicide, and accidents.52 Individuals who do not consume alcohol should not be encouraged to start drinking.53 Acute alcoholism (drunkenness) affects the CNS. Alcohol intoxication causes CNS depression. Depending on the amount consumed, CNS depression is associated with sedation, drowsiness, loss of motor coordination, delirium, altered behaviour, and loss of consciousness. Toxic amounts (65 to 86 mmol/L) result in a lethal coma or respiratory arrest because of medullary centre depression. Investigators studied the effects of snoring and multiple variables, including alcohol. They found that a low level of self-reported physical activity is a risk factor for future habitual snoring complaints in women independent of alcohol dependence, smoking, current weight, and weight gain. Furthermore, increased physical activity can modify the risk.54 Acute alcoholism may induce reversible hepatic and gastric changes.1 Chronic and binge drinking causes alcoholic liver disease (ALD), with a spectrum from hepatic steatosis (fatty change) to steatohepatitis (fatty change and inflammation) and cirrhosis (see Chapter 36). These alterations can eventually lead to hepatocellular carcinoma. The pathogenesis of ALD is not fully characterized, and recent studies reveal a major role of mitochondria. Animal studies have shown that alcohol causes mitochondrial DNA damage, lipid accumulation, and oxidative stress. Acute alcoholism also contributes significantly to motor vehicle fatalities. Chronic alcoholism causes structural alterations in practically all organs and tissues in the body because most tissues contain enzymes capable of ethanol oxidation or nonoxidative metabolism. The most significant activity, however, occurs in the liver. Alcohol is the leading cause of liver-related morbidity and mortality.55 In general, hepatic changes, initiated by acetaldehyde, include inflammation, deposition

of fat, enlargement of the liver, interruption of microtubular transport of proteins and their secretion, increase in intracellular water, depression of fatty acid oxidation in the mitochondria, increase in membrane rigidity, and acute liver cell necrosis (see Chapter 36). Specifically, chronic or binge alcohol consumption causes ALD with a spectrum ranging from simple fatty liver (steatosis), to steatohepatitis (fatty with inflammation), to cirrhosis (Figure 4-19) (see Chapter 36). Cirrhosis is associated with portal hypertension and an increased risk for hepatocellular carcinoma. Cellular damage is increased by ROS and oxidative stress. Activation of proinflammatory cytokines from neutrophils and lymphocytes mediates liver damage.56 Oxidative stress is associated with cell membrane phospholipid depletion, which alters the fluidity and function of cell membranes as well as intercellular transport. Chronic alcoholism is related to several disorders, including injury to the myocardium (alcoholic cardiomyopathy); increased tendency to hypertension, acute gastritis, and acute and chronic pancreatitis; and regressive changes in skeletal muscle. Chronic alcohol consumption is associated with an increased incidence of cancer of the oral cavity, liver, esophagus, and breast.

FIGURE 4-19

Alcoholic Hepatitis. Chicken-wire fibrosis extending between hepatocytes (Mallory trichrome stain). (From Damjanov, I., & Linder, J. [Eds.]. [1996]. Anderson's pathology [10th ed.]. St. Louis: Mosby.)

Ethanol is implicated in the onset of a variety of immune defects, including effects on the production of cytokines involved in inflammatory responses. Alcohol can induce epigenetic variations in the developmental pathways of many types of immune cells (e.g., granulocytes, macrophages, and T lymphocytes) that promote increased inflammation.57 Alcohol increases the development of serious medical conditions related to immune system dysfunction, including acute respiratory distress syndrome (ARDS) as well as liver cancer and ALD.57 Binge and chronic drinking increases susceptibility to many infectious microorganisms and can enhance the progression of human immunodeficiency virus (HIV) by affecting innate and adaptive immunity.57 The deleterious effects of prenatal alcohol exposure can cause mental deficiency and neurobehavioural disorders, as well as fetal alcohol syndrome. Fetal alcohol spectrum disorder includes delayed growth, facial anomalies, cognitive impairment, and ocular malformations (Figure 4-20). It is among the common causes of mental deficiency.58 Evidence of epigenetic alterations has led to the hypothesis that alcohol effects on fetal development may be caused not only by maternal alcohol consumption but also by the father's exposure as well.58 Epigenetic alterations may be carried through the male germline for generations.59 Alcohol crosses the placenta, reaching the fetus, and blood levels of the fetus may reach equivalent levels to maternal levels in 1 to 2 hours.60 Research has demonstrated an unimpeded bidirectional movement of alcohol between the fetus and the mother. The fetus may completely depend on maternal hepatic detoxification because the activity of alcohol dehydrogenase (ADH) in fetal liver is less than 10% of that in the adult liver.60 Additionally, the amniotic fluid acts as a reservoir for alcohol, prolonging fetal exposure.60 The specific mechanisms of injury are unknown; however, acetaldehyde can alter fetal development by disrupting differentiation and growth; DNA and protein synthesis; modification of carbohydrates, proteins, and fats; and flow of nutrients across the placenta; and neurocircuitry dysfunction may be long-lasting.58,60

FIGURE 4-20 Fetal Alcohol Spectrum Disorder. When alcohol enters the fetal blood, the potential result can cause tragic congenital abnormalities, such as microcephaly (“small head”), low birth weight, and cardiovascular defects, as well as developmental disabilities, such as physical and intellectual disability, and even death. Note the small head, thinned upper lip, small eye openings (palpebral fissures), epicanthal folds, and receded upper jaw (retrognathia) typical of fetal alcohol spectrum disorder. (From Fortinash, K.M., & Holoday Worret, P.A. [2012]. Psychiatric mental health nursing [5th ed.]. St. Louis: Mosby.)

Mercury. Mercury is a global threat to human and environmental health. A recent report, Global Mercury Assessment 2013, presents an overview.61 This report provides the most recent information on worldwide atmospheric mercury emissions, releases to the aquatic environment, and the fate of mercury in the global environment. Causes from human activity, called anthropogenic, are responsible for about 30% of annual emissions of mercury to air, another 10% arise from natural geological sources, and the remainder (60%) occurs from re-emissions or earlier released mercury that has increased over decades and centuries in surface soil and water.61 The major sources of anthropogenic mercury emissions to air are artisanal and small-scale gold mining (ASGM) and coal burning. The next major sources are the production of ferrous and nonferrous metals, and cement production. Importantly, investigators report that emissions from industrial sectors have increased since 2005.61 Types of aquatic releases of mercury include industrial sites (power plants, factories), old mines, landfills, and waste disposal locations. ASGM is a significant producer of aquatic mercury release. It is estimated that more than 90% of mercury in marine animals is from anthropogenic emissions.61 Large amounts of inorganic mercury have accumulated in surface soils and in the oceans. Climate change, with thawing of enormous areas of frozen lands, may release even more long-stored mercury and organic matter into lakes, rivers, and oceans.61 Dental amalgams, or “silver fillings,” are made of two almost equal parts of liquid mercury and a powder containing silver, tin, copper, zinc, and other metals.40 When amalgams are placed or removed they can release a small amount of mercury vapour. Chewing can release a small amount of vapour, and people absorb the vapour by inhalation or ingestion.40 Researchers are studying the effects of exposure to magnetic fields, such as from mobile phone use, and the release of mercury from amalgams.62 Susceptibility to mercury toxicity varies in a dose-dependent fashion and, among individuals, based on multiple genes, not all of which have been identified.63,64 Worldwide efforts are under way to phase down or eliminate the use of mercury dental amalgam.64 Thimerosal, a mercury-containing preservative, was removed from all vaccines in 2001, with the exception of inactivated influenza vaccines.65

Quick Check 4-2 1. Why are children more susceptible to the toxic effects of lead exposure? 2. Describe the sources of lead exposure. 3. Describe the mechanisms of cellular injury related to chronic alcoholism. 4. What are the sources of mercury exposure?

Unintentional and Intentional Injuries Unintentional and intentional injuries are an important health problem in Canada. Statistics on nonfatal injuries are harder to document accurately, but they are known to be a significant cause of morbidity and disability and to cost society billions of dollars annually. The more common terms used to describe and classify unintentional and intentional injuries and brief descriptions of important features of these injuries are discussed in Table 4-8. TABLE 4-8 Unintentional and Intentional Injuries Type of Injury

Description

BLUNT-FORCE INJURIES

Mechanical injury to body resulting in tearing, shearing, or crushing; most common type of injury seen in health care settings; caused by blows or impacts; motor vehicle accidents and falls most common cause (see photo A) Contusion (bruise): Bleeding into skin or underlying tissues; initial colour will be red-purple, then blue-black, then yellow-brown or green (see Figure 4-24); duration of bruise depends on extent, location, and degree of vascularization; bruising of soft tissue may be confined to deeper structures; hematoma is collection of blood in soft tissue; subdural hematoma is blood between inner surface of dura mater and surface of brain; can result from blows, falls, or sudden acceleration/deceleration of head as occurs in shaken baby syndrome; epidural hematoma is collection of blood between inner surface of skull and dura; is most often associated with a skull fracture Laceration: Tear or rip resulting when tensile strength of skin or tissue is exceeded; is ragged and irregular with abraded edges; an extreme example is avulsion, where a wide area of tissue is pulled away; lacerations of internal organs are common in blunt-force injuries; lacerations of liver, spleen, kidneys, and bowel occur from blows to abdomen; thoracic aorta may be lacerated in sudden deceleration accidents; severe blows or impacts to chest may rupture heart with lacerations of atria or ventricles Fracture: Blunt-force blows or impacts can cause bone to break or shatter (see Chapter 39)

SHARP-FORCE INJURIES

Sharp-force injuries are characterized by a relatively well-defined traumatic separation of tissues, occurring when a sharp-edged or pointed object comes into contact with the skin and underlying tissues. Three specific subtypes of sharp-force injuries exist, as follows: stab wounds, incised wounds, and chop wounds.a Incised wound: A wound that is longer than it is deep; wound can be straight or jagged with sharp, distinct edges without abrasion; usually produces significant external bleeding with little internal hemorrhage; these wounds are noted in sharp-force injury suicides; in addition to a deep, lethal cut, there will be superficial incisions in same area called hesitation marks (see photo B) Stab wound: A penetrating sharp-force injury that is deeper than it is long; if a sharp instrument is used, depths of wound are clean and distinct but can be abraded if object is inserted deeply and wider portion (e.g., hilt of a knife) impacts skin; depending on size and location of wound, external bleeding may be surprisingly small; after an initial spurt of blood, even if a major vessel or heart is struck, wound may be almost completely closed by tissue pressure, thus allowing only a trickle of visible blood despite copious internal bleeding Puncture wound: Instruments or objects with sharp points but without sharp edges produce puncture wounds; classic example is wound of foot after stepping on a nail; wounds are prone to infection, have abrasion of edges, and can be very deep Chopping wound: Heavy, edged instruments (axes, hatchets, propeller blades) produce wounds with a combination of sharp- and blunt-force characteristics

GUNSHOT WOUNDS

Gunshot wounds are either penetrating (bullet remains in body) or perforating (bullet exits body); bullet also can fragment; most important factors or appearances are whether it is an entrance or exit wound and range of fire Entrance wound: All wounds share some common features; overall appearance is most affected by range of fire Contact range entrance wound: Distinctive type of wound when gun is held so muzzle rests on or presses into skin surface; there is searing of edges of wound from flame and soot or smoke on edges of wound in addition to hole; hard contact wounds of head cause severe tearing and disruption of tissue (because of thin layer of skin and muscle overlying bone); wound is gaping and jagged, known as blow back; can produce a patterned abrasion that mirrors weapon used (see photo C)

Intermediate (distance) range entrance wound: Surrounded by gunpowder tattooing or stippling; tattooing results from fragments of burning or unburned pieces of gunpowder

exiting barrel and forcefully striking skin; stippling results when gunpowder abrades but does not penetrate skin (see photo D) Indeterminate range entrance wound: Occurs when flame, soot, or gunpowder does not reach skin surface but bullet does; indeterminate is used rather than distant because appearance may be same regardless of distance; for example, if an individual is shot at close range through multiple layers of clothing the wound may look the same as if the shooting occurred at a distance Exit wound: Has the same appearance regardless of range of fire; most important factors are speed of projectile and degree of deformation; size cannot be used to determine if hole is an exit or entrance wound; usually has clean edges that can often be re-approximated to cover defect; skin is one of toughest structures for a bullet to penetrate; thus it is not uncommon for a bullet to pass entirely through body but stopped just beneath skin on “exit” side Wounding potential of bullets: Most damage done by a bullet is a result of amount of energy transferred to tissue impacted; speed of bullet has much greater effect than increased size; some bullets are designed to expand or fragment when striking an object, for example, hollowpoint ammunition; lethality of a wound depends on what structures are damaged; wounds of brain may not be lethal; however, they are usually immediately incapacitating and lead to significant long-term disability; a person with a “lethal” injury (wound of heart or aorta) also may not be immediately incapacitated

a

From Prahlow, J.A. (2016). Forensic autopsy of sharp-force injuries. Retrieved from http://emedicine.medscape.com/article/1680082overview.

Asphyxial Injuries Asphyxial injuries are caused by a failure of cells to receive or use oxygen. Deprivation of oxygen may be partial (hypoxia) or total (anoxia). Asphyxial injuries can be grouped into four general categories: suffocation, strangulation, chemical asphyxiants, and drowning.

Suffocation. Suffocation, or oxygen failing to reach the blood, can result from a lack of oxygen in the environment (entrapment in an enclosed space or filling of the environment with a suffocating gas) or blockage of the external airways. Classic examples of these types of asphyxial injuries are a child who is trapped in an abandoned refrigerator or a person who commits suicide by putting a plastic bag over his or her head. A reduction in the ambient oxygen level to 16% (normal is 21%) is immediately dangerous. If the level is below 5%, death can ensue within a matter of minutes. The diagnosis of these types of asphyxial injuries depends on obtaining an accurate and thorough history because there will be no specific physical findings. Diagnosis and treatment in choking asphyxiation (obstruction of the internal airways) depend on locating and removing the obstructing material. Injury or disease also may cause swelling of the soft tissues of the airway, leading to partial or complete obstruction and subsequent asphyxiation. Suffocation also may result from compression of the chest or abdomen (mechanical or compressional asphyxia), preventing normal respiratory movements. Usual signs and symptoms include florid facial congestion and petechiae (pinpoint hemorrhages) of the eyes and face.

Strangulation. Strangulation is caused by compression and closure of the blood vessels and air passages resulting from external pressure on the neck. Strangulation causes cerebral hypoxia or anoxia secondary to the alteration or cessation of blood flow to and from the brain. It is important to remember that the amount of force needed to close the jugular veins (2 kg) or carotid arteries (5 kg) is significantly less than that required to crush the trachea (15 kg). It is the alteration of cerebral blood flow in most types of strangulation that causes injury or death—not the lack of airflow. With complete blockage of the carotid arteries, unconsciousness can occur within 10 to 15 seconds. A noose is placed around the neck, and the weight of the body is used to cause constriction of the noose and compression of the neck in hanging strangulations. The body does not need to be completely suspended to produce severe injury or death. Depending on the type of ligature used, there usually is a distinct mark on the neck—an inverted V with the base of the V pointing toward the point of suspension. Internal injuries of the neck are actually quite rare in hangings, and only in judicial hangings, in which the body is weighted and dropped, is significant soft tissue or cervical spinal trauma seen. Petechiae of the eyes or face may be seen, but they are rare.

In ligature strangulation, the mark on the neck is horizontal without the inverted V pattern seen in hangings. Petechiae may be more common because intermittent opening and closure of the blood vessels may occur as a result of the victim's struggles. Internal injuries of the neck are rare. Variable amounts of external trauma on the neck are found with contusions and abrasions in manual strangulation caused either by the assailant or by the victim clawing at his or her own neck in an attempt to remove the assailant's hands. Internal damage can be quite severe, with bruising of deep structures and even fractures of the hyoid bone and tracheal and cricoid cartilages. Petechiae are common.

Chemical asphyxiants. Chemical asphyxiants either prevent the delivery of oxygen to the tissues or block its utilization. Carbon monoxide is the most common chemical asphyxiant. Cyanide acts as an asphyxiant by combining with the ferric iron atom in cytochrome oxidase, thereby blocking the intracellular use of oxygen. A victim of cyanide poisoning will have the same cherry-red appearance as a carbon monoxide intoxication victim because cyanide blocks the use of circulating oxyhemoglobin. An odour of bitter almonds also may be detected. (The ability to smell cyanide is a genetic trait that is absent in a significant portion of the general population.) Hydrogen sulphide (sewer gas) is a chemical asphyxiant in which victims of hydrogen cyanide poisoning may have brown-tinged blood in addition to the nonspecific signs of asphyxiation.

Drowning. Drowning is an alteration of oxygen delivery to tissues resulting from the inhalation of fluid, usually water. In 2012 there were 495 drowning deaths in Canada.66 Although research in the 1940s and 1950s indicated that changes in blood electrolyte levels and volume as a result of absorption of fluid from the lungs may be an important factor in some drownings, the major mechanism of injury is hypoxemia (low blood oxygen levels). Even in freshwater drownings, where large amounts of water can pass through the alveolar-capillary interface, there is no evidence that increases in blood volume cause significant electrolyte disturbances or hemolysis, or that the amount of fluid loading is beyond the compensatory capabilities of the kidneys and heart. Airway obstruction is the more important pathological abnormality, underscored by the fact that in as many as 15% of drownings little or no water enters the lungs because of vagal nerve–mediated laryngospasms. This phenomenon is called dry-lung drowning. No matter what mechanism is involved, cerebral hypoxia leads to unconsciousness in a matter of minutes. Whether it progresses to death depends on a number of factors, including the age and the health of the individual. One of the most important factors is the temperature of the water. Irreversible injury develops much more rapidly in warm water than it does in cold water. Submersion times of up to 1 hour with subsequent survival have been reported in children who were submerged in very cold water. Complete submersion is not necessary for a person to drown. An incapacitated or helpless individual (epileptic, alcoholic, infant) may drown in water that is only a few centimetres deep. It is important to remember that no specific or diagnostic findings prove that a person recovered from the water is actually a drowning victim. In cases where water has entered the lung, there may be large amounts of foam exiting the nose and mouth, although the same sign also can be seen in certain types of drug overdoses. A body recovered from water with signs of prolonged immersion could just as easily be a victim of some other type of injury with the immersion acting to obscure the actual cause of death. When working with a living victim recovered from water, it is essential to keep in mind that an underlying condition may have led to the person's becoming incapacitated and submerged—a condition that also may need to be treated or corrected while correcting hypoxemia and dealing with its sequelae.

Quick Check 4-3 1. Give examples of intentional and unintentional injury. 2. Describe unintentional injury as a form of injury in health care delivery in Canada. 3. What is the major mechanism of injury with drowning?

Infectious Injury The pathogenicity (virulence) of microorganisms lies in their ability to survive and proliferate in the human body, where they injure cells and tissues. The disease-producing potential of a microorganism depends on its ability to (1) invade and destroy cells, (2) produce toxins, and (3) produce damaging hypersensitivity reactions. (See Chapter 8 for a description of infection and infectious organisms.)

Immunological and Inflammatory Injury Cellular membranes are injured by direct contact with cellular and chemical components of the immune and inflammatory responses, such as phagocytic cells (lymphocytes, macrophages) and substances such as histamine, antibodies, lymphokines, complement, and proteases (see Chapter 6). Complement is responsible for many of the membrane alterations that occur during immunological injury. Membrane alterations are associated with a rapid leakage of K+ out of the cell and a rapid influx of water. Antibodies can interfere with membrane function by binding with and occupying receptor molecules on the plasma membrane. Antibodies also can block or destroy cellular junctions, interfering with intercellular communication. Other mechanisms of cellular injury are genetic and epigenetic factors, nutritional imbalances, and physical agents. These mechanisms are summarized in Table 4-9. TABLE 4-9 Mechanisms of Cellular Injury Mechanism Characteristics

Examples

Genetic Factors Alter cell's nucleus and plasma membrane's structure, shape, receptors, or transport mechanisms

Sickle cell anemia, Huntington's disease, muscular dystrophy, abetalipoproteinemia, familial hypercholesterolemia Gene silencing in cancer

Epigenetic Factors Nutritional Imbalances

Induction of mitotically heritable alterations in gene expression without changing DNA Pathophysiological cellular effects develop when nutrients are not consumed in diet and transported to body's cells or when excessive amounts of nutrients are consumed and transported

Physical Agents Temperature Hypothermic injury results from chilling or freezing of cells, creating high intracellular sodium extremes concentrations; abrupt drops in temperature lead to vasoconstriction and increased viscosity of blood, causing ischemic injury, infarction, and necrosis; reactive oxygen species are important in this process Hyperthermic injury is caused by excessive heat and varies in severity according to nature, intensity, and extent of heat

Ionizing radiation

Illumination Mechanical stresses Noise

Protein deficiency, protein-calorie malnutrition, glucose deficiency, lipid deficiency (hypolipidemia), dyslipidemia (increased lipoproteins in blood causing deposits of fat in heart, liver, and muscle), vitamin deficiencies Frostbite

Burns, burn blisters, heat cramps usually from vigorous exercise with water and salt loss; heat exhaustion with salt and water loss causes heme contraction; heat stroke is life-threatening with a clinical rectal temperature of 41°C (106°F) Tissue injury caused by compressive waves of air or fluid impinging on body, followed by sudden wave of Blast injury (air or immersion), decompression sickness (caisson decreased pressure; changes may collapse thorax, rupture internal solid organs, and cause widespread disease or “the bends”); recently reported in a few individuals hemorrhage: carbon dioxide and nitrogen that are normally dissolved in blood precipitate from solution with subdural hematomas after riding high-speed roller coasters and form small bubbles (gas emboli), causing hypoxic injury and pain Refers to any form of radiation that can remove orbital electrons from atoms; source is usually X-rays, γ-rays, and α- and β-particles cause skin redness, skin environment and medical use; damage is to DNA molecule, causing chromosomal aberrations, damage, chromosomal damage, cancer chromosomal instability, and damage to membranes and enzymes; also induces growth factors and extracellular matrix remodelling; uncertainty exists regarding effects of low levels of radiation Fluorescent lighting and halogen lamps create harmful oxidative stresses; ultraviolet light has been linked Eyestrain, obscured vision, cataracts, headaches, melanoma to skin cancer Injury is caused by physical impact or irritation; they may be overt or cumulative Faulty occupational biomechanics, leading to overexertion disorders Can be caused by acute loud noise or cumulative effects of various intensities, frequencies, and duration of Hearing impairment or loss; tinnitus, temporary threshold shift, noise; considered a public health threat or loss can occur as a complication of critical illness, from mechanical trauma, ototoxic medications, infections, vascular disorders, and noise

Manifestations of Cellular Injury: Accumulations An important manifestation of cellular injury is the intracellular accumulation of abnormal amounts of various substances and the resultant metabolic disturbances. Cellular accumulations, also known as infiltrations, result not only from sublethal, sustained injury by cells but also from normal (but inefficient) cell function. Two categories of substances can produce accumulations: (1) normal cellular substances (such as excess water, proteins, lipids, and carbohydrates) and (2) abnormal substances, either endogenous (such as a product of abnormal metabolism or synthesis) or exogenous (such as infectious agents or a mineral). These products can accumulate transiently or permanently and can be toxic or harmless. Most accumulations are attributed to four types of mechanisms, all abnormal (Figure 4-21). Abnormal accumulations of these substances can occur in the cytoplasm (often in the lysosomes) or in the nucleus if (1) there is insufficient removal of the normal substance because of altered packaging and transport, for example, fatty change in the liver called steatosis; (2) an abnormal substance, often the result of a mutated gene, accumulates because of defects in protein folding, transport, or abnormal degradation; (3) an endogenous substance (normal or abnormal) is not effectively catabolized, usually because of lack of a vital lysosomal enzyme, called storage diseases; or (4) harmful exogenous materials, such as heavy metals, mineral dusts, or microorganisms, accumulate because of inhalation, ingestion, or infection.

FIGURE 4-21

Mechanisms of Intracellular Accumulations. (From Kumar, V., Abbas, A.K., & Aster, J.C. [Eds.]. [2015]. Robbins and Cotran pathologic basis of disease [9th ed.]. Philadelphia: Saunders.)

In all storage diseases, the cells attempt to digest, or catabolize, the “stored” substances. As a result, excessive amounts of metabolites (products of catabolism) accumulate in the cells and are expelled into the ECM, where they are consumed by phagocytic cells called macrophages (see Chapter 6). Some of these scavenger cells circulate throughout the body, whereas others remain fixed in certain tissues, such as the liver or spleen. As more and more macrophages and other phagocytes migrate to tissues that are producing excessive metabolites, the affected tissues begin to swell. This mechanism causes enlargement of the liver (hepatomegaly) or the spleen (splenomegaly) as a clinical manifestation of many storage diseases.

Water Cellular swelling, the most common degenerative change, is caused by the shift of extracellular water into the cells. In hypoxic injury, movement of fluid and ions into the cell is associated with acute failure of metabolism and loss of ATP production. Normally, the pump that transports sodium ions (Na+) out of the cell is maintained by the presence of ATP and adenosinetriphosphatase (ATPase), the active transport enzyme. In metabolic failure caused by hypoxia, reduced levels of ATP and ATPase permit sodium to

accumulate in the cell while potassium (K+) diffuses outward. The increased intracellular sodium concentration increases osmotic pressure, drawing more water into the cell. The cisternae of the ER become distended, rupture, and then unite to form large vacuoles that isolate the water from the cytoplasm, a process called vacuolation. Progressive vacuolation results in cytoplasmic swelling called oncosis (which has replaced the old term hydropic [water] degeneration) or vacuolar degeneration (Figure 4-22). If cellular swelling affects all the cells in an organ, the organ increases in weight and becomes distended and pale.

FIGURE 4-22

The Process of Oncosis (Formerly Referred to as “Hydropic Degeneration”). ATP, adenosine triphosphate.

Cellular swelling is reversible and is considered sublethal. It is, in fact, an early manifestation of almost all types of cellular injury, including severe or lethal cellular injury. It is also associated with high fever, hypokalemia (abnormally low concentrations of potassium in the blood; see Chapter 5), and certain infections.

Lipids and Carbohydrates Certain metabolic disorders result in the abnormal intracellular accumulation of carbohydrates and lipids. These substances may accumulate throughout the body but are found primarily in the spleen, liver, and CNS. Accumulations in cells of the CNS can cause neurological dysfunction and severe intellectual disability. Lipids accumulate in Tay-Sachs disease, Niemann-Pick disease, and Gaucher's disease; whereas in the diseases known as mucopolysaccharidoses, carbohydrates are in excess. The mucopolysaccharidoses are progressive disorders that usually involve multiple organs, including liver, spleen, heart, and blood vessels. The accumulated mucopolysaccharides are found in reticuloendothelial cells, endothelial cells, intimal smooth muscle cells, and fibroblasts throughout the body. These carbohydrate accumulations can cause clouding of the cornea, joint stiffness, and intellectual disability. Although lipids sometimes accumulate in heart, muscle, and kidney cells, the most common site of intracellular lipid accumulation, or fatty change (steatosis), is liver cells (Figure 4-23). Because hepatic metabolism and secretion of lipids are crucial to proper body function, imbalances and deficiencies in these processes lead to major pathological changes. In developed countries, the most common cause of fatty change in the liver is alcohol abuse. Other causes of fatty change include diabetes mellitus, protein malnutrition, toxins, anoxia, and obesity. As lipids fill the cells, vacuolation pushes the nucleus and other organelles aside. The liver's outward appearance is yellow and greasy. Alcohol abuse is one of the most

common causes of fatty liver (see Chapter 36).

FIGURE 4-23

Fatty Liver. The liver appears yellow. (From Damjanov, I., & Linder, J. [2000]. Pathology: A color atlas. St. Louis: Mosby.)

Lipid accumulation in liver cells occurs after cellular injury instigates one or more of the following mechanisms: 1. Increased movement of free fatty acids into the liver (starvation, e.g., increases the metabolism of triglycerides in adipose tissue, releasing fatty acids that subsequently enter liver cells) 2. Failure of the metabolic process that converts fatty acids to phospholipids, resulting in the preferential conversion of fatty acids to triglycerides 3. Increased synthesis of triglycerides from fatty acids (increased levels of the enzyme αglycerophosphatase can accelerate triglyceride synthesis) 4. Decreased synthesis of apoproteins (lipid-acceptor proteins) 5. Failure of lipids to bind with apoproteins and form lipoproteins 6. Failure of mechanisms that transport lipoproteins out of the cell 7. Direct damage to the ER by free radicals released by alcohol's toxic effects Many pathological states show accumulation of cholesterol and cholesterol esters. These states include atherosclerosis, in which atherosclerotic plaques, smooth muscle cells, and macrophages within the intimal layer of the aorta and large arteries are filled with lipid-rich vacuoles of cholesterol and cholesterol esters. Other states include cholesterol-rich deposits in the gallbladder and Niemann-Pick disease (type C), which involve genetic mutations of an enzyme affecting cholesterol transport.

Glycogen Glycogen storage is important as a readily available energy source in the cytoplasm of normal cells. Intracellular accumulations of glycogen are seen in genetic disorders called glycogen storage diseases and in disorders of glucose and glycogen metabolism. As with water and lipid accumulation, glycogen accumulation results in excessive vacuolation of the cytoplasm. The most common cause of glycogen accumulation is the disorder of glucose metabolism (i.e., diabetes mellitus) (see Chapter 19).

Proteins Proteins provide cellular structure and constitute most of the cell's dry weight. The proteins are synthesized on ribosomes in the cytoplasm from the essential amino acids lysine, threonine, leucine, isoleucine, methionine, tryptophan, valine, phenylalanine, and histidine. The accumulation of protein probably damages cells in two ways. First, metabolites, produced when the cell attempts to digest some proteins, are enzymes that when released from lysosomes can damage cellular organelles. Second, excessive amounts of protein in the cytoplasm push against cellular organelles, disrupting organelle function and intracellular communication. Protein excess accumulates primarily in the epithelial cells of the renal convoluted tubules of the nephron unit and in the antibody-forming plasma cells (B lymphocytes) of the immune system. Several

types of renal disorders cause excessive excretion of protein molecules in the urine (proteinuria). Normally, little or no protein is present in the urine, and its presence in significant amounts indicates cellular injury and altered cellular function. Accumulations of protein in B lymphocytes can occur during active synthesis of antibodies during the immune response. The excess aggregates of protein are called Russell bodies (see Chapter 6). Russell bodies have been identified in multiple myeloma (plasma cell tumour) (see Chapter 21). Mutations in protein can slow protein folding, resulting in the accumulation of partially folded intermediates. An example is α1-antitrypsin deficiency, which can cause emphysema. Certain types of cellular injury are associated with the accumulation of cytoskeleton proteins. For example, the neurofibrillary tangle found in the brain in Alzheimer's disease contains these types of proteins.

Pigments Pigment accumulations may be normal or abnormal, endogenous (produced within the body) or exogenous (produced outside the body). Endogenous pigments are derived, for example, from amino acids (e.g., tyrosine, tryptophan). They include melanin and the blood proteins porphyrins, hemoglobin, and hemosiderin. Lipid-rich pigments, such as lipofuscin (the aging pigment), give a yellow-brown colour to cells undergoing slow, regressive, and often atrophic changes. The most common exogenous pigment is carbon (coal dust), a pervasive air pollutant in urban areas. Inhaled carbon interacts with lung macrophages and is transported by lymphatic vessels to regional lymph nodes. This accumulation blackens lung tissues and involved lymph nodes. Other exogenous pigments include mineral dusts containing silica and iron particles, lead, silver salts, and dyes for tattoos.

Melanin Melanin accumulates in epithelial cells (keratinocytes) of the skin and retina. It is an extremely important pigment because it protects the skin against long exposure to sunlight and is considered an essential factor in the prevention of skin cancer (see Chapters 11 and 41). Ultraviolet light (e.g., sunlight) stimulates the synthesis of melanin, which probably absorbs ultraviolet rays during subsequent exposure. Melanin also may protect the skin by trapping the injurious free radicals produced by the action of ultraviolet light on skin. Melanin is a brown-black pigment derived from the amino acid tyrosine. It is synthesized by epidermal cells called melanocytes and is stored in membrane-bound cytoplasmic vesicles called melanosomes. Melanin also can accumulate in melanophores (melanin-containing pigment cells), macrophages, or other phagocytic cells in the dermis. Presumably these cells acquire the melanin from nearby melanocytes or from pigment that has been extruded from dying epidermal cells. This mechanism causes freckles. Melanin also occurs in the benign form of pigmented moles called nevi (see Chapter 41). Malignant melanoma is a cancerous skin tumour that contains melanin. A decrease in melanin production occurs in the inherited disorder of melanin metabolism called albinism. Albinism is often diffuse, involving all the skin, the eyes, and the hair. Albinism is also related to phenylalanine metabolism. In classic types, the person with albinism is unable to convert tyrosine to 3,4dihydroxyphenylalanine (DOPA), an intermediate in melanin biosynthesis. Melanocytes are present in normal numbers, but they are unable to make melanin. Individuals with albinism are very sensitive to sunlight and quickly become sunburned. They are also at high risk for skin cancer.

Hemoproteins Hemoproteins are among the most essential of the normal endogenous pigments. They include hemoglobin and the oxidative enzymes, the cytochromes. Central to an understanding of disorders involving these pigments is knowledge of iron uptake, metabolism, excretion, and storage (see Chapter 20). Hemoprotein accumulations in cells are caused by excessive storage of iron, which is transferred to the cells from the bloodstream. Iron enters the blood from three primary sources: (1) tissue stores, (2) the intestinal mucosa, and (3) macrophages that remove and destroy dead or defective red blood cells. The amount of iron in blood plasma depends also on the metabolism of the major iron transport protein, transferrin.

Iron is stored in tissue cells in two forms: as ferritin and, when increased levels of iron are present, as hemosiderin. Hemosiderin is a yellow-brown pigment derived from hemoglobin. With pathological states, excesses of iron cause hemosiderin to accumulate within cells, often in areas of bruising and hemorrhage and in the lungs and spleen after congestion caused by heart failure. With local hemorrhage, the skin first appears red-blue and then lysis of the escaped red blood cells occurs, causing the hemoglobin to be transformed to hemosiderin. The colour changes noted in bruising reflect this transformation (Figure 4-24).

FIGURE 4-24

Hemosiderin Accumulation Is Noted as the Colour Changes in a “Black Eye.”

Hemosiderosis is a condition in which excess iron is stored as hemosiderin in the cells of many organs and tissues. This condition is common in individuals who have received repeated blood transfusions or prolonged parenteral administration of iron. Hemosiderosis is associated also with increased absorption of dietary iron, conditions in which iron storage and transport are impaired, and hemolytic anemia. Excessive alcohol (e.g., wine) ingestion also can lead to hemosiderosis. Normally, absorption of excessive dietary iron is prevented by an iron absorption process in the intestines. Failure of this process can lead to total body iron accumulations in the range of 60 to 80 g, compared with normal iron stores of 4.5 to 5 g. Excessive accumulations of iron, such as occur in hemochromatosis (a genetic disorder of iron metabolism and the most severe example of iron overload), are associated with liver and pancreatic cell damage. Bilirubin is a normal, yellow-to-green pigment of bile derived from the porphyrin structure of hemoglobin. Excess bilirubin within cells and tissues causes jaundice (icterus), or yellowing of the skin. Jaundice occurs when the bilirubin level exceeds 25 to 34 mmol/L of plasma, compared with the normal values of 6.8 to 17.1 mmol/L. Hyperbilirubinemia occurs with (1) destruction of red blood cells (erythrocytes), such as in hemolytic jaundice; (2) diseases affecting the metabolism and excretion of bilirubin in the liver; and (3) diseases that cause obstruction of the common bile duct, such as gallstones or pancreatic tumours. Certain medications (specifically chlorpromazine [Largactil] and other phenothiazine derivatives), estrogenic hormones, and halothane (Fluothane) (an anaesthetic) can cause

the obstruction of normal bile flow through the liver. Because unconjugated bilirubin is lipid soluble, it can injure the lipid components of the plasma membrane. Albumin, a plasma protein, provides significant protection by binding unconjugated bilirubin in plasma. Unconjugated bilirubin causes two cellular outcomes: uncoupling of oxidative phosphorylation and a loss of cellular proteins. These two changes could cause structural injury to the various membranes of the cell.

Calcium Calcium salts accumulate in both injured and dead tissues (Figure 4-25). An important mechanism of cellular calcification is the influx of extracellular calcium in injured mitochondria. Another mechanism that causes calcium accumulation in alveoli (gas-exchange airways of the lungs), gastric epithelium, and renal tubules is the excretion of acid at these sites, leading to the local production of hydroxyl ions. Hydroxyl ions result in precipitation of calcium hydroxide, Ca(OH)2, and hydroxyapatite, Ca5(PO4)3OH, a mixed salt. Damage occurs when calcium salts cluster and harden, interfering with normal cellular structure and function.

FIGURE 4-25 Free Cytosolic Calcium: A Destructive Agent. Normally, calcium (Ca++) is removed from the cytosol by adenosine triphosphate (ATP)–dependent calcium pumps. In normal cells, calcium is bound to buffering proteins, such as calbindin or parvalbumin, and is contained in the endoplasmic reticulum and the mitochondria. If there is abnormal permeability of calcium-ion channels, direct damage to membranes, or depletion of ATP (i.e., hypoxic injury), calcium increases in the cytosol. If the free calcium cannot be buffered or pumped out of cells, uncontrolled enzyme activation takes place, causing further damage. Uncontrolled entry of calcium into the cytosol is an important final common pathway in many causes of cellular death.

Pathological calcification can be dystrophic or metastatic. Dystrophic calcification occurs in dying and dead tissues in areas of necrosis (see also the types of necrosis: coagulative, liquefactive, caseous, and fatty). It is present in chronic tuberculosis of the lungs and lymph nodes, advanced atherosclerosis (narrowing of the arteries as a result of plaque accumulation), and heart valve injury (Figure 4-26). Calcification of the heart valves interferes with their opening and closing, causing heart murmurs (see Chapter 24). Calcification of the coronary arteries predisposes them to severe narrowing and thrombosis, which can lead to myocardial infarction. Another site of dystrophic calcification is the centre of tumours. Over time, the centre is deprived of its oxygen supply, dies, and becomes calcified. The calcium salts appear as gritty, clumped granules that can become hard as stone. When several layers clump together, they resemble grains of sand and are called psammoma bodies.

FIGURE 4-26

Aortic Valve Calcification. A, This calcified aortic valve is an example of dystrophic calcification. B, This algorithm shows the dystrophic mechanism of calcification. (A, from Damjanov, I. [2012]. Pathology for the health professions [4th ed.]. St. Louis: Saunders.)

Metastatic calcification consists of mineral deposits that occur in undamaged normal tissues as the result of hypercalcemia (excess calcium in the blood; see Chapter 5). Conditions that cause hypercalcemia include hyperparathyroidism, toxic levels of vitamin D, hyperthyroidism, idiopathic hypercalcemia of infancy, Addison's disease (adrenocortical insufficiency), systemic sarcoidosis, milk-alkali syndrome, and the increased bone demineralization that results from bone tumours, leukemia, and disseminated cancers. Hypercalcemia also may occur in advanced renal failure with phosphate retention. As phosphate levels increase, the activity of the parathyroid gland increases, causing higher levels of circulating calcium.

Urate In humans, uric acid (urate) is the major end product of purine catabolism because of the absence of the enzyme urate oxidase. Serum urate concentration is, in general, stable: approximately 297.4 mcmol/L in postpubertal males and 243.9 mcmol/L in postpubertal females. Disturbances in maintaining serum urate levels result in hyperuricemia and the deposition of sodium urate crystals in the tissues, leading to painful disorders collectively called gout. These disorders include acute arthritis, chronic gouty arthritis, tophi (firm, nodular, subcutaneous deposits of urate crystals surrounded by fibrosis), and nephritis (inflammation of the nephron). Chronic hyperuricemia results in the deposition of urate in tissues, cellular injury, and inflammation. Because urate crystals are not degraded by lysosomal enzymes, they persist in dead cells.

Systemic Manifestations Systemic manifestations of cellular injury include a general sense of fatigue and malaise, a loss of wellbeing, and altered appetite. Fever is often present because of biochemicals produced during the

inflammatory response. Table 4-10 summarizes the most significant systemic manifestations of cellular injury. TABLE 4-10 Systemic Manifestations of Cellular Injury Manifestation

Cause

Fever

Release of endogenous pyrogens (interleukin-1, tumour necrosis factor-alpha, prostaglandins) from bacteria or macrophages; acute inflammatory response Increase in oxidative metabolic processes resulting from fever Increase in total number of white blood cells because of infection; normal is 5 000–9 000/mm3 (increase is directly related to severity of infection) Various mechanisms, such as release of bradykinins, obstruction, pressure Release of enzymes from cells of tissuea in extracellular fluid Release from red blood cells, liver, kidney, skeletal muscle

Increased heart rate Increase in leukocytes (leukocytosis) Pain Presence of cellular enzymes Lactate dehydrogenase (LDH) (LDH isoenzymes) Creatine kinase (CK) (CK isoenzymes) Aspartate aminotransferase (AST/SGOT) Alanine aminotransferase (ALT/SGPT) Alkaline phosphatase (ALP) Amylase Aldolase a

Release from skeletal muscle, brain, heart Release from heart, liver, skeletal muscle, kidney, pancreas Release from liver, kidney, heart Release from liver, bone Release from pancreas Release from skeletal muscle, heart

The rapidity of enzyme transfer is a function of the weight of the enzyme and the concentration gradient across the cellular membrane. The specific metabolic and excretory rates of the enzymes determine how long levels of enzymes remain elevated.

Cellular Death In response to significant external stimuli, cellular injury becomes irreversible and cells are forced to die. Cellular death has historically been classified as necrosis and apoptosis. Necrosis is characterized by rapid loss of the plasma membrane structure, swelling of organelles, dysfunction of the mitochondria, and lack of typical features of apoptosis.67 Apoptosis is known as a regulated or programmed cell process characterized by the “dropping off” of cellular fragments called apoptotic bodies. Too little or too much apoptosis is linked to many disorders, including neuro-degenerative diseases, ischemic damage, autoimmune disorders, and cancers. Yet, apoptosis can have normal functions, and unlike necrosis it is not always linked with a pathological process. Until recently, necrosis was only considered passive or accidental cellular death occurring after severe and sudden injury. It is the main outcome in several common injuries including ischemia, toxin exposure, certain infections, and trauma. It has now been proposed that under certain conditions, such as activation of death proteases, necrosis may be regulated or programmed in a well-orchestrated way as a backup for apoptosis (apoptosis may progress to necrosis)68— hence the new term programmed necrosis, or necroptosis. Necroptosis shares traits with both necrosis and apoptosis. Although the identification of the signalling mechanisms for necroptosis is incomplete, necroptosis is recognized in both normal physiological conditions and pathological conditions, including bone growth plate disorders, cellular death in fatty liver disease, acute pancreatitis, reperfusion injury, and certain neuro-degenerative disorders, such as Parkinson's disease.1 Historically, programmed cellular death only referred to apoptosis. Figure 4-27 illustrates the structural changes in cellular injury resulting in necrosis or apoptosis. Table 4-11 compares the unique features of necrosis and apoptosis. Other forms of cell loss include autophagy (self-eating) (see p. 105).

FIGURE 4-27 Schematic Illustration of the Morphological Changes in Cellular Injury Culminating in Necrosis or Apoptosis. Myelin figures come from degenerating cellular membranes and are noted within the cytoplasm or extracellularly. (From Kumar, V., Abbas, A.K., & Aster, J.C. [Eds.]. [2015]. Robbins and Cotran pathologic basis of disease [9th ed.]. Philadelphia: Saunders.)

TABLE 4-11 Features of Necrosis and Apoptosis Feature

Necrosis

Apoptosis

Cell size Nucleus Plasma membrane Cellular contents Adjacent inflammation Physiological or pathological role

Enlarged (swelling) Pyknosis → karyorrhexis → karyolysis Disrupted Enzymatic digestion; may leak out of cell Frequent Invariably pathological (culmination of irreversible cellular injury)

Reduced (shrinkage) Fragmentation into nucleosome-size fragments Intact; altered structure, especially orientation of lipids Intact; may be released in apoptotic bodies No Often physiological, means of eliminating unwanted cells; may be pathological after some forms of cellular injury, especially DNA damage

From Kumar, V., Abbas, A.K., & Aster, J.C. (2015). Cellular responses to stress and toxic insults: Adaptation, injury, and death. In V. Kumar, A.K. Abbas, & J.C. Aster (Eds.), Robbins and Cotran pathologic basis of disease (9th ed., pp. 31–68). Philadelphia: Saunders.

Necrosis Cellular death eventually leads to cellular dissolution, or necrosis. Necrosis is the sum of cellular changes after local cellular death and the process of cellular self-digestion, known as autodigestion or autolysis (see Figure 4-27). Cells die long before any necrotic changes are noted by light microscopy. The structural signs that indicate irreversible injury and progression to necrosis are dense clumping and progressive disruption both of genetic material and of plasma and organelle membranes. Because membrane integrity is lost, necrotic cell contents leak out and may cause the signalling of inflammation in surrounding tissue. In later stages of necrosis, most organelles are disrupted, and karyolysis (nuclear dissolution and lysis of chromatin from the action of hydrolytic enzymes) is under way. In some cells the nucleus shrinks and becomes a small, dense mass of genetic material (pyknosis). The pyknotic nucleus eventually dissolves (by karyolysis) as a result of the action of hydrolytic lysosomal enzymes on DNA. Karyorrhexis means fragmentation of the nucleus into smaller particles, or “nuclear dust.” Although necrosis still refers to death induced by nonspecific trauma or injury (e.g., cell stress or the heat shock response), with the very recent identification of molecular mechanisms regulating the process of necrosis, the study of necrosis has experienced a new twist. Unlike apoptosis, necrosis has been viewed as passive with cellular death occurring in a disorganized and unregulated manner. Some molecular regulators governing programmed necrosis have been identified and demonstrated to be interconnected by a large network of signalling pathways.69 Emerging evidence shows that programmed necrosis is associated with pathological diseases and provides innate immune response to viral infection.69 Different types of necrosis tend to occur in different organs or tissues and sometimes can indicate the mechanism or cause of cellular injury. The four major types of necrosis are coagulative, liquefactive, caseous, and fatty. Another type, gangrenous necrosis, is not a distinctive type of cellular death but refers instead to larger areas of tissue death. These necroses are summarized as follows: 1. Coagulative necrosis. It occurs primarily in the kidneys, heart, and adrenal glands; it commonly results from hypoxia caused by severe ischemia or hypoxia caused by chemical injury, especially ingestion of mercuric chloride. Coagulation is a result of protein denaturation, which causes the protein albumin to change from a gelatinous, transparent state to a firm, opaque state (Figure 4-28, A). The area of coagulative necrosis is called an infarct.

Types of Necrosis. A, Coagulative necrosis. A wedge-shaped kidney infarct (yellow). B, Liquefactive necrosis of the brain. The area of infarction is softened as a result of liquefaction necrosis. C, Caseous necrosis. Tuberculosis of the lung, with a large area of caseous necrosis containing yellow-white and cheesy debris. D, Fat necrosis of pancreas. Interlobular adipocytes are necrotic; acute inflammatory cells surround these. (A and C, from Kumar, V., Abbas, A.K., & Aster, J.C. [Eds.]. [2015]. Robbins and Cotran

FIGURE 4-28

pathologic basis of disease [9th ed.]. Philadelphia: Saunders. B, from Damjanov, I. [2012]. Pathology for the health professions [4th ed.]. St. Louis: Saunders. D, from Damjanov, I., & Linder, J. [Eds.]. [1996]. Anderson's pathology [10th ed.]. St. Louis: Mosby.)

2. Liquefactive necrosis. It commonly results from ischemic injury to neurons and glial cells in the brain (Figure 4-28, B). Dead brain tissue is readily affected by liquefactive necrosis because brain cells are rich in digestive hydrolytic enzymes and lipids, and the brain contains little connective tissue. Cells are digested by their own hydrolases, so the tissue becomes soft, liquefies, and segregates from healthy tissue, forming cysts. This process can be caused by bacterial infection, especially Staphylococci, Streptococci, and Escherichia coli. 3. Caseous necrosis. It usually results from tuberculous pulmonary infection, especially by Mycobacterium tuberculosis (Figure 4-28, C). It is a combination of coagulative and liquefactive necroses. The dead cells disintegrate, but the debris is not completely digested by the hydrolases. Tissues resemble clumped cheese in that they are soft and granular. A granulomatous inflammatory wall encloses areas of caseous necrosis. 4. Fatty necrosis. Fat necrosis is cellular dissolution caused by powerful enzymes, called lipases, that occur in the breast, pancreas, and other abdominal structures (Figure 4-28, D). Lipases break down triglycerides, releasing free fatty acids that then combine with calcium, magnesium, and sodium ions, creating soaps (saponification). The necrotic tissue appears opaque and chalk-white. 5. Gangrenous necrosis. Although it refers to death of tissue, this type of gangrene is not a specific pattern of cellular death. It results from severe hypoxic injury, which commonly occurs because of arteriosclerosis, or blockage, of major arteries, particularly those in the lower leg (Figure 4-29). With hypoxia and subsequent bacterial invasion, the tissues can undergo necrosis. Dry gangrene is usually the result of coagulative necrosis. The skin becomes very dry and shrinks, resulting in wrinkles, and its colour changes to dark brown or black. Wet gangrene develops when neutrophils invade the site, causing liquefactive necrosis. Wet gangrene also usually occurs in internal organs, causing the site to become cold, swollen, and black. A foul odour is present, and if systemic symptoms become severe, death can ensue.

FIGURE 4-29 Gangrene, a Complication of Necrosis. In certain circumstances, necrotic tissue will be invaded by putrefactive organisms that are both saccharolytic and proteolytic. Foul-smelling gases are produced, and the tissue becomes green or black as a result of breakdown of hemoglobin. Obstruction of the blood supply to the bowel almost inevitably is followed by gangrene.

6. Gas gangrene. This type of gangrene is caused by infection of injured tissue by one of many species of Clostridium. These anaerobic bacteria produce hydrolytic enzymes and toxins that destroy connective tissue and cellular membranes and cause bubbles of gas to form in muscle cells. Gas gangrene can be fatal if enzymes lyse the membranes of red blood cells, destroying their oxygen-carrying capacity. Death is caused by shock.

Apoptosis Apoptosis (“dropping off”) is an important distinct type of cellular death that differs from necrosis in several ways (see Figure 4-27 and Table 4-11). Apoptosis is an active process of cellular self-destruction called programmed cellular death and is implicated in both normal and pathological tissue changes. Cells need to die; otherwise, endless proliferation would lead to gigantic bodies. The average adult may create 10 billion new cells every day—and destroy the same number.70 Death by apoptosis causes loss of cells in many pathological states, including the following:

• Severe cellular injury. When cellular injury exceeds repair mechanisms, the cell triggers apoptosis. DNA damage can result either directly or indirectly from production of free radicals. • Accumulation of misfolded proteins. This state may result from genetic mutations or free radicals. Excessive accumulation of misfolded proteins in the ER leads to a condition known as ER stress (see Chapter 1). ER stress results in apoptotic cellular death. This mechanism has been linked to several degenerative diseases of the CNS and other organs (Figure 4-30).

FIGURE 4-30 The Unfolded Protein Response, Endoplasmic Stress, and Apoptosis. A, In normal or healthy cells the newly made proteins are folded with help from chaperones and then incorporated into the cell or secreted. B, Various stressors can cause endoplasmic reticulum (ER) stress whereby the cell is challenged to cope with the increased load of misfolded proteins. The accumulation of the protein load initiates the unfolded protein response in the ER; if restoration of the protein fails, the cell dies by apoptosis. An example of a disease caused by misfolding of proteins is Alzheimer's disease. (From Kumar, V., Abbas, A.K., & Aster, J.C. [Eds.]. [2015]. Robbins and Cotran pathologic basis of disease [9th ed.]. Philadelphia: Saunders.)

• Infections (particularly viral). Apoptosis may be the result of the virus directly or indirectly by the host immune response. Cytotoxic T lymphocytes respond to viral infections by inducing apoptosis and, therefore, eliminating the infectious cells. This process can cause tissue damage, and it is the same for cellular death in tumours and rejection of tissue transplants. • Obstruction in tissue ducts. In organs with duct obstruction, including the pancreas, kidney, and parotid gland, apoptosis causes pathological atrophy. Excessive or insufficient apoptosis is known as dysregulated apoptosis. A low rate of apoptosis can permit the survival of abnormal cells, for example, mutated cells that can increase cancer risk. Defective apoptosis may not eliminate lymphocytes that react against host tissue (self-antigens), leading to autoimmune disorders. Excessive apoptosis is known to occur in several neuro-degenerative diseases, from ischemic injury (such as myocardial infarction and stroke), and from death of virus-infected cells (such as seen in many viral infections). Apoptosis depends on a tightly regulated cellular program for its initiation and execution.70 This death program involves enzymes that divide other proteins—proteases, which are activated by proteolytic activity in response to signals that induce apoptosis. These proteases are called caspases, a family of aspartic acid–specific proteases. The activated suicide caspases cleave and, thereby, activate other members of the family, resulting in an amplifying “suicide” cascade. The activated caspases then cleave other key proteins in the cell, killing the cell quickly and neatly. The two different pathways that converge on caspase activation are called the mitochondrial (intrinsic) pathway and the death receptor (extrinsic) pathway (Figure 4-31). Cells that die by apoptosis release chemical factors that recruit phagocytes that quickly engulf the remains of the dead cell, thus reducing chances of inflammation. With necrosis, cellular death is not tidy because cells that die as a result of acute injury swell, burst, and spill their contents all over their neighbours, causing a likely damaging inflammatory response.

FIGURE 4-31 Mechanisms of Apoptosis. The two pathways of apoptosis differ in their induction and regulation, and both culminate in the activation of “executioner” caspases. The induction of apoptosis by the mitochondrial pathway involves the Bcl-2 family, which causes leakage of mitochondrial proteins. The regulators of the death receptor pathway involve the proteases, called caspases. TNF, tumour necrosis factor. (Adapted from Kumar, V., Abbas, A.K., & Aster, J.C. [Eds.]. [2015]. Robbins and Cotran pathologic basis of disease [9th ed.]. Philadelphia: Saunders.)

Autophagy The Greek term autophagy means “eating of self.” Autophagy, as a “recycling factory,” is a selfdestructive process and a survival mechanism. Basically, autophagy involves the delivery of cytoplasmic contents to the lysosome for degradation. Box 4-3 contains the terms used to describe autophagy.

Box 4-3

The Major Forms of Autophagy Macroautophagy, the most common term to refer to autophagy, involves the sequestration and transportation of parts (cargo) of the cytosol in an autophagic vacuole (autophagosome). Microautophagy is the inward invagination of the lysosomal membrane for cargo delivery. Chaperone-mediated autophagy is the chaperone-dependent proteins that direct cargo across the lysosomal membrane. When cells are starved or nutrient deprived, the autophagic process institutes cannibalization and recycles the digested contents.1,71 Autophagy can maintain cellular metabolism under starvation conditions and remove damaged organelles under stress conditions, improving the survival of cells. With the central role of autophagy in cell homeostasis, autophagy has been implicated in cancer, heart disease, neuro-degenerative diseases, inflammation, and infection.72 Autophagy begins with a membrane, also

known as a phagophore (although controversial) (Figure 4-32).73 This cup-shaped, curved phagophore expands and engulfs intracellular cargo—organelles, ribosomes, proteins—forming a double membrane autophagosome. The cargo-laden autophagosome fuses with the lysosome, now called an autophagolysosome, which promotes the degradation of the autophagosome by lysosomal acid proteases. The phagophore membrane is highly curved along the rim of the open cup, suggesting that mechanisms responsible for its formation and growth may depend on membrane curvature–dependent events.74 Lysosomal transporters export amino acids and other byproducts of degradation out of the cytoplasm where they can be reused for the synthesis of macromolecules and for metabolism.75,76 ATP is generated and cellular damage is reduced during autophagy that removes nonfunctional proteins and organelles.71

FIGURE 4-32 Autophagy. Cellular stresses, such as nutrient deprivation, activate autophagy genes that create vacuoles in which cellular organelles are sequestered and then degraded following fusion of the vesicles with lysosomes. The digested materials are recycled to provide nutrients for the cell.

Investigators are excited about the utilization of autophagy for therapeutic strategies. Autophagy is a critical garbage collecting and recycling process in healthy cells, and this process becomes less efficient and less discriminating as the cell ages. Consequently, harmful agents accumulate in cells, damaging cells and leading to aging: for example, failure to clear protein products in neurons of the CNS can cause dementia; failure to clear ROS-producing mitochondria can lead to nuclear DNA mutations and cancer. Thus these processes may even partially define aging. Therefore normal autophagy may potentially rejuvenate an organism and prevent cancer development as well as other degenerative diseases.77 In addition, autophagy may be the last immune defence against infectious microorganisms that penetrate intracellularly.78

Quick Check 4-4 1. Why is an increase in the concentration of intracellular calcium injurious? 2. Compare and contrast necrosis and apoptosis. 3. Why is apoptosis significant? 4. Define autophagy.

Aging and Altered Cellular and Tissue Biology The terms aging and lifespan tend to be used synonymously; however, they are not equivalent. Aging is usually defined as a normal physiological process that is universal and inevitable, whereas lifespan is the time from birth to death and has been used to study the aging process.79 Aging is associated with a gradual loss of homeostatic mechanisms whose underlying cause is perplexing,80 and is a complex process because of a multiplicity of factors. Investigators are focused on genetic, epigenetic, inflammatory, oxidative stress, and metabolic origins of aging, including the study of genetic signatures in humans with exceptional longevity; the identification and recent discovery of epigenetic mechanisms that modulate gene expression; the role of intrauterine environment and lifelong patterns of health; the effects of personality, behaviour, and social support; the influence of insulin/insulinlike growth factor 1 (IGF-1) signalling; and the contributions of cellular dysfunction and senescence to an inflammatory microenvironment that leads to chronic disease, frailty, and decreased lifespan. To focus more simply, the factors that may be most important for aging include increased damage to the cell, reduced capacity to divide (replicative senescence), reduced ability to repair damaged DNA, and increased likelihood of defective protein balance or homeostasis.1 A major challenge of aging research has been to separate the causes of cell and tissue aging from the vast changes that accompany it.80 Public health issues related to healthy aging require understanding of the nature of aging and the factors that predict healthy aging and delayed transition to increasing vulnerability and frailty. Traditionally, aging has not been considered a disease because it is “normal”; disease is usually considered “abnormal.” Conceptually, this distinction seems clear until the concept of “injury” or “damage” is introduced; disease has been defined by some pathologists as the result of injury. Chronological aging has been defined as the time-dependent loss of structure and function that proceeds very slowly and in such small increments that it appears to be the result of the accumulation of small, imperceptible injuries—a gradual result of wear and tear. One of the hallmarks of aging is the accumulation of damaged macromolecules. DNA damage can lead to cellular dysfunction both directly and indirectly as a consequence of cellular responses to damage that can lead to altered gene expression.81,82 Age-related changes to macromolecules for long-lived cells, such as neurons and myofibres, lead to gradual loss of structure and function. Replicative aging or senescence is the accumulation of cellular damage in continuously dividing cells, for example, epithelia of the skin or gastro-intestinal tract. One mechanism of replicative senescence is the progressive shortening of telomeres—the repeated sequences of DNA at the ends of chromosomes. Replicative aging and chronological aging are particularly important for adult stem cells because they divide throughout life.83 As mutations increase with age, cell fates include apoptosis, malignant transformation, cell-cycle arrest, or senescence.84 Despite the fact that aging and death are inevitable, lifespan, on the other hand, can be experimentally changed.81 Genetic and environmental interventions have extended the lifespan of model organisms, such as the nematode worm Caenorhabditis elegans (C. elegans), the fruit fly Drosophilia melanogaster, and mice.85,86 Extending lifespan, however, is not equivalent to delaying aging!80 For example, treatment of an acute infection can prevent death but the fundamental rate of aging continues. Yet, investigators will study and try to isolate, manipulate, and reset so-called longevity genes to slow the rate of aging. Recent advances in stem cell biology have begun to reveal the molecular mechanisms behind reprogramming events that occur during fertilization and when the nucleus of a mature somatic cell is transferred to an enucleated oocyte. Called somatic cell nuclear transfer (SCNT), this process gave rise to the first cloned mammal, Dolly the sheep, and led to the explosion of research in cloning.80 SCNT is important in terms of demonstrating the ability of the oocyte cytoplasm to reprogram the donor nucleus. These reprogramming events have led to the process to create induced pluripotent stem cells (iPSCs).87 The major emphasis of reprogramming research is the reversal of the differentiated program and attainment of a pluripotent state (differentiated cells in all three germ layers of the embryo) and not the reversal of aging.80,88 Nevertheless, each of these processes is discussed in the context of resetting the aging clock. Restoration of youthfulness to aged cells and tissues has created so-called rejuvenating interventions.

Experiments to test whether cells and tissues from an old animal can be restored to a younger self include the approach called heterochronic (i.e., young-to-old or old-to-young) transplantations and heterochronic parabiosis, when the systemic circulations of two animals are joined. The systemic environment may become more youthful with restoration of protein components in the blood and tissues, especially chemokines and cytokines.89 For example, investigators found a protein, GDF-11, may reverse ageassociated cardiac hypertrophy when injected into old animals.90 Administration of the medication rapamycin (Sirolimus), an mTOR inhibitor, can extend the lifespan of mice.91 These and future studies may not just change differentiation programs of cells and tissue but also possibly alter the aging clock. Observations in C. elegans suggest strongly that the causes of aging may be largely epigenetic.80,92,93

Normal Lifespan, Life Expectancy, and Quality-Adjusted Life Year The maximal lifespan of humans is between 80 and 100 years and does not vary significantly among populations. Life expectancy is the average number of years of life remaining at a given age, however, it does not include quality of life. The quality-adjusted life year (QALY) is a measure of disease burden including quality and not just quantity of live lived. Statistics Canada reported in 2009 that the life expectancy at birth was 79 years and 83 years for males and females, respectively. The lowest life expectancy was in Newfoundland/Labrador at 77 years for males and 81 years for males, and the highest was in British Columbia (80 years for males; 84 years for females).94

Degenerative Extracellular Changes Extracellular factors that affect the aging process include the binding of collagen; the increase in the effects of free radicals on cells; the structural alterations of fascia, tendons, ligaments, bones, and joints; and the development of peripheral vascular disease, particularly arteriosclerosis (see Chapter 24). Aging affects the ECM with increased cross-linking (e.g., aging collagen becomes more insoluble, chemically stable but rigid, resulting in decreased cell permeability), decreased synthesis, and increased degradation of collagen. The ECM determines the tissue's physical properties.95 These changes, together with the disappearance of elastin and changes in proteoglycans and plasma proteins, cause disorders of the ground substance that result in dehydration and wrinkling of the skin (see Chapter 41). Other agerelated defects in the ECM include skeletal muscle alterations (e.g., atrophy, decreased tone, loss of contractility), cataracts, diverticula, hernias, and rupture of intervertebral discs. Free radicals of oxygen that result from oxidative cellular metabolism, oxidative stress (e.g., respiratory chain, phagocytosis, prostaglandin synthesis), damage tissues during the aging process. The oxygen radicals produced include superoxide radical, hydroxyl radical, and hydrogen peroxide. These oxygen products are extremely reactive and can damage nucleic acids, destroy polysaccharides, oxidize proteins, peroxidize unsaturated fatty acids, and kill and lyse cells. Oxidant effects on target cells can lead to malignant transformation, presumably through DNA damage. That progressive and cumulative damage from oxygen radicals may lead to harmful alterations in cellular function is consistent with those alterations of aging. This hypothesis is founded on the wear-and-tear theory of aging, which states that damages accumulate with time, decreasing the organism's ability to maintain a steady state. Because these oxygen-reactive species not only can permanently damage cells but also may lead to cellular death, there is new support for their role in the aging process. Of much interest is the relationship between aging and the disappearance or alteration of extracellular substances important for vessel integrity. With aging, lipid, calcium, and plasma proteins are deposited in vessel walls. These depositions cause serious basement membrane thickening and alterations in smooth muscle functioning, resulting in arteriosclerosis (a progressive disease that causes such problems as stroke, myocardial infarction, renal disease, and peripheral vascular disease).

Cellular Aging Cellular changes characteristic of aging include atrophy, decreased function, and loss of cells, possibly caused by apoptosis (Figure 4-33). Loss of cellular function from any of these causes initiates the

compensatory mechanisms of hypertrophy and hyperplasia of the remaining cells, which can lead to metaplasia, dysplasia, and neoplasia. All of these changes can alter receptor placement and function, nutrient pathways, secretion of cellular products, and neuroendocrine control mechanisms. In the aged cell, DNA, RNA, cellular proteins, and membranes are most susceptible to injurious stimuli. DNA is particularly vulnerable to such injuries as breaks, deletions, and additions. Lack of DNA repair increases the cell's susceptibility to mutations that may be lethal or may promote the development of neoplasia (see Chapter 10).

FIGURE 4-33

Some Biological Changes Associated with Aging. Insets show the proportion of remaining functions in the organs of a person in late adulthood compared with those of a 20-year-old.

Mitochondria are the organelles responsible for the generation of most of the energy used by eukaryotic cells. Mitochondrial DNA (mtDNA) encodes some of the proteins of the electron-transfer chain, the system necessary for the conversion of ADP to ATP. Mutations in mtDNA can deprive the cell of ATP, and mutations are correlated with the aging process. The accumulation of mutations could be caused by errors in replication or by unrepaired damage.96,97 The most common age-related mtDNA mutation in humans is a large rearrangement called the 4977 deletion, or common deletion, and is found in humans older than 40 years. It is a deletion that removes all or part of 7 of the 13 protein-encoding mtDNA genes and 5 of the 22 transfer RNA genes. Individual cells containing this deletion have a condition known as heteroplasmy. Heteroplasmy levels rise with aging. Cumulative damage of mtDNA is implicated in the progression of such common diseases as diabetes, cancer, heart failure, and neuro-degenerative disorders.

Tissue and Systemic Aging It is probably safe to say that every physiological process functions less efficiently with increasing age. The most characteristic tissue change with age is a progressive stiffness or rigidity that affects many systems, including the arterial, pulmonary, and musculo-skeletal systems. A consequence of blood vessel and organ stiffness is a progressive increase in peripheral resistance to blood flow. The movement of intracellular and extracellular substances also decreases with age, as does the diffusion capacity of the lung. Blood flow through organs also decreases. Changes in the endocrine and immune systems include thymus atrophy. Although this occurs at puberty, causing a decreased immune response to T-dependent antigens (foreign proteins), increased formation of autoantibodies and immune complexes (antibodies that are bound to antigens), and an

overall decrease in the immunological tolerance for the host's own cells further diminish the effectiveness of the immune system later in life. In women the reproductive system loses ova, and in men spermatogenesis decreases. Responsiveness to hormones decreases in the breast and endometrium. The stomach experiences decreases in the rate of emptying and secretion of hormones and hydrochloric acid. Muscular atrophy diminishes mobility by decreasing motor tone and contractility. Sarcopenia, loss of muscle mass and strength, can occur into old age. The skin of the aged individual is affected by atrophy and wrinkling of the epidermis and by alterations in the underlying dermis, fat, and muscle. Total body changes include a decrease in height; a reduction in circumference of the neck, thighs, and arms; widening of the pelvis; and lengthening of the nose and ears. Several of these changes are the result of tissue atrophy and of decreased bone mass caused by osteoporosis and osteoarthritis. Some body composition changes include an increase in body weight, which begins in middle age (men gain until 50 years of age and women until 70 years), and an increase in fat mass followed by a decrease in stature, weight, fat-free mass, and body cell mass at older ages. Fat-free mass (FFM) includes all minerals, proteins, and water plus all other constituents except lipids. As the amount of fat increases, the percentage of total body water decreases. Increased body fat and centralized fat distribution (abdominal area) are associated with non–insulin-dependent diabetes and heart disease. Total body potassium concentration also decreases because of decreased cellular mass. An increased sodium–potassium ratio suggests that the decreased cellular mass is accompanied by an increased extracellular compartment. Although some of these alterations are probably inherent in aging, others represent consequences of the process. Advanced age increases susceptibility to disease, and death occurs after an injury or insult because of diminished cellular, tissue, and organ function.

Frailty Frailty is a common clinical syndrome in older adults, leaving a person vulnerable to falls, functional decline, disability, disease, and death. With an increasing aged population worldwide, efforts to promote independence and decrease frailty are challenging and needed. Sarcopenia and cachexia are a common consequence of aging and many acute and chronic illnesses.98 Investigators are grappling with a common nomenclature to develop consensus for definitions of sarcopenia and cachexia. One proposal has been to define each condition simply as “muscle wasting disease,” which can be applied in both acute and chronic settings.98 An acceptable vocabulary and classification system is yet to be developed. The determinants of sarcopenia include environmental and genetic factors, which presently are poorly understood.99 Common themes of mechanisms for sarcopenia include the following: (1) decrease in the number of skeletal muscle fibres, mainly type II fibres; (2) decline in muscle protein synthesis with age; (3) decline in muscle fractions, such as myofibrillar and mitochondrial, with age; (4) reduction in protein turnover adversely affecting muscle function by inducing protein loss and protein accumulation; (5) loss of alpha motor neurons in the spinal column; (6) dysregulation of anabolic hormones; (7) cytokine productions and inflammation; (8) inadequate nutrition; and (9) sedentary history.99,100 For research and clinical purposes, the criteria indicating compromised energetics include low grip strength, slowed walking speed, low physical activity, and unintentional weight loss.101 The syndrome is complex and involves other alterations such as osteopenia, cognitive impairment, and anemia, as well as gender differences.

Somatic Death Somatic death is death of the entire person. Unlike the changes that follow cellular death in a live body, postmortem change is diffuse and does not involve components of the inflammatory response. Within minutes after death, postmortem changes appear, eliminating any difficulty in determining that death has occurred. The most notable manifestations are complete cessation of respiration and circulation. The surface of the skin usually becomes pale and yellowish; however, the lifelike colour of the cheeks and lips may persist after death caused by carbon monoxide poisoning, drowning, or chloroform poisoning.102 Body temperature falls gradually immediately after death and then more rapidly (approximately 1°C/hr [33.8°F/hr]) until, after 24 hours, body temperature equals that of the environment.103 After death caused by certain infective diseases, body temperature may continue to rise for a short time. Postmortem reduction of body temperature is called algor mortis. Blood pressure within the retinal vessels decreases, causing muscle tension to decrease and the pupils to dilate. The face, nose, and chin become sharp or peaked-looking as blood and fluids drain from these areas.104 Gravity causes blood to settle in the most dependent, or lowest, tissues, which develop a purple discoloration called livor mortis. Incisions made at this time usually fail to cause bleeding. The skin loses its elasticity and transparency. Within 6 hours after death, acidic compounds accumulate within the muscles because of the breakdown of carbohydrates and the depletion of ATP. This increased acidity interferes with ATPdependent detachment of myosin from actin (contractile proteins), and muscle stiffening, or rigor mortis, develops. The smaller muscles are usually affected first, particularly the muscles of the jaw. Within 12 to 14 hours, rigor mortis usually affects the entire body. Signs of putrefaction are generally obvious about 24 to 48 hours after death. Rigor mortis gradually diminishes, and the body becomes flaccid at 36 to 62 hours. Putrefactive changes vary depending on the temperature of the environment. The most visible is greenish discoloration of the skin, particularly on the abdomen. The discoloration is thought to be related to the diffusion of hemolyzed blood into the tissues and the production of sulfhemoglobin, choleglobin, and other denatured hemoglobin derivatives.103,104 Slippage or loosening of the skin from underlying tissues occurs at the same time. After this, swelling or bloating of the body and liquefactive changes occur, sometimes causing opening of the body cavities. At a microscopic level, putrefactive changes are associated with the release of enzymes and lytic dissolution called postmortem autolysis.

Quick Check 4-5 1. Aging is a complex process. Describe the multitude of mechanisms of aging. 2. What are the body composition changes that occur with aging? 3. Define frailty and possible endocrine–immune system involvement.

Did You Understand? Cellular Adaptation 1. Cellular adaptation is a reversible, structural, or functional response both to normal or physiological conditions and to adverse or pathological conditions. Cells can adapt to physiological demands or stress to maintain a steady state called homeostasis. 2. The most significant adaptive changes in cells include atrophy, hypertrophy, hyperplasia, and metaplasia. 3. Atrophy is a decrease in cellular size caused by aging, disuse, or reduced/absent blood supply, hormonal stimulation, or neural stimulation. The amounts of endoplasmic reticulum (ER), mitochondria, and microfilaments decrease. The mechanisms of atrophy probably include decreased protein synthesis, increased protein catabolism, or both. A new hypothesis called ribosome biogenesis involves the role of messenger RNA (mRNA) and protein translation. 4. Hypertrophy is an increase in the size of cells in response to mechanical stimuli and consequently increases the size of the affected organ. The amounts of protein in the plasma membrane, ER, microfilaments, and mitochondria increase. Hypertrophy can be classified as physiological or pathological. 5. Hyperplasia is an increase in the number of cells caused by an increased rate of cellular division. Hyperplasia is classified as physiological (compensatory and hormonal) and pathological. 6. Dysplasia, or atypical hyperplasia, is an abnormal change in the size, shape, and organization of mature tissue cells. It is considered atypical rather than a true adaptational change. 7. Metaplasia is the reversible replacement of one mature cell type by another less mature cell type.

Cellular Injury 1. Injury to cells and to the extracellular matrix (ECM) lead to injury of tissues and organs, ultimately determining the structural patterns of disease. Cellular injury occurs if the cell is unable to maintain homeostasis—a normal or adaptive steady state—in the face of injurious stimuli or stress. Injured cells may recover (reversible injury) or die (irreversible injury). 2. Four biochemical themes are important to cellular injury: (a) adenosine triphosphate (ATP) depletion, resulting in mitochondrial damage; (b) accumulation of oxygen and oxygen-derived free radicals, causing membrane damage; (c) protein folding defects; and (d) increased intracellular calcium concentration and loss of calcium steady state. 3. Injury is caused by lack of oxygen (hypoxia), free radicals, caustic or toxic chemicals, infectious agents, inflammatory and immune responses, genetic factors, insufficient nutrients, or physical and mechanical trauma from many causes. 4. The sequence of events leading to cellular death is commonly decreased ATP production, failure of active transport mechanisms (the sodium–potassium pump), cellular swelling, detachment of ribosomes from the ER, cessation of protein synthesis, mitochondrial swelling as a result of calcium accumulation, vacuolation, leakage of digestive enzymes from lysosomes, autodigestion of intracellular structures, lysis of the plasma membrane, and death. 5. The initial insult in hypoxic injury is usually ischemia (the cessation of blood flow into vessels that supply the cell with oxygen and nutrients). 6. Free radicals cause cellular injury because they have an unpaired electron that makes the molecule unstable. To stabilize itself, the molecule either donates or accepts an electron from another molecule. Therefore it forms injurious chemical bonds with proteins, lipids, and carbohydrates— key molecules in membranes and nucleic acids. 7. The damaging effects of free radicals, especially activated oxygen species such as superoxide radical ( ), hydroxyl radical (OH−), and hydrogen peroxide (H2O2), called oxidative stress,

include (a) peroxidation of lipids, (b) alteration of ion pumps and transport mechanisms, (c) fragmentation of DNA, and (d) damage to mitochondria, releasing calcium into the cytosol. 8. Restoration of oxygen, however, can cause additional injury, called reperfusion injury. The mechanisms discussed for reperfusion injury include oxidative stress, increased intracellular calcium concentration, inflammation, and complement activation. 9. Humans are exposed to thousands of chemicals that have inadequate toxicological data. A systems biology approach is now being used to investigate toxicity pathways that include oxidative stress, heat shock proteins, DNA damage response, hypoxia, ER stress, mental stress, inflammation, and osmotic stress. 10. Unintentional and intentional injuries are an important health problem in Canada. Death as a result of these injuries is more common for men than women. 11. Injuries by blunt force are the result of the application of mechanical energy to the body, resulting in tearing, shearing, or crushing of tissues. The most common types of blunt-force injuries include motor vehicle accidents and falls. 12. A contusion is bleeding into the skin or underlying tissues as a consequence of a blow. A collection of blood in soft tissues or an enclosed space may be referred to as a hematoma. 13. An abrasion (scrape) results from removal of the superficial layers of the skin caused by friction between the skin and injuring object. Abrasions and contusions may have a patterned appearance that mirrors the shape and features of the injuring object. 14. A laceration is a tear or rip resulting when the tensile strength of the skin or tissue is exceeded. 15. An incised wound is a cut that is longer than it is deep. A stab wound is a penetrating sharp-force injury that is deeper than it is long. 16. Gunshot wounds may be either penetrating (bullet retained in the body) or perforating (bullet exits the body). The most important factors determining the appearance of a gunshot injury are whether it is an entrance or an exit wound and the range of fire. 17. Asphyxial injuries are caused by a failure of cells to receive or use oxygen. These injuries can be grouped into four general categories: suffocation, strangulation, chemical asphyxiants, and drowning. 18. Activation of inflammation and immunity, which occurs after cellular injury or infection, involves powerful biochemicals and proteins capable of damaging normal (uninjured and uninfected) cells. 19. Genetic disorders injure cells by altering the nucleus and the plasma membrane's structure, shape, receptors, or transport mechanisms. 20. Deprivation of essential nutrients (proteins, carbohydrates, lipids, vitamins) can cause cellular injury by altering cellular structure and function, particularly of transport mechanisms, chromosomes, the nucleus, and DNA. 21. Injurious physical agents include temperature extremes, changes in atmospheric pressure, ionizing radiation, illumination, mechanical stresses, and noise. 22. Errors in health care are a leading cause of injury or death in Canada. Errors involve medicines, surgery, diagnosis, equipment, and laboratory reports. They can occur anywhere in the health care system, including hospitals, clinics, outpatient surgery centres, physicians' and nurse practitioners' offices, pharmacies, and the individual's home.

Manifestations of Cellular Injury: Accumulations 1. An important manifestation of cellular injury is the resultant metabolic disturbances of intracellular accumulation (infiltration) of abnormal amounts of various substances. Two categories of accumulations are (a) normal cellular substances (e.g., excess water, proteins, lipids, and carbohydrates) and (b) abnormal substances, either endogenous (e.g., a product of abnormal metabolism or synthesis) or exogenous (e.g., a virus). 2. Most accumulations are attributed to four types of mechanisms, all abnormal: (a) an endogenous substance is produced in excess or at an increased rate; (b) an abnormal substance, often the result of a mutated gene, accumulates; (c) an endogenous substance is not effectively catabolized; and

(d) a harmful exogenous substance accumulates because of inhalation, ingestion, or infection. 3. Accumulations harm cells by “crowding” the organelles and by causing excessive (and sometimes harmful) metabolites to be produced during their catabolism. The metabolites are released into the cytoplasm or expelled into the ECM. 4. Cellular swelling, the accumulation of excessive water in the cell, is caused by the failure of transport mechanisms and is a sign of many types of cellular injury. Oncosis is a type of cellular death resulting from cellular swelling. 5. Accumulations of organic substances—lipids, carbohydrates, glycogen, proteins, pigments—are caused by disorders in which (a) cellular uptake of the substance exceeds the cell's capacity to catabolize (digest) or use it or (b) cellular anabolism (synthesis) of the substance exceeds the cell's capacity to use or secrete it. 6. Dystrophic calcification (accumulation of calcium salts) is always a sign of pathological change because it occurs only in injured or dead cells. Metastatic calcification, however, can occur in uninjured cells in individuals with hypercalcemia. 7. Disturbances in urate metabolism can result in hyperuricemia and deposition of sodium urate crystals in tissue—leading to a painful disorder called gout. 8. Systemic manifestations of cellular injury include fever, leukocytosis, increased heart rate, pain, and serum elevations of enzymes in the plasma.

Cellular Death 1. Cellular death has historically been classified as necrosis and apoptosis. Necrosis is characterized by rapid loss of the plasma membrane structure, organelle swelling, mitochondrial dysfunction, and the lack of features of apoptosis. Apoptosis is known as regulated or programmed cellular death and is characterized by “dropping off” of cellular fragments, called apoptotic bodies. It is now understood that under certain conditions necrosis is regulated or programmed, hence the new term programmed necrosis, or necroptosis. 2. The four major types of necrosis are coagulative, liquefactive, caseous, and fatty. Different types of necrosis occur in different tissues. 3. Structural signs that indicate irreversible injury and progression to necrosis are the dense clumping and disruption of genetic material and the disruption of the plasma and organelle membranes. 4. Apoptosis, a distinct type of sublethal injury, is a process of selective cellular self-destruction that occurs in both normal and pathological tissue changes. 5. Death by apoptosis causes loss of cells in many pathological states, including (a) severe cellular injury, (b) accumulation of misfolded proteins, (c) infections, and (d) obstruction in tissue ducts. 6. Excessive accumulation of misfolded proteins in the ER leads to a condition known as ER stress. ER stress results in apoptotic cellular death, and this mechanism has been linked to several degenerative diseases of the central nervous system and other organs. 7. Excessive or insufficient apoptosis is known as dysregulated apoptosis. 8. Autophagy means “eating of self,” and as a recycling factory it is a self-destructive process and a survival mechanism. When cells are starved or nutrient deprived, the autophagic process institutes cannibalization and recycles the digested contents. Autophagy can maintain cellular metabolism under starvation conditions and remove damaged organelles under stress conditions, improving the survival of cells. Autophagy declines and becomes less efficient as the cell ages, thus contributing to the aging process. 9. Gangrenous necrosis, or gangrene, is tissue necrosis caused by hypoxia and the subsequent bacterial invasion.

Aging and Altered Cellular and Tissue Biology 1. It is difficult to determine the physiological (normal) from the pathological changes of aging.

Investigators are focused on genetic, epigenetic, inflammatory, oxidative stress, and metabolic origins of aging. 2. Important factors in aging include increased damage to the cell, reduced capacity to divide, reduced ability to repair damaged DNA, and increased likelihood of defective protein balance or homeostasis. 3. Frailty is a common clinical syndrome in older adults, leaving a person vulnerable to falls, functional decline, disability, disease, and death. Sarcopenia and cachexia are a common consequence of aging.

Somatic Death 1. Somatic death is death of the entire person. Postmortem change is diffuse and does not involve components of the inflammatory response. 2. Manifestations of somatic death include cessation of respiration and circulation, gradual lowering of body temperature, dilation of the pupils, loss of elasticity and transparency in the skin, stiffening of the muscles (rigor mortis), and discoloration of the skin (livor mortis). Signs of putrefaction are obvious about 24 to 48 hours after death.

Key Terms Adaptation, 74 Aging, 107 Algor mortis, 110 Anoxia, 80 Anthropogenic, 93 Apoptosis, 105 Asphyxial injury, 93 Atrophy, 75 Autolysis, 102 Autophagic vacuole, 75 Autophagy, 106 Bilirubin, 99 Carbon monoxide (CO), 90 Carboxyhemoglobin, 90 Caseous necrosis, 103 Caspase, 105 Cellular accumulations (infiltrations), 96 Cellular swelling, 97 Chemical asphyxiant, 95 Choking asphyxiation, 93 Coagulative necrosis, 103 Compensatory hyperplasia, 77 Cyanide, 95 Cytochrome, 99 Disuse atrophy, 75 Drowning, 95 Dry-lung drowning, 95 Dysplasia (atypical hyperplasia), 77 Dystrophic calcification, 100 Electrophile, 84 ER stress, 105 Ethanol, 90 Fat-free mass (FFM), 109 Fatty change (steatosis), 98 Fatty necrosis, 103 Fetal alcohol spectrum disorder, 92 Frailty, 109 Free radical, 82 Gangrenous necrosis, 103 Gas gangrene, 105 Hanging strangulation, 95 Hemoprotein, 99 Hemosiderin, 99 Hemosiderosis, 99 Hormonal hyperplasia, 77 Hydrogen sulphide, 95 Hyperplasia, 77 Hypertrophy, 76 Hypoxia, 80

Hypoxia-inducible transcription factor (HIF), 80 Infarct, 103 Irreversible injury, 78 Ischemia, 80 Ischemia-reperfusion injury, 82 Karyolysis, 102 Karyorrhexis, 102 Lead (Pb), 88 Life expectancy, 108 Lifespan, 107 Ligature strangulation, 95 Lipid peroxidation, 83 Lipofuscin, 76 Liquefactive necrosis, 103 Livor mortis, 110 Manual strangulation, 95 Maximal lifespan, 108 Melanin, 99 Mesenchymal (tissue from embryonic mesoderm) cell, 78 Metaplasia, 78 Metastatic calcification, 100 Mitochondrial DNA (mtDNA), 108 Necrosis, 101 Nucleophile, 84 Oncosis (vacuolar degeneration), 97 Oxidative stress, 82 Pathological atrophy, 75 Pathological hyperplasia, 77 Physiological atrophy, 75 Postmortem autolysis, 110 Postmortem change, 109 Programmed necrosis (necroptosis), 101 Proteasome, 75 Protein adduct, 84 Psammoma body, 100 Pyknosis, 102 Quality-adjusted life year (QALY), 108 Reperfusion injury, 82 Reversible injury, 78 Rigor mortis, 110 Sarcopenia, 109 Somatic death, 109 Strangulation, 93 Suffocation, 93 Toxicophore, 84 Ubiquitin, 75 Ubiquitin–proteasome pathway, 75 Urate, 100 Vacuolation, 81 Xenobiotic, 83

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Fluids and Electrolytes, Acids and Bases Sue E. Huether, Stephanie Zettel

CHAPTER OUTLINE Distribution of Body Fluids and Electrolytes, 115 Water Movement Between Plasma and Interstitial Fluid, 115 Water Movement Between ICF and ECF, 116 Alterations in Water Movement, 116 Edema, 116 Sodium, Chloride, and Water Balance, 117 Alterations in Sodium, Chloride, and Water Balance, 120 Isotonic Alterations, 121 Hypertonic Alterations, 121 Hypotonic Alterations, 121 Alterations in Potassium and Other Electrolytes, 122 Potassium, 122 Other Electrolytes—Calcium, Phosphate, and Magnesium, 126 Acid-Base Balance, 126 Hydrogen Ion and pH, 126 Buffer Systems, 126 Acid-Base Imbalances, 128 PEDIATRIC CONSIDERATIONS: Distribution of Body Fluids, 132 GERIATRIC CONSIDERATIONS: Distribution of Body Fluids, 132

The cells of the body live in a fluid environment with electrolyte and acid-base concentrations maintained within a narrow range. Changes in electrolyte concentration affect the electrical activity of nerve and muscle cells and cause shifts of fluid from one compartment to another. Alterations in acid-base balance disrupt cellular functions. Fluid fluctuations also affect blood volume and cellular function. Disturbances in these functions are common and can be life-threatening. Understanding how alterations occur and how

the body compensates or corrects the disturbance is important for comprehending many pathophysiological conditions.

Distribution of Body Fluids and Electrolytes The sum of fluids within all body compartments constitutes total body water (TBW)—about 60% of body weight in adults (Table 5-1). The volume of TBW is usually expressed as a percentage of body weight in kilograms. One litre of water weighs 1 kg. The rest of the body weight is composed of fat and fat-free solids, particularly bone. TABLE 5-1 Total Body Water (%) in Relation to Body Weight Body Build

Adult Male

Adult Female

Child (1–10 yr)

Infant (1 mo–1 yr)

Newborn (Up to 1 mo)

Normal Lean Obese

60 70 50

50 60 42

65 50-60 50

70 80 60

70–80

NOTE:

Total body water is a percentage of body weight.

mo, month; yr, year.

Body fluids are distributed among functional compartments, or spaces, and provide a transport medium for cellular and tissue function. Intracellular fluid (ICF) comprises all the fluid within cells, about two thirds of TBW. Extracellular fluid (ECF) is all the fluid outside the cells (about one third of TBW) and includes interstitial fluid (the space between cells and outside the blood vessels) and intravascular fluid (blood plasma) (Table 5-2). The total volume of body water for a 70-kg person is about 42 litres. Other ECF compartments include lymph and transcellular fluids, such as synovial, intestinal, and cerebrospinal fluid; sweat; urine; and pleural, peritoneal, pericardial, and intraocular fluids. TABLE 5-2 Distribution of Body Water (70-kg Man) Fluid Compartment

% of Body Weight

Volume (L)

Intracellular fluid (ICF) Extracellular fluid (ECF) Interstitial Intravascular Total body water (TBW)

40 20 15 5 60

28 14 11 3 42

Electrolytes and other solutes are distributed throughout the intracellular and extracellular fluid (Table 5-3). Note that ECF contains a large amount of sodium and chloride and a small amount of potassium, whereas the opposite is true of ICF. The concentrations of phosphates and magnesium are greater in ICF, and the concentration of calcium is greater in ECF. These differences are important for the maintenance of electroneutrality between the extracellular and intracellular compartments, the transmission of electrical impulses, and the movement of water among body compartments (see Chapter 1). TABLE 5-3 Representative Distribution of Electrolytes in Body Compartments Electrolytes Cations Sodium Potassium Calcium Magnesium TOTAL Anions Bicarbonate Chloride Phosphate Proteins Other anions TOTAL

ECF (mmol/L)

ICF (mmol/L)

142 4.2 2.5 1 149.7

12 150 0 12 174

24 103 2 16 8 153

12 4 100 65 6 187

ECF, extracellular fluid; ICF, intracellular fluid.

Although the amount of fluid within the various compartments is relatively constant, solutes (e.g.,

salts) and water are exchanged between compartments to maintain their unique compositions. The percentage of TBW varies with the amount of body fat and age. Because fat is water repelling (hydrophobic), very little water is contained in adipose (fat) cells. Individuals with more body fat have proportionately less TBW and tend to be more susceptible to dehydration. The distribution and the amount of TBW change with age (see the Pediatric Considerations and Geriatric Considerations boxes later in this chapter), and although daily fluid intake may fluctuate widely, the body regulates water volume within a relatively narrow range. Water obtained by drinking, water ingested in food, and water derived from oxidative metabolism are the primary sources of body water. Normally, the largest amounts of water are lost through renal excretion, with lesser amounts lost through the stool and vaporization from the skin and lungs (insensible water loss) (Table 5-4). TABLE 5-4 Normal Water Gains and Losses (70-kg Man) Daily Intake (mL) Drinking Water in food Water of oxidation

1 400–1 800 700–1 000 300–400

TOTAL

2 400–3 200

Daily Output (mL) Urine Stool Skin Lungs TOTAL

1 400–1 800 100 300–500 600–800 2 400–3 200

Water Movement Between Plasma and Interstitial Fluid The distribution of water and the movement of nutrients and waste products between the capillary and interstitial spaces occur as a result of changes in hydrostatic pressure (pushes water) and osmotic or oncotic pressure (pulls water) at the arterial and venous ends of the capillary (see Figure 1-24). Water, sodium, and glucose readily move across the capillary membrane. The plasma proteins normally do not cross the capillary membrane and maintain effective osmolality by generating plasma oncotic pressure (particularly albumin). As plasma flows from the arterial to the venous end of the capillary, four forces determine whether fluid moves out of the capillary and into the interstitial space (filtration) or whether fluid moves back into the capillary from the interstitial space (reabsorption). These four forces acting together are described as net filtration or Starling forces: 1. Capillary hydrostatic pressure (blood pressure) facilitates the outward movement of water from the capillary to the interstitial space. 2. Capillary (plasma) oncotic pressure osmotically attracts water from the interstitial space back into the capillary. 3. Interstitial hydrostatic pressure facilitates the inward movement of water from the interstitial space into the capillary. 4. Interstitial oncotic pressure osmotically attracts water from the capillary into the interstitial space. The forces moving fluid back and forth across the capillary wall are summarized as follows:

At the arterial end of the capillary, hydrostatic pressure exceeds capillary oncotic pressure and fluid moves into the interstitial space (filtration). At the venous end of the capillary, capillary oncotic pressure exceeds capillary hydrostatic pressure and fluids are attracted back into the circulation (reabsorption). Interstitial hydrostatic pressure promotes the movement of about 10% of the interstitial fluid along with small amounts of protein into the lymphatics, which then returns to the circulation. Because albumin does not normally cross the capillary membrane, interstitial oncotic pressure is normally minimal. Figure 5-1 illustrates net filtration.

FIGURE 5-1 Net Filtration—Fluid Movement Between Plasma and Interstitial Space. The movement of fluid between the vascular, interstitial spaces and the lymphatics is the result of net filtration of fluid across the semipermeable capillary membrane. Capillary hydrostatic pressure is the primary force for fluid movement out of the arteriolar end of the capillary and into the interstitial space. At the venous end, capillary oncotic pressure (from plasma proteins) attracts water back into the vascular space. Interstitial hydrostatic pressure promotes the movement of fluid and proteins into the lymphatics. Osmotic pressure accounts for the movement of fluid between the interstitial space and the intracellular space. Normally, intracellular and extracellular fluid osmotic pressures are equal (280 to 294 mOsm) and water is equally distributed between the interstitial and intracellular compartments.

Water Movement Between ICF and ECF Water moves between ICF and ECF compartments primarily as a function of osmotic forces. Water moves freely by diffusion through the lipid bilayer cell membrane and through aquaporins, a family of water channel proteins that provide permeability to water.1 Sodium is responsible for the ECF osmotic balance, and potassium maintains the ICF osmotic balance. The osmotic force of ICF proteins and other nondiffusible substances is balanced by the active transport of ions out of the cell. Water crosses cell membranes freely, so the osmolality of TBW is normally at equilibrium. Normally ICF is not subject to rapid changes in osmolality, but when ECF osmolality changes, water moves from one compartment to another until osmotic equilibrium is re-established (see “Isotonic Alterations,” p. 121).

Alterations in Water Movement Edema Edema is excessive accumulation of fluid within the interstitial spaces. The forces favouring fluid movement from the capillaries or lymphatic channels into the tissues are increased capillary hydrostatic pressure, decreased plasma oncotic pressure, increased capillary membrane permeability, and lymphatic channel obstruction2 (Figure 5-2).

FIGURE 5-2

Mechanisms of Edema Formation. H2O, water; Na+, sodium.

Pathophysiology Capillary hydrostatic pressure increases as a result of venous obstruction or salt and water retention. Venous obstruction causes hydrostatic pressure to increase behind the obstruction, pushing fluid from the capillaries into the interstitial spaces. Thrombophlebitis (inflammation of veins), hepatic obstruction, tight clothing around the extremities, and prolonged standing are common causes of venous obstruction. Heart failure, renal failure, and cirrhosis of the liver are associated with excessive salt and water retention, which cause plasma volume overload, increased capillary hydrostatic pressure, and edema. Since plasma albumin acts like a magnet to attract water, loss or diminished production (e.g., from liver disease or protein malnutrition) contributes to decreased plasma oncotic pressure. Plasma proteins are lost in glomerular diseases of the kidney, serous drainage from open wounds, hemorrhage, burns, and cirrhosis of the liver. The decreased oncotic attraction of fluid within the capillary causes filtered capillary fluid to remain in the interstitial space, resulting in edema. Capillaries become more permeable with inflammation and immune responses, especially with trauma such as burns or crushing injuries, neoplastic disease, and allergic reactions. Proteins escape from the vascular space and produce edema through decreased capillary oncotic pressure and interstitial fluid protein accumulation. The lymphatic system normally absorbs interstitial fluid and a small amount of proteins. When lymphatic channels are blocked or surgically removed, proteins and fluid accumulate in the interstitial space, causing lymphedema.3 For example, lymphedema of the arm or leg occurs after surgical removal of axillary or femoral lymph nodes, respectively, for treatment of carcinoma. Inflammation or tumours may cause lymphatic obstruction, leading to edema of the involved tissues. Clinical manifestations Edema may be localized or generalized. Localized edema is usually limited to a site of trauma, as in a

sprained finger. Another kind of localized edema occurs within particular organ systems and includes cerebral, pulmonary, and laryngeal edema; pleural effusion (fluid accumulation in the pleural space); pericardial effusion (fluid accumulation within the membrane around the heart); and ascites (accumulation of fluid in the peritoneal space). Edema of specific organs, such as the brain, lung, or larynx, can be life-threatening. Generalized edema is manifested by a more uniform distribution of fluid in interstitial spaces. Dependent edema, in which fluid accumulates in gravity-dependent areas of the body, might signal more generalized edema. Dependent edema appears in the feet and legs when standing and in the sacral area and buttocks when supine (lying on back). It can be identified by pressing on tissues overlying bony prominences. A pit left in the skin indicates edema (hence the term pitting edema) (Figure 5-3).

FIGURE 5-3

Pitting Edema. (From Bloom, A., & Ireland, J. [1992]. Color atlas of diabetes [2nd ed.]. St. Louis: Mosby.)

Edema usually is associated with weight gain, swelling and puffiness, tight-fitting clothes and shoes, limited movement of affected joints, and symptoms associated with the underlying pathological condition. Fluid accumulations increase the distance required for nutrients and waste products to move between capillaries and tissues. Blood flow may be impaired also. Therefore wounds heal more slowly, and with prolonged edema the risks of infection and pressure sores over bony prominences increase. As edematous fluid accumulates, it is trapped in a “third space” (i.e., the interstitial space, pleural space, pericardial space) and is unavailable for metabolic processes or perfusion. Dehydration can develop as a result of this sequestering. Such sequestration occurs with severe burns, where large amounts of vascular fluid are lost to the interstitial spaces, reducing plasma volume and causing shock (see Chapter 24). Evaluation and Treatment Specific conditions causing edema require diagnosis. Edema may be treated symptomatically until the underlying disorder is corrected. Supportive measures include elevating edematous limbs, using compression stockings, avoiding prolonged standing, restricting salt intake, and taking diuretics. Administration of intravenous (IV) albumin can be required in severe cases.

Quick Check 5-1 1. How does an increase in capillary hydrostatic pressure cause edema? 2. How does a decrease in capillary oncotic pressure cause edema?

Sodium, Chloride, and Water Balance The kidneys and hormones have a central role in maintaining sodium and water balance. Because water follows the osmotic gradients established by changes in salt concentration, sodium concentration and water balance are intimately related. Sodium concentration is regulated by renal effects of aldosterone (see Figure 18-18). Water balance is regulated primarily by antidiuretic hormone (ADH; also known as vasopressin). Sodium (Na+) accounts for 90% of the ECF cations (positively charged ions) (see Table 5-3). Along with its constituent anions (negatively charged ions) chloride and bicarbonate, sodium regulates extracellular osmotic forces and therefore regulates water balance. Sodium is important in other functions, including maintenance of neuromuscular irritability for conduction of nerve impulses (in conjunction with potassium and calcium; see Figure 1-29), regulation of acid-base balance (using sodium bicarbonate and sodium phosphate), participation in cellular chemical reactions, and transport of substances across the cellular membrane. The kidney, in conjunction with neural and hormonal mediators, maintains normal serum sodium concentration within a narrow range (136 to 145 mmol/L) primarily through renal tubular reabsorption. Hormonal regulation of sodium (and potassium) balance is mediated by aldosterone, a mineralocorticoid synthesized and secreted from the adrenal cortex as a component of the renin-angiotensin-aldosterone system. Aldosterone secretion is influenced by circulating blood volume, blood pressure, and plasma concentrations of sodium and potassium. When circulating blood volume or blood pressure is reduced, sodium levels are depressed, or potassium levels are increased, renin, an enzyme secreted by the juxtaglomerular cells of the kidney, is released. Renin stimulates the formation of angiotensin I, an inactive polypeptide. Angiotensin-converting enzyme (ACE) in pulmonary vessels converts angiotensin I to angiotensin II, which stimulates the secretion of aldosterone and ADH and also causes vasoconstriction. The aldosterone promotes renal sodium and water reabsorption and excretion of potassium, increasing blood volume (Figure 5-4; see also Figure 29-9). Vasoconstriction elevates the systemic blood pressure and restores renal perfusion (blood flow). This restoration inhibits the further release of renin.

FIGURE 5-4

The Renin-Angiotensin-Aldosterone System. BP, blood pressure; ECF, extracellular fluid; Na+, sodium. (Modified from Herlihy, B., &

Maebius, N. [2011]. The human body in health and disease [4th ed.]. Philadelphia: Saunders. Borrowed from Lewis, S.L., Bucher, L., Heitkemper, M.M., et al. [2014]. Medical-surgical nursing: Assessment and management of clinical problems [9th ed.]. St. Louis: Mosby.)

Natriuretic peptides are hormones primarily produced by the myocardium. Atrial natriuretic hormone (ANH) is produced by the atria. B-type natriuretic peptide (BNP) is produced by the ventricles. Urodilatin (an ANP analogue) is synthesized within the kidney. Natriuretic peptides are released when there is an increase in transmural atrial pressure (increased volume), which may occur with heart failure

or when there is an increase in mean arterial pressure4 (Figure 5-5). They are natural antagonists to the renin-angiotensin-aldosterone system. Natriuretic peptides cause vasodilation and increase sodium and water excretion, decreasing blood pressure. Natriuretic peptides are sometimes called a “third factor” in sodium regulation. (Increased glomerular filtration rate is thus the first factor and aldosterone the second factor.)

FIGURE 5-5

The Natriuretic Peptide System. ANH, atrial natriuretic hormone; BNP, brain natriuretic peptide; GFR, glomerular filtration rate; Na+, sodium

Chloride (Cl−) is the major anion in ECF and provides electroneutrality, particularly in relation to sodium. Chloride transport is generally passive and follows the active transport of sodium so that increases or decreases in chloride concentration are proportional to changes in sodium concentration. Chloride concentration tends to vary inversely with changes in the concentration of bicarbonate ( ), the other major anion. Water balance is regulated by the secretion of ADH. ADH is secreted when plasma osmolality increases or circulating blood volume decreases and blood pressure drops (Figure 5-6). Increased plasma osmolality occurs with water deficit or sodium excess in relation to TBW. The increased osmolality stimulates hypothalamic osmoreceptors. In addition to causing thirst, these osmoreceptors signal the posterior pituitary gland to release ADH. Thirst stimulates water drinking and ADH increases water reabsorption into the plasma from the distal tubules and collecting ducts of the kidney (see Chapter 29). The reabsorbed water decreases plasma osmolality, returning it toward normal, and urine concentration increases.

FIGURE 5-6

The Antidiuretic Hormone System. ADH, antidiuretic hormone.

With fluid loss (dehydration) from vomiting, diarrhea, or excessive sweating, a decrease in blood volume and blood pressure often occurs. Volume-sensitive receptors and baroreceptors (nerve endings that are sensitive to changes in volume and pressure) also stimulate the release of ADH from the pituitary gland and stimulate thirst. The volume receptors are located in the right and left atria and thoracic vessels; baroreceptors are found in the aorta, pulmonary arteries, and carotid sinus. ADH secretion also occurs when atrial pressure drops, as occurs with decreased blood volume and with the release of angiotensin II (see Figure 29-9). The reabsorption of water mediated by ADH then promotes the restoration of plasma volume and blood pressure (see Figure 5-6).

Quick Check 5-2 1. What forces promote net filtration? 2. How do hormones regulate salt and water balance? 3. What are aquaporins?

Alterations in Sodium, Chloride, and Water Balance Alterations in sodium and water balance are closely related. Sodium imbalances occur with gains or losses of body water. Water imbalances develop with gains or losses of salt. In general, these alterations can be classified as changes in tonicity, the change in the concentration of solutes in relation to water: isotonic, hypertonic, or hypotonic (Table 5-5 and Figure 5-7; see also Figure 1-25). Changes in tonicity also alter the volume of water in the intracellular and extracellular compartments, resulting in isovolemia, hypervolemia, or hypovolemia. TABLE 5-5 Water and Solute Imbalances Tonicity

Mechanism

Isotonic (iso-osmolar) imbalance Serum osmolality = 280–294 mOsm/kg Hypertonic (hyperosmolar) imbalance Serum osmolality >294 mOsm/kg Hypotonic (hypo-osmolar) imbalance Serum osmolality 0.9% salt solution (i.e., water loss or solute gain); cells shrink in hypertonic fluid Imbalance that results in ECF 2.6 mmol/L) Hyperparathyroidism; bone metastases with calcium resorption from breast, prostate, renal, and cervical cancer; sarcoidosis; excess

Hyperphosphatemia (serum concentrations >1.5 mmol/L)

Hypermagnesemia (serum concentrations >1.25 mmol/L) Acute or chronic renal failure with significant loss of Usually renal insufficiency or failure; also glomerular filtration; treatment of metastatic tumours with excessive intake of magnesium-containing

vitamin D; many tumours that produce PTH

Effects

chemotherapy that releases large amounts of phosphate into serum; long-term use of laxatives or enemas containing phosphates; hypoparathyroidism Many nonspecific; fatigue, weakness, lethargy, anorexia, nausea, Symptoms primarily related to low serum calcium levels constipation; impaired renal function, kidney stones; dysrhythmias, (caused by high phosphate levels) similar to results of bradycardia, cardiac arrest; bone pain, osteoporosis hypocalcemia; when prolonged, calcification of soft tissues in lungs, kidneys, joints

Deficit

Hypocalcemia (serum calcium concentration 35 years)

Data from Daroff, R.B., Fenichel, G.M., Jankovic, J., et al. (2012). Bradley's neurology in clinical practice (6th ed.). Philadelphia: Saunders.

The threshold for seizures may be lowered by hypoglycemia, fatigue or lack of sleep, emotional or physical stress, fever, large amounts of water ingestion, constipation, use of antipsychotic medications (i.e., chlorpromazine [Largactil] and clozapine [Clozaril]) especially when combined with alcohol, withdrawal from depressant medications (including alcohol), or hyperventilation (respiratory alkalosis). Some environmental stimuli, such as blinking lights, a poorly adjusted television screen, loud noises, certain music, certain odours, or merely being startled, have been known to initiate a seizure. Women may have increased seizure activity immediately before or during menses.

Types of Seizure Seizures are classified in different ways: by clinical manifestations, site of origin, electroencephalogram (EEG) correlates, or response to therapy. Types of seizures and clinical manifestations are presented in Chapter 17 (see Table 17-6). Terms used to describe seizure activity are defined in Table 15-14. TABLE 15-14 Terminology Applied to a Seizure Disorder Term

Definition

Preictal Phase Prodroma Early clinical manifestation (such as malaise, headache, or sense of depression) that may occur a few days to hours before onset of a seizure Aura A partial seizure experienced as a peculiar sensation preceding onset of generalized seizure that may take the form of gustatory, visual, or auditory experience or a feeling of dizziness, numbness, or just “a funny feeling” Ictal Phase The event of the seizure Tonic phase A state of muscle contraction in which there is excessive muscle tone

Clonic phase Postictal Phase

A state of alternating contraction and relaxation of muscles Time period immediately following cessation of seizure activity

Epilepsy now is considered to be the result of the interaction of complex genetic mutations with environmental effects that cause abnormalities in synaptic transmission, an imbalance in the brain's neurotransmitters, or the development of abnormal nerve connections after injury.22 A group of neurons may exhibit a paroxysmal depolarization shift and function as an epileptogenic focus. These neurons are hypersensitive and are more easily activated by hyperthermia, hypoxia, hypoglycemia, hyponatremia, repeated sensory stimulation, and certain sleep phases. Epileptogenic neurons fire more frequently and with greater amplitude. When the intensity reaches a threshold point, cortical excitation spreads. Excitation of the subcortical, thalamic, and brainstem areas corresponds to the tonic phase (muscle contraction with increased muscle tone) and is associated with loss of consciousness. The clonic phase (alternating contraction and relaxation of muscles) begins when inhibitory neurons in the cortex, anterior thalamus, and basal ganglia react to the cortical excitation. The seizure discharge is interrupted, producing intermittent muscle contractions that gradually decrease and finally cease. The epileptogenic neurons are exhausted. During seizure activity, oxygen is consumed at a high rate—about 60% greater than normal. Although cerebral blood flow (CBF) also increases, oxygen is rapidly depleted, along with glucose, and lactate accumulates in brain tissue. Continued, severe seizure activity has the potential for progressive brain injury and irreversible damage. In addition, if a seizure focus in the brain is active for a prolonged period, a mirror focus may develop in contralateral normal tissue and cause seizure activity. Clinical manifestations The clinical manifestations associated with seizure depend on its type (see Table 17-6). Two types of symptoms signal the preictal phase of a generalized tonic–clonic seizure: prodroma, early manifestations occurring hours to days before a seizure and that may include anxiety, depression, or inability to think clearly; and a partial seizure that immediately precedes the onset of a generalized tonic–clonic seizure. Both may become familiar to the person experiencing recurrent generalized seizures and may enable the person to prevent injuries during the seizure. The ictus is the episode of the epileptic seizure with tonic– clonic activity. Relaxation of urinary and bowel sphincters may occur, leading to bladder and bowel incontinence. Airway maintenance needs to be ensured. Status epilepticus in adults is a state of continuous seizures lasting more than 5 minutes, or rapidly recurring seizures before the person has fully regained consciousness from the preceding seizure, or a single seizure lasting more than 30 minutes. The postictal phase follows an epileptic seizure and can include signs of headache, confusion, dysphasia, memory loss, and paralysis that may last hours or a day or two. Deep sleep also is common.23 Evaluation and treatment The health history, physical examination, and laboratory tests of blood and urine (concentrations of blood glucose, serum calcium, blood urea nitrogen, and urine sodium; and creatinine clearance time) can identify systemic diseases known to promote seizures. Brain imaging and CSF examination help identify neurological diseases associated with seizures. The EEG is used to assess the type of seizure and determine its focus in brain tissue. Treatment for a seizure disorder is to first correct or control its cause, if possible. If this treatment is not possible, the major means of management is the judicious administration of antiseizure medications. Dietary treatments (e.g., ketogenic and Atkins diet) are effective for some individuals. Surgical interventions can improve seizure control and quality of life in people with medication-resistant epilepsy.24,25

Quick Check 15-4 1. What is an epileptogenic focus? 2. Why can so many conditions precipitate seizures?

3. Why is continued seizing dangerous?

Alterations in Cerebral Hemodynamics An injured brain reacts with structural, chemical, and pathophysiological changes. Primary brain injury is the original trauma and secondary brain injury is a consequence of alterations in CBF, intracranial pressure (ICP), and oxygen delivery (Box 15-4 and see Chapter 16).

Box 15-4

Cerebral Hemodynamics Cerebral blood flow to the brain is normally maintained at a rate that matches local metabolic needs of the brain. Cerebral perfusion pressure (70 to 90 mm Hg) is the pressure required to perfuse the cells of the brain. Cerebral blood volume is the amount of blood in the intracranial vault at a given time. Cerebral blood oxygenation is measured by oxygen saturation in the internal jugular vein. Intracranial pressure normally is 1 to 15 mm Hg, or 60 to 180 cm H2O. Alterations in CBF may be related to three injury states: (1) inadequate cerebral perfusion, (2) normal cerebral perfusion but with an elevated ICP, and (3) excessive cerebral blood volume (CBV). Treatments for these injury states are directed at improving or maintaining cerebral perfusion pressure (CPP), as well as controlling ICP.

Increased Intracranial Pressure Increased intracranial pressure (increased ICP) may result from an increase in intracranial content (as occurs with tumour growth), edema, excess CSF, or hemorrhage. It necessitates an equal reduction in volume of the other cranial contents. The most readily displaced content is CSF. If ICP remains high after CSF displacement out of the cranial vault, CBV and blood flow are altered. In stage 1 of intracranial hypertension, vasoconstriction and external compression of the venous system occur in an attempt to further decrease the ICP. Thus, during the first stage of intracranial hypertension, ICP may not change because of the effective compensatory mechanisms, and there may no detectable symptoms (Figure 15-9). Small increases in volume, however, cause an increase in pressure, and the pressure may take longer to return to baseline. This pressure change can be detected with ICP monitoring.

FIGURE 15-9

Clinical Correlates of Compensated and Uncompensated Stages of Intracranial Hypertension. (From Beare, P.G., & Myers, J.L. [1998]. Principles and practice of adult health nursing [3rd ed.]. St. Louis: Mosby.)

In stage 2 of intracranial hypertension, there is continued expansion of intracranial contents. The resulting increase in ICP may exceed the ability of the brain's compensatory mechanisms to adjust. The pressure begins to compromise neuronal oxygenation, and systemic arterial vasoconstriction occurs in an attempt to elevate the systemic blood pressure sufficiently to overcome the increased ICP. Clinical manifestations at this stage usually are subtle and transient, including episodes of confusion, restlessness, drowsiness, and slight pupillary and breathing changes (see Figure 15-9). Interventions at this stage reduce ICP and promote better clinical outcomes. In stage 3 of intracranial hypertension, ICP begins to approach arterial pressure, the brain tissues begin to experience hypoxia and hypercapnia, and the individual's condition rapidly deteriorates. Clinical manifestations include decreasing levels of arousal or central neurogenic hyperventilation, widened pulse pressure, bradycardia, and small, sluggish pupils (see Figure 15-9). Dramatic sustained rises in ICP are not seen until all compensatory mechanisms have been exhausted. Then dramatic rises in ICP occur over a very short period. Autoregulation, the compensatory alteration in the diameter of the intracranial blood vessels designed to maintain a constant blood flow during changes in CPP, is lost with progressively increased ICP. Accumulating carbon dioxide may still cause vasodilation locally, but without autoregulation this vasodilation causes the blood pressure in the vessels to drop and the blood volume to increase. The brain volume is thus further increased and ICP continues to rise. Small increases in volume cause dramatic increases in ICP, and the pressure takes much longer to return to baseline. As the ICP begins to approach systemic blood pressure, CPP falls and cerebral perfusion slows dramatically. The brain tissues experience severe hypoxia, hypercapnia, and acidosis. In stage 4 of intracranial hypertension, brain tissue shifts (herniates) from the compartment of greater pressure to a compartment of lesser pressure and increased ICP in one compartment of the cranial vault is not evenly distributed throughout the other vault compartments (see Figures 15-9 and 15-10). With this shift in brain tissue, the herniating brain tissue's blood supply is compromised, causing further ischemia and hypoxia in the herniating tissues. The volume of content within the lower pressure compartment increases, exerting pressure on the brain tissue that normally occupies that compartment, and thus impairs its blood supply. For example, herniation into the brainstem impairs the vital cardiovascular and respiratory regulatory centres and can cause death. The herniation process markedly and rapidly increases ICP. Mean systolic arterial pressure soon equals ICP, and CBF ceases at this point. The types of brain herniation syndromes are outlined in Box 15-5.

FIGURE 15-10 Brain Herniation Syndromes. Herniations can occur both above and below the tentorial membrane. Supratentorial: 1, uncal (transtentorial); 2, central; 3, cingulate; 4, transcalvarial (external herniation through an opening in the skull). Infratentorial: 5, upward herniation of cerebellum; 6, cerebellar tonsillar move down through foramen magnum.

Box 15-5

Brain Herniation Syndromes Supratentorial Herniation 1. Uncal herniation. It occurs when the uncus or hippocampal gyrus, or both, shifts from the middle fossa through the tentorial notch into the posterior fossa, compressing the ipsilateral third cranial nerve, the contralateral third cranial nerve, and the mesencephalon. Uncal herniation generally is caused by an expanding mass in the lateral region of the middle fossa. The classic manifestations of uncal herniation are a decreasing level of consciousness, pupils that become sluggish before fixing and dilating (first the ipsilateral, then the contralateral pupil), Cheyne-Stokes respirations (which later shift to central neurogenic hyperventilation), and the appearance of decorticate and then decerebrate posturing. 2. Central herniation. It occurs when there is a straight downward shift of the diencephalon through the tentorial notch. It may be caused by injuries or masses located around the outer perimeter of the frontal, parietal, or occipital lobes; extracerebral injuries around the central apex (top) of the cranium; bilaterally positioned injuries or masses; and unilateral cingulate gyrus herniation. The individual rapidly becomes unconscious; moves from Cheyne-Stokes respirations to apnea; develops small, reactive pupils and then dilated, fixed pupils; and passes from decortication to decerebration. 3. Cingulate gyrus herniation. It occurs when the cingulate gyrus shifts under the falx cerebri. Little is known about its clinical manifestations. 4. Transcalvarial. The brain shifts through a skull fracture or a surgical opening in the skull. This type of external herniation may occur during a craniectomy—surgery in which a flap of skull is removed. This type of herniation prevents the piece of skull from being replaced.

Infratentorial Herniation 1. The most common syndrome is cerebellar tonsillar. The cerebellar tonsil shifts through the foramen magnum because of increased pressure within the posterior fossa. The clinical manifestations are an arched stiff neck, paresthesias in the shoulder area, decreased consciousness, respiratory abnormalities, and pulse rate variations. Occasionally the force produces an upward transtentorial herniation of a cerebellar tonsil or the lower brainstem. There is increased intracranial pressure but

no specific set of clinical manifestations associated with infratentorial herniation (see Figure 15-10).

Cerebral Edema Cerebral edema is an increase in the fluid content of brain tissue (Figure 15-11). The result is increased extracellular or intracellular tissue volume. It occurs after brain insult from trauma, infection, hemorrhage, tumour, ischemia, infarction, or hypoxia. The harmful effects of cerebral edema are caused by distortion of blood vessels, displacement of brain tissues, increase in ICP, and eventual herniation of brain tissue to a different brain compartment.

FIGURE 15-11 Brain Edema. This coronal section of the cerebrum demonstrates marked compression in the lateral ventricles (long arrows) and flattening of gyri (short arrows) from extensive bilateral cerebral edema. Edema increases intracranial pressure, leading to herniation. (From Klatt, E.C. [2010]. Robbins and Cotran atlas of pathology [2nd ed.]. Philadelphia: Saunders.)

Three types of cerebral edema are (1) vasogenic edema, (2) cytotoxic (metabolic) edema, and (3) interstitial edema. Vasogenic edema is clinically the most important type and is caused by the increased permeability of the capillary endothelium of the brain after injury to the vascular structure. The selective permeability of capillaries that comprise the blood–brain barrier is disrupted. Plasma proteins leak into the extracellular spaces, drawing water to them and increasing the water content of the brain parenchyma. Vasogenic edema begins in the area of injury and spreads, with fluid accumulating in the white matter of the ipsilateral side because the parallel myelinated fibres separate more easily. Edema promotes more edema because of ischemia from the increasing ICP. Clinical manifestations of vasogenic edema include focal neurological deficits, disturbances of consciousness, and a severe increase in ICP. Vasogenic edema resolves by slow diffusion. In cytotoxic (metabolic) edema, toxic factors directly affect the cellular elements of the brain parenchyma (neuronal, glial, and endothelial cells), causing failure of the active transport systems. The cells lose their potassium and gain larger amounts of sodium. Water follows by osmosis into the cells, so that the cells swell. Cytotoxic edema occurs principally in the grey matter and may increase vasogenic edema. Interstitial edema is seen most often with noncommunicating hydrocephalus. The edema is caused by transependymal movement of CSF from the ventricles into the extracellular spaces of the brain tissues. The brain fluid volume increases predominantly around the ventricles, with increased hydrostatic pressure within the white matter. The size of the white matter is reduced because of the rapid disappearance of myelin lipids.

Hydrocephalus The term hydrocephalus refers to various conditions characterized by excess fluid in the cerebral ventricles, subarachnoid space, or both. Hydrocephalus occurs because of interference with CSF flow caused by increased fluid production, obstruction within the ventricular system, or defective reabsorption of the fluid. A tumour of the choroid plexus may, in rare instances, cause overproduction of CSF. The types of hydrocephalus are reviewed in Table 15-15.

TABLE 15-15 Types of Hydrocephalus Type

Mechanism

Cause

Noncommunicating

Obstruction of CSF flow between ventricles Aqueduct stenosis Arnold-Chiari malformation (brain extension through foramen magnum) Compression by tumour Impaired absorption of CSF within subarachnoid space Compression of subarachnoid space by a tumour High venous pressure in sagittal sinus Head injury Congenital malformation Increased CSF secretion by choroid plexus

Congenital abnormality

Communicating

Infection with inflammatory adhesions

Secreting tumour

CSF, cerebrospinal fluid.

Hydrocephalus may develop from infancy through adulthood. Communicating hydrocephalus is defective resorption of CSF from the cerebral subarachnoid space and is found more often in adults. Noncommunicating hydrocephalus (internal hydrocephalus, intraventricular hydrocephalus) is obstruction within the ventricular system and is seen more often in children (see Figure 17-6). Congenital hydrocephalus is ventricular enlargement before birth and is rare. Pathophysiology The obstruction of CSF flow associated with hydrocephalus produces increased pressure and dilation of the ventricles proximal to the obstruction. The increased pressure and dilation cause atrophy of the cerebral cortex and degeneration of the white matter tracts. Selective preservation of grey matter occurs. When excess CSF fills a defect caused by atrophy, a degenerative disorder, or a surgical excision, this fluid is not under pressure; therefore, atrophy and degenerative changes do not occur. Clinical manifestations Most cases of hydrocephalus develop gradually and insidiously over time. Acute hydrocephalus presents with signs of rapidly developing increased ICP. The person quickly deteriorates into a deep coma if not promptly treated. Normal-pressure hydrocephalus (dilation of the ventricles without increased pressure) develops slowly, with the individual or family noting declining memory and cognitive function. The triad symptoms of an unsteady, broad-based gait with a history of falling; incontinence; and dementia are common and may be treated surgically.26 Evaluation and treatment The diagnosis is based on physical examination, computed tomography (CT) scan, and magnetic resonance imaging (MRI). A radioisotopic cisternogram may be performed to diagnose normal-pressure hydrocephalus. Hydrocephalus can be treated by surgery to resect cysts, neoplasms, or hematomas or by ventricular bypass into the normal intracranial channel or into an extracranial compartment using a shunting procedure, one of the three most common neurosurgical procedures. Excision or coagulation of the choroid plexus occasionally is needed when a papilloma is present. In normal-pressure hydrocephalus, reduction in CSF is achieved through diuresis or placement of a ventriculoperitoneal shunt.27

Quick Check 15-5 1. What are the four stages of increased intracranial pressure? 2. How does supratentorial herniation differ from infratentorial herniation? 3. What are the different types of cerebral edema? 4. How is communicating hydrocephalus different from noncommunicating hydrocephalus?

Alterations in Neuromotor Function Movements are complex patterns of activity controlled by the cerebral cortex, the pyramidal system, the extrapyramidal system, and the motor units. Dysfunction in any of these areas can cause motor dysfunction. General neuromotor dysfunctions are associated with changes in muscle tone, movement, and complex motor performance.

Alterations in Muscle Tone Normal muscle tone involves a slight resistance to passive movement. Throughout the range of motion, the resistance is smooth, constant, and even. The alterations of muscle tone and their characteristics and causes are presented in Table 15-16. TABLE 15-16 Alterations in Muscle Tone Alterations Characteristics

Cause

Hypotonia

Thought to be caused by decreased muscle spindle activity as a result of decreased excitability of neurons (e.g., muscular dystrophy, cerebral palsy)

Flaccidity Hypertonia

Spasticity

Paratonia (gegenhalten) Dystonia

Passive movement of a muscle mass with little or no resistance Muscles may be moved rapidly without resistance Associated with limp, atrophied muscles, and paralysis Increased muscle resistance to passive movement May be associated with paralysis May be accompanied by muscle hypertrophy A gradual increase in tone causing increased resistance until tone suddenly diminishes, which results in clasp-knife phenomenon; increased deep tendon reflexes (hyperreflexia); clonus (spread of reflexes) Resistance to passive movement, which varies in direct proportion to force applied Sustained involuntary muscle contraction with twisting movement

Rigidity

Muscle resistance to passive movement of a rigid limb that is uniform in both flexion and extension throughout the motion Plastic or lead- Increased muscular tone relatively independent of degree of force used in pipe rigidity passive movement; does not vary throughout the passive movement Cogwheel Uniform resistance may be interrupted by a series of brief jerks, resulting in rigidity movements much like a ratchet, cogwheel phenomenon Gamma Characterized by extensor posturing (decerebrate rigidity) rigidity Alpha rigidity Impaired relaxation characterized by extensor rigidity of skeletal muscle after contraction

Occurs typically when nerve impulses necessary for muscle tone are lost Results when lower motor unit reflex arc continues to function but is not mediated or regulated by higher centres (e.g., stroke, brain tumours, multiple sclerosis) Exact mechanism unclear; appears to arise from an increased excitability of alpha motor neurons to any input because of absence of descending inhibition of pyramidal systems (e.g., multiple sclerosis, brain trauma, cerebral palsy) Exact mechanism unclear; associated with frontal lobe injury (e.g., progressive Alzheimer's dementia) Produced by slow muscular contraction; lack of reciprocal inhibition of muscle (e.g., neuroleptic medication adverse effects, meningitis) Occurs as a result of constant, involuntary contraction of muscle—usually involves extrapyramidal tracts (e.g., Parkinson's disease) Associated with basal ganglion damage (e.g., Parkinson's disease) Associated with basal ganglion damage Loss of excitation of extensor inhibitory areas by cerebral cortex decreasing inhibition of alpha and gamma motor neurons Loss of cerebellum input to lateral vestibular nuclei

Hypotonia In hypotonia (decreased muscle tone), passive movement of a muscle occurs with little or no resistance. Causes include cerebellar damage and pure pyramidal tract damage (a rare occurrence). The hypotonia contributes to the ataxia and intention tremor in cerebellar damage and manifests with minimal weakness and normal or slightly exaggerated reflexes. A pure pyramidal tract injury produces hypotonia and weakness. Hypotonia also occurs when the nerve impulses needed for muscle tone are lost, such as in spinal cord injury or cerebrovascular accident. Individuals with hypotonia tire easily or are weak. They may have difficulty rising from a sitting position, sitting down without using arm support, and walking up and down stairs, as well as an inability to stand on their toes. Because of their weakness, accidents during ambulatory and self-care activities are common. The joints become hyperflexible, so persons with hypotonia may be able to assume positions that require extreme joint mobility. The joints may appear loose. The muscle mass atrophies because of decreased input entering the motor unit, and muscles appear flabby and flat. Muscle cells are gradually replaced by connective tissue and fat. Fasciculations may be present in some cases.

Hypertonia In hypertonia (increased muscle tone), passive movement of a muscle occurs with resistance to stretch and is caused by upper motor neuron damage (see p. 381). The four types of hypertonia are spasticity (usually corticospinal in origin) (Figures 15-12 and 15-13), paratonia (gegenhalten), dystonia (Figure 1514), and rigidity (usually extrapyramidal in origin). Four types of rigidity are described: plastic or lead-

pipe, cogwheel, gamma (independent of stretch reflex pathways), and alpha (dependent on stretch reflex pathways) (see Table 15-16).

FIGURE 15-12

Paroxysm of Left-Sided Hemifacial Spasm. (From Perkin, G.D. [2002]. Mosby's color atlas and text of neurology [2nd ed.]. London: Mosby.)

FIGURE 15-13

Dystonic Posturing of the Hand and Foot. (From Perkin, G.D. [2002]. Mosby's color atlas and text of neurology [2nd ed.]. London: Mosby.)

FIGURE 15-14

Spasmodic Torticollis. A characteristic head posture related to spasticity. (From Perkin, G.D. [2002]. Mosby's color atlas and text of neurology [2nd ed.]. London: Mosby.)

Individuals with hypertonia tire easily or are weak. Passive movement and active movement are affected equally, except in paratonia, in which more active than passive movement is possible. As a result of hypertonia and weakness, accidents occur during ambulatory and self-care activities. The muscles may atrophy because of decreased use. However, hypertrophy occasionally occurs as a result of the overstimulation of muscle fibres. Overstimulation occurs when the motor unit reflex arc remains intact and functioning but is not inhibited by higher centres. This lack of higher-centre inhibition causes continual muscle contraction, resulting in enlargement of the muscle mass and the development of firm muscles.

Alterations in Muscle Movement Movement requires a change in the contractile state of muscles. Abnormal movements occur when CNS dysfunction alters muscle innervation. The neurotransmitter dopamine has a role in several movement disorders. Some movement disorders (e.g., the akinesias) result from too little dopaminergic activity, whereas others (e.g., chorea, ballism, tardive dyskinesia) result from too much dopaminergic activity. Still others are not primarily related to dopamine function. Movement disorders are not necessarily associated with muscle mass, strength, or tone but are neurological dysfunctions resulting in insufficient or excessive movement or involuntary movement. Hyperkinesia is excessive, purposeless movement and represents the second broad category of abnormal movements. Within this category are a number of specific dysfunctions including tremors (Table 15-17). Also included under the general category of hyperkinesias are dyskinesias and abnormal involuntary movements. Huntington's disease symptoms are the hallmark of hyperkinesia. TABLE 15-17 Types of Hyperkinesia and Tremor Type Hyperkinesia Choreaa Athetosisa

Ballism

Hyperactivity

Wandering Akathisia

Tremor at Rest Parkinsonian tremor

Characteristics

Causes

Nonrepetitive muscular contractions, usually of extremities of face; random pattern of irregular, involuntary rapid contractions of groups of muscles; disappears with sleep, decreases with resting; increases with emotional stress and attempted voluntary movement Disorder of distal muscle postural fixation; slow, sinuous, irregular movements most obvious in distal extremities, more rhythmic than choreiform movements and always much slower; movements accompany characteristic hand posture; slowly fluctuating grimaces Disorder of proximal muscle postural fixation with wild flinging movement of limbs; movement is severe and stereotyped, usually lateral; does not lessen with sleep; ballism is most common on one side of body, a condition termed hemiballism

Associated with excess concentration of or supersensitivity to dopamine within basal ganglia

State of prolonged, generalized, increased activity that is largely involuntary but may be subject to some voluntary control; not highly stereotyped but rather manifests as continuous changes in total body posture or in excessive performance of some simple activity, such as pacing under inappropriate circumstances Tendency to wander without regard for environment Special type of hyperactivity; mild compulsion to move (usually more localized to legs); severe, frenzied motion possible; movements are partly voluntary and may be transiently suppressed; carrying out movement brings sense of relief; frequent complication of antipsychotic medications Rhythmic, oscillating movement affecting one or more body parts Regular, rhythmic, slower flexion-extension contraction; involves principally metacarpophalangeal and wrist joints; alternating movements between thumb and index finger described as “pill rolling”; disappears during voluntary movement

Postural Tremor Asterixis Irregular flapping movement of hands accentuated by outstretching arms (tremor of hepatic encephalopathy) Metabolic Rapid, rhythmic tremor affecting fingers, lips, and tongue; accentuated by extending body part; enhanced physiological tremor

Occurs most commonly as result of injury to putamen of basal ganglion; exact pathophysiological mechanism is not known Results from injury to subthalamic nucleus (one of nuclei that comprise basal ganglia); thought to be caused by reduced inhibitory influence in nucleus, a release phenomenon; hemiballism results from injury to contralateral subthalamic nucleus May be caused by frontal and reticular activating system injury

“Release phenomenon” associated with bilateral injury to globus pallidus or putamen Dopaminergic transmission may be involved

Caused by regular contraction of opposing groups of muscles Loss of inhibitory influence of dopamine in the basal ganglia, causing instability of basal ganglial feedback circuit within cerebral cortex

Exact mechanisms responsible unknown; thought to be related to accumulation of products normally detoxified by liver (e.g., ammonia)

Occurs in conditions associated with disturbed metabolism or toxicity, as in thyrotoxicosis (hyperthyroidism), alcoholism, and chronic use of barbiturates, amphetamines, lithium, or amitriptyline (Elavil); exact mechanism responsible unknown Tremor of fingers, hands, and feet; absent at rest but accentuated by extension of body part, Not associated with any other neurological abnormalities; cause unknown prolonged muscular activity, and stress

Essential (familial) Intention Tremor Cerebellar Tremor initiated by movement, maximal toward end of movement

Rubral

Rhythmic tremor of limbs that originates proximally by movement

Occurs in disease of dentate nucleus (one of deep cerebellar nuclei responsible for efferent output) and superior cerebellar peduncle (stalklike structure connected to pons); caused by errors in feedback from periphery and errors in preprogramming goal-directed movement Results from lesions involving dentatorubrothalamic tract (a spinothalamic tract connecting red nucleus in reticular formation and dentate nucleus in

Myoclonus

Series of shocklike, nonpatterned contractions of portion of a muscle, entire muscle, or group of muscles that cause throwing movements of a limb; usually appear at random but frequently triggered by sudden startle; do not disappear during sleep

cerebellum) Associated with an irritable nervous system and spontaneous discharge of neurons; structures associated with myoclonus include cerebral cortex, cerebellum, reticular formation, and spinal cord

a

Choreoathetosis involves both chorea and athetosis; precise pathophysiology is unknown.

Paroxysmal dyskinesias are abnormal, involuntary movements that occur as spasms. The type of dyskinesia varies depending on the specific disorder. Tardive dyskinesia is the involuntary movement of the face, lip, tongue, trunk, and extremities. Although the condition occurs occasionally in individuals with Parkinson's disease, it usually occurs as a adverse effect of prolonged antipsychotic medication therapy. The most common symptom of tardive dyskinesia is rapid, repetitive, stereotypical movements, such as continual chewing with intermittent protrusions of the tongue, lip smacking, and facial grimacing. The symptoms also are called extrapyramidal symptoms because the extrapyramidal system controls involuntary reflexes and coordination of movement and posture (see Table 15-19). Other movement disorders in this category are (1) complex repetitive movements, including automatism (unconscious behaviour), stereotypy (ritualistic behaviour such as rocking), complex tics such as Tourette syndrome (see Health Promotion: Tourette Syndrome), compulsions, perseverations, and mannerisms; (2) excessive reactions to certain stimuli; and (3) paroxysmal excessive activity, including cataplexy and excessive startle reaction.

Health Promotion Tourette Syndrome There is growing evidence that Tourette syndrome (TS) occurs worldwide and has common features across all races and cultures. The hallmark of TS is the presence of motor tics (sudden, rapid, repetitive nonrhythmic movements) and vocal tics. The tics may be either simple, involving only an individual muscle group (e.g., eye blinking or grunting), or complex, requiring coordinated movement of muscle groups (e.g., head banging or repeating of another person's words). The syndrome has a complex multifactorial etiology with undetermined genetic, environmental, immune, and hormonal factors. Recent research has indicated that exposure to certain environmental factors during the prenatal, perinatal, and postnatal periods may impact the onset and progression of TS. The pregnancy-related exposures include maternal smoking and prenatal life stressors. Other factors that may cause a worsening of TS-related tics include low birth weight and forceps use during delivery. Further studies have also indicated that exposure to certain pathogens may be linked to the disease. Additional studies exploring these relationships may hold promise for the improvement of the course of TS related to these modifiable risk factors. Data from Hoekstra, P.J., Dietrich, A., Edwards, M.J., et al. (2013). Neurosci Biobehav Rev, 37(6), 1040–1049.

Hypokinesia is decreased amplitude of movement, bradykinesia is decreased speed of movement, and akinesia is absence of voluntary movement. All of these terms represent a deficit of voluntary movement. Parkinson's disease symptoms are the hallmark of a lack of voluntary movement.

Huntington's Disease Huntington's disease (HD), also known as chorea, is a relatively rare, hereditary, degenerative hyperkinetic movement disorder diffusely involving the basal ganglia and cerebral cortex. The onset of HD is usually between 25 and 45 years of age, when the trait may already have been passed to the person's children. The disorder has a prevalence rate of approximately 5 to 10 per 100 000 persons and occurs in all races.28 Pathophysiology HD is inherited from one or both parents who have the autosomal dominant trait with high penetrance.

The genetic defect of HD is on the short arm of chromosome 4. There is an abnormally long polyglutamine tract in the huntingtin (htt) protein that is toxic to neurons caused by a cytosine-adenineguanine (CAG) trinucleotide repeat expansion (40 to 70 repeats instead of 9 to 34) with abnormal protein folding. Age of symptom onset is related to the length of the repeat sequences and mechanisms of toxicity. Repeat lengths greater than 60 cause the juvenile form of the disease.29 Fathers, but not mothers, with high normal alleles do not develop HD but are at risk of transmitting potentially penetrant HD alleles (greater than or equal to 36) to their offspring, who can develop HD.30 The principal pathological feature of HD is severe degeneration of the basal ganglia, particularly the caudate nucleus. Tangles of protein (htt protein) collect in the brain cells and chains of glutamine on the abnormal molecules stick to each other and contribute to neuronal loss. Basal ganglia and nigral depletion of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, is the principal biochemical alteration in HD. It alters the integration of motor and mental function.31 Clinical manifestations Symptoms of HD progress slowly and include involuntary fragmentary movements, such as chorea, athetosis, and ballism (see Table 15-17). Chorea, the most common type of abnormal movement, begins in the face and arms, eventually affecting the entire body. There is emotional lability and progressive dysfunction of intellectual and thought processes (dementia). Any one of these features may mark the onset of the disease. Cognitive deficits include loss of working memory and reduced capacity to plan, organize, and sequence. Thinking is slow, and apathy is present. Restlessness, disinhibition, and irritability are common. Euphoria or depression may be present. Evaluation and treatment The diagnosis of HD is based on family history and clinical presentation of the disorder. Neuroradiological abnormalities can be demonstrated up to 15 years before clinical symptoms. No known treatment is effective in halting the degeneration or progression of symptoms, and the disease is fatal. Symptomatic medication therapies are available.32

Hypokinesia Hypokinesia (decreased movement) is loss of voluntary movement despite preserved consciousness and normal peripheral nerve and muscle function. Types of hypokinesia include akinesia, bradykinesia, and loss of associated movement.

Akinesia and bradykinesia. Akinesia is a decrease in voluntary and associated movements. It is related to dysfunction of the extrapyramidal system and caused by either a deficiency of dopamine or a defect of the postsynaptic dopamine receptors, which occurs in parkinsonism. Bradykinesia is slowness of voluntary movements. All voluntary movements become slow, laboured, and deliberate, with difficulty in (1) initiating movements, (2) continuing movements smoothly, and (3) performing synchronous (at the same time) and consecutive tasks. Both akinesia and bradykinesia involve a delay in the time it takes to start to perform a movement.

Loss of associated movement. In hypokinesia, the normal, habitually associated movements that provide skill, grace, and balance to voluntary movements are lost. Decreased associated movements accompanying emotional expression cause an expressionless face, a statuelike posture, absence of speech inflection, and absence of spontaneous gestures. Decreased associated movements accompanying locomotion cause reduction in arm and shoulder movements, hip swinging, and rotary motion of the cervical spine.

Parkinson's Disease Parkinson's disease (PD) is a complex motor disorder accompanied by systemic nonmotor and neurological symptoms. Etiological classification of parkinsonism includes primary parkinsonism and

secondary parkinsonism. Primary PD begins after the age of 40 years, with the incidence increasing after age 60 years. It is more prevalent in males and a leading cause of neurological disability in individuals older than 60 years. In 2010–11, an estimated 55 000 Canadians aged 18 or older reported that they had been diagnosed with PD.33 The familial form represents about 10% of PD; however, the majority of cases are sporadic or idiopathic. Secondary parkinsonism is parkinsonism caused by disorders other than PD (i.e., head trauma, infection, neoplasm, atherosclerosis, toxins, medication intoxication). Medicationinduced parkinsonism, caused by neuroleptics, antiemetics, and antihypertensives, is the most common secondary form and usually is reversible. Pathophysiology The pathogenesis of primary PD is unknown. Several gene mutations have been identified that influence nerve function in PD. Gene–environment interactions are probable causes of neuro-degeneration in PD. The primary pathology is degeneration of the basal ganglia (see Figure 13-10) with dysfunctional or misfolded α-synuclein protein and loss of dopamine-producing neurons in the substantia nigra and dorsal striatum. The resulting depletion of dopamine, an inhibitory neurotransmitter, and relative excess of cholinergic (excitatory) activity in the feedback circuit are manifested by hypertonia (tremor and rigidity) and akinesia, producing a syndrome of abnormal movement called parkinsonism (Parkinson's syndrome, parkinsonian syndrome, paralysis agitans) (Figure 15-15). Neuroimaging shows degeneration of dopaminergic neurons preceding the onset of motor symptoms by as long as 3 to 6 years.34 Dementia may develop over decades with infiltration of Lewy bodies (accumulation of abnormal protein in nerve cells) and plaque formation similar to AD.35 Loss of cholinergic subcortical input into the cortex is associated with nonmotor symptoms of PD.36

FIGURE 15-15 Pathophysiology of Parkinson's Disease.

Clinical manifestations The classic manifestations of PD are resting tremor, rigidity, bradykinesia or akinesia, postural disturbance, dysarthria, and dysphagia. They may develop alone or in combination, but as the disease progresses, all are usually present. There is no true paralysis. The symptoms are always bilateral but usually involve one side early in the illness. Because the onset is insidious, the beginning of symptoms is difficult to document. Early in the disease, reflex status, sensory status, and mental status usually are normal. Loss of smell can be an early nonmotor symptom. Postural abnormalities (flexed, forward leaning), difficulty walking, and weakness develop as neuro-degeneration progresses (Figure 15-16).

Speech may be slurred.

FIGURE 15-16

Stooped Posture of Parkinson's Disease. (From Perkin, D.G. [2002]. Mosby's color atlas and text of neurology [2nd ed.]. London: Mosby.)

Disorders of equilibrium result from postural abnormalities. The person with PD cannot make the appropriate postural adjustment to tilting or falling and falls like a post when starting to tilt. The festinating gait (short, accelerating steps) of the individual with PD is an attempt to maintain an upright position while walking. Individuals are also unable to right themselves when changing from a reclining or crouching position to a standing position and when rolling over from a supine to a lateral or prone position. Sleep disorders and excessive daytime sleepiness are commonly experienced. Sensory disturbances (pain and impaired smell and vision), urinary urgency, difficulty concentrating, depression, and hallucinations are some of the nonmotor symptoms of PD.37,38 Autonomic–neuroendocrine changes also contribute to nonmotor symptoms and include inappropriate diaphoresis, orthostatic hypotension, drooling, gastric retention, constipation, and urinary retention. Progressive dementia is more common in persons older than 70 years. Mental status may be further compromised by the adverse effects of the medication taken to control symptoms. Evaluation and treatment The diagnosis of PD is based on the history and the clinical features of the disease. Causes of secondary parkinsonism are first excluded. Specific gene panels and imaging studies are evolving for early diagnosis.39 Treatment of PD is symptomatic with medication therapy to decrease akinesia. Because of troublesome adverse effects and loss of effectiveness, however, medication therapy may not be started until the symptoms become incapacitating. Deep brain stimulation (i.e., subthalamic neurostimulation) is replacing surgery to treat persons unresponsive to medication therapy. Implants of stem cells and fetal cells, as well as gene therapy, are strategies for future treatments.40 Dysphagia and general immobility are special problems of the individual with PD requiring interdisciplinary efforts to improve functional status.41

Upper and Lower Motor Neuron Syndromes Paresis and paralysis are symptoms of upper and lower motor neuron syndromes (Table 15-18). Paresis (weakness) is partial paralysis with incomplete loss of muscle power. Paralysis is loss of motor function

so that a muscle group is unable to overcome gravity. TABLE 15-18 Upper and Lower Motor Neuron Syndromes Signs and Symptoms Upper Motor Neuron (Pyramidal Cells—Motor Cortex) Muscle groups are affected Mild weakness Minimal disuse muscle atrophy No fasciculations Increased muscle stretch reflexes (clasp-knife spasticity; resistance to passive flexion that releases abruptly to allow easy flexion) Clonus may be present Hypertonia, spasticity Pathological reflexes (Babinski and Hoffmann signs, loss of abdominal reflexes) Often initial impairment of only skilled movements

Lower Motor Neuron (Cranial Nerve Nuclei—Brainstem; Ventral Horn—Spinal Cord) Individual muscles may be affected Mild weakness Marked muscle atrophy Fasciculations Decreased muscle stretch reflexes Clonus not present Hypotonia, flaccidity Hyporeflexia No Babinski sign Asymmetrical and may involve one limb only in beginning to become generalized as disease progresses

Upper Motor Neuron Syndromes Upper motor neuron syndromes are the result of damage to descending motor pathways at cortical, brainstem, or spinal cord levels. Upper motor neuron paresis or paralysis is known also as spastic paresis/paralysis, and different terms are used to describe the specific disorders (Box 15-6).

Box 15-6

Upper Motor Neuron Paresis or Paralysis Hemiparesis/hemiplegia is paresis/paralysis of the upper and lower extremities on one side. Diplegia is paralysis of corresponding parts of both sides of the body as a result of cerebral hemisphere injuries. Paraparesis/paraplegia is weakness/paralysis of the lower extremities as a result of lower spinal cord injury. Quadriparesis/quadriplegia is paresis/paralysis of all four extremities as a result of upper spinal cord injury (spinal cord injury is discussed in Chapter 16). Upper motor neuron paresis or paralysis is associated with a pyramidal motor syndrome, which involves a series of motor dysfunctions resulting from interruption of the pyramidal system (Figures 1517 and 15-18). The injury may be in the cerebral cortex, the subcortical white matter, the internal capsule, the brainstem, or the spinal cord. The clinical manifestations reflect muscle overactivity and include excessive movements, such as clonus and spasms, occurring regularly as a result of loss of higher motor centre control. There is great variation, depending on the suddenness of onset and the age of the individual.

FIGURE 15-17 Motor Function Syndromes. Disturbances in motor function are classified pathologically along upper and lower motor neuron structures. It should be noted that the same pathological condition occurs at more than one site in an upper motor neuron (top right). A few pathological conditions involve both upper and lower motor neuron structures, as in amyotrophic lateral sclerosis, for example. Other lesion sites include myoneural junction and primary muscle, making it possible to classify conditions as neuromuscular and muscular, respectively.

FIGURE 15-18 Structures of the Upper Motor Neuron, or Pyramidal, System. Pyramidal system fibres are shown to originate primarily in cells in the precentral gyrus of the motor cortex; to converge at the internal capsule; to descend to form the central third of the cerebral peduncle; to descend further through the pons, where small fibres supply cranial nerve motor nuclei along the way; to form pyramids at the medulla, where most of the fibres decussate; and then to continue to descend in the lateral column of white matter of the spinal cord. A few fibres descend without crossing at the level of the medulla (i.e., the ventral [anterior] corticospinal tract).

Spinal shock is the temporary loss of all spinal cord functions below the lesion (below the level of the pons). It is characterized by complete flaccid paralysis, absence of reflexes, and marked disturbances of bowel and bladder function. Hypotension can occur from loss of sympathetic tone at higher levels of spinal cord injury. A major factor in spinal shock is the sudden destruction of the efferent pathways. If destruction occurs more slowly, spinal shock may not develop (see Chapter 16). If the pyramidal system is interrupted above the level of the pons, the hand and arm muscles are greatly affected. Paralysis rarely involves all the muscles on one side of the body, even when the hemiplegia results from complete damage to the internal capsule. Bilateral movements, such as those of the eye, jaw, and larynx, as well as those of the trunk, are affected only slightly, if at all. Predominantly the limbs are influenced. Paralysis associated with a pyramidal motor syndrome rarely remains flaccid for a prolonged time. After a few days or weeks, a gradual return of spinal reflexes marks the end of spinal shock. Reflexes then become hyperactive, and muscle tone increases significantly, particularly in antigravity muscles. Spasticity is common, although rigidity occasionally occurs (see Table 15-16). Most often, passive rangeof-motion movements cause “clasp-knife” rigidity, probably by activating the stretch receptors in the muscle spindles and the Golgi tendon organ. (Muscle function is discussed in Chapter 38.) With pyramidal motor syndrome, predominantly the flexors of the arms and the extensors of the legs are affected.

Lower Motor Neuron Syndromes Lower (primary, alpha) motor neurons are the large motor neurons in the anterior (or ventral) horn of the spinal cord and the motor nuclei of the brainstem. The axons from these nerve cell bodies bring nerve impulses from upper motor neurons to the skeletal muscles through the anterior spinal roots or cranial nerves (Figure 15-19). Lower motor neuron syndromes impair both voluntary and involuntary movement. The degree of paralysis or paresis is proportional to the number of lower motor neurons affected. If only some of the motor units that supply a muscle are affected, only partial paralysis (or paresis) results. If all motor units are affected, complete paralysis results. Other clinical manifestations also are proportional to the degree of dysfunction, but the precise manifestations depend on the location of the dysfunction in the motor unit and in the CNS.

FIGURE 15-19 Structures Composing Lower Motor Neuron, Including Motor (Efferent) and Sensory (Afferent) Elements. (Top) Anterior horn cell (in anterior grey column of spinal cord and its axon), terminating in motor end plate as it innervates extrafusal muscle fibres in quadriceps muscle. (Detailed enlargement) Sensory and motor elements of gamma loop system. Gamma efferent fibres shown innervating the muscle spindle (sensory receptor of skeletal muscle). Contraction of muscle spindle fibres stretches the central portion of the spindle and causes the gamma afferent spindle fibre to transmit impulse centrally to the cord. Muscle spindle gamma afferent fibres in turn synapse on the anterior horn cell, and impulses are transmitted by way of alpha efferent fibres to skeletal (extrafusal) muscle, causing it to contract. Muscle spindle discharge is interrupted by active contraction of skeletal muscle fibres.

Small motor (gamma) neurons, which maintain muscle tone and protect the muscle from injury, are needed for normal motor movement. They depend on input from the muscle spindle (arriving through an afferent limb rising to the cord). Dysfunction in this motor system (the gamma loop) impairs tone and reduces tendon reflexes, causing hyporeflexia. The muscles become susceptible to damage from hyperextensibility. Generally, the large and small motor neuron systems are equally affected. Therefore, the muscle has reduced or absent tone and is accompanied by hyporeflexia or areflexia (loss of tendon reflexes) and flaccid paresis/paralysis. Denervated muscles (i.e., muscles that have lost their nervous system input) atrophy over weeks to months, mostly from disuse, and demonstrate fasciculations (muscle rippling or quivering under the skin). Occasionally, denervated muscles cramp. Fibrillation is isolated contraction of a single muscle fibre because of metabolic changes in denervated muscle and is not clinically visible.

Motor Neuron Diseases Motor neuron diseases result from progressive degeneration of upper or lower motor neurons in the spinal cord, brainstem, or cortex. Amyotrophic lateral sclerosis and paralytic poliomyelitis (see Chapter 8) are examples of these diseases.

Several pathological processes may give rise to motor neuron diseases that can be sporadic or inherited. A virally induced or postinfectious or postvaccination inflammatory process may injure or destroy anterior horn cells or cranial nerve cell bodies. Most of these inflammatory processes are mild and are followed by rapid cellular recovery (Box 15-7).

Box 15-7

Bell's Palsy The etiology of Bell's palsy (unilateral facial nerve palsy) remains unknown. There is usually an inflammatory reaction compressing the facial nerve, particularly in the narrowest segment, followed by demyelinating neural change. The most distressing signs are unilateral facial weakness and the inability to smile or whistle. Bell's palsy may be caused by reactivation of herpes viruses in cranial nerve VII (facial), geniculate ganglia, or an autoimmune response. The signs usually have an acute onset (within 72 hours). Herpes simplex type 1 has been detected in up to 78% of cases, and herpes zoster has been detected in 30% of cases. Severe pain with facial palsy and a vesicular rash in the ear or mouth suggest herpes zoster infection. Ramsay Hunt syndrome (herpes zoster oticus) is rare, but complete recovery is less than 50%. Recovery from Bell's palsy is usually complete. Both disorders may be treated with combination antivirals and oral steroids. Treatment should be individualized according to severity of symptoms. Data from Baugh, R.F., Basura, G.J., Ishii, L.E., et al. (2013). Otolaryngol Head Neck Surg, 149(3 Suppl.), S1–S27. Retrieved from http://oto.sagepub.com/content/149/3_suppl/S1.full); De Ru, J.A., & Van Benthem, P.P. (2014). Evid Based Med, 19(1), 15; Glass, G.E., & Tzafetta, K. (2014). Fam Pract, 31(6), 631–642; Greco, A., Gallo, A., Fusconi, M., et al. (2012). Autoimmun Rev, 12(2), 323–328.

In motor neuron disease, muscle strength, muscle tone, and muscle bulk are affected in the muscles innervated by the involved motor neurons. The paresis and paralysis associated with anterior horn cell injury are segmental, but because each muscle is supplied by two or more roots, the segmental character of the weakness may be difficult to recognize. When cranial nerve motor nuclei are affected (they lack nerve roots and have only small rootlets near the point of exit from the brainstem), the distribution of the motor weakness follows that of the peripheral nerve. The weakness may involve distal muscles, proximal muscles, and the muscles of midline structures. Hypotonia and hyporeflexia or areflexia are present. The atrophy associated with motor neuron disease is segmental when the anterior horn cells of the spinal cord are involved and follows the distribution of the peripheral nerve when the motor nuclei of the cranial nerves are affected. The atrophy may be in distal, proximal, or midline muscles. Fasciculations are particularly associated with primary motor neuron injury, and muscle cramps are common. Mild fatigue is a common complaint. If the pathological process is limited to the primary motor neuron, no sensory changes are evident. Because degenerative disorders can cause loss of nerve cells in the anterior horn or motor nuclei, the surviving cells are small, shrunken, and filled with lipofuscin. Lost neurons are replaced by astrocytes. The roots or rootlets are thin, and the muscles show denervation and atrophy. Several brainstem syndromes involve damage to one or more of the cranial nerve nuclei. These syndromes are called cranial nerve palsy and may be caused by vascular occlusion, tumour, aneurysm, tuberculosis, or hemorrhage. The anterior horn cells and the motor nuclei of the cranial nerves may be affected secondarily in many severe pathological processes that primarily involve the peripheral nerves. The condition may extend proximally to affect the nerve roots or rootlets and the motor neurons themselves, a process commonly seen, for example, in Guillain-Barré syndrome (see Chapter 16). If sufficient numbers of motor neurons are destroyed, permanent loss of motor function results because regeneration of the damaged axons requires a living neuronal cell body. A group of degenerative disorders principally cause progressive motor cell atrophy. One of these disorders is progressive spinal muscular atrophy, in which the anterior horn cells of the spinal cord are the affected motor neurons that degenerate. This disorder occurs in adults and closely resembles the familial progressive muscular atrophies that occur in infants and children and are considered inherited

metabolic disorders (see Chapter 40). If the motor nuclei of the cranial nerves are affected instead of the anterior horn cells, the disorder is labelled progressive bulbar palsy, so named because the myelencephalon originally was called the bulb and a degenerative process causes a progressively more serious condition. When any lower motor neuron syndrome involves the cranial nerves that arise from the bulb (i.e., cranial nerves IX, X, and XII), the dysfunction is called a bulbar palsy. The clinical manifestations of bulbar palsy include paresis or paralysis of the jaw, face, pharynx, and tongue musculature. Articulation is affected, especially articulation of the lingual (r, n, l), labial (b, m, p, f), dental (d, t), and palatal (k, g) consonants. Modulation is impaired, making the voice rasping or nasal. Pharyngeal reflexes are diminished or lost. Palate and vocal cord movement during phonation is impaired, and chewing and swallowing are affected. The facial muscles are weak, and the face appears to droop. The jaw jerk is decreased. Atrophy eventually becomes apparent, as do fasciculations. All of these manifestations become progressively worse, leading to aspiration, malnutrition, possible dehydration, and an inability to communicate verbally.

Amyotrophic Lateral Sclerosis Amyotrophic lateral sclerosis (ALS; sporadic motor neuron disease, sporadic motor system disease, motor neuron disease [MND], Lou Gehrig's disease) is a worldwide neuro-degenerative disorder that diffusely involves lower and upper motor neurons, resulting in progressive muscle weakness. Amyotrophic (without muscle nutrition or progressive muscle wasting) refers to the predominant lower motor neuron component of the syndrome. Lateral sclerosis, scarring of the corticospinal tract in the lateral column of the spinal cord, refers to the upper motor neuron component of the syndrome. ALS occurs in young adults or older adults, but it is most commonly diagnosed in middle to late adulthood. It affects both men and women with about 2 cases per 100 000 population in Canada.42 Most cases of ALS are sporadic. A subset (about 10%) of persons has a familial form with genetic mutations in superoxide dismutase (SOD) that contribute to the neurotoxicity affecting motor neurons. Mutated TAR RNA-binding protein 43 (TDP-43) is a major constituent of the neuronal protein inclusions in ALS. Gene and environmental interactions are being evaluated as a cause of ALS.43 Pathophysiology The cause of ALS is unknown. Oxidative stress, mitochondrial dysfunction, defects in axonal transport, excitotoxicity and glutamate transport, neuronal cytoplasmic inclusions (i.e., TDP-43 protein), and neuroinflammation as causes of neuron degeneration are under investigation.44 The principal pathological feature of ALS is degeneration of lower and upper motor neurons. There is a decrease in large motor neurons in the spinal cord, brainstem, and cerebral cortex (premotor and motor areas), with ongoing degeneration in the remaining motor neurons. Death of the motor neuron results in axonal degeneration and secondary demyelination with glial proliferation and sclerosis (scarring). Widespread neural degeneration of nonmotor neurons in the spinal cord and motor cortices, as well as in the premotor, sensory, and temporal cortices, has been found. Lower motor neuron degeneration denervates motor units. Adjacent, still viable lower motor neurons attempt to compensate by distal intramuscular sprouting, reinnervation, and enlargement of motor units. Clinical manifestations The initial symptoms of the disease are heterogeneous and may be related to lower or upper motor neuron dysfunction or both. About 60% of individuals have a spinal form of the disease with focal muscle weakness beginning in the arms and legs and progressing to muscle atrophy, spasticity, and loss of manual dexterity and gait. No associated mental, sensory, or autonomic symptoms are present. ALS with progressive bulbar palsy presents with difficulty speaking and swallowing, and peripheral muscle weakness and atrophy usually occur within 1 to 2 years. These individuals have a poorer response to treatment with mechanical ventilation.45 FTD may occur concurrently.46 Evaluation and treatment Diagnosis of ALS is based predominantly on the history and physical examination with no evidence of

other neuromuscular disorders. Electromyography and muscle biopsy results verify lower motor neuron degeneration and denervation. Imaging studies and CSF biomarkers can assist in making the diagnosis. Little treatment is available to alter the overall course of the ALS syndrome. The medication riluzole (Rilutek), an antiglutamate, has extended the length of time patients do not require ventilatory assistance. Supportive and rehabilitative management are directed toward preventing complications of immobility. Psychological support of the affected individual and the family is extremely important.47 ALS is fatal from respiratory failure usually within 3 years of diagnosis. A small percentage of individuals live 5 to 10 years or longer.48

Alterations in Complex Motor Performance Alterations in complex motor performance include disorders of posture (stance), disorders of gait, and disorders of expression.

Disorders of Posture (Stance) An inequality of tone in muscle groups, because of a loss of normal postural reflexes, results in a posturing of limbs. Equilibrium and balance are disrupted. Many reflex systems govern tone and posture, but the most important factor in posture control is the stretch reflex, in which extensor (antigravity) muscle stretching causes increased extensor tone and inhibited flexor tone. Four types of disorders of posture are (1) dystonic posture, (2) decorticate posture/response, (3) decerebrate posture/response, and (4) basal ganglion posture. Dystonia is the maintenance of an abnormal posture through muscular contractions. When muscular contractions are sustained for several seconds, they are called dystonic movements; when contractions last for longer periods, they are called dystonic postures. Dystonic postures may last for weeks, causing permanent, fixed contractures. Dystonia has been associated with basal ganglia abnormality, but the exact pathophysiological mechanisms are unknown. One dystonic posture is decorticate posture/response (striatal posture or upper motor neuron dysfunction posture), which may be unilateral or bilateral. Decorticate posture/response (also referred to as antigravity posture or hemiplegic posture) is characterized by upper extremities flexed at the elbows and held close to the body and by lower extremities that are externally rotated and extended (see Figure 15-6). Decorticate posture/response is thought to occur when the brainstem is not inhibited by the cerebral cortex motor area. Upper motor neuron posture is more commonly described as the arm flexed at the elbow with a wrist drop, the leg inadequately bent at the knee, the hip excessively circumabducted, and the presence of footdrop. Decerebrate posture/response refers to increased tone in extensor muscles and trunk muscles, with active tonic neck reflexes. When the head is in a neutral position, all four limbs are rigidly extended (see Figure 15-6). The decerebrate posture is caused by severe injury to the brain and brainstem, resulting in overstimulation of the postural righting and vestibular reflexes. Basal ganglion posture refers to a stooped, hyperflexed posture with a narrow-based, short-stepped gait. This posture abnormality results from the loss of normal postural reflexes and not from defects in proprioceptive, labyrinthine, or visual function. Dysfunctional equilibrium results when the individual loses stability and cannot make the appropriate postural adjustment to tilting or loss of balance, falling instead. Dysfunctional righting is the inability to right oneself when changing from a lying or crouching to a standing position or when rolling from the supine to the lateral or prone position. Dysfunctional postural fixation is the involuntary flexion of the head and neck, causing the person difficulty in maintaining an upright trunk position while standing or walking. Basal ganglion dysfunction accounts for this posture.

Disorders of Gait Four predominant types of gait associated with neurological disorders are (1) upper motor neuron dysfunction gait, (2) cerebellar (ataxic) gait, (3) basal ganglion gait, and (4) frontal lobe ataxic gait. As with posture, equilibrium and balance are affected with gait disturbances.49 Several types of upper motor neuron gait exist. With mild forms, the individual may have footdrop with fatigue and hip and leg pain. A spastic gait, which is associated with unilateral injury, manifests by a shuffling gait with the leg extended and held stiff, causing a scraping over the floor surface. The leg swings improperly around the body rather than being appropriately lifted and placed. The foot may drag on the ground, and the person tends to fall to the affected side. A scissors gait is associated with bilateral injury and spasticity. The legs are adducted so they touch each other. As the person walks, the legs are swung around the body but then cross in front of each other because of adduction. Injury to the pyramidal system accounts for these gaits (e.g., stroke, cerebral palsy, multiple sclerosis, spinal cord

tumour). A cerebellar (ataxic) gait is wide-based, with the feet apart and often turned outward or inward for greater stability. The pelvis is held stiff, and the individual staggers when walking. Cerebellar dysfunction with loss of coordination accounts for this particular gait. A basal ganglion gait is a broad-based gait in which the person walks with small steps and a decreased arm swing. The head and body are flexed and the arms semiflexed and abducted, whereas the legs are flexed and rigid in more advanced states. Basal ganglion dysfunction accounts for this gait and is associated with PD. A frontal lobe ataxic gait is wide-based with increased body sway and falls, loss of control of truncal motion, gait ignition failure, start hesitation, shuffling, and freezing. The gait is associated with frontal lobe damage or degeneration. The pattern may change as the frontal disease progresses. The slowness of walking, lack of heel–shin or upper limb ataxia, dysarthria, or nystagmus distinguishes the wide stance from cerebellar ataxic gait.50 Gait disorders are often accompanied by balance, coordination, and sensory dysfunction that further alter mobility and increase risk for falls. Assessment and intervention strategies are important for prevention of injury.

Disorders of Expression Disorders of expression involve the motor aspects of communication and include (1) hypermimesis, (2) hypomimesis, and (3) apraxia or dyspraxia. Hypermimesis commonly manifests as pathological laughter or crying. Pathological laughter is associated with right hemisphere injury, and pathological crying is associated with left hemisphere injury. The exact pathophysiology is not known. Hypomimesis manifests as aprosody—the loss of emotional language. Receptive aprosody involves an inability to understand emotion in speech and facial expression. Expressive aprosody involves the inability to express emotion in speech and facial expression. Aprosody is associated with right hemisphere damage. Apraxia or dyspraxia is a disorder of learned skilled movements with difficulty planning and executing coordinated motor movements. The term is often used interchangeably with dyspraxia. It can be developmental, beginning at birth (developmental apraxia), or associated with vascular disorders (common in stroke), trauma, tumours, degenerative disorders, infections, or metabolic disorders. People with apraxia have difficulty performing tasks requiring motor skills, including speaking, writing, using tools or utensils, playing sports, following instructions, and focusing.51 True apraxias occur when the connecting pathways between the left and right cortical areas are interrupted. Apraxias may result from any pathological process that disrupts the cortical areas necessary for the conceptualization and execution of a complex motor act or the communication pathways within the left hemisphere or between the hemispheres.51,52

Extrapyramidal Motor Syndromes Because the extrapyramidal system encompasses all the motor pathways except the pyramidal system, two types of motor dysfunction make up the extrapyramidal motor syndromes: (1) basal ganglia motor syndromes and (2) cerebellar motor syndromes. Unlike pyramidal motor syndromes, both extrapyramidal motor syndromes result in movement or posture disturbance without significant paralysis, along with other distinctive symptoms (Table 15-19). TABLE 15-19 Pyramidal Versus Extrapyramidal Motor Syndrome Manifestations Pyramidal Motor Syndrome

Extrapyramidal Motor Syndrome

Unilateral movement Tendon reflexes Babinski sign Involuntary movements Muscle tone

Paralysis of voluntary movement

Little or no paralysis of voluntary movement

Increased tendon reflexes Present Absence of involuntary movements

Normal or slightly increased tendon reflexes Absent Presence of tremor, chorea, athetosis, or dystonia

Spasticity in muscles (e.g., clasp-knife phenomenon) Hypertonia present in flexors of arms and extensors of legs

Plastic rigidity (equal throughout movement) or intermittent—cogwheel rigidity (generalized but predominantly in flexors of limbs and trunk) Hypotonia, weakness and gait disturbances in cerebellar disease

Basal ganglia motor syndromes are caused by an imbalance of dopaminergic and cholinergic activity in the corpus striatum. A relative excess of cholinergic activity produces akinesia and hypertonia. A relative excess of dopaminergic activity produces hyperkinesia and hypotonia. Symptoms associated with Parkinson's and Huntington's diseases are exemplary of disorders of the basal ganglia. Cerebellar motor syndromes are associated with ataxia and other symptoms affecting coordinated movement. Cerebellar motor syndromes primarily influence the same side of the body; for example, damage to the right cerebellum generally causes symptoms on the right side of the body. Medication-induced extrapyramidal effects may also be encountered with short- or long-term use of certain medications. The medications involved, including the antipsychotic haloperidol (Haldol) and the antiemetic metoclopramide (Metoclopramide), antagonize the dopamine D2 receptors, resulting in extrapyramidal adverse effects.

Quick Check 15-6 1. Why are there so many causes of hypertonia? 2. How is chorea different from athetosis? 3. Why is paresis/paralysis a type of hypokinesia? 4. What structures are involved in alterations of complex motor performance?

Did You Understand? Alterations in Cognitive Systems 1. Full consciousness is an awareness of oneself and the environment with an ability to respond to external stimuli with a wide variety of responses. 2. Consciousness has two components: arousal (level of awakeness) and awareness (content of thought). 3. An altered level of arousal occurs by diffuse bilateral cortical dysfunction, bilateral subcortical (reticular formation, brainstem) dysfunction, localized hemispheric dysfunction, and metabolic disorders. 4. An alteration in breathing pattern and the level of consciousness reflect the level of brain dysfunction. 5. Pupillary changes reflect changes in level of brainstem function, medication action, and response to hypoxia and ischemia. 6. Abnormal eye movements, including nystagmus, reflect alterations in brainstem function. 7. Level of brain function manifests by changes in generalized motor responses or no responses. 8. Loss of cortical inhibition associated with decreased consciousness produces abnormal flexor and extensor movements. 9. Brain death results from irreversible brain damage, with an inability to maintain internal homeostasis. 10. Cerebral death, or irreversible coma, represents permanent brain damage, with an ability to maintain cardiac, respiratory, and other vital functions. 11. Arousal returns in vegetative states, but awareness is absent. 12. Alterations in awareness include alterations in executive attention (abstract reasoning, planning, decision making, judgement, error correction, and self-control) and memory. 13. With a deficit in selective attention, mediated by midbrain, thalamus, and parietal lobe structures, the individual cannot focus on selective stimuli and thus neglects those stimuli. 14. In retrograde amnesia, some past memories are lost; and in anterograde amnesia, new memories cannot be formed. 15. Frontal areas mediate vigilance, detection, and working (short-term) memory. 16. With vigilance deficits, the person cannot maintain sustained concentration. 17. With detection deficits, the person is unmotivated and may be perceived by others as lazy or apathetic, demonstrated by the inability to set goals and plan. 18. Data-processing deficits include agnosias, dysphasias, acute confusional states, and dementias. 19. Agnosias are defects of recognition and may be tactile, visual, or auditory. They are caused by dysfunction in the primary sensory area or the interpretive areas of the cerebral cortex. 20. Dysphasia (aphasia) is an impairment of comprehension or production of language. Most dysphasias are expressive or receptive. 21. Acute confusional states are characterized chiefly by a loss of detection and, in the case of delirium, intense autonomic nervous system hyperactivity. 22. Alzheimer's disease is a chronic irreversible dementia that is related to altered production or failure to clear amyloid from the brain with plaque formation, formation of neurofibrillary tangles, and loss of basal forebrain cholinergic neurons. 23. Frontotemporal dementias are rare early-onset degenerative diseases similar to Alzheimer's disease. 24. Seizures represent a sudden, chaotic discharge of cerebral neurons with transient alterations in brain function. Seizures may be generalized or focal and can result from cerebral lesions, biochemical disorders, trauma, or epilepsy.

Alterations in Cerebral Hemodynamics

1. Alterations in cerebral blood flow are related to changes in cerebral perfusion pressure, changes in cerebral blood volume, and cerebral blood oxygenation. 2. Increased intracranial pressure (increased ICP) may result from edema, excess cerebrospinal fluid (CSF), hemorrhage, or tumour growth. When ICP approaches arterial pressure, hypoxia and hypercapnia produce brain damage. 3. Cerebral edema is an increase in the fluid content of the brain resulting from infection, hemorrhage, tumour, ischemia, infarction, or hypoxia. Cerebral edema can cause increased ICP. 4. The shifting or herniation of brain tissue from one compartment to another disrupts the blood flow of both compartments and damages brain tissue. 5. Supratentorial herniation involves the temporal lobe and hippocampal gyrus shifting from the middle fossa to posterior fossa; transtentorial herniation involves a downward shift of the diencephalon through the tentorial notch; and shifting of the cingulate gyrus can occur under the falx cerebri. 6. The most common infratentorial herniation is a shift of the cerebellar tonsils through the foramen magnum. 7. Hydrocephalus comprises a variety of disorders characterized by an excess of fluid within the ventricles, subarachnoid space, or both. Hydrocephalus occurs because of interference with CSF flow caused by increased fluid production or obstruction within the ventricular system or by defective reabsorption of the fluid.

Alterations in Neuromotor Function 1. General neuromotor dysfunctions are associated with changes in muscle tone, movement, and complex motor performance. 2. Hypotonia and hypertonia are the main categories of altered tone. 3. Hypotonia is associated with pyramidal tract or cerebellar injury. Muscles are flaccid and weak with atrophy. 4. The four types of hypertonia are spasticity, paratonia (gegenhalten), dystonia, and rigidity. 5. Hyperkinesia, hypokinesia, paresis, and paralysis are the main categories of alterations in muscle movement. 6. Included in the category of hyperkinesia are chorea, athetosis, ballism, akathisia, tremor, and myoclonus. 7. Huntington's disease (chorea) is a rare hereditary disease involving the basal ganglia and cerebral cortex that commonly manifests between 25 and 45 years of age. 8. The major pathological feature of Huntington's disease is severe degeneration of the basal ganglia and the cerebral cortex with an excess of dopaminergic activity that causes involuntary, fragmentary hyperkinetic movements. 9. Types of hypokinesia include akinesia, bradykinesia, and loss of associated movement. 10. Parkinson's disease is a commonly occurring degenerative disorder of the basal ganglia (corpus striatum) involving degeneration of the dopamine-secreting nigrostriatal pathway. 11. Dopamine depletion in the basal ganglia and excess cholinergic activity in the cortex, basal ganglia, and thalamus cause tremor and rigidity in Parkinson's disease. Progressive dementia may be associated with an advanced stage of the disease. 12. An upper motor neuron syndrome is characterized by paresis or paralysis, hypertonia, and hyperreflexia. 13. Two subtypes of paresis or paralysis are upper motor neuron spastic paresis/paralysis and lower motor neuron flaccid paresis/paralysis. 14. Upper motor neuron syndromes are the result of damage to descending motor pathways at cortical, brainstem, or spinal cord levels and result in spastic paralysis. 15. Spinal shock is temporary loss of all spinal cord function below the lesion (below the level of the pons). It is characterized by complete flaccid paralysis, absence of reflexes, and marked disturbances of bowel and bladder function. 16. Lower motor neuron syndromes manifest by impaired voluntary and involuntary movements

and flaccid paralysis. 17. Partial paralysis occurs with only partial loss of alpha motor neurons, and total paralysis is complete loss of alpha motor neurons. Loss of gamma motor neurons impairs muscle tone and decreases tendon reflexes. 18. Lower (primary, alpha) motor neuron syndromes involve the large motor neurons in the anterior (or ventral) horn of the spinal cord and the motor nuclei of the brainstem and cause flaccid paralysis. 19. Amyotrophic lateral sclerosis involves degeneration of both upper and lower motor neurons with progressive muscle weakness and atrophy.

Alterations in Complex Motor Performance 1. Alterations in complex motor performance include disorders of posture (stance), disorders of gait, and disorders of expression. 2. Disorders of posture include dystonic posture, decerebrate posture/response, basal ganglion posture, and senile posture. 3. Disorders of gait include upper motor neuron gait, cerebellar (ataxic) gait, basal ganglion gait, and frontal lobe ataxic gait. 4. Disorders of expression include hypermimesis, hypomimesis, and apraxia (dyspraxia). 5. Apraxia is an impairment of the conceptualization or execution of a complex motor act.

Extrapyramidal Motor Syndromes 1. Extrapyramidal motor syndromes include basal ganglia and cerebellar motor syndromes. 2. Basal ganglia motor syndromes manifest by alterations in muscle tone and posture, including rigidity, involuntary movements, and loss of postural reflexes. 3. Cerebellar motor syndromes result in loss of muscle tone, difficulty with coordination, and disorders of equilibrium and gait.

Key Terms Acute confusional state, 371 Acute hydrocephalus, 380 Agnosia, 371 Akinesia, 384 Alzheimer's disease (AD) (dementia of Alzheimer's type [DAT], senile disease complex), 374 Amnesia, 369 Amyotrophic lateral sclerosis, 388 Anterograde amnesia, 369 Aphasia, 371 Apraxia or dyspraxia, 390 Areflexia, 387 Arousal, 363 Autoregulation, 378 Awareness, 369 Basal ganglia motor syndrome, 390 Basal ganglion gait, 389 Basal ganglion posture, 389 Bradykinesia, 384 Brain death (total brain death), 368 Bulbar palsy, 388 Cerebellar (ataxic) gait, 389 Cerebellar motor syndrome, 390 Cerebral blood flow (CBF), 377 Cerebral blood oxygenation, 378 Cerebral blood volume (CBV), 377 Cerebral death (irreversible coma), 368 Cerebral edema, 379 Cerebral perfusion pressure (CPP), 378 Clonic phase, 377 Communicating hydrocephalus, 380 Consciousness, 363 Convulsion, 376 Cytotoxic (metabolic) edema, 380 Decerebrate posture/response, 389 Decorticate posture/response (antigravity posture, hemiplegic posture), 389 Delirium (hyperactive confusional state), 373 Dementia, 373 Diplegia, 386 Dysphasia, 371 Dyspraxia, 375 Dystonia, 389 Dystonic movement, 389 Dystonic posture, 389 Epilepsy, 376 Epileptogenic focus, 377 Excited delirium syndrome (ExDS), 373 Executive attention deficit, 369 Extinction, 369 Extrapyramidal motor syndrome, 390

Fasciculation, 387 Fibrillation, 387 Flaccid paresis/paralysis, 387 Frontal lobe ataxic gait, 389 Frontotemporal dementia (FTD) (Pick disease), 376 Guillain-Barré syndrome, 388 Hemiparesis, 386 Hemiplegia, 386 Hiccup, 367 Huntington's disease (HD), 382 Hydrocephalus, 380 Hyperkinesia, 382 Hypermimesis, 389 Hypertonia, 381 Hypoactive delirium (hypoactive confusional state), 373 Hypokinesia, 384 Hypomimesis, 389 Hypotonia, 380 Ictus, 377 Image processing, 369 Increased intracranial pressure (increased ICP), 378 Interstitial edema, 380 Intracranial pressure (ICP), 377 Level of consciousness, 364 Locked-in syndrome, 369 Lower motor neuron syndromes, 386 Memory, 369 Memory disorder, 369 Minimally conscious state (MCS), 369 Mirror focus, 377 Motor response, 367 Neglect syndrome, 369 Neuritic plaques, 374 Neurofibrillary tangle, 375 Noncommunicating hydrocephalus (internal hydrocephalus, intraventricular hydrocephalus), 380 Normal-pressure hydrocephalus, 380 Oculomotor response, 364 Paralysis, 385 Paraparesis, 386 Paraplegia, 386 Paratonia (gegenhalten), 381 Paresis, 385 Parkinsonism (Parkinson's syndrome, parkinsonian syndrome, paralysis agitans), 384 Parkinson's disease (PD), 384 Paroxysmal dyskinesia, 382 Patterns of breathing, 364 Persistent vegetative state (VS), 369 Postictal phase, 377 Preictal phase, 377 Prodroma, 377 Progressive bulbar palsy, 388 Progressive spinal muscular atrophy, 388 Psychogenic alterations in arousal (unresponsiveness), 364

Pupillary change, 364 Pyramidal motor syndrome, 385 Quadriparesis, 386 Quadriplegia, 386 Retrograde amnesia, 369 Rigidity, 381 Secondary parkinsonism, 384 Seizure, 376 Selective attention, 369 Selective attention deficit, 369 Sensory inattentiveness, 369 Spasticity, 381 Spinal shock, 386 Status epilepticus, 377 Structural alterations in arousal, 363 Tardive dyskinesia, 382 Tentorium cerebelli, 363 Tonic phase, 377 Tourette syndrome, 382 Upper motor neuron gait, 389 Upper motor neuron paresis or paralysis, 385 Vasogenic edema, 379 Vomiting, 367 Yawning, 367

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Disorders of the Central and Peripheral Nervous Systems and Neuromuscular Junction Barbara J. Boss, Sue E. Huether, Kelly Power-Kean

CHAPTER OUTLINE Central Nervous System Disorders, 394 Traumatic Brain and Spinal Cord Injury, 394 Degenerative Disorders of the Spine, 402 Cerebrovascular Disorders, 406 Headache, 410 Infection and Inflammation of the Central Nervous System, 411 Demyelinating Disorders, 415 Peripheral Nervous System and Neuromuscular Junction Disorders, 416 Peripheral Nervous System Disorders, 416 Neuromuscular Junction Disorders, 417 Tumours of the Central Nervous System, 417 Brain Tumours, 417 Spinal Cord Tumours, 421

Alterations in central nervous system (CNS) function are caused by traumatic injury, vascular disorders, tumour growth, infectious and inflammatory processes, and metabolic derangements (including those arising from nutritional deficiencies and medications or chemicals). Alterations in peripheral nervous system function involve the nerve roots, a nerve plexus or the nerves themselves, or the neuromuscular junction.

Central Nervous System Disorders Traumatic Brain and Spinal Cord Injury Traumatic Brain Injury Traumatic brain injury (TBI) is an alteration in brain function or other evidence of brain pathology caused by an external force. In Canada, TBI is the primary cause of death and disability in individuals under the age of 40, occurring at a rate of 500 out of 100 000 individuals annually. TBI has an annual incidence rate greater than all combined cases of multiple sclerosis, spinal cord injury, human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), and breast cancer. It is reported that 30% of all TBIs are sustained by children and youth, many of them while participating in sports and recreational-related activities. The incidence of TBI among First Nations people is estimated to be four to five times the rate of the general population.1 In recent years, individuals with TBI have shown improved survival outcomes. Advancements have been made in enhanced safety measures (e.g., passive seat restraints, air bags, protective head gear), reduced transport time to hospitals or trauma centres, improved on-scene medical management, and prevention and management of secondary brain injury. TBI can be classified as primary or secondary. Primary brain injury is caused by direct impact and can be focal, affecting one area of the brain, or diffuse (diffuse axonal injury [DAI]), involving more than one area of the brain.2 Focal brain injury and DAI each account for half of all injuries. Focal brain injury accounts for more than two thirds of head injury deaths. DAI accounts for less than one third of deaths. More severely disabled survivors, including those surviving in an unresponsive state or reduced level of consciousness, have DAI. Secondary injury is an indirect consequence of the primary injury and includes systemic responses and a cascade of cellular and molecular cerebral events. TBI can be mild, moderate, or severe. The Glasgow Coma Scale is used to grade severity of injury (Table 16-1). Most TBIs are mild. The hallmark of a severe TBI is loss of consciousness for 6 hours or more.3 Review Chapter 15 for information about increased intracranial pressure (ICP). TABLE 16-1 Glasgow Coma Scalea Scoreb

Best Eye Response Score (4)

Best Verbal Response Score (5)

Best Motor Response Score (6)

1 2 3 4 5 6

No eye opening Eye opening to pain Eye opening to verbal command Eyes open spontaneously NA NA

No verbal response Incomprehensible sounds Inappropriate words Confused Oriented NA

No motor response Extension to pain Flexion to pain Withdrawal from pain Localizing pain Obeys commands

a

The Glasgow Coma Scale (GCS) is scored between 3 and 15, with 3 being the worst and 15 the best. It is composed of the sum of three parameters: Best Eye Response, Best Verbal Response, and Best Motor Response. Mild Brain Injury = 13 or higher; Moderate Brain Injury = 9 to 12; Severe Brain Injury = 8 or less. b

It is important to break the scoring report into its components, for example, E3V3M5 = GCS 11. A total score is meaningless without this information. Age affects the GCS. Older adults with traumatic brain injury (TBI) have better GCS scores than younger individuals with TBI with similar TBI severity (i.e., older adults have higher GCS scores than those of younger individuals with TBI with similar anatomical TBI severity). Data from Salottolo, K., Levy, A.S., Slone, D.S., et al. (2014). JAMA Surg, 149(7), 727–734; Teasdale, G., & Jennett, B. (1974). Lancet, 2, 81–84.

Primary brain injury Focal brain injury. Focal brain injury can be caused by closed (blunt) trauma or open (penetrating) trauma. Closed injury is more common and involves either the head striking a hard surface or a rapidly moving object striking the head, or by blast waves. The dura remains intact, and brain tissues are not exposed to the environment. Blunt trauma may result in both focal brain injuries and diffuse axonal injuries, and they can occur at the

same time (Table 16-2). Open injury occurs with penetrating trauma or skull fracture. A break in the dura results in exposure of the cranial contents to the environment.3 TABLE 16-2 Classification of Brain Injuries Type of Injury

Mechanism

Primary Brain Injury Focal Brain Injury Localized injury from impact Closed injury Blunt trauma Coup Injury is directly below site of forceful impact Contrecoup Injury is on opposite side of brain from site of forceful impact Epidural (extradural) Vehicular accidents, minor falls, sporting accidents hematoma Subdural hematoma Forceful impact: vehicular accidents or falls, especially in older adults or persons with chronic alcohol misuse Subarachnoid Bleeding caused by forceful impact, usually vehicular accidents or long-distance falls hemorrhage Open injury Penetrating trauma: missiles (bullets) or sharp projectiles (knives, ice picks, axes, screwdrivers) Compound fracture Objects strike head with great force or head strikes object forcefully; temporal blows, occipital blows, upward impact of cervical vertebrae (basilar skull fracture) Diffuse Axonal Traumatic shearing forces; tearing of axons from twisting and rotational forces with injury over widespread brain areas; moving head strikes hard, unyielding surface Injury or moving object strikes stationary head; torsional head motion without impact (can occur with focal injury) Secondary Brain Injury Secondary brain Decrease in CBF caused by edema, hemorrhage, increased ICP; neuro-inflammation injury Cell death Release of excitatory neurotransmitters (glutamate); failure of cell ion pumps, mitochondrial failure

CBF, cerebral blood flow; ICP, intracranial pressure.

Closed brain injuries are specific, grossly observable brain lesions that occur in a precise location; 75 to 90% of blunt trauma injuries are mild. Injury to the vault, vessels, and supporting structures can produce more severe damage, including contusions and epidural, subdural, and intracerebral hematomas. The injury may be a coup injury (at the site of impact) or contrecoup injury (from brain rebounding and hitting opposite side of skull) (Figure 16-1). Compression of the skull at the point of impact produces contusions or brain bruising from blood leaking from an injured vessel. The severity of contusion varies with the amount of energy transmitted by the skull to underlying brain tissue. The smaller the area of impact, the more severe the injury because of the concentration of force. Brain edema forms around and in damaged neural tissues, contributing to increasing ICP (see Chapter 15). Multiple hemorrhages, edema, infarction, and necrosis can occur within the contused areas. The tissue has a pulpy quality. The maximal effects of these injuries peak 18 to 36 hours after severe head injury.

FIGURE 16-1 Coup and Contrecoup Focal Injury With Acceleration/Deceleration Axonal Shearing. A, Sagittal force causing coup (c) and contrecoup injury (cc). B, Lateral force causing coup (c) and contrecoup (cc) injury. C, Axial or rotational injury with shearing of axons, particularly at base of brain. Acceleration/deceleration axonal shearing injury occurs throughout the brain (red and blue directional arrows in all three images). (Borrowed from Pascual, J.M., & Preito, R. [2012]. Chapter 133: Surgical management of severe closed head injury in adults. In A. Quinones-Hinojosa [Ed.], Schmidek and Sweet operative neurosurgical techniques [6th ed., Vol. 2, pp. 1513–1538]. Philadelphia: Saunders. Originally redrawn from Adams, J.H. [1990]. Brain damage in fatal nonmissile head injury in man. In R. Braakman [Ed.], Handbook of clinical neurology, head injury [Vol. 13, pp. 43–63]. Amsterdam: Elsevier Science Publishers BV; Gennarelli, T.A., Thibault, L.E., Adams, J.H., et al. [1982]. Ann Neurol, 12, 564– 574.)

Contusions are found most commonly in the frontal lobes, particularly at the poles and along the inferior orbital surfaces; in the temporal lobes, especially at the anterior poles and along the inferior surface; and at the frontotemporal junction. They cause changes in attention, memory, executive attention functions (see Chapter 15), affect, emotion, and behaviour. Less commonly, contusions occur in the parietal and occipital lobes. Focal cerebral contusions are usually superficial, involving just the gyri. Hemorrhagic contusions may coalesce into a large confluent intracranial hematoma. A contusion may be evidenced by immediate loss of consciousness (generally accepted to last no longer than 5 minutes), loss of reflexes (individual falls to the ground), transient cessation of respiration, brief period of bradycardia, and decrease in blood pressure (lasting 30 seconds to a few minutes). Increased cerebrospinal fluid (CSF) pressure and electrocardiogram (ECG) and electroencephalogram (EEG) changes occur on impact. Vital signs may stabilize to normal values in a few seconds; reflexes then return and the person regains consciousness over minutes to days. Residual deficits may persist, and some persons never regain a full level of consciousness. Evaluation is based on results of the health history, level of consciousness according to the Glasgow Coma Scale (see Table 16-1), outcomes of imaging studies (e.g., computed tomography [CT], magnetic resonance imaging [MRI], and positron emission tomography [PET] scans), and assessment of vital parameters (e.g., ICP and EEG). Large contusions and lacerations with hemorrhage may be surgically excised. Treatment is otherwise directed at controlling ICP and managing symptoms.

Epidural (extradural) hematomas (bleeding between the dura mater and the skull) represent 1 to 2% of major head injuries and occur in all age groups, but most commonly in those 20 to 40 years old. An artery is the source of bleeding in 85% of epidural hematomas, usually accompanied by a skull fracture; 15% of these injuries result from injury to the meningeal vein or dural sinus (Figure 16-2). The temporal fossa is the most common site of epidural hematoma caused by injury to the middle meningeal artery or vein. The temporal lobe shifts medially, precipitating uncal and hippocampal gyrus herniation through the tentorial notch. Epidural hemorrhages are found occasionally in the subfrontal area, especially in the young and older adult populations, caused by injury to the anterior meningeal artery or a venous sinus; and in the occipital-suboccipital area, resulting in herniation of the posterior fossa contents through the foramen magnum (see Figure 15-10).

FIGURE 16-2

Brain Hematomas.

Individuals with temporal epidural hematomas lose consciousness at injury; one third of those affected then become lucid for a few minutes to a few days (if a vein is bleeding). As the hematoma accumulates, a headache of increasing severity, vomiting, drowsiness, confusion, seizure, and hemiparesis may develop. Because temporal lobe herniation occurs, the level of consciousness is rapidly lost, with ipsilateral pupillary dilation and contralateral hemiparesis. A CT scan or MRI usually is needed to diagnose epidural hematoma. The prognosis is good if intervention is initiated before bilateral dilation of the pupils occurs. Epidural hematomas are almost always medical emergencies requiring monitoring and evaluation or surgical evacuation of the hematoma.4 Subdural hematomas (bleeding between the dura mater and the brain) arise in 10 to 20% of persons with TBI. Acute subdural hematomas develop rapidly, commonly within hours, and usually are located at the top of the skull (the cerebral convexities). Bilateral hematomas occur in 15 to 20% of persons. Subacute subdural hematomas develop more slowly, often over 48 hours to 2 weeks. Chronic subdural hematomas (commonly found in older adults and persons who abuse alcohol and have some degree of brain atrophy with a subsequent increase in extradural space) develop over weeks to months. Bridging veins tear, causing both rapidly and subacutely developing subdural hematomas, although torn cortical veins or venous sinuses and contused tissue also may be the source. These subdural hematomas act like expanding masses, increasing ICP that eventually compresses the bleeding vessels (see Figure 16-2). Brain herniation can result. With a chronic subdural hematoma, the existing subdural space gradually fills with blood. A vascular membrane forms around the hematoma in approximately 2 weeks. Further enlargement may take place. In acute, rapidly developing subdural hematomas, the expanding clots directly compress the brain. As ICP rises, bleeding veins are compressed. Thus, bleeding is self-limiting, although cerebral compression and displacement of brain tissue can cause temporal lobe herniation.

An acute subdural hematoma classically begins with headache, drowsiness, restlessness or agitation, slowed cognition, and confusion. These symptoms worsen over time and progress to loss of consciousness, respiratory pattern changes, and pupillary dilation (i.e., the symptoms of temporal lobe herniation). Homonymous hemianopia (defective vision in either the right or the left field [see Figure 1411]), dysconjugate gaze, and gaze palsies also may occur. Of those individuals affected by chronic subdural hematomas, 80% have chronic headaches and tenderness over the hematoma on palpation. Most persons appear to have a progressive dementia with generalized rigidity (paratonia). Chronic subdural hematomas require a craniotomy to evacuate the gelatinous blood. Percutaneous drainage for chronic subdural hematomas has proven successful. However, reaccumulation often occurs unless the surrounding membrane is removed. Intracerebral hematomas (bleeding within the brain) occur in 2 to 3% of persons with head injuries, may be single or multiple, and are associated with contusions. Although most commonly located in the frontal and temporal lobes, they may occur in the hemispheric deep white matter. Penetrating injury or shearing forces traumatize small blood vessels. The intracerebral hematoma then acts as an expanding mass, increasing ICP, compressing brain tissues, and causing edema (see Figure 16-2). Delayed intracerebral hematomas may appear 3 to 10 days after the head injury. Intracerebral hematomas also can occur with nontraumatic brain injury, such as hemorrhagic stroke (see p. 408). Intracerebral hematomas cause a decreasing level of consciousness. Coma or a confusional state from other injuries, however, can make the cause of this increasing unresponsiveness difficult to detect. Contralateral hemiplegia also may occur and, as ICP rises, temporal lobe herniation may appear. In delayed intracerebral hematoma, the presentation is similar to that of a hypertensive brain hemorrhage— sudden, rapidly progressive decreased level of consciousness with pupillary dilation, breathing pattern changes, hemiplegia, and bilateral positive Babinski reflexes. History and physical examination help to establish the diagnosis, and CT scan, MRI, and cerebral angiography confirm it. Evacuation of a singular intracerebral hematoma has only occasionally been helpful, mostly for subcortical white matter hematomas. Otherwise, treatment is directed at reducing the ICP and allowing the hematoma to reabsorb slowly. Open brain injury (trauma that penetrates the dura mater) produces both focal and diffuse injuries and includes compound skull fractures and missile injuries (e.g., bullets, rocks, shell fragments, knives, and blunt instruments). A compound skull fracture opens a communication between the cranial contents and the environment and should be investigated whenever lacerations of the scalp, tympanic membrane, sinuses, eye, or mucous membranes are present. Such fractures may involve the cranial vault or the base of the skull (basilar skull fracture). Cranial nerve damage and spinal fluid leak may occur with a basilar skull fracture. The mechanisms of open brain trauma are crush injury (laceration and crushing of whatever the missile touches) and stretch injury (blood vessels and nerves damaged without direct contact as a result of stretching). The tangential injury is to the coverings and the brain (scalp and brain lacerations) and may also include skull fractures and meningeal or cerebral lacerations from projectiles and debris driven into the brain substance. Most persons lose consciousness with open brain injury. The depth and duration of the coma are related to the location of injury, extent of damage, and amount of bleeding. Open brain injury often requires debridement of the traumatized tissues to prevent infection and to remove blood clots, thereby reducing ICP. Intracranial pressure also is managed with steroids, dehydrating agents, osmotic diuretics, or a combination of these medications. Broad-spectrum antibiotics are administered to prevent infection. A compound fracture may be diagnosed through physical examination, skull X-ray films, or both. Basilar skull fracture is determined on the basis of clinical findings, such as spinal fluid leaking from the ear or nose. Skull X-rays often do not demonstrate the fracture, although intracranial air or air in the sinuses on X-ray film, CT scan, or MRI is indirect evidence of a basilar skull fracture. Bed rest and close observation for meningitis and other complications are prescribed for a basilar skull fracture. Diffuse brain injury. Diffuse brain injury (diffuse axonal injury [DAI]) involves widespread areas of the brain. Mechanical effects from high levels of acceleration and deceleration, such as whiplash, or rotational forces cause

shearing of delicate axonal fibres and white matter tracts that project to the cerebral cortex (see Figure 161). The most severe axonal injuries are located more peripheral to the brainstem, causing extensive cognitive and affective impairments, as seen in survivors of TBI from motor vehicle crashes. Axonal damage reduces the speed of information processing and responding and disrupts the individual's attention span.5 Pathophysiologically, axonal damage can be seen only with an electron microscope and involves numerous axons, either alone or in conjunction with actual tissue tears. Advanced imaging techniques assist in defining areas of injury. Areas where axons and small blood vessels are torn appear as small hemorrhages, particularly in the corpus callosum and dorsolateral quadrant of the rostral brainstem at the superior cerebellar peduncle. More damaged axons are visible 12 hours to several days after the initial injury. The severity of diffuse injury correlates with how much shearing force was applied to the brainstem. DAI is not associated with intracranial hypertension immediately after injury; however, acute brain swelling caused by increased intravascular blood flow within the brain, vasodilation, and increased cerebral blood volume is seen often and can result in death. Several categories of diffuse brain injury exist: mild concussion, classic cerebral concussion, mild DAI, moderate DAI, and severe DAI. Mild concussion (mild traumatic brain injury) is characterized by immediate but transitory clinical manifestations. CSF pressure rises, and ECG and EEG changes occur without loss of consciousness.6 Approximately 75 to 90% of blunt trauma injuries cause mild concussion. The Glasgow Coma Scale score for mild concussion is 13 to 15. The initial confusional state lasts for 1 to several minutes, possibly with amnesia for events preceding the trauma (retrograde amnesia). Anterograde amnesia (lack of memories) may also exist transiently. Persons may experience headache and complain of nervousness and “not being themselves” for up to a few days. Classic cerebral concussion is any loss of consciousness lasting less than 6 hours accompanied by retrograde and anterograde amnesia with a confusional state lasting for hours to days. Transient cessation of respiration can occur with brief periods of bradycardia and a decrease in blood pressure lasting 30 seconds or less. Vital signs stabilize within a few seconds to within normal limits. Reflexes fail and are regained as responsiveness returns. DAI is a severe brain injury and produces coma lasting more than 6 hours because of axonal disruption. Three forms of DAI exist: mild, moderate, and severe. In mild diffuse axonal injury, coma lasts 6 to 24 hours with 30% of persons displaying decerebrate or decorticate posturing (see Figure 15-6). They may experience prolonged periods of stupor or restlessness. In moderate diffuse axonal injury, the score on the Glasgow Coma Scale is 4 to 8 initially and 6 to 8 by 24 hours; 35% of victims have transitory decerebration or decortication, with unconsciousness lasting days or weeks. On awakening, the person is confused and suffers a long period of post-traumatic anterograde and retrograde amnesia. There is often permanent deficit in memory, attention, abstraction, reasoning, problem solving, executive functions, vision or perception, and language. Mood and affect changes range from mild to severe. In severe diffuse axonal injury, injury involves both hemispheres and the brainstem. Coma may last days to months. The person experiences immediate autonomic dysfunction (hypertension, tachycardia, tachypnea, extensor posturing) that disappears in a few weeks. increased ICP appears 4 to 6 days after injury. Pulmonary complications occur often. Profound sensorimotor and cognitive system deficits are present, including spastic paralysis, dysarthria, dysphagia, memory loss, inability to learn and reason, and failure to modulate behaviour. Irreversible coma and death can occur. High-resolution CT scan and MRI assist in the diagnosis of focal and diffuse injuries. Medical management must address endocrine and metabolic derangements. The goal of treatment is to maintain cerebral perfusion and oxygenation, and promote neuroprotection. Implementation of TBI guidelines decreases death and improves neurological outcome. The Corticosteroid Randomization After Significant Head Injury (CRASH) trial showed that corticosteroids increase mortality with acute TBI; consequently, these medications are no longer used.3,7 Guidelines are available to direct treatment.8

Secondary brain injury. Secondary brain injury is an indirect result of primary brain injury, including trauma and stroke

syndromes. Systemic and cerebral processes are contributing factors. Systemic processes include hypotension, hypoxia, anemia, hypercapnia, and hypocapnia. Cerebral contributions include inflammation, cerebral edema, increased ICP, decreased cerebral perfusion pressure, cerebral ischemia, and brain herniation. Cellular and molecular brain damage from the effects of primary injury develops hours to days later. Astrocyte swelling and proliferation alter the blood–brain barrier and cause increased ICP. Ischemia contributes to excitotoxicity with release of excitatory neurotransmitters, such as glutamate and aspartate. They cause cellular influx of calcium, damage mitochondria, and cause neuronal hyperexcitability. A hypermetabolic state, poor perfusion, influx of inflammatory mediators, fluctuations in cellular sodium and potassium ion channels, and mitochondrial failure all contribute to cytotoxic edema, axonal swelling, and neuronal death.2 The management of secondary brain injury is related to prevention and includes removal of hematomas and management of hypotension, hypoxemia, anemia, ICP, fluid and electrolyte balance, body temperature, and ventilation. Thyrotropin-releasing hormone, statins, and other agents are under investigation and may be neuroprotective by decreasing excitotoxicity, neuro-inflammation, and other mechanisms of secondary injury.2,9 Progress is difficult because of the lack of predictive biomarkers and medications that can cross the blood–brain barrier. Fluid and nutrition management has emerged as critically important in the care of individuals with severe brain injury.10 Long-term recovery can be influenced by systemic complications, such as pneumonia, fever, infections, and immobility that contribute to further brain injury, and delays in repair and recovery.

Complications of Traumatic Brain Injury Many complications are associated with TBI and are related to the severity of injury and the parts of the brain that are affected. Altered states of consciousness can range from confusion to deep coma (see Table 15-3). Cognitive deficits; hydrocephalus; sensory-motor disorders, including pain, paresis, and paralysis; and loss of coordination may be present. Three of the most common post-traumatic brain syndromes are summarized next. Postconcussion syndrome, including headache, dizziness, fatigue, nervousness or anxiety, irritability, insomnia, depression, inability to concentrate, and forgetfulness, may last for weeks to months after a concussion. Treatment entails reassurance and symptomatic relief in addition to 24 hours of close observation after the concussion in the event bleeding or swelling in the brain occurs. Symptoms requiring further evaluation and treatment include drowsiness or confusion, nausea or vomiting, severe headache, memory deficit, seizures, drainage of CSF from the ear or nose, weakness or loss of feeling in the extremities, asymmetry of the pupils, and double vision. Guidelines for the management of pediatric and adult concussion are available.11-13 Guidelines have been published for the management of sportsrelated concussion.14 Post-traumatic seizures occur in about 2 to 16% of TBIs, with the highest risk among open brain injuries. Seizures can occur early, within days, and up to 2 to 5 years or longer after the trauma. Causal mechanisms are poorly understood, and cellular and molecular changes in the brain associated with injury and repair, such as sprouting of new neurons with hyperexcitability and decreases in GABAergic inhibition, may cause the hyperexcitable state that leads to epileptogenesis. Seizure prevention using medications, such as phenytoin (Dilantin), is initiated for moderate to severe TBI at the time of injury. Clinical trials are ongoing to test medications that prevent the development of post-traumatic seizures.15 Chronic traumatic encephalopathy (CTE) (previously called dementia pugilistica) is a progressive dementing disease that develops with repeated brain injury associated with sporting events, blast injuries in soldiers, or work-related head trauma. Tau neurofibrillary tangles are present in the brain, and research is in progress to discover the mechanistic link between neurotrauma and CTE. It is diagnosed from history and clinical evaluation, and at autopsy.16,17

Quick Check 16-1 1. How is a concussion different from a contusion?

2. Why do epidural, subdural, and intracerebral hematomas act like expanding masses? 3. Why is head motion the principal causative mechanism of diffuse brain injury?

Spinal Cord and Vertebral Injury Each year, approximately 4 259 persons in Canada experience serious spinal cord injury. Male gender and ages 20 to 39 years are strong risk factors for experiencing a traumatic spinal cord injury. Motor vehicle accidents, sports activities, and violence are the leading cause of injury in this age group. A significant number of injuries also occurs in persons aged 70 years and older, mainly as a result of falls.18 Older adults are particularly at risk for trauma that results in serious spinal cord injury because of pre-existing degenerative vertebral disorders. Pathophysiology Primary spinal cord injury occurs with the initial mechanical trauma and immediate tissue destruction. Injuries to the cord are summarized in Table 16-3. Primary spinal cord injury occurs if an injured spine is not adequately immobilized immediately following injury. Primary spinal cord injury also may occur in the absence of vertebral fracture or dislocation from longitudinal stretching of the cord with or without flexion or extension of the vertebral column, or both. The stretching causes altered axon transport, edema, myelin degeneration, and retrograde or Wallerian degeneration (see Chapter 13). TABLE 16-3 Spinal Cord Injuries Injury

Description

Cord concussion Cord contusion Cord compression Laceration

Results in temporary disruption of cord-mediated functions Bruising of neural tissue causes swelling and temporary loss of cord-mediated functions Pressure on cord causes ischemia to tissues; must be relieved (decompressed) to prevent permanent damage to spinal cord Tearing of neural tissues of spinal cord; may be reversible if only slight damage sustained by neural tissues; may result in permanent loss of cordmediated functions if spinal tracts are disrupted Severing of spinal cord causes permanent loss of function All tracts in spinal cord are completely disrupted; all cord-mediated functions below transection are completely and permanently lost Some tracts in spinal cord remain intact, together with functions mediated by these tracts; has potential for recovery although function is temporarily lost Some demonstrable sensation below level of injury Preserved motor function without useful purpose; sensory function may or may not be preserved Preserved voluntary motor function that is functionally useful Bleeding into neural tissue as a result of blood vessel damage; usually no major loss of function Causes local ischemia

Transection Complete Incomplete Preserved sensation only Preserved motor nonfunctional Preserved motor functional Hemorrhage Damage or obstruction of spinal blood supply

Secondary spinal cord injury is a pathophysiological cascade of vascular, cellular, and biochemical events that begins within a few minutes after injury and continues for weeks. Edema, ischemia, excitotoxicity (excessive stimulation by excitatory neurotransmitters such as glutamate), inflammation, oxidative damage, and activation of necrotic and apoptotic cell death signal events similar to those previously described for TBI.19 With secondary spinal cord injury, microscopic hemorrhages appear in the central grey matter and piaarachnoid, increasing in size until the entire grey matter is hemorrhagic and necrotic. Edema in the white matter occurs, impairing the microcirculation of the cord. Hemorrhages and edema are followed by reduced vascular perfusion and development of ischemic areas, which are maximal at the level of injury and two cord segments above and below it. Cellular and subcellular alterations and tissue necrosis occur. Cord swelling increases the individual's degree of dysfunction, making it difficult to distinguish functions permanently lost from those temporarily impaired. In the cervical region, cord swelling may be life-threatening. Diaphragm function may be impaired because phrenic nerves exit at C3 to C5. Cardiovascular and respiratory functions mediated by the medulla oblongata can be lost. Circulation in the white matter tracts of the spinal cord returns to normal in about 24 hours, but grey matter circulation remains altered. Phagocytes appear 36 to 48 hours after injury, and microglia proliferate with altered astrocytes. Red blood cells then begin to disintegrate, and resorption of hemorrhages and edema begins. Degenerating axons are engulfed by macrophages in the first 10 days after injury. The traumatized cord is replaced by acellular collagenous tissue, usually in 3 to 4 weeks. Meninges thicken as part of the scarring process. Vertebral injuries result from acceleration, deceleration, or deformation forces occurring at impact.

These forces cause vertebral fractures, dislocations, and bone fragments that can cause compression to the tissues, pull or exert traction (tension) on the tissues, or cause shearing of tissues so they slide into one another (Figures 16-3 to 16-6). Vertebral injuries can be classified as (1) simple fracture—a single break usually affecting transverse or spinous processes; (2) compressed (wedged) vertebral fracture—vertebral body compressed anteriorly; (3) comminuted (burst) fracture—vertebral body shattered into several fragments; and (4) dislocation.

FIGURE 16-3

Hyperextension Injuries of the Spine. Hyperextension injuries of the spine can result in fracture or nonfracture injuries with spinal cord damage.

FIGURE 16-4

Flexion Injury of the Spine. Hyperflexion produces translation (subluxation) of vertebrae that compromises the central canal and compresses spinal cord parenchyma or vascular structures.

FIGURE 16-5

Axial Compression Injuries of the Spine. In axial compression injuries of the spine, the spinal cord is contused directly by retropulsion of bone or disc material into the spinal canal.

FIGURE 16-6

Flexion-Rotation Injuries of the Spine.

The vertebrae fracture readily with both direct and indirect trauma. When the supporting ligaments are torn, the vertebrae move out of alignment and dislocations occur. A horizontal force moves the vertebrae straight forward; if the individual is in a flexed position at the time of injury, the vertebrae are then angulated. Flexion and extension injuries may result in dislocations. (Bone, ligament, and joint injuries are presented in Table 16-4.) TABLE 16-4 Mechanisms of Vertebral Injury Involving Bone, Ligaments, and Joints Mechanism of Location of Vertebral Injury Injury Hyperextension Hyperflexion Vertical compression (axial loading) Rotational forces (flexion-rotation)

Fracture and dislocation of posterior elements, such as spinous processes, transverse processes, laminae, pedicles, or posterior ligaments Fracture or dislocation of vertebral bodies, discs, or ligaments Shattering fractures

Rupture support ligaments in addition to producing fractures

Forces of Injury

Location of Injury

Results from forces of acceleration–deceleration and sudden reduction in anteroposterior diameter of spinal cord Results from sudden and excessive force that propels neck forward or causes an exaggerated lateral movement of neck to one side Results from a force applied along an axis from top of cranium through vertebral bodies

Cervical area

Add shearing force to acceleration forces

Cervical area

Cervical area T12 to L2

Vertebral injuries in adults occur most often at vertebrae C1 to C2 (cervical), C4 to C7, and T10 (thoracic) to L2 (lumbar) (see Figure 13-11), the most mobile portions of the vertebral column. The spinal cord occupies most of the vertebral canal in the cervical and lumbar regions, so it can be easily injured in these locations. Clinical Manifestations Spinal shock develops immediately after injury because of loss of continuous tonic discharge from the brain or brainstem and inhibition of suprasegmental impulses caused by cord hemorrhage, edema, or anatomical transection. Normal activity of spinal cord cells at and below the level of injury ceases with complete loss of reflex function, flaccid paralysis, absence of sensation, loss of bladder and rectal control, transient drop in blood pressure, and poor venous circulation. The condition also results in disturbed thermal control because the sympathetic nervous system is damaged. The hypothalamus cannot regulate body heat through vasoconstriction and increased metabolism; therefore, the individual assumes the temperature of the air (poikilothermia). Spinal shock generally lasts 7 to 20 days, with a range of a few days to 3 months. It terminates with the reappearance of reflex activity, hyper-reflexia, spasticity, and reflex emptying of the bladder. Table 16-5 summarizes the clinical manifestations of spinal cord injury. TABLE 16-5 Clinical Manifestations of Spinal Cord Injury Stage

Clinical Manifestations

Spinal Shock Stage Complete spinal cord transection

Loss of motor function 1. Quadriplegia with injuries of cervical spinal cord 2. Paraplegia with injuries of thoracic spinal cord Muscle flaccidity Loss of all reflexes below level of injury Loss of pain, temperature, touch, pressure, and proprioception below level of injury Pain at site of injury caused by zone of hyperesthesia above injury Atonic bladder and bowel Paralytic ileus with distension

Loss of vasomotor tone in lower body parts; low and unstable blood pressure Loss of perspiration below level of injury Loss or extreme depression of genital reflexes such as penile erection and bulbocavernous reflex Dry and pale skin; possible ulceration over bony prominences Respiratory impairment Partial spinal cord transection Asymmetrical flaccid motor paralysis below level of injury Asymmetrical reflex loss Preservation of some sensation below level of injury Vasomotor instability less severe than that seen with complete cord transection Bowel and bladder impairment less severe than that seen with complete cord transection Preservation of ability to perspire in some portions of body below level of injury Brown-Séquard's syndrome (associated with penetrating injuries, hyperextension and flexion, locked facets, and compression fractures) 1. Ipsilateral paralysis or paresis below level of injury 2. Ipsilateral loss of touch, pressure, vibration, and position sense below level of injury 3. Contralateral loss of pain and temperature sensations below level of injury Central cervical cord syndrome (acute cord compression between bony bars or spurs anteriorly and thickened ligamentum flavum posteriorly associated with hyperextension) 1. Motor deficits in upper extremities, especially hands, more dense than in lower extremities 2. Varying degrees of bladder dysfunction Burning hand syndrome (variant of central cord syndrome; in 50% of cases an underlying spine fracture/dislocation is present) 1. Severe burning paresthesias and dysesthesias in the hands or feet Anterior cord syndrome (compromise of anterior spinal artery by occlusion or pressure effect of disc) 1. Loss of motor function below level of injury 2. Loss of pain and temperature sensations below level of injury 3. Touch, pressure, position, and vibration senses intact Posterior cord syndrome (associated with hyperextension injuries with fractures of vertebral arch) 1. Impaired light touch and proprioception Conus medullaris syndrome (compression injury at T12 from disc herniation or burst fracture of body of T12) 1. Flaccid paralysis of legs 2. Flaccid paralysis of anal sphincter 3. Variable sensory deficits Cauda equina syndrome (compression of nerve roots below L1 caused by fracture and dislocation of spine or large posterocentral intervertebral disc herniation) 1. Lower extremity motor deficits 2. Variable sensorimotor dysfunction 3. Variable reflex dysfunction 4. Variable bladder, bowel, and sexual dysfunction Syndrome of neuropraxia (postathletic injury, associated with congenital spinal stenosis) 1. Dramatic but transient neurological deficits, including quadriplegia Horner's syndrome (injury to preganglionic sympathetic trunk or postganglionic sympathetic neurons of superior cervical ganglion) 1. Ipsilateral pupil smaller than contralateral pupil 2. Sunken ipsilateral eyeball 3. Ptosis of affected eyeball 4. Lack of perspiration on ipsilateral side of face Heightened Reflex Activity Emergence of Babinski reflexes, possibly progressing to a triple reflex; possible development of still later flexor spasms Stage Reappearance of ankle and knee reflexes, which become hyperactive Contraction of reflex detrusor muscle leading to urinary incontinence Appearance of reflex defecation Mass reflex with flexion spasms, profuse sweating, piloerection, and bladder and occasional bowel emptying may be evoked by autonomic stimulation of skin or from full bladder Episodes of hypertension Defective heat-induced sweating Eventual development of extensor reflexes, first in muscles of hip and thigh, later in leg Possible paresthesias below level of transection: dull, burning pain in lower back, abdomen, buttocks, and perineum

Neurogenic shock, also called vasogenic shock, occurs with cervical or upper thoracic cord injury above T5 and may be seen in addition to spinal shock. Neurogenic shock is caused by the absence of sympathetic activity through loss of supraspinal control and unopposed parasympathetic tone mediated by the intact vagus nerve. Symptoms include vasodilation, hypotension, bradycardia, and failure of body temperature regulation. Neurogenic shock may be complicated by hypovolemic or cardiogenic shock if there is concurrent heart failure or blood loss (see Chapter 24). Autonomic hyper-reflexia (dysreflexia) is a syndrome of sudden, massive reflex sympathetic discharge associated with spinal cord injury at level T6 or above where descending inhibition is blocked (Figure 16-7). It may occur after spinal shock resolves and be a recurrent complication. Characteristics involve changes in the body's autonomic functions, including paroxysmal hypertension (up to 300 mm Hg, systolic), a pounding headache, blurred vision, sweating above the level of the lesion with flushing of the skin, nasal congestion, nausea, piloerection caused by pilomotor spasm, bradycardia (30 to 40 beats/min), and automatic bladder emptying. The symptoms may develop singly or in combination. The condition can cause serious complications (stroke, seizures, myocardial ischemia, and death) and requires immediate treatment.

FIGURE 16-7

Autonomic Hyper-Reflexia. A, Normal response pathway. B, Autonomic dysreflexia pathway. SA, sinoatrial. (Modified from Rudy, E.B. [1984]. Advanced neurological and neurosurgical nursing. St. Louis: Mosby.)

In autonomic hyper-reflexia, sensory receptors below the level of the cord lesion are stimulated. The intact autonomic nervous system reflexively responds with an arteriolar spasm that increases blood pressure. Baroreceptors in the cerebral vessels, the carotid sinus, and the aorta sense the hypertension and stimulate the parasympathetic system. The heart rate decreases, but the visceral and peripheral vessels do not dilate because efferent impulses cannot pass through the cord. The most common cause is a distended bladder or rectum; however, any sensory stimulation (i.e., skin or pain receptors) can elicit autonomic hyper-reflexia. Intravenous fluids may be required to maintain blood pressure. Medication therapy may be required to lower blood pressure and reduce complications. Bladder, bowel, and skin care management are important preventive strategies. Education of the individual and family regarding triggers and acute management are important, as is wearing a medic alert tag.20 Evaluation and Treatment Diagnosis of spinal cord injury is based on physical examination and imaging studies. Neurogenic shock must be differentiated from other kinds of shock (i.e., hypovolemic shock). For a suspected or confirmed vertebral fracture or dislocation, regardless of the presence or absence of spinal cord injury, the

immediate intervention is immobilization of the spine to prevent further injury. Decompression and surgical fixation may be necessary. Corticosteroids may be given at the time of injury to decrease secondary cord injury from inflammation and thereafter for several days.21 Therapeutic hypothermia has shown some encouraging evidence for improved outcomes, particularly for cervical cord injuries; however, more research is needed.22 Clinical trials are in progress to treat acute spinal cord injury, including cell-based therapies, immune modulators, vasculature selective treatments, and functional electrical stimulation.23 Nutrition; lung function; skin integrity; prevention of pressure ulcers, in particular; and bladder and bowel management must be addressed. Plans for rehabilitation need early consideration.

Degenerative Disorders of the Spine Low Back Pain Low back pain (LBP) affects the area between the lower rib cage and gluteal muscles and often radiates into the thighs. The incidence rate of LBP in Canada is estimated to be 18.6%, with a higher percentage among older adults.24 LBP is the primary cause of disability worldwide.25 The burdens of disability include psychological, financial, occupational, and social effects on the person and family members. Risk factors include occupations that require repetitious lifting in the forward bent-and-twisted position; exposure to vibrations caused by vehicles or industrial machinery; obesity; and cigarette smoking. Some people have a genetic predisposition for LBP. Pathogenesis Most cases of LBP are idiopathic or nonspecific, and no precise diagnosis is possible. Acute LBP is often associated with muscle or ligament strain and is more common in individuals younger than 50 years of age without a history of cancer. Common causes of chronic LBP include degenerative disc disease, spondylolysis, spondylolisthesis (vertebra slides forward or slips in relation to a vertebra below), spinal osteochondrosis, spinal stenosis, and lumbar disc herniation. Other causes include tension caused by tumours or disc prolapse, bursitis, synovitis, rising venous and tissue pressures (found in degenerative joint disease), abnormal bone pressures, spinal immobility, inflammation caused by infection (as in osteomyelitis), and pain referred from viscera or the posterior peritoneum. Systemic causes of LBP include bone diseases, such as osteoporosis or osteomalacia, and hyperparathyroidism. Anatomically, LBP must originate from innervated structures, but deep pain is widely referred and varies. The nucleus pulposus has no intrinsic innervation, but when extruded or herniated through a prolapsed disc, it irritates the spinal nerve dural membranes and causes pain referred to the segmental area26 (Figure 16-8).

FIGURE 16-8

Herniated Nucleus Pulposus.

The interspinous bursae can be a source of pain between L3, L4, L5, and S1 but also may affect L1, L2, and L3 spinous processes. The anterior and posterior longitudinal ligaments of the spine and the interspinous and supraspinous ligaments are abundantly supplied with pain receptors, as is the

ligamentum flavum. All of these ligaments are vulnerable to traumatic tears (sprains) and fracture. Discogenic pain also may be related to inflammation and nerve sprouting within the disc.27 Clinical Manifestations About 1% of individuals with acute LBP have pain along the distribution of a lumbar nerve root (radicular pain), most commonly involving the sciatic nerve (sciatica). Sciatica is often accompanied by sensorineural and motor deficits, such as tingling, numbness, and weakness in various parts of the leg and foot. Major or progressive motor or sensory deficit, cauda equina syndrome (new-onset bowel or bladder incontinence or urinary retention, loss of anal sphincter tone, and saddle anaesthesia), history of cancer metastasis to bone, and suspected spinal infection can be associated with chronic LBP. Evaluation and Treatment Diagnosis of LBP is based on the history and physical examination. Imaging and nerve conduction studies are obtained with severe neurological deficit or serious underlying disease. Diagnosis and treatment guidelines are available to plan therapy.28 Most individuals with acute LBP benefit from a nonspecific short-term treatment regimen of analgesic medications, exercises, physiotherapy, and education. Individuals should be advised to stay active and continue their usual activity, including work, within the limits permitted by pain. Surgical treatments, specifically discectomy and spinal fusions, are used for individuals not responding to medical management or for emergency management of cauda equina syndrome. Individuals with chronic LBP may benefit from anti-inflammatory and muscle relaxant medications, exercise programs, massage, topical heat, spinal manipulation, acupuncture, cognitivebehavioural therapies, and interdisciplinary care.29 There is scant evidence for efficacy of opioids for chronic LBP, but a high risk for addiction.30 The complexity of causes contributes to the difficulty in defining pathogenesis and clearly defining the most effective therapies.

Degenerative Joint Disease Degenerative disc disease. Degenerative disc disease (DDD) is common in individuals 30 years of age and older. It is, in part, a process of normal aging as a response to continuous vertical compression of the spine (axial loading). DDD includes a genetic component, involving genes that code the cartilage intermediate layer protein (CILP). The combination of environmental interactions and genetic predisposition increases susceptibility to lumbar disc disease by disrupting normal building and maintenance of cartilage.27 Causes include biochemical (e.g., inflammatory mediators) and biomechanical alterations (e.g., mechanical loading and compression) of the intervertebral disc tissue. For example, loss of disc proteoglycans and collagen with disc dehydration and loss of hydrostatic pressure alters disc structure and function. The annulus can tear and the disc can herniate, pinching nerves or placing strain on the spine. The pathological findings in DDD include disc protrusion; spondylolysis, subluxation (spondylolisthesis), or both; degeneration of vertebrae; and spinal stenosis. Lumbar disc disease causes one third of all back pain that affects 70 to 90% of adults at some point in their lives. However, only a small percentage of people with DDD have any functional incapacity because of pain.

Spondylolysis. Spondylolysis is a structural defect (degeneration, fracture, or developmental defect) in the pars interarticularis of the vertebral arch (the joining of the vertebral body to the posterior structures). The lumbar spine at L5 is affected most often. Mechanical pressure may cause an anterior or posterior displacement of the deficient vertebra (spondylolisthesis). Heredity plays a significant role, and spondylolysis is associated with an increased incidence of other congenital spinal defects. Symptoms include lower back and lower limb pain.

Spondylolisthesis. Spondylolisthesis, an osseous defect of the pars interarticularis, allows a vertebra to slide anteriorly in

relation to the vertebra below, commonly occurring at L5-S1. Spondylolisthesis is graded from 1 to 4 based on the percentage of slip that occurs. Grades 1 and 2 have symptoms of pain in the lower back and buttocks, muscle spasms in the lower back and legs, and tightened hamstrings. Conservative management includes exercise, rest, and back bracing. Vertebral slippage in grades 3 and 4 usually requires surgical decompression, stabilization, or both.

Spinal stenosis. Spinal stenosis is a narrowing of the spinal canal that causes pressure on the spinal nerves or cord and can be congenital or acquired (more common) and associated with trauma or arthritis. It is categorized by the area of the spine affected: cervical, thoracic, or lumbar. Acquired conditions include a bulging disc, facet hypertrophy, or a thick ossified posterior longitudinal ligament. Symptoms are related to the area of the spine affected and can produce pain; numbness; and tingling in the neck, hands, arms, or legs with weakness and difficulty walking. Surgical decompression is recommended for those with chronic symptoms and those who do not respond to medical management.

Herniated Intervertebral Disc Herniation of an intervertebral disc is a displacement of the nucleus pulposus or annulus fibrosus beyond the intervertebral disc space (see Figure 16-8). Rupture of an intervertebral disc usually is caused by trauma, DDD, or both. Risk factors are weight-bearing sports, light weight lifting, and certain work activities, such as repeated lifting. Men are affected more often than women, with the highest incidence in the 30- to 50-year age group. Most commonly affected are the lumbosacral discs L4-L5 and L5-S1. Herniation is typically at higher vertebrae in older adults. Disc herniation occasionally occurs in the cervical area, usually at C5-C6 and C6-C7. Herniations at the thoracic level are extremely rare. The herniation may occur immediately, within a few hours, or months to years after injury. Pathophysiology In a herniated disc, the ligament and posterior capsule of the disc are usually torn, allowing the nucleus pulposus to extrude and compress the nerve root. The vascular supply may be compromised and cause inflammatory changes in the nerve root (radiculitis). Occasionally, the injury tears the entire disc loose, causing the disc capsule and nucleus pulposus to protrude onto the nerve root or compress the spinal cord. Multiple nerve root compression may be found at the L5-S1 level, where the cauda equina may be compressed, causing cauda equina syndrome (see Table 16-5). Clinical Manifestations The location and size of the herniation into the spinal canal, together with the amount of space in the canal, determine the clinical manifestations associated with the injury (Figure 16-9). Compression or inflammation, or both, of a spinal nerve resulting from disc herniation follows a dermatomal distribution called radiculopathy (Figure 16-10). A herniated disc in the lumbosacral area is associated with pain that radiates along the sciatic nerve course over the buttock and into the calf or ankle. The pain occurs with straining, including coughing and sneezing, and usually on straight leg raising. Other clinical manifestations include limited range of motion of the lumbar spine; tenderness on palpation in the sciatic notch and along the sciatic nerve; impaired pain, temperature, and touch sensations in the L4-L5 or L5-S1 dermatomes of the leg and foot; decreased or absent ankle jerk reflex; and mild weakness of the foot. More rarely, there is development of cauda equina syndrome.

FIGURE 16-9

FIGURE 16-10

Clinical Features of a Herniated Nucleus Pulposus.

Sensory Nerve Distribution of Skin Dermatomes. (Redrawn from Patton, H.D., Sundsten, J.W., Crill, W.E., et al. [Eds.]. [1976]. Introduction to basic neurology. Philadelphia: Saunders. Borrowed from Canale, S.T., & Beaty, J.H. [2013]. Campbell's operative orthopaedics [12th ed.]. St. Louis: Mosby.)

With the herniation of a lower cervical disc, paresthesias and pain are present in the upper arm, forearm, and hand along the affected nerve root distribution. Neck motion and straining, including

coughing and sneezing, may increase neck and nerve root pain. Neck range of motion is diminished. Slight weakness and atrophy of biceps or triceps muscles may occur; the biceps or triceps reflex may decrease. Occasionally, signs of corticospinal and sensory tract impairments appear, including motor weakness of the lower extremities, sensory disturbances in the lower extremities, and presence of a Babinski reflex. Evaluation and Treatment Diagnosis of a herniated intervertebral disc is made through the history and physical examination, spinal X-ray films, electromyelography, CT scan, MRI, myelography, discography, and nerve conduction studies. Evidence-based practice guidelines have been published to guide treatment options.31 Most herniated discs heal spontaneously over time and do not require surgery. A surgical approach is indicated if there is evidence of severe compression (weakness or decreased deep tendon, bladder, or bowel reflexes) or if a conservative approach is unsuccessful.32 Cauda equina syndrome requires emergency surgical evaluation.33

Cerebrovascular Disorders Cerebrovascular disease is the most frequently occurring neurological disorder, accounting for more than 50% of the persons admitted to general hospitals with neurological problems. Any abnormality of the brain caused by a pathological process in the blood vessels is referred to as a cerebrovascular disease. Included in this category are lesions of the vessel wall, occlusion of the vessel lumen by thrombus or embolus, rupture of the vessel, and alteration in blood quality such as increased blood viscosity. The brain abnormalities induced by cerebrovascular disease are either (1) ischemia with or without infarction (death of brain tissues) or (2) hemorrhage. The common clinical manifestation of cerebrovascular disease is a cerebrovascular accident (CVA) or stroke. The symptoms occur suddenly and are focal (i.e., slurred speech, difficulty swallowing, limb weakness, or paralysis). In its mildest form, a CVA is so minimal that it is almost unnoticed. In its most severe form, hemiplegia, coma, and death result.

Cerebrovascular Accidents (Stroke Syndromes) CVAs are the leading cause of disability and the third leading cause of death in Canada, with over 13 000 persons dying from CVAs annually. It is estimated that about 80% of all CVAs can be prevented34 (see Health Promotion: Prevention of Stroke in Women). Persons with both hypertension and type 2 diabetes mellitus have a fourfold increase of CVA incidence and an eightfold increase in stroke mortality.35 Research has shown that First Nations people, Inuit, and Métis are more likely to be diagnosed with hypertension and type 2 diabetes, which puts them at a higher risk for CVAs than the general population.36 The mortality rate of stroke has decreased by more than 75% over the past 60 years, and is associated with improved control of hypertension, diabetes, and dyslipidemia, as well as smoking cessation.37

Health Promotion Prevention of Stroke in Women Stroke is a leading cause of death in Canadian women. The number of women with stroke will increasingly outnumber men in the future. The Heart and Stroke Foundation of Canada recommends a number of ways women can reduce the risk for stroke. A summary of these recommendations is as follows: • Become and remain smoke-free • Achieve and maintain a healthy body weight

• Be physically active for at least 150 minutes of moderate to vigorous-intensity aerobic physical activity per week • Maintain a healthy blood pressure through lifestyle changes (such as increased physical activity) and, when needed, through medication • Eat a healthy diet that is lower in fat and higher in fibre, and includes foods from each of the four food groups in Canada's Food Guide • Use medications to reduce the risk for stroke as prescribed by your health care provider; for example, medications for hypertension, dyslipidemia, and diabetes, or other medications such as acetylsalicylic acid (Aspirin) • Identify causes of excess stress and employ strategies to reduce them • Be aware of a possible increased risk for stroke related to your family background • Be aware of stroke risk factors (e.g., obesity, hypertension, and diabetes) at an early age • Be aware that hormone therapy (conjugated equine estrogen) with or without medroxyprogesterone (Provera) should not be used for primary or secondary prevention of stroke in postmenopausal women From Heart and Stroke Foundation of Canada. (2017). Women's unique risk factors. Retrieved from http://www.heartandstroke.ca/heart/riskand-prevention/womens-unique-risk-factors.

CVAs (stroke syndromes) are classified pathophysiologically as ischemic, hemorrhagic, or associated with hypoperfusion. Risk factors for stroke include the following:

• Poorly or uncontrolled arterial hypertension • Smoking, which increases the risk for stroke by 50% • Insulin resistance and diabetes mellitus • Polycythemia and thrombocythemia • High total cholesterol or low high-density lipoprotein (HDL) cholesterol, elevated lipoprotein-a • Congestive heart disease and peripheral vascular disease • Hyperhomocysteinemia • Atrial fibrillation • Chlamydia pneumoniae infection Ischemic stroke. Ischemic stroke occurs when there is obstruction to arterial blood flow to the brain from thrombus formation, an embolus, or hypoperfusion related to decreased blood volume or heart failure. The inadequate blood supply results in ischemia (inadequate cellular oxygen) and can progress to infarction (death of tissue). Transient ischemic attacks (TIAs) are episodes of neurological dysfunction lasting no more than 1 hour and resulting from focal cerebral ischemia. The clinical manifestations of a TIA may include weakness, numbness, sudden confusion, loss of balance, or a sudden severe headache. The use of brain imaging modalities often reveals a brain infarction. About 3 to 17% of individuals who experience a TIA will have a stroke within 90 days.38 Thrombotic strokes (cerebral thromboses) arise from arterial occlusions caused by thrombi formation in arteries supplying the brain or intracranial vessels. Conditions causing increased coagulation or inadequate cerebral perfusion (e.g., dehydration, hypotension, prolonged vasoconstriction from malignant hypertension) increase the risk for thrombosis. Cerebral thrombosis develops most often from atherosclerosis and inflammatory disease processes that damage arterial walls. It may take as long as 20

to 30 years for obstruction to develop at the branches and curvature found in the cerebral circulation (see Chapter 24 for a discussion of atherogenesis). The smooth stenotic area can degenerate, forming an ulcerated area of the vessel wall. Platelets and fibrin adhere to the damaged wall, and a clot forms, gradually occluding the artery. The clot may enlarge both distally and proximally. Thrombotic strokes also occur when parts of a clot detach, travel upstream, and obstruct blood flow, causing acute ischemia. Embolic stroke involves fragments that break from a thrombus formed outside the brain, usually in the heart, aorta, or common carotid artery. Other sources of embolism include fat, air, tumour, bacterial clumps, and foreign bodies. The embolus usually involves small brain vessels and obstructs at a bifurcation or other point of narrowing, thus causing ischemia. An embolus may plug the lumen entirely and remain in place or shatter into fragments and become part of the vessel's blood flow. Risk factors for an embolic stroke include atrial fibrillation, left ventricular aneurysm or thrombus, left atrial thrombus, recent myocardial infarction, endocarditis, rheumatic valve disease, mechanical valvular prostheses, atrioseptal defects, patent foramen ovale, and primary cardiac tumours. In persons who experience an embolic stroke, a second stroke usually follows because the source of emboli continues to exist. Embolization is usually in the distribution of the middle cerebral artery (the largest cerebral artery). Ischemic strokes in children are associated with congenital heart disease, cerebral arteriovenous malformations, and sickle cell disease (see Chapter 17). Lacunar strokes (lacunar infarcts or small vessel disease) are usually caused by occlusion of a single, deep perforating artery that supplies small penetrating subcortical vessels, causing ischemic lesions (0.5 to 15 mm, or lacunes) predominantly in the basal ganglia, internal capsules, and pons. These strokes are rare and, because of the location and small area of infarction, they may have pure motor or sensory deficits.39 Hypoperfusion, or hemodynamic stroke, is associated with systemic hypoperfusion caused by cardiac failure, pulmonary embolism, or bleeding that results in inadequate blood supply to the brain. Stroke may occur more readily if there is carotid artery occlusion. Symptoms are usually bilateral and diffuse.40 Pathophysiology Cerebral infarction results when an area of the brain loses its blood supply because of vascular occlusion. Causes include (1) abrupt vascular occlusion (e.g., embolus or thrombi), (2) gradual vessel occlusion (e.g., atheroma), and (3) partial occlusion of stenotic vessels. Cerebral thrombi and cerebral emboli most commonly produce occlusion, but atherosclerosis and hypertension are the dominant underlying processes. There is a central core of irreversible ischemia and necrosis with cerebral infarction. The central core is surrounded by a zone of borderline ischemic tissue, the ischemic penumbra. Ischemia in the penumbra is not severe enough to result in structural damage. Prompt restoration of perfusion in the penumbra by injection of thrombolytic agents promotes perfusion and may prevent necrosis and loss of neurological function. The window of opportunity for protecting the penumbra is about 3 hours. Cerebral infarctions are ischemic or hemorrhagic. In ischemic infarcts, the affected area becomes pale and softens 6 to 12 hours after the occlusion. Necrosis, swelling around the insult, and mushy disintegration appear by 48 to 72 hours after infarction. There is infiltration of macrophages and phagocytosis of necrotic tissue. The necrosis resolves by about the second week, ultimately leaving a cavity surrounded by glial scarring. In hemorrhagic infarcts, bleeding occurs into the infarcted area through leaking vessels when the embolic fragments resolve and reperfusion begins to occur. Hemorrhagic transformation of ischemic stroke may be exacerbated by thrombolytic therapy.41 Clinical Manifestations Clinical manifestations of thrombotic and embolic stroke vary, depending on the artery obstructed. Different sites of obstruction create different occlusion syndromes (e.g., carotid artery, dysphasia and contralateral motor [i.e., paresis] sensory [i.e., numbness] deficits, conjugate ipsilateral eye deviation), middle cerebral artery syndromes (dysphasia and contralateral motor and sensory deficits), or vertebrobasilar system syndromes (dizziness and ataxia, can progress to quadriplegia and coma).42 Contralateral motor and sensory manifestations occur on the opposite side of the body from the location

of the brain lesion because motor tracts originate in the cortex and most cross over in the medulla. Sensory tracts originate in the periphery and cross over in the spinal cord. Ipsilateral manifestations occur on the same side as the brain lesion. See Figure 16-11 for the Heart and Stroke Foundation of Canada's simple assessment tool for persons presenting with signs and symptoms of stroke.

FIGURE 16-11

Signs of Stroke. (From Heart and Stroke Foundation of Canada. [2017]. Signs of stroke. Retrieved from http://www.heartandstroke.ca/stroke/signs-of-stroke.)

Evaluation and Treatment Imaging is used to diagnose stroke. Treatment of ischemic stroke is focused on (1) restoring brain perfusion in a time frame that does not contribute to reperfusion injury, (2) counteracting the ischemic cascade pathways, (3) lowering cerebral metabolic demand so that the susceptible brain tissue is protected against impaired perfusion, (4) preventing recurrent ischemic events, and (5) promoting tissue restoration. Thrombolysis, using tissue-type plasminogen activator (tPA), is given within 3 and up to 4.5 hours of onset of symptoms. Endovascular intra-arterial thrombolysis may be used to treat those who cannot receive tPA.43 Supportive management is given to control cerebral edema and increased ICP and to provide neuroprotection. Arresting the disease process by control of risk factors is critical, and antiplatelet therapy may be instituted. A template and guidelines are available for the assessment and management of acute ischemic stroke.44,45 In embolic strokes, treatment is directed at preventing further embolization by instituting anticoagulation therapy and correcting the primary problem. Rehabilitation is indicated for ischemic strokes, and recovery of function is often possible.

Hemorrhagic stroke. Hemorrhagic stroke (intracranial hemorrhage) is the third most common cause of CVA. A hemorrhagic stroke can occur within the brain tissue (intraparenchymal) or in the subarachnoid or subdural spaces. The primary cause of intraparenchymal hemorrhagic stroke is hypertension with other causes including tumours, coagulation disorders, trauma, or illicit drug use, particularly cocaine. Prevention or control of hypertension reduces the incidence of hemorrhagic stroke. Subarachnoid hemorrhage is associated with ruptured aneurysms or arteriovenous malformations (see p. 409) or brain trauma. Subdural hemorrhage (hematoma) is usually associated with brain trauma (see p. 394). Hypertensive causes of hemorrhagic stroke involve primarily smaller arteries and arterioles, resulting in thickening of the vessel walls and increased cellularity of the vessels. Necrosis may be present. Microaneurysms in these smaller vessels or arteriolar necrosis may precipitate the bleeding. Pathophysiology A mass of blood is formed as bleeding continues into the brain tissue. Adjacent brain tissue is deformed, compressed, and displaced, producing ischemia, edema, increased ICP, and necrosis. Rupture or seepage of blood into the ventricular system often occurs and is associated with higher mortality. Hemorrhages are described as massive, small, slit, or petechial. Massive hemorrhages are several centimetres in diameter, small hemorrhages are 1 to 2 cm in diameter, a slit hemorrhage lies in the subcortical area, and a petechial hemorrhage is the size of a pinhead bleed. The most common sites for hypertensive

hemorrhages are in the putamen of the basal ganglia, the thalamus, the cortex and subcortex, the pons, the caudate nucleus, and the cerebellar hemispheres. Because neurons surrounding the ischemic or infarcted areas undergo changes that disrupt plasma membranes, cellular edema results, causing further compression of capillaries. Maximal cerebral edema develops in approximately 72 hours and takes about 2 weeks to subside. Most persons survive an initial hemispheric ischemic stroke unless there is massive cerebral edema, which is nearly always fatal. The cerebral hemorrhage resolves through reabsorption. Macrophages and astrocytes clear blood from the area. A cavity forms, surrounded by a dense gliosis (glial scar) after removal of the blood. Clinical Manifestations The clinical manifestations of hemorrhagic stroke are similar to those for embolic and thrombotic stroke and depend on the location and size of the bleed. Symptoms can occur suddenly and with activity. Once a deep unresponsive state occurs, the person rarely survives. The immediate prognosis is grave; however, if the person survives, recovery of function is often possible. It is difficult to differentiate ischemic from hemorrhagic stroke based on symptoms. Individuals experiencing intracranial hemorrhage from a ruptured or leaking aneurysm have one of three sets of symptoms: (1) onset of an excruciating generalized headache with an almost immediate lapse into an unresponsive state, (2) headache but with consciousness maintained, and (3) sudden lapse into unconsciousness. If the hemorrhage is confined to the subarachnoid space, there may be no local signs. If bleeding spreads into the brain tissue, hemiparesis or paralysis, dysphasia, or homonymous hemianopia may be present. Warning signs of an impending aneurysm rupture include headache, transient unilateral weakness, transient numbness and tingling, and transient speech disturbance. However, such warning signs are often absent. Evaluation and Treatment Treatment of an intracranial bleed, regardless of cause, focuses on stopping or reducing the bleeding, controlling the increased ICP, preventing a rebleed, and preventing vasospasm. There are some attempts to drain blood in a cerebral bleed, but the benefit is not documented in studies. Microsurgical interventions are under investigation.46 Surgical treatments are options for ruptured aneurysms, vascular malformations, and subarachnoid hemorrhage.

Intracranial aneurysm. Intracranial aneurysms may result from arteriosclerosis, congenital abnormality, cocaine use, trauma, inflammation, and vascular sheer wall stress. The size may vary from 2 mm to 2 or 3 cm. Most aneurysms are located at bifurcations in or near the circle of Willis, in the vertebrobasilar arteries, or within the carotid system where there is higher wall sheer stress and flow turbulence (see Figures 13-19 and 13-20). Aneurysms may be single, but in 20 to 25% of the cases, more than one is present. In these instances, the aneurysms may be unilateral or bilateral. Peak incidence of rupture occurs in persons 50 to 59 years of age, with the incidence in postmenopausal women slightly higher than that in men. Pathophysiology No single pathological mechanism exists. Aneurysms may be classified on the basis of shape and form. Saccular aneurysms (berry aneurysms) occur frequently (in approximately 2% of the population) and likely result from congenital abnormalities in the tunica media of the arterial wall and hemodynamic and molecular changes.47 The sac gradually grows over time. A saccular aneurysm may be (1) round with a narrow stalk connecting it to the parent artery, (2) broad-based without a stalk, or (3) cylindrical (Figure 16-12). Saccular aneurysms are rare in childhood; their highest incidence of rupturing or bleeding (subarachnoid hemorrhage) is among persons 20 to 50 years of age.

FIGURE 16-12 Berry Aneurysm, Angiogram. In this lateral view, with contrast filling a portion of the cerebral arterial circulation, a berry aneurysm (arrow) involving the middle cerebral artery of the circle of Willis at the base of the brain is shown. (From Klatt, E.C. [2015]. Robbins and Cotran atlas of pathology [3rd ed.]. Philadelphia: Saunders.)

Fusiform aneurysms (giant aneurysms) are less common, occur as a result of diffuse arteriosclerotic changes, and are found most commonly in the basilar arteries or terminal portions of the internal carotid arteries. They act as space-occupying lesions. Aneurysms rupture through thin areas often at bifurcation sites, causing hemorrhage into the subarachnoid space that spreads rapidly, producing localized changes in the cerebral cortex and focal irritation of nerves and arteries (see the discussion of Laplace law in Chapter 23). Bleeding ceases when a fibrin-platelet plug forms at the point of rupture and as a result of compression. Blood undergoes reabsorption through arachnoid villi within 3 weeks. Clinical Manifestations Aneurysms often are asymptomatic. Of all persons undergoing routine autopsy, 5% are found to have one or more intracranial aneurysms. Clinical manifestations include dizziness or headache and cranial nerve compression, but the signs vary depending on the location and size of the aneurysm. Cranial nerves III, IV, V, and VI (see Table 13-6) are affected most often. Unfortunately, the most common first indication of the presence of an aneurysm is an acute subarachnoid hemorrhage, intracerebral hemorrhage, or combined subarachnoid-intracerebral hemorrhage (see “Hemorrhagic Stroke,” p. 408). Evaluation and Treatment Diagnosis before a bleeding episode is made through arteriography. After a subarachnoid or intracerebral hemorrhage, a tentative diagnosis of an aneurysm is based on clinical manifestations, history, and imaging. Treatments for intracranial aneurysm are both medical (i.e., control of hypertension) and surgical (i.e., microvascular clipping or placement of endovascular coils).48

Vascular malformation. Vascular malformations are rare congenital vascular lesions. An arteriovenous malformation (AVM) is a mass of dilated vessels between the arterial and venous systems (arteriovenous fistula) without an intervening capillary bed, may occur in any part of the brain, and vary in size from a few millimetres to large malformations extending from the cortex to the ventricle. AVMs occur equally in males and females and occasionally occur in families. Although AVMs are usually present at birth, symptoms exhibit a delayed age of onset and commonly occur before 30 years of age. Pathophysiology AVMs have abnormal blood vessel structure, are abnormally thin, and have complex growth and remodelling patterns.49 There is direct shunting of arterial blood into the venous vasculature without the dissipation of the arterial blood pressure with increased risk for rupture. One or several arteries may feed the AVM and, over time, they become tortuous and dilated. With moderate to large AVMs, sufficient blood is shunted into the malformation to deprive surrounding tissue of adequate blood perfusion.

Clinical Manifestations Twenty percent of persons with an AVM have a characteristic chronic, nondescript headache, although some experience migraine. Fifty percent of persons experience seizures. The other 50% experience an intracerebral, subarachnoid, or subdural hemorrhage with progressive neurological deficits. Bleeding from an AVM into the subarachnoid space causes symptoms identical to those associated with a ruptured aneurysm. If bleeding is into the brain tissue, focal signs that develop resemble a stroke that is progressing in severity. Ten percent of persons experience hemiparesis or other focal signs. At times, noncommunicating hydrocephalus (see Chapter 15) develops with a large AVM that extends into the ventricular lining. Evaluation and Treatment A systolic bruit over the carotid artery in the neck or the mastoid process (or the eyeball in a young person), representing audible turbulent blood flow, is almost always diagnostic of an AVM. Confirming diagnosis is made by CT and MRI, followed by magnetic resonance angiography (MRA). Treatment options include direct surgical excision, endovascular embolization, or radiotherapy.50

Subarachnoid hemorrhage. Subarachnoid hemorrhage (SAH) is the escape of blood from a defective or injured vessel into the subarachnoid space. Individuals at risk for a subarachnoid hemorrhage are those with intracranial aneurysm, intracranial AVM, hypertension, or a family history of SAH, and those who have sustained head injuries. Subarachnoid hemorrhages often recur, especially from a ruptured intracranial aneurysm. Pathophysiology When a vessel is leaking, blood oozes into the subarachnoid space. When a vessel tears, blood under pressure is pumped into the subarachnoid space. The blood increases the intracranial volume, and it is also extremely irritating to the neural tissues and produces an inflammatory reaction. In addition, the blood coats nerve roots, clogs arachnoid granulations (impairing CSF reabsorption), and obstructs foramina within the ventricular system (impairing CSF circulation). Intracranial pressure immediately increases to almost diastolic levels but returns to near baseline in about 10 minutes. Cerebral blood flow and cerebral perfusion pressure decrease. Autoregulation of blood flow is impaired, and there is a compensatory increase in systolic blood pressure.51 The expanding hematoma acts like a space-occupying lesion, compressing and displacing brain tissue with increased ICP, decreased cerebral blood flow, blood–brain barrier breakdown, brain edema, inflammation, and cell death. Secondary brain injury can occur as described for TBI. Granulation tissue is formed, and meningeal scarring with impairment of CSF reabsorption and secondary hydrocephalus often results. Mortality in subarachnoid hemorrhage is 50% at 1 month. Delayed cerebral ischemia, a syndrome of progressive neurological deterioration, is associated with cerebral artery vasospasm. From 40 to 60% of persons with an SAH experience vasospasms in adjacent and, occasionally, in nonadjacent vessels. Vasospasm may occur because of leukocyte–endothelial cell interactions or the effects of vasoactive substances (e.g., calcium, prostaglandins, serotonin, catecholamines) on the arteries of the subarachnoid space. Edema, medial necrosis, and proliferation of the tunica intima in cerebral arterioles have been found. Vasospasm causes decreased cerebral blood flow, ischemia, and possibly infarct and can lead to delayed ischemic injury and death 3 to 14 days after the initial hemorrhage.52 Clinical Manifestations Early manifestations associated with leaking vessels are episodic and include headache, changes in mental status or level of consciousness, nausea or vomiting, and focal neurological defects. A ruptured vessel causes a sudden, throbbing, “explosive” headache, accompanied by nausea and vomiting, visual disturbances, motor deficits, and loss of consciousness related to a dramatic rise in ICP. Meningeal irritation and inflammation often occur, causing neck stiffness (nuchal rigidity), photophobia, blurred vision, irritability, restlessness, and low-grade fever. A positive Kernig sign (straightening the knee with the hip and knee in a flexed position produces pain in the back and neck regions) and a positive

Brudzinski sign (passive flexion of the neck produces neck pain and increased rigidity) may appear. No localizing signs are present if the bleed is confined completely to the subarachnoid space. The Hunt and Hess SAH grading system is based on description of the clinical manifestations (Table 16-6).53 Rebleeding is a significant risk with a high mortality (up to 70%). The period of greatest risk is during the first 72 hours and up to 2 weeks after the initial bleed. Rebleeding is manifested by a sudden increase in blood pressure and ICP, along with a deteriorating neurological status.54 TABLE 16-6 Subarachnoid Hemorrhage Classification Scale Category Description Grade I Grade II Grade III Grade IV Grade V

Neurological status intact; mild headache, slight nuchal rigidity Neurological deficit evidenced by cranial nerve involvement; moderate to severe headache with more pronounced meningeal signs (e.g., photophobia, nuchal rigidity) Drowsiness and confusion with or without focal neurological deficits; pronounced meningeal signs Stuporous with pronounced neurological deficits (e.g., hemiparesis, dysphasia); nuchal rigidity Deep coma state with decerebrate posturing and other brainstem functioning

From Tateshima, S., & Duckwiler, G. (2012). Vascular diseases of the nervous system. In R.B. Daroff, G.M. Fenichel, J. Jankovic, et al. (Eds.), Bradley's neurology in clinical practice. Philadelphia: Saunders.

Seizures occur in 25% of persons with an SAH, and hydrocephalus after a bleed occurs in 20% of cases. Hypothalamic dysfunction, manifested by salt wasting, hyponatremia, and ECG changes, is common. Evaluation and Treatment The diagnosis of an SAH is based on the clinical presentation, imaging, and CSF evaluation. Treatment is directed at controlling ICP, improving cerebral perfusion pressure, preventing ischemia and hypoxia of neural tissues, and avoiding rebleeding episodes. Surgical intervention is common. Treatment guidelines are available to direct therapy.48

Quick Check 16-2 1. Why is atherosclerosis a risk factor for thrombotic stroke? 2. Why do the signs and symptoms of a TIA resolve completely? 3. Why do lacunar strokes involve small infarcts? 4. How is an arteriovenous malformation different from an aneurysm?

Headache Headache is a common neurological disorder and is usually a benign symptom. However, it can be associated with serious disease such as brain tumour, meningitis, or cerebrovascular disease (e.g., giant cell arteritis, cerebral aneurysm, or cerebral bleeds). The headache syndromes discussed here are the chronic, recurring type not associated with structural abnormalities or systemic disease and include migraine, cluster, and tension-type headaches. Characteristics of the major types of headache syndromes are summarized in Table 16-7. TABLE 16-7 Characteristics of Common Headaches Migraine Without Aura Age of onset Gender Family history of headaches Onset and evolution Time course Quality

With Aura (25–30%)

Cluster Headache/ Proximal Hemicrania

Tension-Type Headache

Childhood, adolescence, or young adulthood Higher in females Yes

Childhood, adolescence, or young adulthood

Young adulthood, middle age

Higher in females Yes

Male No

Young adulthood, middle age Not gender specific Yes

Slow to rapid Episodic

Slow to rapid Episodic

Rapid Clusters in time

Usually throbbing

Usually throbbing

Steady

Slow to rapid Episodic, may become constant Steady

Location Associated features

Variable, unilateral to bilateral Prodrome, vomiting

Variable, unilateral to bilateral Aura: visual, sensory, language, and motor disturbance Prodrome, vomiting

Orbit, temple, cheek Lacrimation, rhinorrhea, Horner syndrome

Variable None

Migraine Migraine is an episodic neurological disorder characterized by a headache lasting 4 to 72 hours. It is diagnosed when any two of the following features occur: unilateral head pain, throbbing pain, pain worsens with activity, moderate or severe pain intensity; and at least one of the following: nausea and/or vomiting, or photophobia and phonophobia.55 Migraine is broadly classified as (1) migraine with aura with visual, sensory, or motor symptoms; and, more commonly, (2) migraine without aura. Migraine occurs in 11.8% of women and 4.7% of men in Canada, and can occur in children. It is more common in those who are in their 30s and 40s. There often is a family history of migraine. In susceptible women, migraine occurs most frequently before and during menstruation and is decreased during pregnancy and menopause. The cyclic withdrawal of estrogen and progesterone may trigger attacks of migraine.56,57 Migraine is caused by a combination of multiple genetic and environmental factors. Persons with migraine have an increased risk for epilepsy, depression, anxiety disorders, cardiovascular disease, and stroke. Migraine may be precipitated by triggers. Individuals with migraine are likely to have a genetically determined reduced threshold for triggers. Triggers can include becoming tired or oversleeping, missed meals, overexertion, weather change, stress or relaxation from stress, hormonal changes (menstrual periods), excess afferent stimulation (bright lights, strong smells), and chemicals (alcohol or nitrates). The pathophysiological basis for migraine is complex and not clearly established. There is no identifiable pathology, but there are associated changes in brain metabolism and blood flow. Current theories includes neurological, vascular, hormonal, and neurotransmitter components. Migraine aura is associated with cortical spreading depression (CSD). CSD is a spontaneous self-propagating wave of glial and neuronal depolarization resulting in hyperactivity that starts in the occipital region and spreads across the cortex.58 CSD initiates the release of neurotransmitters that activate the trigeminal vascular system (afferent projections from cranial nerve V), stimulating vasodilation of dural blood vessels, activation of inflammation, peripheral and central sensitization of pain receptors (hypersensitivity to pain), and activation of areas of the brainstem and forebrain that modulate pain. Release of inflammatory mediators with sterile meningeal inflammation and edema of blood vessels may be an important component of migraine pain. Vasodilation of blood vessels is not sufficient to account for the pain of migraine. Calcitonin gene-related peptide (CGRP) release by the trigeminal vascular system is related to migraine pain. The mechanism is not clear, but CGRP antagonists stop the headache. Glutamate (an excitatory neurotransmitter) concentration is increased and 5-hydroxytryptamine (5-HT, serotonin) concentration is decreased. 5-HT causes vasoconstriction and antagonizes CGRP. Consequently, 5HT(1B/1D) receptor agonists (i.e., triptans) and CGRP receptor and glutamate receptor antagonists have been used for the acute treatment of migraine.59-61 The clinical phases of a migraine attack are as follows: 1. Premonitory phase: Up to one third of persons have premonitory symptoms hours to days before onset of aura or headache. These symptoms may include tiredness, irritability, loss of concentration, stiff neck, and food cravings. 2. Migraine aura: Up to one third of persons have aura symptoms at least some of the time that may last up to 1 hour. Symptoms can be visual, sensory, or motor. 3. Headache phase: Throbbing pain usually begins on one side and spreads to include the entire head. Headache may be accompanied by fatigue, nausea, and vomiting or dizziness. There may be hypersensitivity to anything touching the head. Symptoms may last from 4 to 72 hours (usually about a day). 4. Recovery phase: Irritability, fatigue, or depression may take hours or days to resolve. Differentiation of types of migraine headache is summarized in Table 16-7. The diagnosis of migraine is

made from medical history and physical examination. Differential diagnosis is confirmed by imaging and EEG. Functional neuroimaging and genetic studies are advancing the understanding of the mechanisms involved in migraine attacks and individual variants involved with disease susceptibility.62 The management of migraine includes avoidance of triggers (e.g., darkening the room, applying ice). Sleeping can provide some relief with the onset of acute migraine. Pharmacological management for the treatment and prevention of migraine is available.63,64 A transcutaneous electrical stimulation device providing trigeminal neurostimulation has been approved by Health Canada for the prevention of migraine.65 Chronic migraines usually begin as episodic migraines that increase in frequency over time. Chronic migraine occurs at least 15 days in a month (can occur daily or on a near-daily basis) for more than 3 months. Chronic migraines are associated with overuse of analgesic migraine medications (sometimes called rebound headaches), obesity, and caffeine overuse. Treatment is similar to that for episodic migraine. Individuals with chronic migraine unresponsive to medical treatment should be evaluated for intracranial hypertension without papilledema and the possibility of sinus venous stenosis.66

Cluster Headache Cluster headaches are one of a group of disorders referred to as trigeminal autonomic cephalagias (headaches involving the autonomic division of the trigeminal nerve).67 They occur in one side of the head, primarily in men between 20 and 50 years of age. The pain may alternate sides with each headache episode and is severe, stabbing, and throbbing. These uncommon headaches occur in clusters (up to 8 attacks per day) and last for minutes to hours for a period of days, followed by a long period of spontaneous remission. Cluster headache has an episodic and a chronic form with extreme pain intensity and short duration. If the cluster of attacks occurs more frequently without sustained spontaneous remission, they are classified as chronic cluster headaches (10 to 20% of cases) (see Table 16-7). Triggers are similar to those that cause migraine headache. Trigeminal activation occurs but the mechanism is unclear. Functional imaging indicates a role for concomitant posterior hypothalamic and pain neuromatrix activation with opioid system involvement.68 The pathogenic mechanism for pain is related to the release of vasoactive substances and the formation of neurogenic inflammation. Autonomic dysfunction is characterized by sympathetic underactivity and parasympathetic activation. There is unilateral trigeminal distribution of severe pain with ipsilateral autonomic manifestations, including tearing on affected side, ptosis of the ipsilateral eye, and congestion of the nasal mucosa. Prophylactic medications are used to treat cluster headache, as well as avoidance of triggers. Acute attacks are managed with oxygen inhalation, sumatriptan (Imitrex) or inhaled ergotamine tartrate (Medihaler Ergotamine) administration, and nerve stimulation.69 New medications are under investigation.

Tension-Type Headache Tension-type headache (TTH) is the most common type of headache. The average age of onset is during the second decade of life. It is a mild to moderate bilateral headache with a sensation of a tight band or pressure around the head with gradual onset of pain. The headache occurs in episodes and may last for several hours or several days. It is not aggravated by physical activity. Chronic tension-type headache (CTTH) evolves from episodic TTH and represents headache that occurs at least 15 days per month for at least 3 months. Both central and peripheral mechanisms operate in causing tension headaches. The central pain mechanism is associated with CTTH, and a peripheral mechanism is associated with episodic TTH. The central pain mechanism probably involves hypersensitivity of pain fibres from the trigeminal nerve that leads to central sensitization. The peripheral sensitization of myofascial sensory nerves may contribute to muscular hypersensitivity and the development of CTTH. Headache sufferers have more localized pain and tenderness of pericranial muscles. Many individuals have both TTHs and migraines. Mild TTHs are treated with ice, and more severe forms are treated with Aspirin or nonsteroidal antiinflammatory medications. CTTHs are best managed with a tricyclic antidepressant and behavioural and relaxation therapy. Some individuals benefit from injection of botulinum toxin A. Long-term use of analgesics or other medications, such as muscle relaxants, antihistamines, tranquilizers, caffeine, and ergot alkaloids, should be avoided.70

Infection and Inflammation of the Central Nervous System The CNS may be infected by bacteria, viruses, fungi, parasites, and mycobacteria. The invading organisms enter the nervous system either by spreading through arterial blood vessels (Figure 16-13) or by directly invading the nervous tissue from another site of infection. Neurological infections produce disease by several mechanisms: direct neuronal or glial infection, mass lesion formation, inflammation with subsequent edema, interruption of CSF pathways, neuronal or vascular damage, and secretion of neurotoxins. An immune process may initiate an inflammatory reaction.

FIGURE 16-13 Viral Infection in the Central Nervous System. Viruses infect specific cell types within the central nervous system, depending on the particular properties of the virus together with individual cell membrane proteins expressed on permissive cell types. Normally the brain is protected from circulating pathogens and toxins by the blood–brain barrier. CMV, cytomegalovirus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; HTLV-1, human T-cell lymphotropic virus type 1 (causes T-cell leukemia); JCV, John Cunningham virus (a polyomavirus causing progressive multifocal leukoencephalopathy); SSPE, subacute sclerosing panencephalitis; VZV, varicella-zoster virus. (Adapted from Power, C., & Noorbakhsh, G. [2007]. Central nervous system viral infections: Clinical aspects and pathogenic mechanisms. In S. Gilman [Ed.], Neurobiology of disease [p. 488]. Burlington, MA: Elsevier.)

Meningitis Meningitis is inflammation of the brain or spinal cord. Infectious meningitis may be caused by bacteria, viruses, fungi, parasites, or toxins. The infection may be acute, subacute, or chronic with the pathophysiology, clinical manifestations, and treatment differing for each type of microorganism. Fungal meningitis is a chronic, much less common condition than bacterial or viral meningitis. The infection most often occurs in persons with impaired immune responses or alterations in normal body flora. It develops insidiously, usually over days or weeks. Fungi in the nervous system usually produce a granulomatous reaction, forming granulomata or gelatinous masses in the meninges at the base of the brain. Fungi also may extend along the perivascular sites in the subarachnoid space and into the brain tissue, producing arteritis with thrombosis, infarction, and communicating hydrocephalus. Meningeal fibrosis develops later in the inflammatory process. Cranial nerve dysfunction, caused by compression, often results from the granulomata and fibrosis. The first manifestations are often those of dementia (see Chapter 15) or communicating hydrocephalus (see Chapter 15). The individual is characteristically afebrile. Viral meningitis (aseptic or nonpurulent meningitis) is thought to be limited to the meninges. An identifiable bacterium cannot be found in the CSF. The most common viruses are enteroviral viruses (echovirus, coxsackievirus, and nonparalytic poliomyelitis), arboviruses, and herpes simplex type 2. Viruses enter the nervous system by crossing the blood–brain barrier, by direct spread along peripheral nerves, or through the choroid plexus epithelium. Recognition of viral antigens by immune cells activates

the inflammatory response. The clinical manifestations of viral meningitis are similar to those of bacterial meningitis, but milder. Viral meningitis is managed pharmacologically with antiviral medications and steroids. Bacterial meningitis is primarily an infection of the pia mater and arachnoid, the subarachnoid space, the ventricular system, and the CSF. Meningococci (Neisseria meningitidis) and pneumococci (Streptococcus pneumoniae) are the most common pathogens. An increase of medication-resistant strains of S. pneumoniae is an emerging problem worldwide. About 1 in 100 000 persons are affected by bacterial meningitis annually.71 Meningococcus has been identified worldwide, and there are six serogroups: A, B, C, W-135, X, and Y. Most cases are sporadic and occur predominantly in children younger than 1 year of age and adolescents. Local outbreaks may occur in student residences, military bases, or sub-Saharan Africa. With pneumococcal meningitis, young persons and those more than 40 years of age are mostly affected. Predisposing conditions are otitis or sinusitis (25%), immunocompromised status (16%), and pneumonia (12%). The disease is spread by respiratory droplets and contact with contaminated saliva or respiratory tract secretions (kissing, coughing, sneezing, or sharing utensils, food, and drink).72 Carriers of the meningococcal bacteria do not develop meningitis but may pass it on to others. Pathophysiology Meningococci and pneumococci are inhaled and attach to epithelial cells in the nasopharynx where they cross the mucosal barrier, enter the bloodstream, travel to cerebral blood vessels, cross the blood–brain barrier, and infect the meninges. With bacterial infection, large numbers of neutrophils are recruited to the subarachnoid space. Release of cytotoxic inflammatory agents and bacterial toxins alter the blood– brain barrier, cause cerebral edema, and damage brain tissue. The inflammatory exudate thickens the CSF and interferes with normal CSF flow around the brain and spinal cord, possibly obstructing arachnoid villi and producing hydrocephalus. Meningeal cells become edematous, and the combined exudate and edematous cells increase ICP. Engorged blood vessels and thrombi can disrupt blood flow, causing further injury.73 Acute infectious purpura fulminans is a rare rapidly progressive syndrome of hemorrhagic infarction of the skin and disseminated intravascular coagulation that can lead to multiple organ failure, ischemic necrosis of digits and limbs with amputation required, and death. It is caused by bacterial endotoxin and inflammatory cytokines. Clinical Manifestations The clinical manifestations of bacterial meningitis can be grouped into infectious signs, meningeal signs, and neurological signs. The clinical manifestations of systemic infection include fever, tachycardia, and chills. The clinical manifestations of meningeal irritation are a severe throbbing headache, severe photophobia, nuchal rigidity, and positive Kernig and Brudzinski signs. The neurological signs include a decrease in consciousness, cranial nerve palsies, focal neurological deficits (such as hemiparesis or hemiplegia and ataxia), and seizures. Often there is projectile vomiting. As ICP increases, papilledema develops and delirium may progress to unconsciousness and death. With meningococcal meningitis, a petechial or purpuric rash covers the skin and mucous membranes. Evaluation and Treatment Rapid diagnosis, antibiotic administration, and supportive treatment are important to prevent morbidity and mortality from bacterial meningitis. Diagnosis is based on physical examination, blood cultures, and the results of nasopharyngeal smear and antigen tests. CSF analysis and cultures are required for differential diagnosis.73,74 Serious complications, including septic shock, disseminated intravascular coagulation, purpura fulminans, limb damage, and multiple organ failure, require intensive multidisciplinary care. Vaccinations are available to prevent meningococcal, pneumococcal, and Haemophilus influenzae meningitis.75 Meningococcal vaccine promotes antibody protection within 7 to 14 days.76 Vaccination of children ages 11 or 12 years is recommended, with a booster to be given between ages 16 and 18 years or older, particularly postsecondary students living in student residences.

Brain or Spinal Cord Abscess

Abscesses, localized collections of pus, may form within the parenchyma of the brain or spinal cord but are rare. Brain abscesses are classified as epidural, subdural, or intracerebral. Epidural brain abscesses (empyemas) are associated with osteomyelitis in a cranial bone. Subdural brain abscesses (empyemas) arise from a sinus infection or a vascular source. Intracerebral brain abscesses arise from a vascular source. Spinal cord abscesses are classified as epidural or intramedullary. Epidural spinal abscesses usually originate as osteomyelitis in a vertebra; the infection then spreads into the epidural space. (Osteomyelitis is discussed in Chapter 39.) Pathophysiology Microorganisms gain entrance to the CNS by direct extension or distribution along the wall of a vein. Infective emboli carry organisms from distant sites. Users of illicit drugs who share needles are at risk, as are immunosuppressed persons. For example: Toxoplasma gondii is producing an ever-increasing number of CNS abscesses in persons with AIDS.77 Streptococci, staphylococci, and Bacteroides, often combined with anaerobes, are the most common bacteria that cause abscesses; however, yeast and fungi also may be involved.78 Brain abscesses progress from localized inflammation to a necrotic core with the formation of a connective tissue capsule, usually within 14 days or longer.79 Existing abscesses also tend to spread and form daughter abscesses. Clinical Manifestations Early manifestations include low-grade fever, headache (most common symptom), nausea and vomiting, neck pain and stiffness, confusion, drowsiness, sensory deficits, and communication deficits. Later manifestations are associated with an expanding mass and include decreased attention span, memory deficits, decreased visual acuity and narrowed visual fields, papilledema, ocular palsy, ataxia, dementia, and seizures. The development of symptoms may be very insidious, often making an abscess difficult to diagnose.80 Extradural brain abscesses are associated with localized pain, purulent drainage from the nasal passages or auditory canal, fever, localized tenderness, and neck stiffness. Clinical manifestations of spinal cord abscesses have four stages: (1) spinal aching; (2) severe root pain, accompanied by spasms of the back muscles and limited vertebral movement; (3) weakness caused by progressive cord compression; and (4) paralysis. Evaluation and Treatment The diagnosis is suggested by clinical features and confirmed by imaging studies. Antibiotics and surgical aspiration or excision is usually indicated. Intracranial pressure may have to be managed. Spinal cord abscesses are treated with surgical decompression or aspiration, antibiotic therapy, and supportive therapy.

Encephalitis Encephalitis is an acute febrile illness, usually of viral origin, with nervous system involvement. The most common forms are caused by bites of mosquitoes, ticks, or flies. Herpes simplex type 1 is the most common sporadic cause of encephalitis. Viruses infect specific cell types in the CNS, as shown in Figure 16-13. Referred to as infectious viral encephalitides, encephalitis may occur as a complication of systemic viral diseases such as poliomyelitis, rabies, or mononucleosis, or it may arise after recovery from viral infections such as rubella, varicella, rubeola, or yellow fever. Encephalitis also may follow vaccination with a live attenuated virus vaccine if the vaccine has an encephalitis component, for example, measles, mumps, and rubella. Typhus, trichinosis, malaria, and schistosomiasis also are associated with encephalitis. Toxoplasmosis may acutely reactivate in immunosuppressed persons when the oncedormant parasite in cyst form disseminates in brain tissues.81 With the exception of the California viral encephalitis, which is endemic, the arthropodborne encephalitides occur in epidemics, varying in geographic and seasonal incidence (Table 16-8 and Health Promotion: West Nile Virus). Eastern equine encephalitis is the most serious but least common of the

encephalitides. TABLE 16-8 Common Arboviruses of North America Virus

Distribution

Insect Vector

Immediate Vertebrate Host

West Nile

United States, Canada, Mexico

Mosquito (Culex sp)

St. Louis encephalitis Eastern equine encephalitis

United States, Canada, Mexico Atlantic and Gulf Coast states, upper New York, Michigan, Eastern Canada Western United States, Canada Mexico, Florida, Texas

Mosquito (Culex sp) Mosquito (Culex sp)

Passiform birds (jays, blackbirds, crows, finches, sparrows) Passerine birds (sparrows, house finches) Fresh water swamp birds

Western equine encephalitis Venezuelan encephalitis Powassan encephalitis La Crosse or Jamestown encephalitis Colorado tick fever Dengue

Northern United States, Canada North central and northeast United States

Mosquito (Culex sp) Mosquito (Culex and Aedes sp) Ixodes ticks Mosquito (Aedes triseriatus)

Passerine birds, jackrabbit Rodents, aquatic birds

Rocky Mountain states, Canada Mexico and Florida

Tick (Dermacentor andersoni) Chipmunks, squirrels, small mammals Mosquito (Aedes sp) Humans and nonhuman primates

Squirrels, mice, ground hogs, voles Chipmunks, squirrels

From Davis, L.E., Beckham, J.D., & Tyler, K.L. (2008). Neurol Clin, 26(3), 727–757 (Table 2). doi:10.1016/j.ncl.2008.03.012

Health Promotion West Nile Virus West Nile virus (WNV), a Flavivirus transmitted predominantly by the Culex mosquito, emerged in New York State in 1999. It is the most common cause of epidemic meningoencephalitis and the leading cause of arboviral encephalitis in North America. The first human case of WNV infection in Canada was reported in 2002. Humans and horses, as well as other mammals, are incidental hosts. Birds and mosquitoes are life cycle hosts. In most parts of Canada, the risk of becoming infected with WNV starts mid-April and ends after the first hard frost. Besides mosquito transmission, WNV can be transmitted through blood transfusions and organ transplants. Health experts think that transmission from mother to unborn child and through breast milk is possible. The most effective way to avoid infection with WNV is to prevent mosquito bites. Since mosquitoes are most active at dawn and dusk, avoiding outdoor activities during those times reduces the risk of bites. It is recommended during outdoor activities to wear long pants and long-sleeved loose shirts, socks, and a hat, and light-coloured clothing. In addition, the use of an insect repellant that contains DEET or icaridin is recommended. Since mosquitoes lay their eggs in standing water, eliminating any areas of standing water around the home is suggested. The use of window and door screens also assists in preventing mosquitoes from entering the home. Data from Government of Canada. (2016). Prevention of West Nile virus. Retrieved from http://healthycanadians.gc.ca/diseases-conditionsmaladies-affections/disease-maladie/west-nile-nil-occidental/prevention-eng.php; Petersen, L.R., Brault, A.C., & Nasci, R.S. (2013). JAMA, 310(3), 308–315; Reisen, W.K. (2013). Viruses, 5(9), 2079–2105.

Pathophysiology Viruses gain access to the CNS through the bloodstream, olfactory bulb, or choroid plexus, or through an intraneuronal route from peripheral nerves. Meningeal involvement is present in all encephalitides. The various encephalitides may cause widespread nerve cell degeneration. Edema, necrosis with or without hemorrhage, and increased ICP develop. Clinical Manifestations Encephalitis ranges from a mild infectious disease to a life-threatening disorder. Mild symptoms include malaise, headache, body aches, nausea, and vomiting. Dramatic clinical manifestations include fever, delirium, or confusion progressing to unconsciousness, difficulty with word finding, seizure activity, cranial nerve palsies, paresis and paralysis, involuntary movement, and abnormal reflexes. Signs of marked ICP may be present.

Evaluation and Treatment Diagnosis is made by history and clinical presentation aided by CSF examination and culture, serological studies, white blood cell count, CT scan, or MRI. Empirical treatment is specific to the type of virus and may include antiviral agents, antibiotics, and steroids. Herpes encephalitis is treated with antiviral agents, such as acyclovir (Zovirax). Measures to control ICP are paramount.82

Neurological Complications of AIDS From 40 to 60% of all persons with AIDS (see Chapter 8) have neurological complications. The most common neurological disorder is HIV-associated neurocognitive disorder. Others are peripheral neuropathies, vacuolar (spongy softening) myelopathy, opportunistic infections of the CNS, neoplasms, and, less commonly, stroke syndromes.83

HIV-associated neurocognitive disorder. A variety of names are used for HIV-associated neurocognitive disorder (HAND), including HIVassociated cognitive dysfunction, HIV encephalopathy, subacute encephalitis, HIV-associated dementia complex, HIV cognitive motor complex, AIDS encephalopathy, AIDS dementia complex, and AIDS-related dementia. Both adults and children may be affected by progressive cognitive dysfunction with motor and behavioural alterations. The syndrome typically develops later in the disease but may be an early or singular manifestation in some persons. The syndrome is more prevalent in drug users with HIV. Highly active antiretroviral therapy (HAART) with more efficient CNS medication penetration has reduced the prevalence and improved survival for severe HAND, but milder forms of the disease may persist because of longer life. The neurological syndromes develop from properties of the virus, genetic characteristics of the host, and interactions with the environment (including treatment). At the time of primary HIV infection, HIV infects the perivascular macrophages, microglial cells, and astrocytes, particularly the basal ganglia and deep white matter. Affected macrophages, macrophage-derived multinucleated cells, and microglia cause an immune-mediated demyelination process in white matter. Focal and diffuse demyelination of white matter and spongy changes of the spinal cord are present. HAND is insidious in onset and unpredictable in its course. Most persons experience a steady progression of mental decline characterized by abrupt accelerations of signs over several months to more than 1 year. The triad of clinical manifestations are neurocognitive impairment, behavioural disturbance, and motor abnormalities. Specific manifestations can include an organic psychosis with agitation, inappropriate behaviour, and hallucinosis. Motor signs include difficulty speaking; progressive loss of balance; gait ataxia; spastic paraparesis or paralysis; and generalized hyper-reflexia sometimes accompanied by decreased writing ability, tremor, myoclonus, and seizure. Diagnosis is difficult, especially in early stages, and CSF analysis, CT scan, and MRI data help establish the diagnosis. HIV antiretroviral treatment is continued. Although CNS medication penetration is reduced, there is decreased prevalence and improved survival for individuals with severe HAND.84

HIV myelopathy. HIV myelopathy involves diffuse degeneration of the spinal cord in persons with HIV. Vacuolar myelopathy is thought to be a direct consequence of HIV. The lateral and posterior columns of the lumbar spinal cord are affected. Progressive spastic paraparesis with ataxia is the predominant clinical manifestation. Leg weakness, upper motor neuron signs, incontinence, and posterior column sensory loss may be present. Diagnosis is made on the basis of history, physical findings, and supporting data from diagnostic procedures. Treatment is supportive.

HIV-associated peripheral neuropathy. HIV may directly infect nerves and cause HIV distal symmetric polyneuropathy, most commonly sensory neuropathy.85 Persons experience neuropathic pain, including pain burning sensations and numbness commonly in the extremities. Weakness and decreased or absent distal reflexes may be present. Diagnosis is established through the history and physical findings, laboratory data, and nerve

conduction and electromyogram (EMG) studies.

Viral meningitis and HIV. Some persons develop acute viral meningitis at approximately the time of seroconversion. The presentation of acute viral meningitis may represent the initial infection of the nervous system by the virus. Symptoms include headache, fever, and meningismus (headache, photophobia, nuchal rigidity). Cranial nerve involvement, especially V and VII, may appear, but the disease is self-limiting and requires only symptomatic treatment.

Opportunistic infections and HIV. Opportunistic infections may be bacterial, fungal, or viral in origin and may produce neurological disease. Typically, bacterial infections are caused by unusual microorganisms. Cryptococcal infection is the most common fungal disorder and the third leading cause of neurological disease in persons with AIDS. The symptoms are vague, such as fever, headache, malaise, and meningismus. Herpes encephalitis and herpes varicella-zoster radiculitis may develop. Papovavirus may produce a demyelinating disorder. Cytomegalovirus encephalitis, toxoplasmosis (a protozoal infection), and tuberculosis meningitis have a high incidence in African countries.86,87

Central nervous system neoplasms and HIV. The incidence of HIV-associated CNS neoplasms has declined significantly with HAART, particularly primary CNS lymphoma. Other neoplasms associated with HIV include systemic non-Hodgkin's lymphoma and metastatic Kaposi sarcoma. Primary CNS lymphoma is a large-cell tumour that presents as rapidly developing and expanding multicentric intracranial mass lesions. The meninges and, possibly, the cranial nerves and spinal cord are invaded in systemic non-Hodgkin's lymphoma. Metastasis of a Kaposi sarcoma to the CNS is uncommon.88

Demyelinating Disorders Demyelinating disorders result from damage to the myelin nerve sheath and affect neural transmission. They can occur in either the central (i.e., multiple sclerosis) or the peripheral (i.e., Guillain-Barré syndrome) nervous system. Contributing factors include genetics, infections, autoimmune reactions, environmental toxins, and unknown factors.

Multiple Sclerosis Multiple sclerosis (MS) is a chronic inflammatory disease involving degeneration of CNS myelin, scarring (sclerosis or plaque formation), and loss of axons. Canada has the highest rate of MS in the world, with an estimated 100 000 Canadians living with the disease.89 MS is caused by an autoimmune response to self or microbial antigens in genetically susceptible individuals. The onset of MS is usually between 20 and 40 years of age and is more common in women. Men may have a more severe progressive course. The prevalence rate is higher in northern latitudes. Risk factors that may be involved include smoking, vitamin D deficiency, and Epstein-Barr virus infection.90 The etiology of MS is unknown. Pathophysiology MS is a diffuse and progressive disease with patches of damage that can occur throughout the brain and spinal cord. Autoreactive T lymphocytes (T cells) and B lymphocytes (B cells) cross the blood–brain barrier and recognize myelin and oligodendrocyte autoantigens, triggering inflammation and loss of oligodendrocytes (myelin-producing cells). Activation of microglia cells (brain macrophages) contributes to inflammation and injury with plaque formation and axonal degeneration. Loss of myelin disrupts nerve conduction with subsequent death of neurons and brain atrophy. Normal-appearing white matter can be microscopically very abnormal, and grey matter lesions and atrophy have been documented during later stages of the disease process.91 These degenerative processes begin before symptom onset

and progress throughout a person's life (Figure 16-14).92 Myelin degeneration also can present as optic neuritis or involve the spinal cord. Spinal MS can occur concurrently or independently of brain lesions. The multifocal, multistaged features of MS lesions in established disease produce symptoms that are multiple and variable.

FIGURE 16-14

Pathogenesis of Multiple Sclerosis.

Clinical Manifestations The most common initial symptoms of MS are paresthesias of the face, trunk, or limbs; weakness; impaired gait; visual disturbances; or urinary incontinence, indicating diffuse CNS involvement. Cerebellar and corticospinal involvement presents as nystagmus, ataxia, and weakness with all four limbs involved. Intention tremor and slurred speech may also occur. The onset, duration, and severity of symptoms are different for each person. Disease exacerbations (also known as relapses or flares) are the temporary occurrence or worsening of symptoms. The symptoms may be mild or serious, may last for several days or weeks, and may be followed by progressive symptoms, including paresthesias, difficulty speaking, ataxia, or visual changes. The mechanism of these exacerbations is related to delayed or blocked conduction caused by inflammation and demyelination. Various events can occur immediately before the exacerbation of symptoms and are regarded as precipitating factors or triggers, including trauma, emotional stress, and pregnancy. Painful sensory events, spastic paralysis, and bowel and bladder incontinence are common with spinal involvement.93 Recovery from symptoms during remissions is caused by downregulation of inflammation and the restoration of axonal function, either by remyelination, the resolution of inflammation, or the

restoration of conduction to demyelinated axons. The subtypes of MS are based on the clinical course: (1) remitting-relapsing, initial onset of symptoms followed by remission and exacerbations; (2) primary-progressive, a steady decline from onset; (3) secondary-progressive, initial remitting and relapsing symptoms with a steady decline in function; and (4) progressive-relapsing, a progressive course from onset with superimposed relapses. Initially, 85 to 90% of persons present with a remitting-relapsing course and without treatment transition to the progressive types with insidious neurological decline. Early cognitive changes are common and may include poor judgement, apathy, emotional lability, and depression. Evaluation and Treatment There is no single test available to diagnose or rule out MS. Diagnostic criteria include the history and clinical examination in combination with MRI (most sensitive test), CSF findings, and evoked potentials.94 Persistently elevated levels of CSF immunoglobulin G (IgG) are found in about two thirds of individuals with MS, and oligoclonal IgG bands on electrophoresis are found in more than 90% of MS patients. Evoked potential studies aid diagnosis by detecting decreased conduction velocity in visual, auditory, and somatosensory pathways. MRI is the most sensitive available method of detecting demyelinated plaques and monitoring disease. The treatment goal in MS is prevention of exacerbations, prevention of permanent neurological damage, and control of symptoms. Disease-modifying medications are initiated with diagnosis and include corticosteroids, immunosuppressants, and immune system modulators. Continuous monitoring is important because of the increased risk for infection when taking these medications. Plasma exchange may be used in persons who do not respond to steroids. Medications are also available for symptom control. The long-term benefit of these medications is under investigation.95 Supportive care includes participation in a regular exercise program; cessation of smoking; and avoidance of overwork, extreme fatigue, and heat exposure. The administration of vitamin D to prevent disease progression is being evaluated.96 Stem cell therapy is under investigation.97 A recent theory has emerged associating chronic cerebrospinal venous insufficiency (CCSVI) with the symptoms of MS. It has been suggested that the presence of a blockage or narrowing of the veins in the head and neck does not allow for efficient removal of blood from the CNS, causing these symptoms. The proposed treatment for CCSVI, referred to as “liberation therapy,” is an angioplasty procedure, which involves opening blocked or narrowed veins to allow for improved blood flow and drainage of blood from the brain. Global clinical studies have been conducted on this treatment with conflicting results. The procedure is not approved for treatment of MS in Canada.98

Guillain-Barré Syndrome Guillain-Barré syndrome is a rare demyelinating disorder caused by a humoral and cell-mediated immunological reaction directed at the peripheral nerves. It usually occurs after a respiratory tract or gastro-intestinal infection. The clinical manifestations can vary from paresis of the legs to complete quadriplegia, respiratory insufficiency, and autonomic nervous system instability. Intravenous immunoglobulin or plasmapheresis is used during the acute phase and followed by aggressive rehabilitation.99 Recovery occurs within weeks to months or up to 2 years. About 30% of individuals have residual weakness.

Quick Check 16-3 1. What are two differences between the symptoms of migraine and cluster headaches? 2. How can bacterial meningitis lead to an amputation? 3. What are the autoimmune mechanisms that cause multiple sclerosis lesions?

Peripheral Nervous System and Neuromuscular Junction Disorders Peripheral Nervous System Disorders Disease processes may injure the axons travelling to and from the brainstem and spinal cord neuronal cell bodies. The injury may affect a distinct anatomical area on the axon, or the spinal nerves may be injured at the roots, at the plexus (plexus injuries) before peripheral nerve formation, or at the nerves themselves. The cranial nerves do not have roots or plexuses and are affected only within themselves. Autonomic nerve fibres may be injured as they travel in certain cranial nerves and emerge through the ventral root and plexuses to pass through the peripheral nerves of the body. Peripheral nervous system disorders are summarized in Table 16-9. TABLE 16-9 Peripheral Nervous System Disorders Disorder

Pathology

Clinical Manifestations

Radiculopathies

Involves injury to spinal roots as they exit or enter vertebral canal; caused by compression, inflammation, direct trauma

Strength, tone, and bulk of muscles innervated by involved roots affected; pattern is similar to that seen in amyotrophies, with tone and deep tendon reflexes decreased, rarely absent; fasciculations; mild fatigue; sensory alterations, pain Motor weakness, muscle atrophy, sensory loss in affected areas; paralysis common

Plexus injuries

Involve nerve plexus distal to spinal roots but proximal to formation of peripheral nerves; caused by trauma, compression, infiltration, or iatrogenic (positioning or intramuscular injection) Neuropathies Called sensorimotor if sensory, motor, and reflex effects; pure sensory caused by leprosy, industrial solvents, chloramphenicol, and hereditary mechanisms; motor caused by Guillain-Barré syndrome, infectious mononucleosis, viral hepatitis, acute porphyria, or lead, mercury, and triorthocresylphosphate (TCP) poisoning Guillain-Barré Involves acute onset of motor, sensory, or autonomic symptoms caused by syndrome autoimmune inflammatory response, resulting in axonal demyelination; most (several antibody commonly manifests as ascending motor paralysis; often preceded by subtypes have respiratory tract or gastro-intestinal viral infection been identified)

Muscle strength, tone, and bulk affected; whole muscles or groups may be paretic or paralyzed; muscles of feet and legs first, then hands and arms; tone and deep tendon reflexes generally decreased with atrophy and fasciculation; mild fatigue; some specific symptoms of paresthesia and dysesthesia; altered reflexes; autonomic disturbances; deformities; metabolic changes Clinical manifestations are related to antibody subtypes; manifestations can include paresis of legs to complete quadriplegia, paralysis of eye muscles, respiratory insufficiency, autonomic nervous system instability; sensory symptoms (pain, numbness, paresthesias); may progress to respiratory arrest or cardiovascular collapse

From Vucic, S., Kiernan, M.C., & Cornblath, D.R. (2009). J Clin Neurosci, 16(6), 733–741.

Neuromuscular Junction Disorders Transmission of the nerve impulse at the neuromuscular junction requires the release of adequate amounts of neurotransmitter from the presynaptic terminals of the axon and effective binding of the released transmitter to the receptors on the membranes of muscle cells (see Figure 13-15). Myasthenia gravis is the most prevalent of the neuromuscular junction disorders and is presented next.

Myasthenia Gravis Myasthenia gravis is an acquired chronic autoimmune disease mediated by antibodies against the acetylcholine receptor (AChR) at the postsynaptic membrane of the neuromuscular junction. The Canadian incidence of this disease is about 5.3 per million population,100 and it is more common in women. Thymic tumours, pathological changes in the thymus, and other autoimmune diseases are associated with the disorder. (Autoimmune mechanisms are discussed in Chapter 8.) Ocular myasthenia, more common in males, involves weakness of the eye muscles and eyelids, and may include swallowing difficulties and slurred speech. Pathophysiology Myasthenia gravis results from a defect in nerve impulse transmission at the neuromuscular junction. The postsynaptic AChRs on the muscle cell's plasma membrane are no longer recognized as “self” and elicit T-cell–dependent formation of IgG autoantibodies. The autoantibodies fix onto AChR sites, blocking the binding of acetylcholine. Eventually the antibody action destroys receptor sites. This loss of AChR sites causes diminished transmission of the nerve impulse across the neuromuscular junction and decreased muscle depolarization. Symptomatic individuals without anti-AChR antibodies may have antibodies

against muscle-specific kinase (MuSK) with similar symptoms. Why this autosensitization occurs is unknown. Clinical Manifestations Myasthenia gravis has an insidious onset. The variable distribution of AChR sites or the number of and different isoforms of antibodies may determine when and which muscle groups are affected first. The muscles of the eyes, face, mouth, throat, and neck usually are affected first. There can be drooling and difficulty chewing and swallowing food. These problems can affect nutrition and put the person at risk for respiratory aspiration. The muscles of the neck, shoulder girdle, and hip flexors are less frequently affected, but muscle fatigue is common after exercise and there can be progressive weakness. The respiratory muscles of the diaphragm and chest wall can become weak with impaired ventilation. Clinical manifestations may first appear during pregnancy, during the postpartum period, or in conjunction with the administration of certain anaesthetic agents. The progression of myasthenia gravis varies, appearing first as a mild case that spontaneously remits, with a series of relapses and symptom-free intervals ranging from weeks to months. Over time, the disease can progress. Myasthenic crisis can develop as the disease progresses and occurs when severe muscle weakness causes extreme quadriparesis or quadriplegia, respiratory insufficiency with shortness of breath, and extreme difficulty in swallowing. The individual in myasthenic crisis is in danger of respiratory arrest. Cholinergic crisis may arise from anticholinesterase medication toxicity with increased intestinal motility, episodes of diarrhea and complaints of intestinal cramping, bradycardia, pupillary constriction, increased salivation, and diaphoresis. These symptoms are caused by the smooth muscle hyperactivity secondary to excessive accumulation of acetylcholine at the neuromuscular junctions and excessive parasympatheticlike activity. As in myasthenic crisis, the individual is in danger of respiratory arrest. Evaluation and Treatment The diagnosis of myasthenia gravis is made on the basis of a response to edrophonium chloride (Tensilon), results of EMG studies, and detection of anti-AChR or MuSK antibodies. With the intravenous administration of the medication, immediate demonstrable improvement in muscle strength usually persists for several minutes. Mediastinal tomography and MRI help determine whether a thymoma is present. Current treatments for myasthenia gravis have improved prognosis, including in those who have ocular myasthenia. Anticholinesterase medications, steroids, and immunosuppressant medications (e.g., azathioprine [Imuran] and cyclosporine [Sandimmune] are used to treat myasthenia gravis and prevent myasthenic crisis. For individuals with cholinergic crisis, anticholinergic medications are withheld until blood levels are nontoxic; in addition, ventilatory support is provided and respiratory complications are prevented. Plasmapheresis may be lifesaving. Thymectomy is the treatment of choice in individuals with a thymoma and those with anti-AChR antibodies because this terminates the production of self-reactive T cells and B cells that produce the antibodies.101,102

Quick Check 16-4 1. Where in the peripheral nervous system can disease occur? 2. Why do antibodies contribute to the symptoms of myasthenia gravis? 3. How do myasthenic crisis and cholinergic crisis differ in terms of cause and treatment?

Tumours of the Central Nervous System CNS tumours include both brain and spinal cord tumours. In 2012, the estimated number of new cases of primary brain tumours in Canada was 2 800, and the estimated number of deaths was 1 850.103 The incidence of cancer increases with age, with 69% of new cases and 62% of cancer deaths occurring among those 50 to 79 years of age. CNS tumours are the second most common type of cancer occurring in children, second to leukemia.104 Approximately 70 to 75% of all intracranial tumours in children are located infratentorially (see Chapter 17), and in adults 70% are located supratentorially. Peripheral nerve tumours are rare in children and common in adults. Carcinogenesis is discussed in Chapter 10, pituitary tumours are discussed in Chapter 19, and cerebral tumours in children are discussed in Chapter 17.

Brain Tumours Tumours within the cranium can be either primary or metastatic. Primary brain tumours originate from brain substance, including neuroglia, neurons, cells of blood vessels, and connective tissue. Extracerebral tumours originate outside substances of the brain and include meningiomas, acoustic nerve tumours, and tumours of pituitary and pineal glands. Metastatic (secondary) brain tumours arise in organ systems outside the brain and spread to the brain. Common sites of intracranial tumours are illustrated in Figure 16-15.

FIGURE 16-15

Common Sites of Intracranial Tumours.

Local effects of cranial tumours are caused by the destructive action of the tumour itself on a particular site in the brain and by compression causing decreased cerebral blood flow. Generalized effects result from increased ICP caused by growth of the tumour, obstruction of the ventricular system, hemorrhages in and around the tumour, or cerebral edema (Figure 16-16). Manifestations include seizures, visual disturbances, unstable gait, and cranial nerve dysfunction.

FIGURE 16-16

Origin of Clinical Manifestations Associated With an Intracranial Neoplasm.

Intracranial brain tumours do not metastasize as readily as tumours in other organs because there are no lymphatic channels within the brain substance. If metastasis does occur, it is usually through seeding of cerebral blood or CSF during cranial surgery or through artificial shunts.

Primary Brain (Intracerebral) Tumours Primary brain (intracerebral) tumours, also called gliomas, include astrocytomas, oligodendrogliomas, and ependymomas. They make up 50 to 60% of all adult brain tumours and about 2% of all cancers in Canada (Table 16-10). The World Health Organization (WHO) divides gliomas into four grades based on histopathological features, cellular density, atypia, mitotic activity, microvascular proliferation, and necrosis (Table 16-11). Grades I and II are generally benign or slow growing. Grades III and IV are malignant tumours. Etiology for primary brain tumours is not clearly known. Ionizing radiation is the only known environmental risk factor. There may be an association between mobile phone use and gliomas and acoustic neuromas.105,106 TABLE 16-10 Brain and Spinal Cord Tumours Neoplasm

Location

Gliomas Astrocytoma Anywhere in brain or spinal cord Glioblastoma Predominantly in cerebral hemispheres multiforme Oligodendrocytoma Most commonly in frontal lobes deep in white matter; may arise in brainstem, cerebellum, and spinal cord Ependymoma Intramedullary: wall of ventricles; may arise in caudal tail of spinal cord

Neuronal Cell Medulloblastoma

Posterior cerebellar vermis, roof of fourth ventricle

Mesodermal Tissue Meningioma Intradural, extramedullary: sylvian fissure region, superior parasagittal surface of frontal and parietal lobes, olfactory groove, wing of sphenoid bone, superior surface of cerebellum, cerebellopontine angle, spinal cord Choroid Plexus Papillomas Choroid plexus of ventricular system, lateral ventricle in children, fourth ventricle in adults Cranial Nerves and Spinal Nerve Roots Neurilemmoma Cranial nerves (most commonly vestibular division of cranial nerve VIII) Neurofibroma Extramedullary—spinal cord Pituitary Tumours Pituitary gland; may extend to or invade floor of third ventricle

Characteristics

Cell of Origin

Slow growing, invasive Highly invasive and malignant

Astrocytes Thought to arise from mature astrocytes

Relatively avascular; tends to be encapsulated; Oligodendrites more malignant form called oligodendroblastoma More common in children, variable growth rates; Ependymal cells more malignant, invasive form is called ependymoblastoma; may extend into ventricle or invade brain tissue Well demarcated but infiltrating, rapid growing; fills fourth ventricle

Embryonic cells

Slow growing, circumscribed, encapsulated, sharply demarcated from normal tissues, compressive in nature

Arachnoid cells; may be from fibroblasts

Usually benign; slow expansion inducing hemorrhage and hydrocephalus; malignant tumour is rare

Epithelial cells

Slow growing

Schwann cells

Slow growing

Neurilemma, Schwann cells

Age linked, several types, slow growing, macroadenomas and microadenomas

Pituitary cells, pituitary chromophobes, basophils, eosinophils

Rare, 0.5% of all primary brain tumours

Several types—germinoma, embryonal carcinoma, yolk sac tumour, choriocarcinoma, teratoma, mixed germ cell tumour—with different cell origins Several types with different cell origins

Germ Cell Tumours

Pineal region

Neurohypophysis, hypothalamus, pineal region Primarily in adolescents More common in males than females Variable prognosis Pineal region; pineal parenchyma

Several types (germinoma, pineocytoma, teratoma)

Blood Vessel Tumours Angioma Predominantly in posterior cerebral hemispheres

Slow growing

Hemangioblastomas Predominantly in cerebellum

Slow growing

Arising from congenitally malformed arteriovenous connections Embryonic vascular tissue

TABLE 16-11 Grades of Astrocytomas Gradea Type I Pilocytic astrocytoma II

III

IV

Diffuse, low-grade astrocytoma (fibrillary, gemistocytic, protoplasmic) Oligodendroglioma Anaplastic (malignant) astrocytoma Anaplastic oligodendroglioma Glioblastoma (glioblastoma multiforme)

Description Common in children and young adults and people with neurofibromatosis type 1; common in cerebellum Common in young adults; more common in cerebrum but can occur in any part of brain

Characteristics Least malignant, well differentiated; grows slowly; near-normal microscopic appearance, noninfiltrating Abnormal microscopic appearance; grows slowly; infiltrates to adjacent tissue; may recur at higher grade

Common in young adults

Malignant; many cells undergoing mitosis; infiltrates adjacent tissue; frequently recurs at higher grade

Common in older adults, particularly men Predominant in cerebral hemispheres

Poorly differentiated; increased number of cells undergoing mitosis; bizarre microscopic appearance; widely infiltrates; neovascularization; central necrosis

a

World Health Organization Grading of Central Nervous System Tumours.

Data from American Brain Tumor Association. (2010). Brain tumor primer (9th ed.). Chicago: Author. Retrieved from http://neurosurgery.mgh.harvard.edu/abta/; Louis, D.N., Ohgaki, H., Wiestler, O.D., et al. (2007). Acta Neuropathol, 114(2), 97–109.

Surgical or radiosurgical excision, surgical decompression, chemotherapy, radiotherapy, and hyperthermia are treatment options for these tumours. Supportive treatment is directed at reducing edema. New treatment options are emerging. (Cancer treatment is discussed in Chapter 10.)

Astrocytoma. Astrocytomas are the most common glioma (about 35 to 50% of all tumours of the brain and spinal cord)104 and are classified by grade and type (see Table 16-11). These tumour cells are thought to have lost normal growth restraint and thus proliferate uncontrollably. Astrocytomas are graded I through IV, with grades I and II being slow-growing tumours that are most common in children. Grade I and II astrocytomas commonly progress to a higher grade, faster growing tumour. They may occur anywhere in the brain or spinal cord, and are generally located in the cerebrum, hypothalamus, or pons. Low-grade astrocytomas tend to be located laterally or supratentorially in adults and in a midline or near-midline position in children. Headache and subtle neurobehavioural changes may be early signs, with other neurological symptoms evolving slowly and increased ICP occurring late in the tumour's course. Onset of a focal seizure disorder between the second and sixth decade of life suggests an astrocytoma. Low-grade astrocytomas are treated with surgery or by external radiation, and at least 50% of persons survive 5 years when surgery is followed by radiation therapy.104,107 Grades III and IV astrocytomas are found predominantly in the frontal lobes and cerebral hemispheres, although they may occur in the brainstem, cerebellum, and spinal cord. Men are twice as likely to have astrocytomas as women; in the 15- to 34-year-old age group they are the third most common brain cancer, whereas in the 35- to 54-year-old age group they are the fourth most common. Grade IV astrocytoma, glioblastoma multiforme, is the most lethal and common type of primary brain tumour. This type is highly vascular and extensively irregular and infiltrative, making it difficult to remove surgically. Fifty percent of glioblastomas are bilateral or at least occupy more than one lobe at the time of death. The typical clinical presentation for a glioblastoma multiforme is that of diffuse, nonspecific clinical signs, such as headache, irritability, and “personality changes” that progress to more clear-cut manifestations of increased ICP, including headache on position change, papilledema, vomiting, or seizure activity. Symptoms may progress to include definite focal signs, such as hemiparesis, dysphasia, dyspraxia, cranial nerve palsies, and visual field deficits. Higher grade astrocytomas are treated surgically and with radiotherapy and chemotherapy. Recurrence is common, and survival time is less than 5 years.108

Oligodendroglioma. Oligodendrogliomas constitute about 2% of all brain tumours and 10 to 15% of all gliomas. They are typically slow-growing tumours, and most oligodendrogliomas are macroscopically indistinguishable

from other gliomas and may be a mixed type of oligodendroglioma and astrocytoma. Most are found in the frontal and temporal lobes, often in the deep white matter, but they are found also in other parts of the brain and spinal cord. Many are found in young adults with a history of temporal lobe epilepsy. Malignant degeneration occurs in approximately one third of persons with oligodendrogliomas, and the tumours are then referred to as oligodendroblastomas. More than 50% of individuals experience a focal or generalized seizure as the first clinical manifestation. Only half of those with an oligodendroglioma have increased ICP at the time of diagnosis and surgery, and only one third develop focal manifestations. Treatment includes surgery, radiotherapy, and chemotherapy.

Ependymoma. Ependymomas are nonencapsulated gliomas that arise from ependymal cells; they are rare in adults, usually occurring in the spinal cord.109 However, in children ependymomas are typically located in the brain. They constitute about 6% of all primary brain tumours in adults and 10% in children and adolescents. Approximately 70% of these tumours occur in the fourth ventricle, with others found in the third and lateral ventricles and caudal portion of the spinal cord. Approximately 40% of infratentorial ependymomas occur in children younger than 10 years. Cerebral (supratentorial) ependymomas occur at all ages. Fourth ventricle ependymomas present with difficulty in balance, unsteady gait, uncoordinated muscle movement, and difficulty with fine motor movement. The clinical manifestations of a lateral and third ventricle ependymoma that involves the cerebral hemispheres are seizures, visual changes, and hemiparesis. Blockage of the CSF pathway produces hydrocephalus and presents with headache, nausea, and vomiting. The interval between first manifestations and surgery may be as short as 4 weeks or as long as 7 or 8 years. Ependymomas are treated with radiotherapy, radiosurgery, and chemotherapy. About 20 to 50% of persons survive 5 years. Some persons benefit from a shunting procedure when the ependymoma has caused a noncommunicating hydrocephalus.

Primary Extracerebral Tumours Meningioma. Meningiomas constitute about 34% of all intracranial tumours. These tumours usually originate from the arachnoidal (meningeal) cap cells in the dura mater and rarely from arachnoid cells of the choroid plexus of the ventricles. Meningiomas are located most commonly in the olfactory grooves, on the wings of the sphenoid bone (at the base of the skull), in the tuberculum sellae (next to the sella turcica), on the superior surface of the cerebellum, and in the cerebellopontine angle and spinal cord. Rarely, they can involve the optic nerve sheath with loss of visual acuity.110 The cause of meningiomas is unknown. A meningioma is sharply circumscribed and adapts to the shape it occupies. It may extend to the dural surface and erode the cranial bones or produce an osteoblastic reaction. A few meningiomas exhibit malignant, invasive qualities. Meningiomas are slow growing, and clinical manifestations occur when they reach a certain size and begin to indent the brain parenchyma. Focal seizures are often the first manifestation, and increased ICP is less common than with gliomas. There is a 20% recurrence rate even with complete surgical excision. If only partial resection is possible, the tumour recurs. Radiation therapies also are used to slow growth.

Nerve sheath tumours. Neurofibromas (benign nerve sheath tumours) are a group of autosomal dominant disorders of the nervous system. They include neurofibromatosis type 1 (NF1) (previously known as von Recklinghausen's disease) and neurofibromatosis type 2 (NF2); NF1 and NF2 are also known as peripheral neurofibromatosis and central neurofibromatosis, respectively. NF1 is the most prevalent type of nerve sheath tumour, with an incidence of about 1 in 3 500 people,

and causes multiple cutaneous neurofibromas, cutaneous macular lesions (café-au-lait spots and freckles), and less commonly bone and soft tissue tumours. Inactivation of the NF1 gene results in loss of function of neurofibromin in Schwann cells and promotes tumourigenesis (neurofibromas). Learning disabilities are present in about 50% of affected individuals.111 NF2 is rare and occurs in about 1 in 60 000 people. The NF2 gene product is neurofibromin 2 (merlin), a tumour-suppressor protein, and mutations promote development of CNS tumours, particularly schwannomas, although other tumour types can occur (meningiomas, ependymomas, astrocytomas, and neurofibromas). Schwannomas of the vestibular nerves present with hearing loss and deafness. Other symptoms may include loss of balance and dizziness. Schwannomas also may develop in other cranial, spinal, and peripheral nerves, and cutaneous signs are less prominent. Genetic testing is available for the management of families susceptible to NF, and prenatal diagnosis is possible. Diagnosis is based on clinical manifestations and neuroimaging studies, and diagnostic criteria have been established for NF1.112,113 Surgery is the major treatment. Individuals with NF2 have extensive morbidity and reduced life expectancy, particularly with early age of onset. Genetically tailored medications are likely to provide personalized therapy for both of these devastating conditions.

Metastatic brain tumours. Metastatic brain tumours from systemic cancers are 10 times more common than primary brain tumours, and 20 to 40% of persons with cancer have metastasis to the brain.114 Common primary sites include lung, breast, and skin (e.g., melanomas), as well as kidney, colorectal, and other types of cancer. Metastasis to the brain is thought to be through vascular channels (see Chapter 10). Metastatic brain tumours produce signs resembling those of glioblastomas, although several unusual syndromes do exist. Carcinomatous (metastatic cancer) encephalopathy causes headache, nervousness, depression, trembling, confusion, forgetfulness, and gait disorder. In carcinomatosis of the cerebellum, headache, dizziness, and ataxia are found. Carcinomatosis of the craniospinal meninges (also called carcinomatous meningitis) manifests with headache, confusion, and symptoms of cranial or spinal nerve root dysfunction. Metastatic brain tumours carry a poor prognosis. Treatment is guided by the pathology of the original tumour; number, size and location of the brain metastasis; and prior cancer treatments. With the development of new medications that cross the blood–brain barrier, chemotherapy is increasingly recommended.115 Survival is about 1 year.

Spinal Cord Tumours Primary spinal cord tumours are rare and represent about 2% of CNS tumours. They may be extramedullary extradural, intradural extramedullary, or intradural intramedullary. Intramedullary tumours originate within the neural tissues of the spinal cord. Extramedullary tumours originate from tissues outside the spinal cord. Intramedullary tumours are primarily gliomas (astrocytomas and ependymomas). Gliomas are difficult to resect completely, and radiotherapy is required. Spinal ependymomas may be completely resected and are more common in adults. Extramedullary tumours are either peripheral nerve sheath tumours (neurofibromas or schwannomas) or meningiomas. Neurofibromas are generally found in the thoracic and lumbar region, whereas meningiomas are more evenly distributed through the spine. Complete resection of these tumours can be curative. Other extramedullary tumours are sarcomas, vascular tumours, chordomas, and epidermoid tumours. Intramedullary tumours include ependymoma, astrocytoma, and hemangioblastoma. Metastatic spinal cord tumours are usually carcinomas (i.e., from breast, lung, or prostate cancer), lymphomas, or myelomas. Their location is often extradural, having proliferated to the spine through direct extension from tumours of the vertebral structures or from extraspinal sources extending through the interventricular foramen or bloodstream. Pathophysiology Intramedullary spinal cord tumours produce dysfunction by both invasion and compression. Extramedullary spinal cord tumours produce dysfunction by compressing adjacent tissue, not by direct invasion. Metastases from spinal cord tumours occur from direct extension or seeding through the CSF or

bloodstream. Clinical Manifestations An acute onset of clinical manifestations suggests a vascular occlusion of vessels supplying the spinal cord, whereas gradual and progressive symptoms suggest compression. The compressive syndrome (sensorimotor syndrome) involves both the anterior and the posterior spinal tracts, and motor function and sensory function are affected as the tumour grows. Pain is usually a presenting symptom. The irritative syndrome (radicular syndrome) combines the clinical manifestations of a cord compression with radicular pain that occurs in the sensory root distribution and indicates root irritation. The segmental manifestations include segmental sensory changes, such as paresthesias and impaired pain and touch perception; motor disturbances, including cramps, atrophy, fasciculations, and decreased or absent deep tendon reflexes; and continuous spinal pain. Evaluation and Treatment The diagnosis of a spinal cord tumour is made through bone scan, PET, CT-guided needle biopsy, or open biopsy. Involvement of specific cord segments is established. Any metastases also are identified. Treatment varies depending on the nature of the tumour and the person's clinical status, but surgery is essential for all spinal cord tumours.116

Quick Check 16-5 1. How is an encapsulated central nervous system (CNS) tumour different from a nonencapsulated CNS tumour? 2. What are three types of spinal cord tumours? 3. What are some common signs and symptoms of compressive and irritative spinal cord tumour syndromes?

Did You Understand? Central Nervous System Disorders 1. Thirty percent of all traumatic brain injuries are sustained by children and youth, many of them while participating in sports and recreational-related activities. 2. Primary brain injury is caused by direct impact and involves neural injury, primary glial injury, and vascular responses. 3. Primary brain injuries can be focal or diffuse. 4. Focal brain injury can be caused by closed (blunt) trauma or open (penetrating) trauma. Closed injury is more common. Open injury involves a skull fracture with exposure of the cranial vault to the environment. 5. Focal brain injury includes contusion, laceration, epidural (extradural) hematoma, subdural hematoma, intracerebral hematoma, and open brain injury. 6. Diffuse brain injury (diffuse axonal injury [DAI]) results from shearing forces that result in axonal damage ranging from mild concussion to severe DAI. 7. Secondary brain injury develops from systemic and intracranial responses to primary brain trauma that result in further brain injury and neuronal death. 8. Spinal cord injury involves damage to neural tissues by compressing tissue, pulling or exerting tension on tissue, or shearing tissues so that they slide into one another. Vertebral fracture occurs with direct or indirect trauma. 9. Spinal cord injury may cause spinal shock with cessation of all motor, sensory, reflex, and autonomic functions below the transected area. Loss of motor and sensory function depends on the level of injury. 10. Neurogenic shock occurs with cervical or upper thoracic cord injury (above T5) and can occur concurrently with spinal shock. 11. Autonomic hyper-reflexia (dysreflexia) is a syndrome of sudden, massive reflex sympathetic discharge associated with spinal cord injury at level T6 or above. Flexor spasms are accompanied by profuse sweating, piloerection, and automatic bladder emptying. 12. Complete spinal cord transection results in paralysis. Paralysis of the lower half of the body with both legs involved is called paraplegia. Paralysis involving all four extremities is called quadriplegia. 13. Return of spinal neuron excitability occurs slowly. Reflex activity can return in 1 to 2 weeks in most persons with acute spinal cord injury. A pattern of flexion reflexes emerges, involving first the toes, then the feet and the legs. Eventually, reflex voiding and bowel elimination appear. 14. Low back pain is pain between the lower rib cage and gluteal muscles and often radiates into the thighs. 15. Most causes of low back pain are unknown; however, some secondary causes are disc prolapse, tumours, bursitis, synovitis, degenerative joint disease, osteoporosis, fracture, inflammation, and sprain. 16. Degenerative disc disease is an alteration in intervertebral disc tissue and can be related to normal aging. 17. Spondylolysis is a structural defect of the spine with displacement of the deficient vertebra. 18. Spondylolisthesis involves forward slippage of a vertebra and can include a crack or fracture of the pars interarticularis, usually at the L5-S1 vertebrae. 19. Herniation of an intervertebral disc is a displacement of the nucleus pulposus or annulus fibrosus beyond the intervertebral disc space. Herniation most commonly affects the lumbosacral discs L5S1 and L4-5. The extruded pulposus compresses the nerve root, causing pain that radiates along the sciatic nerve course. 20. Cerebrovascular disease is the most frequently occurring neurological disorder. Any abnormality of the blood vessels of the brain is referred to as a cerebrovascular disease. 21. Cerebrovascular disease is associated with two types of brain abnormalities: (a) ischemia with or without infarction and (b) hemorrhage.

22. Transient ischemic attacks are episodes of neurological dysfunction lasting no more than 1 hour and resulting from focal cerebral ischemia. 23. Cerebrovascular accidents (stroke syndromes) are classified pathophysiologically as ischemic (thrombotic or embolic), hemorrhagic (intracranial hemorrhage), or associated with hypoperfusion. 24. Intracranial aneurysms result from defects in the vascular wall and are classified on the basis of form and shape. They are often asymptomatic, but the signs vary depending on the location and size of the aneurysm. 25. An arteriovenous malformation is a mass of dilated blood vessels. Although usually present at birth, symptoms are delayed and usually occur before age 30. 26. A subarachnoid hemorrhage occurs when blood escapes from defective or injured vasculature into the subarachnoid space. When a vessel tears, blood under pressure is pumped into the subarachnoid space. The blood produces an inflammatory reaction in these tissues and increased intracranial pressure results. 27. Migraine is an episodic headache that can be associated with triggers, and it may have an aura associated with a cortical spreading depression that alters cortical blood flow. Pain is related to overactivity in the trigeminal vascular system. 28. Cluster headaches are a group of disorders known as trigeminal autonomic cephalalgias and occur primarily in men. They occur in clusters over a period of days with extreme pain intensity and short duration, and are associated with trigeminal activation. 29. Tension-type headache is the most common headache. Episodic-type headaches involve a peripheral pain mechanism, and the chronic type involves a central pain mechanism and may be related to hypersensitivity to pain in craniocervical muscles. 30. Infection and inflammation of the central nervous system (CNS) can be caused by bacteria, viruses, fungi, protozoa, and rickettsiae. Bacterial infections are pyogenic or pus producing. 31. Meningitis (infection of the meninges) is classified as bacterial (i.e., meningococci), aseptic (viral or nonpurulent), or fungal. Bacterial meningitis primarily is an infection of the pia mater, the arachnoid, and the fluid of the subarachnoid space. Aseptic meningitis is thought to be limited to the meninges. Fungal meningitis is a chronic, less common type of meningitis. 32. Brain abscesses often originate from infections outside the CNS. Organisms gain access to the CNS from adjacent sites or spread along the wall of a vein. A localized inflammatory process develops with formation of exudate. After a few days, the infection becomes delimited with a centre of pus and a wall of granular tissue. 33. Encephalitis is an acute febrile illness of viral origin with nervous system involvement. The most common encephalitides are caused by bites of mosquitoes, ticks, or flies; viruses; and herpes simplex type 1. Meningeal involvement appears in all encephalitides. 34. Herpes encephalitis is treated with antiviral agents. No definitive treatment exists for the other encephalitides. 35. The common neurological complications of AIDS are HIV-associated neurocognitive disorder, HIV myelopathy, opportunistic infections, cytomegalovirus encephalitis, parasitic infection, and neoplasms. Pathologically, there may be diffuse CNS involvement, focal pathological changes, and obstructive hydrocephalus. 36. Multiple sclerosis is a chronic inflammatory demyelinating disorder with scarring (sclerosis) and loss of axons. Although the pathogenesis is unknown, the demyelination is thought to result from an immunogenetic-viral cause in genetically susceptible individuals. 37. Guillain-Barré syndrome is a demyelinating disorder caused by a humoral and cell-mediated immunological reaction directed at the peripheral nerves.

Peripheral Nervous System and Neuromuscular Junction Disorders 1. With disorders of the roots of spinal cord nerves, the roots may be compressed, inflamed, or torn. Clinical manifestations include local pain or paresthesias in the sensory root distribution. Treatment may involve surgery, antibiotics, steroids, radiation therapy, and chemotherapy.

2. Plexus injuries involve the plexus distal to the spinal roots. Paralysis can occur with complete plexus involvement. 3. When peripheral nerves are affected, axon and myelin degeneration may be present. These syndromes are classified as sensorimotor, sensory, or motor and are characterized by varying degrees of sensory disturbance, paresis, and paralysis. Secondary atrophy may be present. 4. Myasthenia gravis is a disorder of voluntary muscles characterized by muscle weakness and fatigability. It is considered an autoimmune disease and is associated with an increased incidence of other autoimmune diseases. 5. Myasthenia gravis results from a defect in nerve impulse transmission at the postsynaptic membrane of the neuromuscular junction. Immunoglobulin G antibody is secreted against the “self” acetylcholine receptors and blocks the binding of acetylcholine. The antibody action destroys the receptor sites, causing decreased transmission of the nerve impulse across the neuromuscular junction.

Tumours of the Central Nervous System 1. Two main types of tumours occur within the cranium: primary and metastatic. Primary tumours are classified as intracerebral tumours (astrocytomas, oligodendrogliomas, and ependymomas) or extracerebral tumours (meningioma or nerve sheath tumours). Metastatic tumours can be found inside or outside the brain substance. 2. CNS tumours cause local and generalized manifestations. The effects are varied, and local manifestations include seizures, visual disturbances, unstable gait, and cranial nerve dysfunction. 3. Spinal cord tumours are classified as intramedullary tumours (within the neural tissues) or extramedullary tumours (outside the spinal cord). Metastatic spinal cord tumours are usually carcinomas, lymphomas, or myelomas. 4. Extramedullary spinal cord tumours produce dysfunction by compression of adjacent tissue, not by direct invasion. Intramedullary spinal cord tumours produce dysfunction by both invasion and compression.

Key Terms Arteriovenous malformation (AVM), 409 Astrocytomas, 418 Autonomic hyper-reflexia (dysreflexia), 402 Bacterial meningitis, 412 Brain abscess, 413 Brudzinski sign, 410 Cauda equina syndrome, 403 Cerebral infarction, 407 Cerebrovascular accident (CVA), 406 Cholinergic crisis, 417 Chronic traumatic encephalopathy (CTE), 399 Classic cerebral concussion, 398 Closed brain injuries, 394 Cluster headache, 411 Compound skull fracture, 397 Compressive syndrome (sensorimotor syndrome), 421 Contrecoup injury, 395 Contusion, 395 Coup injury, 395 Degenerative disc disease (DDD), 403 Diffuse brain injury (diffuse axonal injury [DAI]), 397 Embolic stroke, 407 Encephalitis, 413 Ependymoma, 420 Epidural (extradural) hematoma, 395 Focal brain injury, 394 Fungal meningitis, 412 Fusiform aneurysm (giant aneurysm), 408 Glioblastoma multiforme, 419 Glioma, 418 Guillain-Barré syndrome, 416 Headache, 410 Hemorrhagic stroke (intracranial hemorrhage), 408 HIV-associated neurocognitive disorder (HAND), 414 HIV distal symmetric polyneuropathy, 414 HIV myelopathy, 414 Hypoperfusion, or hemodynamic stroke, 407 Intracerebral hematoma, 397 Intracranial aneurysm, 408 Irritative syndrome (radicular syndrome), 421 Ischemic penumbra, 407 Ischemic stroke, 407 Kernig sign, 410 Lacunar stroke (lacunar infarct or small vessel disease), 407 Low back pain (LBP), 402 Meningioma, 420 Meningitis, 412 Metastatic brain tumours, 421 Migraine, 410

Mild concussion, 398 Mild diffuse axonal injury, 398 Moderate diffuse axonal injury, 398 Multiple sclerosis (MS), 415 Myasthenia gravis, 417 Myasthenic crisis, 417 Neurofibroma (benign nerve sheath tumour), 420 Neurofibromatosis type 1 (NF1), 420 Neurofibromatosis type 2 (NF2), 420 Neurogenic shock, 402 Ocular myasthenia, 417 Oligodendroglioma, 420 Open brain injury, 397 Open (penetrating) trauma, 394 Plexus injury, 416 Postconcussion syndrome, 398 Post-traumatic seizure, 398 Primary brain (intracerebral) tumour, 418 Primary spinal cord injury, 399 Purpura fulminans, 412 Radiculopathy, 405 Saccular aneurysm (berry aneurysm), 408 Secondary brain injury, 398 Secondary spinal cord injury, 399 Severe diffuse axonal injury, 398 Spinal cord abscess, 413 Spinal cord tumours, 421 Spinal shock, 400 Spinal stenosis, 405 Spondylolisthesis, 404 Spondylolysis, 404 Subarachnoid hemorrhage (SAH), 409 Subdural hematoma, 396 Tension-type headache (TTH), 411 Thrombotic stroke (cerebral thrombosis), 407 Transient ischemic attack (TIA), 407 Traumatic brain injury (TBI), 394 Viral meningitis (aseptic or nonpurulent meningitis), 412 West Nile virus (WNV), 414

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17

Alterations of Neurological Function in Children Lynne M. Kerr, Sue E. Huether, Vinodh Narayanan *, Kelly Power-Kean

CHAPTER OUTLINE Development of the Nervous System in Children, 426 Structural Malformations, 427 Defects of Neural Tube Closure, 427 Craniostenosis, 430 Malformations of Brain Development, 431 Alterations in Function: Encephalopathies, 433 Static Encephalopathies, 433 Inherited Metabolic Disorders of the Central Nervous System, 433 Acute Encephalopathies, 434 Infections of the Central Nervous System, 435 Cerebrovascular Disease in Children, 435 Perinatal Stroke, 435 Childhood Stroke, 435 Epilepsy and Seizure Disorders in Children, 436 Childhood Tumours, 436 Brain Tumours, 436 Embryonal Tumours, 438

Neurological disorders in children can occur from infancy through adolescence and include congenital malformations, genetic defects in metabolism, brain injuries, infection, tumours, and other disorders that affect neurological function.

Development of the Nervous System in Children The nervous system develops from the embryonic ectoderm through a complex, sequential process that can be arbitrarily divided into stages. These include (1) formation of the neural tube (3 to 4 weeks' gestation), (2) development of the forebrain from the neural tube (2 to 3 months' gestation), (3) neuronal proliferation and migration (3 to 5 months' gestation), (4) formation of network connections and synapses (5 months' gestation to many years postnatally), and (5) myelination (birth to many years postnatally). Many different events happen simultaneously, and critical periods must pass uninterrupted if the vulnerable fetus is to develop normally. Genetic and environmental factors (e.g., nutrition, hormones, oxygen levels, toxins, alcohol, medications, drugs, maternal infections, maternal disease) can have a significant effect on neural development1,2 (see Health Promotion: Prevention of Fetal Alcohol Spectrum Disorders).

Health Promotion Prevention of Fetal Alcohol Spectrum Disorders The term fetal alcohol spectrum disorder (FASD) is used to describe the full range of damage that prenatal alcohol exposure can cause in the unborn child. Alcohol crosses the placenta and the blood–brain barrier and exerts teratogenic effects on the developing brain throughout fetal development. Damage can vary from mild to severe physical defects and cognitive, behavioural, emotional, and adaptive functioning deficits. FASD includes diagnoses of fetal alcohol syndrome (FAS), partial FAS, alcohol-related neurodevelopmental disorder (ARND), and alcohol-related birth defects (ARBD).1,2 ARND has longlasting neurobehavioural and cognitive deficiencies. It is among the most common causes of mental deficits that persist throughout adulthood. ARND is 100% preventable. Rates of alcohol consumption by women during pregnancy range from 5 to 15%.2-5 Studies indicate that the incidence of FAS in Canada is higher among Indigenous people.6 As there is no known amount of alcohol that is safe to consume while pregnant, the Canadian Paediatric Society has made the following recommendations related to screening, education, and prevention programs to promote alcohol-free pregnancies: • Address the effects of FAS through classroom or community education programs. • Encourage women to avoid consuming alcohol before conception and throughout pregnancy. • Identify women who are drinking while pregnant and promote reduction in their consumption. • Recommend abstinence from alcohol during the first prenatal visit.6 • Promptly refer pregnant individuals who are unable to stop drinking alcohol for alcohol treatment.4-5

References 1. Interagency Coordinating Committee on Fetal Alcohol Spectrum Disorders. Consensus statement on recognizing alcohol-related neurodevelopmental disorder (ARND) in primary health care of children. [Retrieved from] https://niaaa.nih.gov/sites/default/files/ARNDConferenceConsensusStatementBooklet_Complete.pdf 2011. 2. Roussotte FF, Sulik KK, Mattson SN, et al. Human Brain Mapping. 2012;33(4):920–937. 3. Centers for Disease Control and Prevention. MMWR Morbidity and Mortality Weekly Report. 2012;61(28):534–538. 4. May PA, Blankenship J, Marais AS, et al. Drug and Alcohol Dependence. 2013;133(2):502–512. 5. Zelner I, Koren G. Journal of Population Therapeutics and Clinical Pharmacology. 2013;20(2):e201– e206. 6. Canadian Paediatric Society. Position statement: Fetal alcohol syndrome [Reaffirmed February 1, 2016]. [Retrieved from] http://www.cps.ca/en/documents/position/fetal-alcohol-syndrome; 2002. The growth and development of the brain occurs most rapidly from the third month of gestation through the first year of life, reflecting the proliferation of neurons and glial cells. Although basically all of the neurons that an individual will ever have are present at birth, development of skills, such as walking, talking, and thinking, depends on these cells making correct connections with other cells and on myelination of the axons making those connections. The head is the fastest-growing body part during infancy. One half of postnatal brain growth is achieved by the first year and is 90% complete by age 6 years. The cortex thickens with maturation, and the sulci deepen as a result of rapid expansion of the surface area of the brain. Cerebral blood flow and oxygen consumption during these years are about twice those of the adult brain. The bones of the infant's skull are separated at the suture lines, forming two fontanelles, or “soft spots”: one diamond-shaped anterior fontanelle and one triangular-shaped posterior fontanelle. The sutures allow for expansion of the rapidly growing brain. The posterior fontanelle may be open until 2 to 3 months of age; the anterior fontanelle normally does not fully close until 18 months of age (Figure 17-1). Head growth almost always reflects brain growth. Monitoring the fontanelles and careful measurement and plotting of the head circumference on standardized growth charts are essential elements of the pediatric examination. A common cause of accelerating head growth and macrocephaly is hydrocephalus, a condition in which the cerebrospinal fluid (CSF) compartment (ventricles) is enlarged. Increased intracranial pressure (ICP), with distension or bulging of the fontanelles, and separation of the sutures are key signs of hydrocephalus. Microcephaly (head circumference below the second percentile for age) can be the result of prenatal infection, toxin exposure, or malnutrition, or have a primary genetic etiology (see p. 427).

FIGURE 17-1 Cranial Sutures and Fontanelles in Infancy. Fibrous union of suture lines and interlocking of serrated edges (occurs by 6 months; solid union requires approximately 12 years). (Head growth charts are available from the Centers for Disease Control and Prevention at http://www.cdc.gov/nchs/data/series/sr_11/sr11_246.pdf.)

Because of the immaturity of much of the human forebrain at birth, neurological examination of the infant detects mostly reflex responses that require an intact spinal cord and brainstem. Some of these reflex patterns are inhibited as cerebral cortical function matures, and these patterns disappear at predictable times during infancy (Table 17-1). TABLE 17-1 Reflexes of Infancy Reflex

Age of Appearance of Reflex

Age at Which Reflex Should No Longer Be Obtainable

Moro Stepping Sucking

Birth Birth Birth

Rooting

Birth

Palmar grasp Plantar grasp Tonic neck Neck righting Landau Parachute reaction

Birth Birth 2 months 4 to 6 months 3 months 9 months

3 months 6 weeks 4 months awake 7 months asleep 4 months awake 7 months asleep 6 months 10 months 5 months 24 months 24 months Persists indefinitely

Absence of expected reflex responses at the appropriate age indicates general depression of central or peripheral motor functions. Asymmetrical responses may indicate lesions in the motor cortex or peripheral nerves, or may occur with fractures of bones after traumatic delivery or postnatal injury. As the infant matures, the neonatal reflexes disappear in a predictable order as voluntary motor functions supersede them. Abnormal persistence of these reflexes is seen in infants with developmental delays or with central motor lesions.

Quick Check 17-1 1. When does development of neuronal myelination occur? 2. What is a major function of the fontanelles? 3. Why do many of the reflexes of infancy disappear by 1 year of age?

Structural Malformations Central nervous system (CNS) malformations are responsible for 75% of fetal deaths and 40% of deaths during the first year of life. CNS malformations account for 33% of all apparent congenital malformations, and 90% of CNS malformations are defects of neural tube closure.

Defects of Neural Tube Closure Neural tube defects (NTDs) are caused by an arrest of the normal development of the brain and spinal cord during the first month of embryonic development. This disorder is relatively common, with a prevalence rate of approximately 4.1 per 10 000 births in Canada (although there are significant provincial prevalence variations).3 Fetal death often occurs in the more severe forms, thereby reducing the actual prevalence of neural defects at birth.4 Defects of neural tube closure are divided into two categories: (1) anterior midline defects (ventral induction) and (2) posterior defects (dorsal induction). Anterior midline defects may cause brain and face abnormalities with the most extreme form being cyclopia, in which the child has a single midline orbit and eye with a protruding noselike proboscis above the orbit. Spina bifida (split spine) is the most common NTD and includes anencephaly (an, “without”; enkephalos, “brain”), encephalocele, meningocele, and myelomeningocele. Vertebrae fail to close in spina bifida. Myelomeningocele is a form of spina bifida with incomplete development of the spine and protrusion of both the spinal cord and the meninges through the skin. Meningocele is a form of spina bifida in which there is protrusion of the meninges, but the spinal cord remains in the spinal canal. Disorders of embryonic neural development are summarized in Figure 17-2.

FIGURE 17-2

Disorders Associated With Specific Stages of Embryonic Development. CSF, cerebrospinal fluid.

The cause of NTDs is believed to be multifactorial (a combination of genes and environment). No single gene has been found to cause NTDs, but there can be associated mutations in folate-responsive or folatedependent pathways.5 Folic acid deficiency during preconception and early stages of pregnancy increases the risk for NTDs, and supplementation (400 mcg of folic acid per day) ensures adequate folate status.6 Results have shown that the introduction of the mandatory fortification of flour with folic acid in Canada has resulted in a significant reduction in the incidence of NTDs. Other considerations include the increasing use of folic acid supplements and increased prenatal screening and diagnosis leading to pregnancy termination.3 Other risk factors include a previous NTD pregnancy, maternal diabetes or obesity, use of anticonvulsant medications (particularly valproic acid [Valproate Sodium]), and maternal hyperthermia.7,8 Anencephaly is an anomaly in which the soft, bony component of the skull and part of the brain are missing.9 There is a prevalence rate of 0.8 per 10 000 births in Canada each year.3 These infants are stillborn or die within a few days after birth. The pathological mechanism is unknown. Diagnosis is often made prenatally by using ultrasound or evaluating maternal serum alpha fetoprotein (AFP).

Encephalocele refers to a herniation or protrusion of the brain and meninges through a defect in the skull, resulting in a saclike structure.10 There is a prevalence rate of 0.6 per 10 000 births in Canada each year.3 Meningocele is a saclike cyst of meninges filled with spinal fluid and is a mild form of spina bifida (Figure 17-3). It develops during the first 4 weeks of pregnancy when the neural tube fails to close completely. The cystic dilation of meninges protrudes through the vertebral defect but does not involve the spinal cord or nerve roots and may produce no neurological deficit or symptoms. Meningoceles occur with equal frequency in the cervical, thoracic, and lumbar spine areas.

FIGURE 17-3

Normal Spine, Spina Bifida, Meningocele, and Myelomeningocele. (From Hockenberry, M.J., & Wilson, D. [2015]. Wong's nursing care of infants and children [10th ed.]. St. Louis: Mosby.)

Myelomeningocele (meningomyelocele; spina bifida cystica) is a hernial protrusion of a saclike cyst (containing meninges, spinal fluid, and a portion of the spinal cord with its nerves) through a defect in the posterior arch of a vertebra. Eighty percent of myelomeningoceles are located in the lumbar and lumbosacral regions, the last regions of the neural tube to close. Myelomeningocele is one of the most common developmental anomalies of the nervous system, affecting 1 out of every 1 200 children born in Canada.11

Meningocele and myelomeningoceles are evident at birth as a pronounced skin defect on the infant's back (see Figure 17-3). The bony prominences of the unfused neural arches can be palpated at the lateral border of the defect. The defect usually is covered by a transparent membrane that may have neural tissue attached to its inner surface. This membrane may be intact at birth or may leak CSF, thereby increasing the risks of infection and neuronal damage. The spinal cord and nerve roots are malformed below the level of the lesion, resulting in loss of motor, sensory, reflex, and autonomic functions. A brief neurological examination concentrating on motor function in the legs, reflexes, and sphincter tone is usually sufficient to determine the level above which spinal cord and nerve root function is preserved (Table 17-2). This examination is useful to predict whether the child will ambulate, require bladder catheterization, or be at high risk of developing scoliosis (see Chapter 40). TABLE 17-2 Functional Alterations in Myelodysplasia Related to Level of Lesion Level of Lesion Thoracic High lumbar Mid lumbar Low lumbar Sacral

Functional Implications Flaccid paralysis of lower extremities; variable weakness in abdominal trunk musculature; high thoracic level may mean respiratory compromise; absence of bowel and bladder control Voluntary hip flexion and adduction; flaccid paralysis of knees, ankles, and feet; may walk with extensive braces and crutches; absence of bowel and bladder control Strong hip flexion and adduction; fair knee extension; flaccid paralysis of ankles and feet; absence of bowel and bladder control Strong hip flexion, extension, and adduction and knee extension; weak ankle and toe mobility; may have limited bowel and bladder function Normal function of lower extremities; normal bowel and bladder function

Modified from Sandler, A.D. (2010). Pediatr Clin North Am, 57(4), 879–892.

Hydrocephalus occurs in 85% of infants with myelomeningocele.12 Seizures also occur in 30% of those with myelodysplasia. Visual and perceptual problems, including ocular palsies, astigmatism, and visuoperceptual deficits, are common. Motor and sensory functions below the level of the lesions are altered. Often these problems worsen as the child grows and the cord ascends within the vertebral canal, pulling primary scar tissue and tethering the cord.13 Several musculo-skeletal deformities are related to this diagnosis, as are spinal deformities. Myelomeningoceles are almost always associated with the Chiari II malformation (Arnold-Chiari malformation).12 This structural defect is a complex malformation of the brainstem and cerebellum in which the cerebellar tonsils are displaced downward into the cervical spinal canal; the upper medulla and lower pons are elongated and thin; and the medulla is also displaced downward and sometimes has a “kink” (Figure 17-4). The Chiari II malformation is associated with hydrocephalus from pressure that blocks the flow of CSF; syringomyelia, an abnormality causing cysts at multiple levels within the spinal cord; and cognitive and motor deficits.14

FIGURE 17-4 Normal Brain and Chiari II Malformation. A, Diagram of normal brain. B, Diagram of Chiari II malformation with downward displacement of cerebellar tonsils and medulla through foramen magnum causing compression and obstruction to flow of cerebrospinal fluid. (B, Used with permission from Barrow Neurological Institute, Phoenix, Arizona.)

Other types of Chiari malformations are not associated with spina bifida. Type I Chiari malformation does not involve the brainstem and may be asymptomatic. In type III, the brainstem or cerebellum extends into a high cervical myelomeningocele. Type IV is characterized by lack of cerebellar development. Most cases of meningocele and myelomeningocele are diagnosed prenatally by a combination of maternal serological testing (AFP) and prenatal ultrasound. In these cases, the fetus is usually delivered by elective Caesarean section to minimize trauma during labour. Surgical repair is critical and can be performed by in utero fetal surgery or during the first 72 hours of life.15,16 It is possible for a defect to occur without any visible exposure of meninges or neural tissue, and the term spina bifida occulta is then used. The defect is common and occurs to some degree in 10 to 25% of infants. Spina bifida occulta usually causes no neurological dysfunction because the spinal cord and spinal nerves are normal. Tethered cord syndrome may develop after surgical correction for myelomeningocele. The cord becomes abnormally attached or tethered as a result of scar tissue as the cord transcends the vertebral canal with growth.17

Craniostenosis

Skull malformations range from minor, insignificant defects to major defects that are incompatible with life. Craniostenosis (also termed craniosynostosis) is the premature closure of one or more of the cranial sutures (sagittal, coronal, lambdoid, metopic) during the first 18 to 20 months of the infant's life. The incidence of craniostenosis is 1 per 1 800 to 2 500 live births.18 Males are affected twice as often as females. Fusion of a cranial suture prevents growth of the skull perpendicular to the suture line, resulting in an asymmetrical shape of the skull. The general term plagiocephaly, meaning “misshapen skull,” is used to describe deformities that result from craniostenosis or from asymmetrical head posture (positional). When a single coronal suture fuses prematurely, the head is flattened on that side in front. When the sagittal suture fuses prematurely, the head is elongated in the anteroposterior direction (scaphocephaly).19 Single suture craniostenosis is usually only a cosmetic issue. Rarely, when multiple sutures fuse prematurely, brain growth may be restricted, and surgical repair may prevent neurological dysfunction (Figure 17-5). Syndromic craniostenosis involves deformities in other systems (i.e., the heart, limbs, and CNS).

FIGURE 17-5 Normal and Abnormal Head Configurations. Normal skull: Bones separated by membranous seams until sutures gradually close. Microcephaly and craniostenosis: Microcephaly is head circumference more than 2 standard deviations below the mean for age, gender, race, and gestation and reflects a small brain; craniostenosis is premature closure of sutures. Scaphocephaly or dolichocephaly (frequency 56%): Premature closure of sagittal suture, resulting in restricted lateral growth. Brachycephaly: Premature closure of coronal suture, resulting in excessive lateral growth. Oxycephaly or acrocephaly (frequency 5.8 to 12%): Premature closure of all coronal and sagittal sutures, resulting in accelerated upward growth and small head circumference. Plagiocephaly (frequency 13%): Unilateral premature closure of coronal suture, resulting in asymmetrical growth. (From Hockenberry, M.J., & Wilson, D. [2015]. Wong's nursing care of infants and children [10th ed.]. St. Louis: Mosby.)

Malformations of Brain Development Reduced proliferation or accelerated apoptosis causes congenital microcephaly (microencephaly—small brain) and increased proliferation causes megalencephaly (abnormally large brain). Microcephaly is a defect in brain growth as a whole (see Figure 17-5). Cranial size is significantly below average for the infant's age, gender, race, and gestation. The small size of the skull reflects a small brain (microencephaly), which is caused by reduced proliferation or accelerated apoptosis (Table 17-3). True (primary) microcephaly is usually caused by an autosomal recessive genetic or chromosomal defect.

Secondary (acquired) microcephaly is associated with various causes including infection, trauma, metabolic disorders, maternal anorexia experienced during the third trimester of pregnancy, and the presence of other genetic syndromes. Children with microcephaly are usually developmentally delayed. TABLE 17-3 Causes of Microcephaly Defects in Brain Development

Intrauterine Infections

Perinatal and Postnatal Disorders

Hereditary (recessive) microcephaly Down syndrome and other trisomy syndromes Fetal ionizing radiation exposure Maternal phenylketonuria Cornelia de Lange's syndrome Rubinstein-Taybi syndrome Smith-Lemli-Opitz syndrome Fetal alcohol spectrum disorder Angelman syndrome Seckel's syndrome

Congenital rubella Cytomegalovirus infection Congenital toxoplasmosis Zika virus infection

Intrauterine or neonatal anoxia Severe malnutrition in early infancy Neonatal herpesvirus infection

Cortical dysplasias are a heterogeneous group of disorders caused by defects in brain development. These disorders may range from a small area of abnormal tissue (e.g., heterotopia, which are pieces of grey matter that did not migrate to their normal position in the cortex of the brain; and focal cortical dysplasias, where brain organization in one small area is abnormal) to an entire brain that is smooth without the normal configuration of gyri and sulci of a developed brain (lissencephaly). The malformation occurs during brain formation. There is a specific genetic defect for some of these disorders; others are multifactorial or acquired (e.g., intrauterine trauma or infection). Cortical dysplasias increase the risk for seizures that are difficult to control, and cause developmental delay and motor dysfunction. Genetic testing assesses risk in other family members and guides therapy.20 Congenital hydrocephalus is present at birth and characterized by increased CSF pressure. It may be caused by blockage within the ventricular system where the CSF flows, an imbalance in the production of CSF, or a reduced reabsorption of CSF.21 The increased pressure within the ventricular system dilates the ventricles and pushes and compresses the brain tissue against the skull cavity (Figure 17-6). When hydrocephalus develops before fusion of the cranial sutures, the skull can expand to accommodate this additional space-occupying volume and preserve neuronal function (see photo in Figure 17-6, C). The overall incidence of hydrocephalus is approximately 1 to 3 per 1 000 live births.22 The incidence of hydrocephalus that is not associated with myelomeningocele is approximately 0.5 to 1 per 1 000 live births.22 (Types of hydrocephalus are discussed in Chapter 15.)

FIGURE 17-6 Hydrocephalus. A block in the flow of cerebrospinal fluid (CSF). A, Patent CSF circulation. B, Enlarged lateral and third ventricles caused by obstruction of circulation (e.g., stenosis of aqueduct of Sylvius). C, Infant born with hydrocephalus. (C, from McCance, K.L., & Huether, S.E. [2014]. Pathophysiology: The biological basis for disease in adults and children [7th ed.]. St. Louis: Elsevier, p. 668.)

Congenital hydrocephalus may cause fetal death in utero, or the increased head circumference may require Caesarean delivery of the infant. Symptoms depend directly on the cause and rate of hydrocephalus development. When there is separation of the cranial sutures, a resonant note sounds when the skull is tapped, a manifestation termed Macewen sign (“cracked pot” sign). The eyes may assume a staring expression, with sclera visible above the cornea, called sunsetting. Cognitive impairment in children with hydrocephalus is often related to associated brain malformations, or episodes of shunt failure or infection. Approximately 30 to 40% of children with uncomplicated congenital hydrocephalus complete schooling and are employed when treated successfully with shunting or endoscopic third ventriculostomy and choroid plexus cauterization.23-25 The Dandy-Walker malformation (DWM) is a congenital defect of the cerebellum characterized by a large posterior fossa cyst that communicates with the fourth ventricle and an atrophic, upwardly rotated cerebellar vermis.26 DWM is commonly associated with hydrocephalus caused by compression of the aqueduct of Sylvius. Other causes of obstructions within the ventricular system that can result in hydrocephalus include brain tumours, cysts, trauma, arteriovenous malformations, blood clots,

infections, and the Chiari malformations (see p. 429).

Quick Check 17-2 1. List two defects of neural tube closure. 2. Why do motor and sensory functions worsen with growth in a child with a neural tube defect? 3. What food source or dietary supplement helps to prevent neural tube defects?

Alterations in Function: Encephalopathies Encephalopathy, which means brain pathology, is a general category that includes a number of syndromes and diseases (see Chapter 16). These disorders may be acute or chronic, as well as static or progressive.

Static Encephalopathies Static or nonprogressive encephalopathy describes a neurological condition caused by a fixed lesion without active and ongoing disease. Causes include brain malformations (disorders of neuronal migration) or brain injury that may occur during gestation or birth, or at any time during childhood. The degree of neurological impairment is directly related to the extent of the injury or malformation. Anoxia, trauma, and infections are the most common factors that cause injury to the nervous system in the perinatal period. Infections, metabolic disturbances (acquired or genetic), trauma, toxins, and vascular disease may injure the nervous system in the postnatal period.27 Cerebral palsy is a disorder of movement, muscle tone, or posture that is caused by injury or abnormal development in the immature brain before, during, or after birth up to 1 year of age. Cerebral palsy is one of the most common crippling disorders of childhood, affecting nearly 50 000 children in Canada alone. Although the exact incidence is unknown, studies suggest that the prevalence is approximately 1 in 500, and 1 in 1 000 newborns in Canada.28 Risk factors include prenatal or perinatal cerebral hypoxia, hemorrhage, infection, genetic abnormalities, or low birth weight. Cerebral palsy can be classified on the basis of neurological signs and motor symptoms, with the major types involving spasticity, dystonia, ataxia, or a combination of these symptoms (mixed). Diplegia, hemiplegia, or tetraplegia may be present. Pyramidal/spastic cerebral palsy results from damage to corticospinal pathways (upper motor neurons) and is associated with increased muscle tone, persistent primitive reflexes, hyperactive deep tendon reflexes, clonus, rigidity of the extremities, scoliosis, and contractures. This form of cerebral palsy accounts for approximately 70 to 80% of cases. Extrapyramidal/nonspastic cerebral palsy is caused by damage to cells in the basal ganglia, thalamus, or cerebellum and includes two subtypes: dystonic and ataxic. Dystonic cerebral palsy is associated with extreme difficulty in fine motor coordination and purposeful movements. Movements are stiff, uncontrolled, and abrupt, resulting from injury to the basal ganglia or extrapyramidal tracts. This form of cerebral palsy accounts for approximately 10 to 20% of cases. Ataxic cerebral palsy is caused by damage to the cerebellum with alterations in coordination and movement. There is a broad based gait in an attempt to maintain balance and tremor is common with intentional movements. This form of cerebral palsy accounts for approximately 5 to 10% of cases. A child may have symptoms of each of these cerebral palsy types, which leads to a mixed disorder accounting for approximately 13% of cases.29 Children with cerebral palsy often have associated neurological disorders, such as seizures (about 50%), and intellectual impairment ranging from mild to severe (about 67%). Other complications include visual impairment, communication disorders, respiratory problems, bowel and bladder problems, and orthopedic disabilities.30

Inherited Metabolic Disorders of the Central Nervous System A large number of inherited metabolic disorders have been identified, typically leading to diffuse brain dysfunction. Early diagnosis and treatment is vital if these infants are to survive without severe neurological problems. Newborn screening in Canada for specific metabolic conditions varies by province or territory and has led to children at risk of developing metabolic conditions being identified before symptoms develop. Table 17-4 lists some of these inherited metabolic disorders. Inborn errors of metabolism are present at birth, and most cause disturbances of the nervous system, although they may not manifest until childhood or even adulthood. Defects in amino acid and lipid metabolism are among the most common.

TABLE 17-4 Inherited Metabolic Disorders of the Central Nervous System Age of Onset Neonatal period Early infancy

Disorder Pyridoxine dependency, galactosemia, urea cycle defects, maple syrup urine disease and its variant, phenylketonuria (PKU), Menkes' kinky hair syndrome

Tay-Sachs disease and its variants, infantile Gaucher's disease, infantile Niemann-Pick disease, Krabbe disease (leukodystrophy), Farber lipogranulomatosis, PelizaeusMerzbacher disease and other sudanophilic leukodystrophies, spongy degeneration of central nervous system (Canavan disease), Alexander's disease, Alpers disease, Leigh disease (subacute necrotizing encephalomyelopathy), congenital lactic acidosis, Zellweger encephalopathy, Lowe disease (oculocerebrorenal disease) Late Disorders of amino acid metabolism, metachromatic leukodystrophy, adrenoleukodystrophy, late infantile GM1 gangliosidosis, late infantile Gaucher's and Niemann-Pick infancy and diseases, neuroaxonal dystrophy, mucopolysaccharidosis, mucolipidosis, fucosidosis, mannosidosis, aspartylglycosaminuria, neuronal ceroid lipofuscinoses (Janskyearly Bielschowsky disease, Batten's disease, Vogt-Spielmeyer disease, neuronal ceroid lipofuscinosis), Cockayne's syndrome, ataxia telangiectasia childhood Later Progressive cerebellar ataxias of childhood and adolescence, hepatolenticular degeneration (Wilson's disease), Hallervorden-Spatz disease, Lesch-Nyhan syndrome, Aicardichildhood Goutieres syndrome, progressive myoclonus epilepsies, homocystinuria, Fabry's disease and adolescence

Data from Volpe, J.J. (2008). Neurology of the newborn (5th ed.). Philadelphia: Saunders. For information regarding screening and parent education, see Medical Home Portal at http://www.medicalhomeportal.org.

Defects in Amino Acid Metabolism Biochemical defects in amino acid metabolism include (1) those in which the transport of an amino acid is impaired, (2) those involving an enzyme or cofactor deficiency, and (3) those encompassing certain chemical components, such as branched-chain or sulphur-containing amino acids. Most of these disorders are caused by genetic defects resulting in lack of a normal protein and absence of enzymatic activity.

Phenylketonuria. Phenylketonuria (PKU) is an example of an inborn error of metabolism characterized by phenylalanine hydroxylase deficiency and the inability of the body to convert the essential amino acid phenylalanine to tyrosine (Figure 17-7). PKU is an autosomal recessive inborn error of metabolism characterized by mutations of the phenylalanine hydroxylase (PAH) gene. PKU has an incidence of 1 per 12 000 live births in North America.31,32

FIGURE 17-7

Metabolic Error and Consequences in Phenylketonuria. (From Hockenberry, M.J., & Wilson, D. [2015]. Wong's nursing care of infants and children [10th ed.]. St. Louis: Mosby.)

Most natural food proteins contain about 15% phenylalanine, an essential amino acid. Phenylalanine hydroxylase controls the conversion of this essential amino acid to tyrosine in the liver. The body uses

tyrosine in the biosynthesis of proteins, melanin, thyroxine, and the catecholamines in the brain and adrenal medulla. Phenylalanine hydroxylase deficiency causes an accumulation of phenylalanine in the serum. Elevated phenylalanine levels result in developmental abnormalities of the cerebral cortical layers, defective myelination, and cystic degeneration of the grey and white matter. Unfortunately, brain damage occurs before the metabolites can be detected in the urine, and damage continues as long as phenylalanine levels remain high. Nonselective newborn screening is used to detect PKU in Canada and in more than 30 other countries. Treatment, consisting of reduction of dietary phenylalanine (PKU diet), is effective and allows for normal development. Supplementation with other essential amino acids and nutrients is required to promote adequate growth and development. Mutations in the PAH gene are by far the most common cause of PKU, although there are other types of PKU as well. In one such variation, there is impaired synthesis of cofactors (e.g., tetrahydrobiopterin [BH4]), which contributes to elevated levels of phenylalanine. Individuals with impaired synthesis of BH4 have a positive response when sapropterin (Kuvan), a synthetic form of tetrahydrobiopterin, is included in their treatment.33

Storage Diseases Disorders of lipid metabolism are termed lysosomal storage diseases because each disorder in this group can be traced to a missing lysosomal enzyme. Lysosomal storage disorders are rare and include more than 50 known genetic disorders. The prevalence of lysosomal storage disorders ranges from 1 : 50 000 births to 1 : 4 000 000 births.1,34 These disorders cause an excessive accumulation of a particular cell product, occurring in the brain, liver, spleen, bone, and lung, and thus involving several organ systems. Generally, these disorders are not included in newborn screening. Some of these disorders may be treated with enzyme replacement therapy.35 Perhaps the best known of the lysosomal storage disorders is TaySachs disease (GM2 gangliosidosis), an autosomal recessive disorder (HexA gene on chromosome 15) caused by deficiency of the lysosomal enzyme hexosaminidase A (HexA), an enzyme that degrades GM2 gangliosides (fatty acids) within nerve cell lysosomes. Approximately 80% of individuals diagnosed are of Jewish ancestry, although sporadic cases appear in the non-Jewish population. Onset of this disease usually occurs when the infant is 4 to 6 months old. Symptoms of Tay-Sachs include an exaggerated startle response to loud noise, seizures, developmental regression, dementia, and blindness. Death from this disease is almost universal and occurs by 5 years of age. Screening for carriers of the gene defect concomitant with counselling to prevent disease transmission is possible.36

Quick Check 17-3 1. List three types of cerebral palsy. 2. Why does failure to metabolize phenylalanine produce such widespread and devastating effects on development?

Acute Encephalopathies Intoxications of the Central Nervous System Medication-induced encephalopathies must always be considered a possibility in the child with unexplained neurological changes. Such encephalopathies may result from accidental ingestion, therapeutic overdose, intentional overdose, or ingestion of environmental toxins (the most commonly ingested poisons are listed in Table 17-5). Approximately 900 children are hospitalized, and approximately 3 children die annually in Canada as a result of unintentional poisoning.37,38 TABLE 17-5 Common Poisons Pharmacological Agents

Heavy Metals

Miscellaneous Agents

Acetaminophen Amphetamines Anticonvulsants Antidepressants Antihistamines Atropine Barbiturates Methadone Phencyclidine Salicylates Tranquilizers

Lead Acute exposure Chronic exposure Mercury Thallium Arsenic Iron supplements

Botulinum toxin Alcohols Ethyl Isopropyl Methyl Pesticides Organophosphates Chlorinated hydrocarbons Mushrooms Venoms Snakebite Tick paralysis Ethylene glycol Furniture polish Paint solvents

Data from Shannon, M.W., Borron, S.W., & Burns, M. (2007). Haddad and Winchester's clinical management of poisoning and drug overdose (4th ed.). Philadelphia: Saunders; Swaiman, K.F., Ashwal, S., Ferriero, D.M., et al. (2012). Pediatric neurology: Principles and practice (5th ed., Vol 2). St. Louis: Mosby.

Lead poisoning results in high blood levels of lead. If lead poisoning is untreated, lead encephalopathy results and is responsible for serious and irreversible neurological damage. Those at greatest risk are children ages 2 to 3 years and children prone to the practice of pica—the habitual, purposeful, and compulsive ingestion of non-food substances, such as clay, soil, and paint chips or paint dust. Lead intoxication also may occur from chronic exposure to lead in cosmetics, inhalation of gasoline vapors, and ingestion of airborne lead.39 National statistics on current blood lead levels in Canadian children are not available. However, in the United States, an estimated 535 000 children 1 to 5 years of age (2.2% of children 1 month to 5 years of age) have excessive amounts of lead in their blood.40,41 Data from one Canadian study revealed that Indigenous infants had greater prenatal exposure to lead.41 The Canadian Family Physician has published recommendations for the treatment of lead poisoning, depending on blood lead levels.42 Fetal neurotoxicity occurs with maternal lead exposure, particularly during the first trimester.43

Infections of the Central Nervous System Meningitis is an infection of the meninges and subarachnoid space of the brain and spinal cord, whereas the word encephalitis reflects inflammation within the brain. In many infections of the meninges, encephalitis also is present and the term meningoencephalitis is used. The origin of such inflammation and acute encephalopathy can be caused by bacteria, viruses, or other microorganisms. Aseptic meningitis has no evidence of bacterial infection but may be associated with viral infection, systemic disease, or medications.

Bacterial Meningitis Acute bacterial meningitis is one of the most serious infections to which infants and children are susceptible. Between 2006 and 2011, approximately 196 cases of bacterial meningitis was reported annually in Canada, with an incidence of 0.58 cases per 100 000 population and a fatality ratio of 8.1%. The highest incidence rates were among infants aged less than 1 year.44 The introduction of conjugate vaccines against Haemophilus influenzae type B, Streptococcus pneumoniae, and Neisseria meningitidis (meningococcus) has decreased the incidence of bacterial meningitis.45 A vaccine for serogroup B N. meningitidis has been newly licensed in Canada but is not recommended for routine immunization programs for infants, children, adolescents, or adults.46 Group B Streptococcus causes lethal meningitis and sepsis in neonates and is transmitted to the child from the mother's birth canal. S. pneumoniae is the most common microorganism in children 1 to 23 months of age. Staphylococcal or streptococcal meningitis can occur in children of any age but shows a predilection for children who have had neurosurgery, skull fracture, or a complication of systemic bacterial infection. Infections that originate in the middle ear, sinuses, or mastoid cells also may lead to S. pneumoniae infection in children. Children with sickle cell disease or who have had a splenectomy are particularly at high risk for infection.47 Escherichia coli and group B beta-hemolytic streptococci are the most common causes of meningitis in the newborn period. The second most common microorganism causing bacterial meningitis, particularly in children younger than 4 years, is Neisseria meningitidis (meningococcus) and it has the potential to occur in epidemics. Approximately 2 to 5% of healthy children are carriers of N. meningitidis. As the

incidence of N. meningitidis infection increases in adolescence and with crowded environments, such as in student residences and among military personnel, it is recommended that all individuals 11 to 18 years of age receive two immunizations against this pathogen.48 Pathogens enter the nervous system by direct extension from a contiguous source (e.g., paranasal sinuses or mastoid cells) or, more commonly, by hematogenous spread (e.g., infective endocarditis, pneumonia, neurosurgical procedures, severe burns). Pathogens then cross the blood–brain barrier, enter the CSF, and multiply. Bacterial toxins increase cerebrovascular permeability, causing alterations in blood flow and edema. Increased cranial pressure may intensify further by obstruction to the CSF circulation. Herniation of the brainstem causes death. Acute bacterial meningitis often is preceded by an upper respiratory tract or a gastro-intestinal infection. Inflammation leads to the general symptoms of fever, headache, vomiting, and irritability and the CNS symptoms of photophobia, nuchal and spinal rigidity, decreased level of consciousness, and seizures. Irritation of the meninges and spinal roots causes pain and resistance to neck flexion (nuchal rigidity), a positive Kernig sign (resistance to knee extension in the supine position with the hips and knees flexed against the body), and a positive Brudzinski sign (flexion of the knees and hips when the neck is flexed forward rapidly). With severe meningeal irritation, the child may demonstrate opisthotonic posturing (rigid arching of the back with the head extended). Infants may have bulging fontanelles. Meningococcal meningitis can produce a characteristic petechial rash. Viral meningitis (aseptic or nonpurulent meningitis) may result from a direct infection of a virus, or it may be secondary to disease, such as measles, mumps, herpes, or leukemia. The hallmark of viral meningitis is a mononuclear response in the CSF and the presence of normal glucose levels as well. The clinical manifestations are similar to those in bacterial meningitis, although usually milder. Viral encephalitis in children is similar to viral encephalitis in adults (see Chapter 16, Figure 16-13) and can be difficult to distinguish from viral meningitis. Viruses can directly invade the brain, causing inflammation; or postinfectious encephalitis can develop as a result of an autoimmune response.49 Encephalopathy resulting from human immunodeficiency virus (HIV) is discussed in Chapter 8 and Chapter 16.

Cerebrovascular Disease in Children Perinatal Stroke Perinatal arterial ischemic stroke is estimated at 1 in 4 000 live births and is a leading cause of perinatal brain injury, cerebral palsy, and lifelong disability. Although a cause for perinatal stroke is usually not found, clotting abnormalities may make the child prone to further vascular events.

Childhood Stroke Childhood stroke occurs in 1.3 to 1.6 per 100 000 children per year and may be divided into two categories: ischemic and hemorrhagic.50,51 Ischemic (occlusive) stroke is rare in children and may result from embolism, sinovenous thrombosis, or congenital or iatrogenic narrowing of vessels leading to decreased flow of blood and oxygen to areas of the brain. Children with arterial ischemic stroke do not have the typical adult risk factors of atherosclerosis and hypertension. Risk factors include cardiac diseases, hematological and vascular disorders, and infection. Approximately 40% of children with acute ischemic stroke have no identifiable risk factors.52 Sickle cell disease, cerebral arteriopathies, and cardiac anomalies are the common disorders associated with arterial ischemic stroke.53 Hemorrhagic stroke (intracranial hemorrhage) is most commonly caused by bleeding from congenital cerebral arteriovenous malformations and is rare in children younger than 19 years. Intraventricular hemorrhage associated with premature birth is related to immature blood vessels and unstable blood pressure. There is a high risk of developing posthemorrhagic hydrocephalus.54 Moyamoya disease is a rare, chronic, progressive vascular stenosis of the circle of Willis. There is obstruction of arterial flow to the brain and the development of basal arterial collateral vessels that vascularize hypoperfused brain distal to the occluded vessels.55 Moyamoya means a “puff of smoke” in Japanese. The disease is idiopathic or associated with other disorders (moyamoya syndrome). Clinical presentation varies according to the vessels involved, the cause of the disease, and the age of the individual. Symptoms include hemiplegia, weakness, seizures, headaches, high fever, nuchal rigidity, hemianopia, sensory changes, facial palsy, and temporary aphasia. Obtaining a thorough history of evolving symptoms and risk factors is important for diagnosis. Laboratory studies may be indicated. Neuroimaging studies assist in determining the cause of the disease. Surgery is an option for treatment, and anticoagulants and antithrombotics may be used in selected cases.

Epilepsy and Seizure Disorders in Children The incidence of epilepsy varies greatly with age, geographical location, and study design. In Canada, 44% of children diagnosed with epilepsy are under the age of 5 years, 55% are under the age of 10 years, and 75 to 85% are under the age of 18 years. Approximately 15 500 people in Canada are newly diagnosed each year.56 Seizures are the abnormal discharge of electrical activity within the brain. When a sufficient number of neurons become overexcited, they discharge abnormally, which sometimes results in clinical manifestations (seizures) with alterations in motor function, sensation, autonomic function, behaviour, and consciousness. The manifestations depend on the site and spread of abnormal electrical activity. If a child has more than one unprovoked seizure, that child is said to have epilepsy, although there are a few exceptions—one example being febrile seizures. Seizures may result from diseases that are primarily neurological (CNS) or are systemic and affect CNS function secondarily (such as diabetes). Seizures can be caused by structural abnormalities of the brain, hypoxia, intracranial hemorrhage, CNS infection, traumatic injury, electrolyte imbalance, or inborn metabolic disturbances. Febrile seizures occur in about 2 to 5% of children between ages 6 months and 5 years; they are benign and the most common type of childhood seizure. Seizures are sometimes clearly familial. Often the cause of epilepsy is unknown and presumed to have a genetic basis. Table 17-6 summarizes the major types of seizure disorders found in children (see also Chapter 15 and Table 15-14).

TABLE 17-6 Major Types of Seizure Disorders Found in Children Disorder Manifestations Generalized Seizure Tonic-clonic Atonic Myoclonic Absence seizure Partial (Focal) Seizure Simple Complex Epilepsy Syndromes Infantile spasms (West's syndrome) LennoxGastaut syndrome Juvenile myoclonic epilepsy Benign rolandic epilepsy Status Epilepticus Febrile Seizure

First clinical manifestations indicate that seizure activity starts in or involves both cerebral hemispheres; consciousness may be impaired; bilateral manifestations; may be preceded by an aura Musculature stiffens, then intense jerking as trunk and extremities undergo rhythmic contraction and relaxation Sudden, momentary loss of muscle tone; drop attacks Sudden, brief contractures of a muscle or group of muscles Brief loss of consciousness with minimal or no loss of muscle tone; may experience 20 or more episodes a day lasting approximately 5 to 10 sec each; may have minor movement, such as lip smacking, twitching of eyelids Seizure activity that begins with and usually is limited to one part of left or right hemisphere; an aura is common

Seizure activity that occurs without loss of consciousness Seizure activity that occurs with impairment of consciousness Seizure disorders that display a group of signs and symptoms that occur collectively and characterize or indicate a particular condition Form of epilepsy with episodes of sudden flexion or extension involving neck, trunk, and extremities; clinical manifestations range from subtle head nods to violent body contractions (jackknife seizures); onset between 3 and 12 months of age; may be idiopathic, genetic, result of metabolic disease, or in response to central nervous system insult; spasms occur in clusters of 5 to 150 times per day; EEG shows large-amplitude, chaotic, and disorganized pattern called hypsarrhythmia Epileptic syndrome with onset in early childhood, 1 to 5 years of age; includes various generalized seizures—tonic-clonic, atonic (drop attacks), akinetic, absence, and myoclonic; EEG has characteristic “slow spike and wave” pattern; results in intellectual disability and delayed psychomotor developments Onset in adolescence; multifocal myoclonus; seizures often occur early in morning, aggravated by lack of sleep or after excessive alcohol intake; occasional generalized convulsions; require long-term medication treatment Epileptic syndrome typically occurring in the preadolescent age (6 to 12 years); strong association with sleep (seizures typically occur a few hours after sleep onset or just before waking in morning); complex partial seizures with orofacial signs (drooling, distortion of facial muscles); characteristic EEG with centrotemporal (Rolandic fissure) spikes Continuing or recurring seizure activity in which recovery from seizure activity is incomplete; unrelenting seizure activity can last 30 min or more; medical emergency that requires immediate intervention Seizure activity associated with a high body temperature but without any serious underlying health issue occurring most commonly in children between the ages of 6 months and 5 years

EEG, electroencephalogram.

Childhood Tumours Brain Tumours Brain tumours are the most common solid tumour and second most common primary neoplasm in children. In Canada, CNS tumours account for nearly 20% of all childhood cancers under the age of 15 years, with approximately 94% of CNS cancers occurring in the brain. About 3% are malignancies of the cerebral meninges, and the remainder occur in the spinal cord or cranial nerves.57 Five-year survival for childhood brain tumours is about 73%, varying significantly by tumour type, although there is often significant morbidity. Primary brain tumours arise from brain tissue and do not metastasize outside the brain. The cause of brain tumours is unknown, although genetic, environmental, and immune factors have been investigated. Exposure to radiation therapy has been the only environmental factor consistently related to the development of brain tumours.58 Brain tumours can arise from any CNS cell, and tumours are classified by cell type. The types and characteristics of childhood brain tumours are summarized in Table 17-7. Medulloblastoma, ependymoma, astrocytoma, brainstem glioma, craniopharyngioma, and optic nerve glioma constitute approximately 75 to 80% of all pediatric brain tumours. Germ cell tumours are rare. Two thirds of all pediatric brain tumours in children are located in the posterior fossa (Figure 17-8). Treatment strategies and prognoses vary, depending on diagnosis. TABLE 17-7 Brain Tumours in Children Type

Characteristics

Astrocytoma

Arises from astrocytes, often in cerebellum or lateral hemisphere Slow growing, solid or cystic Often very large before diagnosed Varies in degree of malignancy Arises from optic chiasm or optic nerve (association with neurofibromatosis type 1) Slow-growing, low-grade astrocytoma Often located in cerebellum, extending into fourth ventricle and spinal fluid pathway Rapidly growing malignant tumour Can extend outside central nervous system Arises from pons Numerous cell types Compresses cranial nerves V through X Arises from ependymal cells lining ventricles Circumscribed, solid, nodular tumours Arises near pituitary gland, optic chiasm, and hypothalamus Cystic and solid tumours that affect vision, pituitary, and hypothalamic functions Arises from germ cells and is most common in pineal and suprasellar region, usually occurring during adolescence

Optic nerve glioma Medulloblastoma (infiltrating glioma)

Brainstem glioma

Ependymoma Craniopharyngioma Germ cell tumour

FIGURE 17-8 Location of Brain Tumours in Children.

Signs and symptoms of brain tumours in children vary from generalized and vague to localized and related specifically to an anatomical area. Signs of increased ICP may occur, including headache, vomiting, lethargy, and irritability. If a young child complains of repeated and worsening headache, a thorough investigation should take place because headache is an uncommon complaint in young children. Headache caused by increased ICP usually is worse in the morning and gradually improves during the day when the child is upright and venous drainage is enhanced. The frequency of headache and other symptoms increases as the tumour grows. Irritability or possible apathy and increased somnolence also may result. Like headache, vomiting occurs more commonly in the morning. Often it is not preceded by nausea and may become projectile, differing from a gastro-intestinal disturbance in that the child may be ready to eat immediately after vomiting. Other signs and symptoms include increased head circumference with bulging fontanelles in the child younger than 2 years, cranial nerve palsies, and papilledema (Box 17-1).

Box 17-1

Clinical Manifestations of Brain Tumours Headache Recurrent and progressive In frontal or occipital area Worse on arising; pain lessens during the day Intensified by lowering head and straining, such as when defecating, coughing, sneezing

Vomiting With or without nausea or feeding Progressively more projectile More severe in morning Relieved by moving and changing position

Neuromuscular Changes Uncoordination or clumsiness Loss of balance (use of wide-based stance, falling, tripping, banging into object) Poor fine motor control Weakness Hyporeflexia or hyper-reflexia Positive Babinski sign Spasticity Paralysis

Behavioural Changes Irritability Decreased appetite Failure to thrive Fatigue (frequent naps) Lethargy Coma Bizarre behaviour (staring, automatic movements)

Cranial Nerve Neuropathy Cranial nerve involvement varies according to tumour location Most common signs: Head tilt Visual defects (nystagmus, diplopia, strabismus, episodic “greying out” of vision, and visual field defects)

Vital Sign Disturbances Decreased pulse and respiratory rates Increased blood pressure Decreased pulse pressure Hypothermia or hyperthermia

Other Signs Seizures Cranial enlargement* Tense, bulging fontanelle at rest* Separating suture* Nuchal rigidity Papilledema (edema of optic nerve)

*

Present only in infants and young children.

From Hockenberry, M.N. (2007). Wong's essentials of pediatric nursing (7th ed.). St. Louis: Mosby.

Localized findings relate to the degree of disturbance in physiological functioning in the area where the

tumour is located. Children with infratentorial tumours exhibit localized signs of impaired coordination and balance, including ataxia, gait difficulties, truncal ataxia, and loss of balance. Medulloblastoma occurs as an invasive malignant tumour that develops in the vermis of the cerebellum and may extend into the fourth ventricle. Ependymoma develops in the fourth ventricle and arises from the ependymal cells that line the ventricular system. Because both tumours are located in the posterior fossa region along the midline, presenting signs and symptoms are similar and are usually related to hydrocephalus and increased ICP. In contrast, cerebellar astrocytomas are located on the surface of the right or left cerebellar hemisphere and cause unilateral symptoms (occurring on the same side as the tumour), such as head tilt, limb ataxia, and nystagmus. Brainstem gliomas often cause a combination of cranial nerve involvement (facial weakness, limitation of horizontal eye movement), cerebellar signs of ataxia, and corticospinal tract dysfunction. Increased ICP generally does not occur. The area of the sella turcica, the structure containing the pituitary gland, is the site of several childhood brain tumours; most common of this group is the craniopharyngioma. This tumour originates from the pituitary gland or hypothalamus. Usually slow growing, it may be quite large by the time of diagnosis. Symptoms include headache, seizures, diabetes insipidus, early onset of puberty, and growth delay. Other tumours located in this region of the brain include optic gliomas. Optic nerve gliomas are associated with neurofibromatosis type 1, a neurocutaneous condition characterized by café-au-lait macules on the skin and benign tumours of the skin. Tumours that involve the optic tract may cause complete unilateral blindness and hemianopia of the other eye. Optic atrophy is another common finding. Supratentorial tumours of the cerebral hemispheres are more common in neonates and adolescents.59

Embryonal Tumours Neuroblastoma Neuroblastoma is an embryonal tumour originating outside the CNS in the developing sympathetic nervous system (sympathetic ganglia and the adrenal medulla). Because neuroblastoma involves a defect of embryonic tissue and is the most common cancer in infants less than 1 year of age, 75% of neuroblastomas are found before the child is 5 years old and is rare after 10 years of age. Occasionally, these tumours have been diagnosed at birth with metastasis apparent in the placenta. Approximately 50 to 70 new cases of neuroblastoma are diagnosed every year in Canada. Although it accounts for only about 6% of pediatric malignancies, neuroblastoma causes about 15% of cancer deaths in children.60,61 Neuroblastoma is the most common and immature form of the sympathetic nervous system tumours. Areas of necrosis and calcification often are present in the tumour. More than with any other cancer, neuroblastoma has been associated with spontaneous remission, commonly in infants. Prognosis is worse for children older than 2 years of age with disseminated disease.62 Although familial tendency has been noted in individual cases, a nonfamilial or sporadic pattern is found in most children with neuroblastoma. Familial cases of neuroblastoma are considered to have an autosomal dominant pattern of inheritance (mechanisms of inheritance are discussed in Chapter 2). The most common location of neuroblastoma is in the retroperitoneal region (65% of cases), most often the adrenal medulla. The tumour is evident as an abdominal mass and may cause anorexia, bowel and bladder alteration, and sometimes spinal cord compression. The second most common location of neuroblastoma is the mediastinum (15% of cases), where the tumour may cause dyspnea or infection related to airway obstruction. Less commonly, neuroblastoma may arise from the cervical sympathetic ganglion (3 to 4% of cases). Cervical neuroblastoma often causes Horner's syndrome, which consists of miosis (pupil contraction), ptosis (drooping eyelid), enophthalmos (backward displacement of the eyeball), and anhidrosis (sweat deficiency). Neuroblastoma rarely presents with a cerebellar neurological syndrome called opsoclonus-myoclonus syndrome.63 Children develop conjugate chaotic eye movements, jerky movements of the limbs, and ataxia. A number of systemic signs and symptoms are characteristic of neuroblastoma, including weight loss, irritability, fatigue, and fever. Intractable diarrhea occurs in 7 to 9% of children and is caused by tumour secretion of a hormone called vasoactive intestinal polypeptide. More than 90% of children with neuroblastoma have increased amounts of catecholamines and

associated metabolites in their urine. High levels of urinary catecholamines and serum ferritin are associated with a poor prognosis.

Retinoblastoma Retinoblastoma is a rare congenital eye tumour of young children that originates in the retina of one or both eyes (Figure 17-9). Two forms of retinoblastoma are exhibited: inherited and acquired. The inherited form of the disease generally is diagnosed during the first year of life. The acquired disease most commonly is diagnosed in children 2 to 3 years of age and involves unilateral disease.64

FIGURE 17-9

Retinoblastoma. The tumour occupies a large portion of the inside of the eye globe. (From Damjanov, I. [2006]. Pathology for the health professions [3rd ed.]. St. Louis: Saunders. Courtesy Dr. Walter Richardson and Dr. Jamsheed Khan, Kansas City, KS.)

Approximately 40% of retinoblastomas are inherited as an autosomal dominant trait with incomplete penetrance (see Figure 2-22). The remaining 60% are acquired. In the early 1970s, Knudson proposed the “two-hit” hypothesis to explain the occurrence of both hereditary and acquired forms of the disease.65 This hypothesis predicts that two separate transforming events or “hits” must occur in a normal retinoblast cell to cause the cancer. Further, it proposes that in the inherited form, the first hit or mutation occurs in the germ cell (inherited from either parent), and the mutation is contained in every cell of the child's body. Only a second, random mutation in a retinoblast cell is needed to transform that cell into cancer. Multiple tumours are observed in the inherited form because these second mutations are likely to occur in several of the approximately 1 to 2 million retinoblast cells. In contrast, the acquired form of retinoblastoma requires two independent hits or mutations to occur in the same somatic cell (after the egg is fertilized) for the transformation to cancer. As a result, the acquired form of retinoblastoma is much less likely to occur. Figure 17-10 illustrates the two-mutation model for these two patterns of mutation.

FIGURE 17-10 The Two-Mutation Model of Retinoblastoma Development. In inherited retinoblastoma, the first mutation is transmitted through the germline of an affected parent. The second mutation occurs somatically in a retinal cell, leading to development of the tumour. In sporadic retinoblastoma, development of a tumour requires two somatic mutations.

The primary sign of retinoblastoma is leukocoria, a white pupillary reflex (white reflex) also called cat's eye reflex, which is caused by the mass behind the lens (see Figure 17-9). This easy-to-identify sign can be missed. Other signs and symptoms include strabismus; a red, painful eye; and limited vision. Because retinoblastoma is a treatable tumour, dual priorities are saving the child's life and restoring useful vision. The prognosis for most children with retinoblastoma is excellent, with a greater than 90% long-term survival.

Quick Check 17-4 1. Why are the principal symptoms of brain tumours in children related to brainstem function?

Did You Understand? Development of the Nervous System in Children 1. The growth and development of the brain occur most rapidly from the third month of gestation through the first year of life. 2. The bones of the skull are separated at the suture lines; and the wide, membranous junctions of the suture lines (known as fontanelles) allow for brain growth and close by 18 months of age.

Structural Malformations 1. Spina bifida (split spine) is the most common disorder of neural tube closure and includes anencephaly (absence of part of the skull and brain), encephalocele (herniation of the meninges and brain through a skull defect), meningocele (a saclike meningeal cyst that protrudes through a vertebral defect), and myelomeningocele. 2. Premature closure of one or more of the cranial sutures causes craniostenosis and prevents normal skull expansion, resulting in compression of growing brain tissue. 3. Microcephaly is lack of brain growth with delayed mental and motor development. 4. Congenital hydrocephalus results from overproduction, impaired absorption, or blockage of circulation of cerebrospinal fluid. Dandy-Walker malformation is caused by cystic dilation of the fourth ventricle and aqueductal compression.

Alterations in Function: Encephalopathies 1. Static encephalopathies are nonprogressive disorders of the brain that can occur during gestation, birth, or at any time during childhood and can be caused by endogenous or exogenous factors. 2. Cerebral palsy can be caused by prenatal cerebral hypoxia or perinatal trauma. Symptoms may include motor dysfunction (including increased muscle tone, increased reflexes, and loss of fine motor coordination), intellectual disability, seizure disorders, or developmental delays. 3. Inherited metabolic disorders that damage the nervous system include defects in amino acid metabolism (phenylketonuria) and lipid metabolism (Tay-Sachs disease) and result in abnormal behaviour, seizures, and deficient psychomotor development. 4. Accidental poisonings from a variety of toxins can cause serious neurological damage. 5. Bacterial meningitis is commonly caused by Neisseria meningitidis or Streptococcus pneumoniae and may result from respiratory tract or gastro-intestinal infections; symptoms include fever, headaches, photophobia, seizures, rigidity, and stupor. 6. Viral meningitis may result from direct infection or be secondary to a systemic viral infection (e.g., measles, mumps, herpes, or leukemia).

Cerebrovascular Disease in Children 1. Ischemic (occlusive) stroke is rare in children but can occur from embolism, sickle cell disease, cerebral arteriopathies, and cardiac anomalies. 2. Hemorrhagic stroke can occur in association with immature blood vessels associated with prematurity or congenital cerebral arteriovenous malformations. 3. Moyamoya disease is a rare, chronic, progressive vascular stenosis of the circle of Willis that obstructs arterial blood flow to the brain. 4. Seizure disorders involve abnormal discharges of electrical activity within the brain. They are associated with numerous nervous system disorders and more often are a generalized rather than

a partial type of seizure. 5. Generalized seizures include tonic-clonic, atonic, myoclonic, and absence seizures. 6. Partial seizures suggest more localized brain dysfunction. 7. Febrile seizures are provoked and usually limited to children between the ages of 6 months and 5 years. They are benign in nature and the most common type of childhood seizure.

Childhood Tumours 1. Brain tumours are the most common tumours of the nervous system and the second most common type of childhood cancer. 2. Tumours in children most often are located below the tentorial plate (infratentorial tumours). 3. Symptoms of brain tumours may be generalized or localized. The most common general symptoms are the result of increased intracranial pressure and include headache, irritability, vomiting, somnolence, and bulging of fontanelles. 4. Localized signs of infratentorial tumours in the cerebellum include impaired coordination and balance. Cranial nerve signs occur with tumours in or near the brainstem. 5. Signs and symptoms associated with brain tumours and the degree of physiological functioning disturbance depend on the specific location of the tumour. 6. Neuroblastoma is an embryonal tumour of the sympathetic nervous system and can be located anywhere there is sympathetic nervous tissue. Symptoms are related to tumour location and size of metastasis. 7. Retinoblastoma is a congenital eye tumour that has two forms: inherited and acquired.

Key Terms Acute bacterial meningitis, 435 Anencephaly, 429 Aseptic meningitis, 435 Ataxic cerebral palsy, 433 Brainstem glioma, 438 Cerebellar astrocytoma, 438 Cerebral palsy, 433 Chiari II malformation (Arnold-Chiari malformation), 429 Congenital hydrocephalus, 432 Cortical dysplasia, 431 Craniopharyngioma, 438 Craniostenosis, 430 Cyclopia, 428 Dandy-Walker malformation (DWM), 432 Dystonic cerebral palsy, 433 Encephalitis, 435 Encephalocele, 429 Encephalopathy, 433 Ependymoma, 437 Epilepsy, 436 Extrapyramidal/nonspastic cerebral palsy, 433 Fontanelle, 426 Hemorrhagic stroke (intracranial hemorrhage), 435 Ischemic (occlusive) stroke, 435 Lead poisoning, 435 Lysosomal storage disease, 434 Macewen sign (“cracked pot” sign), 432 Medulloblastoma, 437 Meningitis, 435 Meningocele, 429 Microcephaly, 431 Moyamoya disease, 436 Myelomeningocele, 429 Neural tube defect (NTD), 427 Neuroblastoma, 438 Optic glioma, 438 Phenylketonuria (PKU), 433 Pica, 435 Pyramidal/spastic cerebral palsy, 433 Retinoblastoma, 439 Spina bifida (split spine), 428 Spina bifida occulta, 430 Tay-Sachs disease (GM2 gangliosidosis), 434 Tethered cord syndrome, 430 Viral encephalitis, 435 Viral meningitis (aseptic or nonpurulent meningitis), 435

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Maintenance of H2O in extracellular compartment; they act as buffers and function in membrane excitability

Sodium (Na+) Potassium (K+) Calcium (Ca++) Magnesium (Mg++) Chloride (Cl−) Bicarbonate ( )

136–145 mmol/L 3.5–5.0 mmol/L 2.25–2.75 mmol/L 0.74–1.07 mmol/L 98–106 mmol/L 21–28 mmol/L

Phosphate (PO43+)

0.97–1.45 mmol/L

Proteins Albumins Globulins Fibrinogen Transferrin

64–83 g/L 35–50 g/L 23–34 g/L 5.8–11.8 mcmol/L Adult male: 2–5.0 g/L Adult female: 1.9–4.4 g/L Male: 12–300 mcg/L Female: 10–150 mcg/L

Provision of colloid osmotic pressure of plasma; they act as buffers (see text for other functions)

35–45 mm Hg

By-product of oxygenation; most CO content is from

PaO2 80–100 mm Hg (arterial); PvO2 40–50 mm Hg (venous) 0.64 mmol/L

Oxygenation

Ferritin Gases Carbon dioxide (CO2) content

and acts as a buffer

2

Oxygen (O2) Nitrogen gas (N2) Nutrients Glucose and other carbohydrates Total amino acids Total lipids Cholesterol Individual vitamins Individual trace elements Iron Waste Products Urea (BUN) Creatinine (from creatine) Uric acid (from nucleic acids) Indirect bilirubin (from heme) Individual hormones

By-product of protein catabolism Provide nutrition and substances for tissue repair

5.6 mmol/L 2.2 mmol/L 7.5 mmol/L 38°C [100.4°F], drenching night sweats, or weight loss >10% of body weight

a

The number of lymph node regions involved may be indicated by a subscript (e.g., II3).

From National Comprehensive Cancer Network. (2014). Hodgkin lymphoma. In NCCN practice guidelines, Version 2. 2014: Hodgkin lymphoma (originally adapted from Carbono, P.P., Kaplan, H.S., Musshoff, K., et al. [1971]. Cancer Res, 31[11], 1860–1861).

The effectiveness of treatment is related to the age, gender, and general health of the individual; signs and symptoms; stage of the disease; blood test results; type of HL; and classification of the disease as recurrent or progressive. Adult HL can usually be cured with early diagnosis and treatment.51 Three types of treatment are used: chemotherapy, radiation therapy, and surgery. Treatment for pregnant women includes watchful waiting and steroid therapy. Newer treatments undergoing testing include chemotherapy and radiation therapy with stem cell transplant and monoclonal antibody therapy.51 Treatment with chemotherapy or radiation therapy, or both, may increase the risk for secondary cancers, cardiovascular disease, and other health problems for many months or years after treatment.

Non-Hodgkin's Lymphoma Non-Hodgkin's lymphoma (NHL) is not a single disease, but a heterogeneous group of proliferative lymphoid tissue neoplasms with differing clinical patterns of behaviour and responses to treatment. The generic classification of NHL that was used in the past has been reclassified into (1) B-cell neoplasms, a group that consists of a variety of lymphomas including myelomas that originate from B cells at various stages of differentiation; and (2) T-cell neoplasms and NK-cell neoplasms, a group that includes lymphomas that originate from either T or NK cells. These cancers are differentiated from HL by a lack of RS cells and other cellular changes not characteristic of HL. In 2017, it was estimated that 8 300 Canadians would be diagnosed with NHL, and 2 700 Canadians would die from the disease.35 The median age of diagnosis is 67 years and the highest incidences of NHL are in North America, Europe, Oceania, and several African countries.53 The occurrence of NHL is higher in men than in women. For unknown reasons, incidence increased in many high-income countries between the 1950s and 1990s and no further increase has been observed during the last decade.53 Part of the increased incidence has been attributed to diagnostic improvements as well as AIDS-related cancers following the HIV epidemic.53 Conversely, the mortality has risen at a slower rate. It is thought that newer treatment modalities are improving survival rates. Pathophysiology NHL is best described as a progressive clonal expansion of B cells, T cells, or NK cells. B cells account for 85 to 90% of NHLs, with most of the remainder being T cells and rarely NK cells. Oncogenes may be activated by chromosomal translocations, or the tumour-suppressor loci may be inactivated by deletion or mutation of chromosomes. Certain subtypes may have altered genomes by oncogenic viruses. The various subtypes of NHL may be identified by specific diagnostic markers related to various cytogenetic lesions. The most common type of chromosomal alteration in NHL is translocation, which disrupts the genes encoded at the breakpoints. Unlike HL, NHL spreads in a less predictable way and spreads widely early.36 Diffuse large B-cell lymphoma (DLBCL) is the most common form of NHL. Risk factors for adult NHL include being older, male, or White and having one of the following: being afflicted by certain inherited immune disorders, an autoimmune disease, or HIV/AIDS; exposure to a variety of mutagenic chemicals or certain pesticides; infection with certain cancer-related viruses (e.g., EBV, HIV, human T-cell lymphotropic virus type 1 [HTLV-1]); consumption of a diet high in meats and fat; and use of immunosuppression medications after an organ transplant. Gastric infection with H. pylori

increases the risk for gastric lymphomas. NHL is a disease of middle age, usually found in persons more than 50 years old. Clinical manifestations Clinical manifestations of NHL usually begin as localized or generalized lymphadenopathy, similar to HL. Differences in clinical features are noted in Table 21-8. The cervical, axillary, inguinal, and femoral lymph node chains are the most commonly affected sites. Generally, the swelling is painless and the nodes have enlarged and transformed over a period of months or years. Other sites of involvement are the nasopharynx, GI tract, bone, thyroid, testes, and soft tissue. Some individuals have retroperitoneal and abdominal masses with symptoms of abdominal fullness, back pain, ascites (fluid in the peritoneal cavity), skin rash or itchy skin, fatigue, fever of unknown origin, drenching night sweats, and leg swelling. TABLE 21-8 Clinical Differences Between Non-Hodgkin's Lymphoma and Hodgkin's Lymphoma Characteristics

Non-Hodgkin's Lymphoma

Hodgkin's Lymphoma

Nodal involvement

Multiple peripheral nodes Mesenteric nodes and Waldeyer's tonsillar ring commonly involved Noncontiguous Uncommon Common Rarely localized

Localized to single axial group of nodes (i.e., cervical, mediastinal, para-aortic) Mesenteric nodes and Waldeyer's tonsillar ring rarely involved Orderly spread by contiguity Common Rare Often localized

Spread B symptomsa Extranodal involvement Extent of disease a

Fever, weight loss, night sweats.

Lymphomas are classified as low, intermediate, or high grade. A low-grade lymphoma, which also may be termed indolent, has a slow progression. Individuals with low-grade lymphoma commonly present with a painless, peripheral adenopathy. Spontaneous regression of these nodes may occur, mimicking the presence of an infection. Night sweats with an elevated temperature (more than 38°C [100.4°F]) and weight loss, as well as extranodular involvement, are not commonly present in the early stages but are common in advanced or end-stage disease. Cytopenia, or reduction in the number of blood cells, reflective of bone marrow involvement is often observed. Hepatomegaly is common; however, splenomegaly is present in approximately 40% of individuals. Fatigue and weakness are more prevalent with advanced stages. Intermediate- and high-grade lymphomas, which are more aggressive, have a more varied clinical presentation. A high-grade lymphoma also may be termed aggressive. Evaluation and treatment The primary means for diagnosis of NHL is physical examination and history, blood tests, urine tests, flow cytometry, and bone marrow aspirate and biopsy. A common finding in NHL is noncontiguous lymph node involvement, which is not common in HL. Treatment for NHL is quite diverse and depends on type (B cell or T cell), tumour stage, histological status (low, intermediate, or high grade), symptoms, age, and presence of comorbidities.54 Depending on the type (B cell or T cell) of the tumour, stage of disease, and aggressiveness of the tumour, treatment is usually initiated at the time of diagnosis. However, because treatment is not curative for some low-grade indolent lymphomas that are widely disseminated, observation without treatment may be the most appropriate choice. These indolent tumours are often not symptomatic for the individual and this approach improves quality of life. In some cases, the disease may be so slow growing that treatment is not needed for an extended period of time. Standard treatment for NHL includes radiation therapy, chemotherapy, target therapy (monoclonal antibody therapy, proteasome inhibitor therapy), plasmapheresis (if the blood becomes thick), biological therapy (e.g., interferon), and watchful waiting. Several factors affect prognosis, including the stage of the cancer, the type of NHL, the blood levels of lactate dehydrogenase, the amount of β2-microglobulin in the blood (for Waldenström macroglobulinemia), the age and general health of the patient, and the properties of the lymphoma (i.e., whether it was recently diagnosed or is a recurrence). Indolent NHL types can have a median survival as long as 20 years but are not curable in advanced stages.55 Those with the

aggressive type of NHL have a more limited survival, but a significant number of individuals can achieve a cure with an intensive combination of chemotherapy. With modern treatments for NHL, the overall survival at 5 years for nonaggressive NHL is greater than 60%, and for aggressive types greater than 50%. High-grade NHL is seen with increasing frequency in persons with AIDS and has an extremely poor prognosis. New research suggests that a novel therapeutic approach may hold promise for individuals with chemotherapy-refractory advanced large B-cell lymphoma and indolent B-cell malignancies using engineered T cells that express an anti-CD19 chimeric antigen receptor.56

Burkitt lymphoma. Burkitt lymphoma is a B-cell tumour with unique clinical and epidemiological features. Although more common in Africa, Burkitt lymphoma is not confined to the African continent and is documented in Canada, the United States, Latin America, and other Western countries. Classification of Burkitt lymphoma includes (1) African (endemic) Burkitt lymphoma, (2) sporadic (nonendemic) Burkitt lymphoma, and (3) a subset of aggressive lymphomas in individuals infected with HIV. Burkitt lymphomas, in these classifications, are histologically identical but differ in some genetic, virological, and clinical characteristics.36 Burkitt lymphoma is a fast-growing tumour that often appears as a large tumour mass in the jaw and sometimes the abdomen (Figure 21-14). It is now understood that Burkitt lymphoma is heterogeneous, and pathological confirmation is sometimes challenging.

FIGURE 21-14

Burkitt Lymphoma. Burkitt lymphoma involving the jaw in a young African boy. (Courtesy I. Magrath, MD, Bethesda, MD. From Zitelli, B.J., McIntire, S.C., & Nowalk, A.J. [2012]. Zitelli and Davis' atlas of pediatric physical diagnosis [6th ed.]. Philadelphia: Saunders.)

Pathophysiology Basically, all endemic Burkitt lymphomas are latently infected with EBV, which also is present in about 25% of HIV-associated tumours and 15 to 20% of sporadic cases.36 It is suspected that suppression of the immune system by other illnesses (e.g., HIV infection, chronic malaria) increases the individual's susceptibility to EBV. B cells are particularly sensitive because of specific surface receptors for EBV. As a result, the B cell undergoes chromosomal translocations that result in overexpression of the c-MYC protooncogene and loss of control of cell growth (Figure 21-15). The most common translocation (75% of individuals) is between chromosomes 8 (containing the c-MYC gene) and 14 (containing the immunoglobulin heavy chain genes). When the t(8;14) translocation occurs, the MYC gene becomes regulated by the B-cell immunoglobulin gene (IG) on chromosome 14, and overproduction of MYC protein forces proliferation and blocks cellular differentiation. MYC is a transcriptional regulator that increases genes responsible for aerobic glycolysis (Warburg effect). When glucose and glutamine are available, the Warburg metabolism enables cells to synthesize nutrients that are needed for growth and cell division. Therefore, investigators believe that Burkitt lymphoma is the fastest-growing tumour.36

Other translocations have been reported between chromosome 8 and chromosomes 2 or 22, which contain genes for immunoglobulin light chains.

FIGURE 21-15

Burkitt Lymphoma Cells. The 8,14 chromosomal translocation and associated oncogenes in Burkitt lymphoma. IG, immunoglobulin; MYC, myelocytomatosis viral oncogene homologue.

Clinical manifestations The endemic (mainly occurring in Africa) and sporadic Burkitt lymphomas (the most common type in North America and European countries and without obvious infectious cofactors) are found mostly in children or young adults. Most tumours manifest at extranodal locations. Endemic Burkitt lymphoma usually presents as a mass of the mandible and an unusual tendency for involvement of the abdominal viscera, including the kidneys, ovaries, and adrenal glands. Sporadic Burkitt lymphoma usually appears as a mass involving the ileocecum and peritoneum. More advanced disease may involve other organs— eyes, ovaries, kidneys, glandular tissue (breast, thyroid, tonsil)—and presents with type B symptoms (night sweats, fever, weight loss). Evaluation and treatment The distribution of tumours and biopsies of enlarged lymph nodes or the bone marrow containing malignant B cells are usually indicative of Burkitt lymphoma. It is one of the most aggressive and quickly growing malignancies. Burkitt lymphoma, however, responds successfully to intensive chemotherapy in most children and adults. The outcome is more cautious in older adults.

Lymphoblastic lymphoma. Lymphoblastic lymphoma (LL) is a relatively rare variant of NHL overall (2 to 4%) but accounts for almost one-third of cases of NHL in children and adolescents, with a male predominance. The vast majority of LL (90%) is of T-cell origin; the remainder arises from B cells. LL is similar to acute lymphoblastic leukemia and may be considered a variant of that disease. Pathophysiology The disease arises from a clone of relatively immature T cells that becomes malignant in the thymus. As with most lymphoid tumours, LL is frequently associated with translocations, primarily of the chromosomes that encode for the T-cell receptor (chromosomes 7 and 14). These aberrations result in increased expression of a variety of transcription factors and loss of growth control. Clinical manifestations The first sign of LL is usually a painless lymphadenopathy in the neck. Peripheral lymph nodes in the chest become involved in about 70% of individuals. Involved nodes are located mostly above the diaphragm. LL is a very aggressive tumour that presents as stage IV in most people. T-cell LL is associated with a unique mediastinal mass (up to 75%) because of the apparent origin of the tumour in

the thymus. The mass results in dyspnea and chest pain and may cause compression of bronchi or the superior vena cava. The tumour may infiltrate the bone marrow in about half of those affected, and suppression of bone marrow hematopoiesis leads to increased susceptibility to infections. Other organs, including the liver, kidney, spleen, and brain, also may be affected. Many individuals express type B symptoms: fever, night sweats, and significant weight loss. Evaluation and treatment The most common therapeutic approach is combined chemotherapy (intensive therapy). Bulky tumour masses are sometimes treated with radiation therapy. In early stages of the disease, the response rate is high with increased survival; the 5-year survival in children is 80 to 90% and 45 to 55% in adults. Although LL is easily treated, there is a high relapse rate: 40 to 60% of adults.

Multiple myeloma. Multiple myeloma (MM) is a plasma cell (a white blood cell neoplasm called myeloma cells) cancer characterized by the slow proliferation of malignant cells, with tumour cell masses in the bone marrow usually resulting in destruction of the bone (Figure 21-16).57 Myeloma cells reside in the bone marrow and are usually not found in the peripheral blood. As the number of myeloma cells increases, fewer red blood cells, white blood cells, and platelets are produced. Myeloma may spread to other tissues, especially in very advanced stages of the disease. The reported incidence of MM has doubled in the past two decades, possibly as a result of more sensitive testing used for diagnosis. The annual incidence rate in Western industrialized countries is 4 per 100 000, and it was estimated that 2 900 new cases would be diagnosed in Canada in 2017.35,58 MM occurs in all races, but in the United States the incidence in Blacks is about twice that of Whites. It rarely occurs before the age of 40 years—the peak age of incidence is between 65 and 70 years. It is slightly more common in men than in women. Other risk factors include exposure to radiation or certain chemicals and a history of monoclonal gammopathy of undetermined significance (MGUS; see “Clinical Manifestations”) or plasmacytoma.

FIGURE 21-16 Multiple Myeloma, Bone Marrow Aspirate. Normal marrow cells are largely replaced by plasma cells, including atypical forms with multiple nuclei (arrow), and cytoplasmic droplets containing immunoglobulin. (From Kumar, V., Abbas, A.K., & Aster, J.C. [Eds.]. [2015]. Robbins and Cotran pathologic basis of disease [9th ed.]. Philadelphia: Saunders.)

Pathophysiology MM is a plasma cell neoplasia that causes lytic bone lesions (bony disease; radiologically appears as punched-out defects), hypercalcemia, renal failure, anemia, and immune abnormalities.36,59 Multiple mutations in different pathways alter the intrinsic biology of the plasma cell, generating the features of myeloma.60 MM tumours are highly heterogeneous.61 Defining driver mutations and heterogeneity is essential for treatment decisions. Many myelomas are aneuploidy and, in most individuals with myeloma, chromosomal translocations are the most common. The primary translocation involves the immunoglobulin heavy chain on chromosome 14 and fibroblast growth factor receptor on chromosome 4.62 Other reported chromosomal abnormalities include deletion of chromosome 13 and deletion of

chromosome 17.62 Development of further secondary genetic alterations causes progression to an aggressive MM. Investigators are studying various epigenetic alterations and interactions with extracellular matrix proteins. For example, myeloma cells interact and secrete peptides that adhere to stromal cells, inducing cytokines that possibly promote inflammation. Myeloma cells are prone to the accumulation of misfolded protein, such as unpaired immunoglobulin chains. Misfolded proteins activate apoptosis. Malignant plasma cells arise from one clone of B cells that produce abnormally large amounts of one class of immunoglobulin (usually IgG, occasionally IgA, and rarely IgM, IgD, or IgE). The malignant transformation may begin early in B-cell development, possibly before encountering antigens in the secondary lymphoid organs. The myeloma cells return either to the bone marrow or to other soft tissue sites. Their return is aided by cell adhesion molecules that help them target favourable sites that promote continued expansion and maturation. Cytokines, particularly IL-6, have been identified as essential factors that promote the growth and survival of MM cells. (Lymphocytes and cytokines are described in Chapter 6.) Myeloma cells in the bone marrow produce several cytokines themselves (e.g., IL-6, IL-1, IL-11, tumour necrosis factor-alpha [TNF-α]). IL-6 in particular acts as an osteoclast-activating factor and stimulates osteoclasts to reabsorb bone. This process results in bone lesions and hypercalcemia (high calcium levels in the blood) attributable to the release of calcium from the breakdown of bone. The antibody produced by the transformed plasma cell is frequently defective, containing truncations, deletions, and other abnormalities, and is often referred to as a paraprotein (abnormal protein in the blood). Because of the large number of malignant plasma cells, the abnormal antibody, called the M protein, becomes the most prominent protein in the blood (as Figure 21-18 shows). Suppression of normal plasma cells by the myeloma results in diminished or absent normal antibodies. The excessive amount of M protein also may contribute to many of the clinical manifestations of the disease. Frequently, the myeloma produces free immunoglobulin light chain (Bence Jones protein) that is present in the blood and urine and contributes to damage of renal tubular cells. Clinical manifestations The common presentation of MM is characterized by elevated levels of calcium in the blood (hypercalcemia), renal failure, anemia, and bone lesions. The hypercalcemia and bone lesions result from infiltration of the bone by malignant plasma cells and stimulation of osteoclasts to reabsorb bone. This process results in the release of calcium (hypercalcemia) and the development of “lytic lesions” (round, “punched-out” regions of bone) (Figure 21-17). Destruction of bone tissue causes pain, the most common presenting symptom, and pathological fractures. The bones most commonly involved, in decreasing order of frequency, are the vertebrae, ribs, skull, pelvis, femur, clavicle, and scapula. Spinal cord compression, because of the weakened vertebrae, occurs in about 10% of individuals. A condition called amyloidosis may occur, in which antibody proteins increase and stick together in peripheral nerves and organs, such as the kidney and heart. Signs and symptoms of amyloidosis include fatigue, purple spots on the skin, enlarged tongue, diarrhea, edema, and numbness or tingling in the legs and feet.

FIGURE 21-17 Multiple (Plasma Cell) Myeloma. A, Roentgenogram of femur showing extensive bone destruction caused by tumour. Note the absence of reactive bone formation. B, Gross specimen from the same individual; myelomatous sections appear as dark granular sections. (From Kissane, J.M. [Ed.]. [1990]. Anderson's pathology [9th ed.]. St. Louis: Mosby.)

Proteinuria is observed in 90% of individuals. Renal failure may be either acute or chronic and is usually secondary to the hypercalcemia. Bence Jones protein may lead to damage of the proximal tubules. Anemia is usually normocytic and normochromic and results from inhibited erythropoiesis caused by tumour cell infiltration of the bone marrow. The high concentration of paraprotein in the blood may lead to hyperviscosity syndrome. The increased viscosity interferes with blood circulation to various sites (brain, kidneys, extremities). Hyperviscosity syndrome is observed in up to 20% of persons. Additional neurological symptoms (e.g., confusion, headaches, blurred vision) may occur secondary to hypercalcemia or hyperviscosity. Suppression of the humoral (antibody-mediated) immune response results in repeated infections, primarily pneumonias and pyelonephritis. The most commonly involved microorganisms are encapsulated bacteria that are particularly sensitive to the effects of antibody; pneumonia caused by Streptococcus pneumoniae, Staphylococcus aureus, or K. pneumoniae; or pyelonephritis caused by E. coli or other Gram-negative organisms. Cell-mediated (T-cell) function is relatively normal. Overwhelming infection is the leading cause of death from MM. MM is a progressive disorder and is often preceded by a condition known as monoclonal gammopathy of undetermined significance (MGUS). MGUS is diagnosed by the presence of an M protein in the blood or urine without additional evidence of MM.63 MGUS is present in approximately 1% of the general population and in 3% of individuals older than 70 years. Although MGUS is considered nonpathological and requires no treatment, about 2% of individuals with MGUS progress to malignant plasma cell disorders. Progression of MM following MGUS advances to asymptomatic MM and finally symptomatic MM. Asymptomatic MM also may be referred to as smouldering myeloma and indolent myeloma.63 Smouldering myeloma is usually characterized by the presence of an M protein and clonal bone marrow plasma cells, but with no indication of end-organ damage. Evaluation and treatment Diagnosis of MM is made by symptoms and radiographic and laboratory studies; a definitive diagnosis requires a bone marrow biopsy. The International Myeloma Working Group's new criteria63 for the diagnosis of MM include biomarkers (monoclonal components in serum and urine; quantification of immunoglobulins IgG, IgA, and IgM; and characterization of the heavy and light chains by immunofixation) and the presence of hypercalcemia, renal failure, anemia, and bone lesions (CRAB). Other criteria include evaluation of bone marrow plasma cell infiltration by bone marrow biopsy and radiological evaluation of lytic bone lesions. Biomarkers based on quantitation of plasma cells (serum-free light chains) may help stratify risk for people with asymptomatic MM and identification, staging, prognosis, and monitoring of those with smouldering MM who are at an “ultra-high” risk of developing aggressive MM.

New techniques use microRNAs extracted from serum to measure immunoglobulins (IgG, IgM, IgA). Typically, one class of immunoglobulin (the M protein produced by the myeloma cell) is greatly increased, whereas the others are suppressed. Serum electrophoretic analysis shows increased levels of M protein (see Figure 21-18). Because the M protein is monoclonal, each molecule has the same electric charge and migrates at about the same site on electrophoresis, resulting in a highly concentrated protein (M spike) (see Figure 21-18). Bence Jones protein may be observed in the urine or serum by immunoelectrophoresis or in the serum using available enzyme-linked immunosorbent assays (ELISAs). Usually an intact antibody paraprotein coexists with Bence Jones protein. However, variants of MM include individuals in which free light chain only is produced and a rare variant that produces only free heavy chain; about 1% of cases are nonsecretory so that neither M protein nor Bence Jones protein is produced. Measurement of another protein, free β2-microglobulin, is used as an indicator of prognosis or effectiveness of therapy.

FIGURE 21-18 M Protein. Serum protein electrophoresis (PEL) is used to screen for M proteins in multiple myeloma. A, In normal serum the proteins separate into several regions between albumin (Alb) and a broad band in the gamma (γ) region, where most antibodies (gamma globulins) are found. Immunofixation (IFE) can identify the location of IgG (G), IgA (A), IgM (M), and kappa (κ) and lambda (L) light chains. B, Serum from an individual with multiple myeloma contains a sharp M protein (M spike). The M protein is monoclonal and contains only one heavy chain and one light chain. In this instance, the IFE identifies the M protein as an IgG containing a lambda light chain. C, Serum and urine protein electrophoretic patterns in an individual with multiple myeloma. Serum demonstrates an M protein (Immunoglobulin) in the gamma region, and the urine has a large amount of the smaller-sized light chains with only a small amount of the intact immunoglobulin. Ig, immunoglobulin. (A and B, from Abeloff, M., Armitage, J., Niederhuber, J., et al. [2008]. Abeloff's clinical oncology [4th ed.]. Philadelphia: Churchill Livingstone. C, from McPherson, R., & Pincus, M. [2012]. Henry's clinical diagnosis and management by laboratory methods [22nd ed.]. Edinburgh: Saunders.)

Although combinations of chemotherapy, radiation therapy, plasmapheresis (exchange), and stem cell transplant have been used for treatment, the prognosis for persons with MM remains poor. However, with the new high-sensitivity biomarkers that are associated with inevitable development of clinical symptoms, early diagnosis and treatment may be possible before individuals develop more advanced disease and organ damage. Conventional combinations of chemotherapeutic agents have included melphalan (Alkeran) and prednisone (Deltasone); prednisone with vincristine (Oncovin); carmustine (BiCNU) and cyclophosphamide (Procytox); vincristine, doxorubicin (Adriamycin), and dexamethasone (Decadron); and thalidomide (Thalomid) and dexamethasone. Thalidomide disrupts the stromal marrow–MM cell interaction by modulating cell-surface adhesion molecules and inhibiting angiogenesis. In addition, it increases apoptosis and G1 growth arrest (i.e., the cell cycle gap 1; see Chapter 1) of MM cells. Hematopoietic stem cell transplantation has prolonged life but has not yet proven to be curative.36 Controversy exists concerning whether tandem stem cell transplant offers the best outcome. Bisphosphonate therapy is the primary treatment for bone lesions. Individuals with multiple bone

lesions, if untreated, rarely survive more than 6 to 12 months. Individuals with inactive (indolent) myeloma, however, can survive for many years. With chemotherapy and aggressive management of complications, the prognosis can improve significantly, with a median survival of 24 to 30 months and a 10-year survival rate of 3%. Promising new therapies include the use of proteasome inhibitors because proteasome degrades misfolded and unwanted proteins. The rates of new myeloma cases are increasing 0.7% each year and the death rates have decreased an average of 1.3% each year from 2002 to 2011. The 5year survival for all stages of MM is 45.1%.

Quick Check 21-4 1. Contrast the principal features of Hodgkin's lymphoma with those of non-Hodgkin's lymphoma. 2. What is Burkitt lymphoma? 3. Define what is meant by the following statement: Multiple myeloma (MM) is heterogeneous. 4. What are the main pathological features of MM?

Alterations of Splenic Function The complexities of splenic function are not totally understood, and its mysteries are still being studied. The normal functions of the spleen that may impact disease states include (1) phagocytosis of blood cells and particulate matter (e.g., bacteria), (2) antibody production, (3) hematopoiesis, and (4) sequestration of formed blood elements. The spleen is part of the mononuclear phagocyte system and is involved in all systemic inflammations, hematopoietic disorders, and many metabolic disorders. In the past, splenomegaly (enlargement of the spleen) has been associated with various disease states. It is now recognized that splenomegaly is not necessarily pathological; an enlarged spleen may be present in certain individuals without any evidence of disease. Splenomegaly may be, however, one of the first physical signs of underlying conditions, and its presence should not be ignored. In conditions where splenomegaly is present, the normal functions of the spleen may become overactive, producing a syndrome known as hypersplenism. Hypersplenism is characterized by anemia, leukopenia, and thrombocytopenia alone or in combination. Some individuals may seek treatment for problems even though they have not met all the aforementioned clinical criteria; therefore, the relevance and significance of hypersplenism are still uncertain. Pathophysiology Specific conditions causing splenomegaly and resulting hypersplenism are many and are related to other categories of disease (Box 21-1). Different pathological processes that produce splenomegaly are described briefly next.

Box 21-1

Diseases Related to Classification of Splenomegaly Inflammation or Infection Acute: viral (hepatitis, infectious mononucleosis, cytomegalovirus), bacterial (salmonella, Gramnegative), parasitic (typhoid) Subacute or chronic: bacterial (subacute bacterial endocarditis, tuberculosis), parasitic (malaria), fungal (histoplasmosis), Felty's syndrome, systemic lupus erythematosus, rheumatoid arthritis, thrombocytopenia

Congestive Cirrhosis, heart failure, portal vein obstruction (portal hypertension), splenic vein obstruction

Infiltrative Gaucher's disease, amyloidosis, diabetic lipemia

Tumours or Cysts Malignant: polycythemia rubra vera, chronic or acute leukemias, Hodgkin's lymphoma, metastatic solid tumours

Nonmalignant: Hamartoma

Cysts: true cysts (lymphangiomas, hemangiomas, epithelial, endothelial); false cysts (hemorrhagic, serous, inflammatory) Acute inflammatory or infectious processes cause splenomegaly because of an increased demand for defensive activities. Acutely enlarged spleens secondary to infection may become so filled with erythrocytes that their natural rubbery resilience is lost and they become fragile and vulnerable to blunt trauma. Splenic rupture is a complication associated with IM; rupture occurs mostly in males between days 4 and 21 of acute illness. Congestive splenomegaly is accompanied by ascites, portal hypertension, and esophageal varices and is most commonly seen in those with hepatic cirrhosis. Splenic hyperplasia develops in disorders that increase splenic workload and is associated most commonly with various types of anemia (e.g., hemolytic) and chronic myeloproliferative disorders (i.e., PV). Infiltrative splenomegaly is caused by engorgement by the macrophages with indigestible materials associated with various “storage diseases.” Tumours and cysts cause actual growth of the spleen. Metastatic tumours in the spleen are rare and may result from primary tumours of the skin, lung, breast, and cervix. Clinical manifestations Overactivity of the spleen results in hematological alterations that affect all blood components. Sequestering of red blood cells, granulocytes, and platelets results in a reduction of all circulating blood cells. The spleen may sequester up to 50% of the red blood cell population, thereby upsetting the normal physiological concentration of red blood cells in the circulation. The rate of splenic pooling is directly related to spleen size and the degree of increased blood flow through it. Sequestering exposes the red blood cells to splenic conditions that accelerate destruction, further contributing to the decreased red blood cell concentration. Anemia is the result of these combined activities. Anemia may be further potentiated by an increase in blood volume, which produces a dilutional effect on the already reduced concentration of red blood cells. The dilutional effect, as well as the removal and destruction of red blood cells, depends primarily on the degree of splenomegaly. White blood cells and platelets also are affected by sequestering, although not to the same degree as the red blood cell. Again, the size of the spleen is the determining factor in the number of cells sequestered. Evaluation and treatment Treatment for hypersplenism is splenectomy; however, it may not always be indicated. A splenectomy is considered necessary to alleviate the destructive effects on red blood cells. Clinical indicators should determine the need for splenectomy, not necessarily specific conditions. Splenectomy for splenic rupture is no longer considered mandatory because of the possibility of overwhelming sepsis after removal. Repair and preservation are now considered before the decision to remove the spleen. Splenectomy also may be performed as treatment for hairy cell leukemia, Felty's syndrome, agnogenic myeloid metaplasia, thalassemia major, Gaucher's disease, hemodialysis, splenomegaly, splenic venous thrombosis, and thrombotic thrombocytopenic purpura (TTP). Individuals are able to lead normal lives after splenectomy, but blood cell abnormalities often exist after removal of the spleen (i.e., red blood cells become thinner, broader, and wrinkled; white blood cell counts initially increase and then plateau; platelet counts rise after surgery and then stabilize). A major postoperative complication following splenectomy is overwhelming postsplenectomy infection. Unless treated in time, overwhelming postsplenectomy infection may rapidly progress to septic shock and possibly disseminated intravascular coagulation.

Quick Check 21-5 1. Identify the major causes of splenomegaly. 2. How does splenomegaly differ from hypersplenism?

Hemorrhagic Disorders and Alterations of Platelets and Coagulation The arrest of bleeding, or hemostasis, is dependent on adequate numbers of platelets, normal levels of coagulation factors, and absence of defects in vessels walls. The spectrum of abnormal bleeding varies widely from massive bleeds, such as rupture of large vessels like the aorta, to small bleeds in skin or mucosal membranes. Diminished or excessive levels of coagulation factors can lead to defective hemostasis or spontaneous and unnecessary clotting. (Hemostasis is discussed in Chapter 20.) Diminished hemostasis results in either internal or external hemorrhage. A classification of hemorrhagic disorders is presented in Table 21-9. TABLE 21-9 Classification of Hemorrhagic Disorders Type of Defect Defects of primary hemostasis Defects of secondary hemostasis Generalized defects of small vessels

Example

Manifestation

Platelet defects or von Willebrand's disease Coagulation factor defects

Usually present with small bleeds in skin or mucosal membrane; bleeds are usually petechiae (3-mm red-purple discolorations); common in capillaries; also includes epistaxis (nose bleeds), gastro-intestinal bleeds, or excessive menstruation Bleeds into soft tissue, muscle, or joints; intracranial bleeds may occur

Palpable purpura and Extravasated blood creates a palpable mass (or palpable purpura), ecchymoses (simply called a bruise), or a larger palpable lesion (or hematoma); ecchymoses systemic disorders disrupt small blood vessels, called vasculitis

Purpuric disorders occur when there is a deficiency of normal platelets necessary to plug damaged vessels or prevent leakage from the tiny tears that occur daily in capillaries. More serious internal bleeding occurs from events that simply overwhelm hemostatic mechanisms, such as rupture of large blood vessels, trauma, and diseases associated with massive hemorrhage including abdominal aneurysm. Between these smaller bleeds and massive bleeds are deficiencies of coagulation factors found with the hemophilias (see Chapter 21). Disorders that result in spontaneous clotting can develop from genetic disorders of the clotting system components or from acquired diseases that activate clotting. These disorders are known collectively as thromboembolic disease. Additionally, any disorder of the blood that predisposes to clotting of blood or thrombosis is called hypercoagulability (thrombophilia).

Disorders of Platelets Quantitative or qualitative abnormalities of platelets can interrupt normal blood coagulation and prevent hemostasis.64 The quantitative abnormalities are thrombocytopenia, a decrease in the number of circulating platelets, and thrombocythemia, an increase in the number of platelets. Qualitative disorders affect the structure or function of individual platelets and can coexist with the quantitative disorders. Qualitative disorders usually prevent platelet adherence and aggregation, preventing formation of a platelet plug.

Thrombocytopenia Thrombocytopenia is defined as a platelet count less than 150 × 109/L of blood, although most individuals do not consider the decrease significant unless it falls below 100 × 109/L of blood.65 The risk for hemorrhage associated with minor trauma does not appreciably increase until the count falls below 50 × 109/L. Spontaneous bleeding without trauma can occur with counts ranging from 10 to 15 × 109/L, resulting in skin manifestations (i.e., petechiae, ecchymoses, and larger purpuric spots) or frank bleeding from mucous membranes. Severe spontaneous bleeding may result if the count is less than 10 × 109/L and can be fatal if it occurs in the GI tract, respiratory tract, or CNS. Before the diagnosis of thrombocytopenia is made, pseudothrombocytopenia must be ruled out. This phenomenon occurs in approximately 1 in 1 000 to 1 in 10 000 laboratory samples and results from an error in platelet counting when a blood sample is analyzed by an automated cell counter. Platelets in the

blood sample may become nonspecifically agglutinated by immunoglobulins in the presence of ethylenediaminetetraacetic acid (EDTA), a preservative in banked blood. The agglutinated platelets are not counted, thus giving an apparent, but false, thrombocytopenia. Thrombocytopenia also may be falsely diagnosed because of a dilutional effect observed after massive transfusion of platelet-poor packed cells to treat a hemorrhage. This occurs when more than 10 units of blood have been transfused within a 24-hour period. The hemorrhage that necessitated the transfusion also accelerates the loss of platelets, contributing to the pseudothrombocytopenic state. Splenic sequestering of platelets in hypersplenism (congestive) also induces an apparent thrombocytopenia, as does hypothermia (less than 25°C [77°F]), which is reversed when temperatures return to normal, suggesting an increased platelet sequestration in response to chilling. Pathophysiology Thrombocytopenia results from decreased platelet production, increased consumption, or both. The condition may also be either congenital or acquired and may be either primary or secondary to other acquired or congenital conditions.66,67 Thrombocytopenia secondary to congenital conditions occurs in a large number of different diseases, although each is relatively rare.68 These include thrombocytopenia– absent radius (TAR) syndrome, Wiskott-Aldrich syndrome (see Chapter 8), various forms of MYH9 gene mutation (e.g., May-Hegglin anomaly), X-linked thrombocytopenia, and many other examples. Acquired thrombocytopenia is more common and may occur as a result of decreased platelet production secondary to viral infections (e.g., EBV, rubella, CMV, HIV), medications (e.g., thiazides, estrogens, quinine-containing medications, chemotherapeutic agents, ethanol), nutritional deficiencies (vitamin B12 or folic acid in particular), chronic renal failure, bone marrow hypoplasia (e.g., aplastic anemia), radiation therapy, or bone marrow infiltration by cancer. Most common forms of thrombocytopenia are the result of increased platelet consumption. Examples include heparin-induced thrombocytopenia, idiopathic (immune) thrombocytopenia purpura, TTP, and DIC.

Heparin-induced thrombocytopenia. Heparin is the most common cause of medication-induced thrombocytopenia.69 Approximately 4% of individuals treated with unfractionated heparin develop heparin-induced thrombocytopenia (HIT). The incidence is lower (about 0.1%) with the use of low-molecular-weight heparin. HIT is an immunemediated, adverse drug reaction caused by IgG antibodies against the heparin–platelet factor 4 complex leading to platelet activation through platelet Fc γIIa receptors.70 The release of additional platelet factor 4 from activated platelets and activation of thrombin lead to increased platelet consumption and a decrease in platelet counts beginning 5 to 10 days after administration of heparin. Clinical manifestations The hallmark of HIT is thrombocytopenia. A decrease of approximately 50% in the platelet count is observed in more than 95% of individuals. However, 30% or more of those with thrombocytopenia are also at risk for venous or arterial thrombosis because a prothrombotic state is caused by antibody binding to platelets, inducing activation, aggregation, and consumption (thus the term thrombocytopenia in the syndrome name) of platelets. Venous thrombosis is more common and results in deep venous thrombosis (also called deep vein thrombosis) and pulmonary emboli. Arterial thrombosis affects the lower extremities, causing limb ischemia. Arterial thrombosis may lead to cerebrovascular accidents and myocardial infarctions. Other major arteries also may be affected (e.g., renal, mesenteric, upper limb). Although platelet counts are low, bleeding is uncommon. Evaluation and treatment Diagnosis is primarily based on clinical observations. The individual presents with dropping platelet counts after 5 days or longer of heparin treatment. On average, platelet counts may reach 60 × 109/L. Because most individuals are postsurgery and the onset of symptoms, including thrombosis, may be delayed until after release from the hospital, other possible causes of thrombocytopenia (e.g., infection, other medication reactions) must be considered. Tests are available to measure antiheparin-platelet factor 4 antibodies. The sensitivity of this test is extremely high (greater than 90%), but the specificity is less

because of false-positive reactions (e.g., those receiving dialysis). Treatment is the withdrawal of heparin and use of alternative anticoagulants.

Immune thrombocytopenia purpura. The most common cause of thrombocytopenia, secondary to increased platelet destruction, is immune thrombocytopenic purpura (ITP). ITP, formerly known as idiopathic thrombocytopenic purpura, however, is widely recognized now as an immune process, hence the change from idiopathic to immune.71 Although results and estimates are conflicting, the incidence of ITP is estimated to range from 9.5 to 20 per 100 000 in the general population and tends to increase with age. In individuals younger than 60 years, females have a higher incidence than males.72 ITP may be acute or chronic. The acute form is frequently observed in children and typically lasts 1 to 2 months with a CR. In some instances it may last for up to 6 months, and some children (7 to 28%) may progress to the chronic condition (see Chapter 22). Acute ITP is usually secondary to infections (particularly viral) or other conditions that lead to large amounts of antigen in the blood, such as medication allergies or systemic lupus erythematosus. Under these conditions, the antigen usually forms immune complexes with circulating antibody, and it is thought that the immune complexes bind to Fc receptors on platelets, leading to their destruction in the spleen. The acute form of ITP usually resolves as the source of antigen is resolved (infection) or removed (medications). Recently, H. pylori has been implicated in various autoimmune disorders, including PA and ITP.73-75 Similar to other autoimmune diseases, the epidemiology and gene–environment interactions and potential triggers for ITP need much study. Chronic ITP is caused by autoantibody-mediated destruction against platelet-specific antigens. This form is more commonly observed in adults, being most prevalent in women between 20 and 40 years old, although it can be found in all ages. The chronic form tends to get progressively worse. It can occur from a variety of predisposing conditions or exposures (secondary) or have no known risk factors (primary). The autoantibodies are generally of the IgG class and are against one or more of several platelet glycoproteins (e.g., GPIIb/IIIa, GPIIb/IX, GPIa/IIa). The antibodies bind directly to the platelet antigens, after which the antibody-coated platelets are recognized and removed from the circulation by macrophages in the spleen. Autoreactive T cells also play a large role in the crosstalk between antigenpresenting cells and autoantibody-producing B cells and may play a role in ITP.76 Clinical manifestations Initial manifestations range from minor bleeding problems (development of petechiae and purpura) over the course of several days to major hemorrhage from mucosal sites (epistaxis, hematuria, menorrhagia, bleeding gums). Rarely will an individual present with intracranial bleeding or other sites of internal bleeding. During pregnancy, a woman with ITP may have a newborn that is also thrombocytopenic. If the fetal platelets express the same antigen as the mother, the maternal antibody will coat the platelets, potentially resulting in thrombocytopenia in utero. A variant of neonatal thrombocytopenia (neonatal alloimmune thrombocytopenia) occurs when the mother does not have ITP but makes IgG antibodies against an antigen inherited from the father found on fetal platelets but not on maternal platelets.77 Evaluation and treatment Diagnosis of ITP is based on a history of bleeding and associated symptoms (weight loss, fever, headache). Physical examination includes notations on the type, location, and severity of bleeding. In addition, evidence of infections (bacterial, HIV and other viral), medication history, family history, and evidence of thrombosis are assessed. Other diagnostic tests include CBC and peripheral blood smear. Unlike some other forms of thrombocytopenia, there is usually no evidence of splenectomy. Testing for antiplatelet antibodies is usually not helpful. Although most cases of ITP are associated with elevated levels of IgG on platelets, other forms of thrombocytopenia also have a high incidence of plateletassociated antibodies; thus, the specificity is low (50 to 65%).78 In addition, some cases of ITP will not present with elevated platelet-associated antibodies; the sensitivity is 75 to 94%; therefore, a negative test does not rule out ITP. The acute form of ITP usually resolves without major clinical consequences, but the chronic form (like

many autoimmune diseases) is variable with multiple remissions and exacerbations. Treatment is palliative, not curative, and focuses on prevention of platelet destruction. Initial therapy for ITP is glucocorticoids (e.g., prednisone), which suppress the immune response and prevent sequestering and further destruction of platelets. If steroid therapy is ineffective, other reagents have been used. Treatment with intravenous immune globulin (IVIg) is used to prevent major bleeding. The response rate is 80%, but the effects are transient, lasting only days to a few weeks. Anti-Rho(D) (RhoGAM) has been used with limited success to treat individuals who are Rh-positive. The newer medications romiplostin (Nplate) and eltrombopag (Promacta) are now available and show promise in successfully treating ITP. If platelet counts do not increase appropriately, splenectomy is considered to remove the site of platelet destruction. However, splenectomy is not without risks, and approximately 10 to 20% of individuals who undergo a splenectomy suffer a relapse and require further treatment. In that situation, it is believed that the liver has become the site for platelet destruction. If splenectomy is unsuccessful and life-threatening thrombocytopenia persists, more aggressive immunosuppressive medications (e.g., azathioprine [Nuazathioprine], cyclophosphamide) are usually recommended. Because of potential complications, these medications are reserved for individuals who are severely thrombocytopenic and refractive to other therapies.

Thrombotic thrombocytopenic purpura. Thrombotic thrombocytopenic purpura (TTP) is a multisystem disorder characterized by thrombotic microangiopathy (TMA) (small or microvessel disease) in which platelets aggregate and cause occlusion of arterioles and capillaries within the microcirculation.79,80 Aggregation may lead to increased platelet consumption and organ ischemia. TTP is relatively uncommon, occurring in about 5 per million individuals per year. The incidence is increasing and does appear to be an actual increase and not just the result of improved recognition. One suspected etiological factor for TMA, TTP, and hemolytic uremic syndrome (HUS) is medication-induced, and a recent report found definite evidence from three medications: quinine sulphate (Novo-Quinine), cyclosporine (Sandimmune), and tacrolimus (Advagraf, Prograf).81 There are two types of TTP: familial and acquired idiopathic. The familial type is the more rare type and is usually chronic, relapsing, and typically seen in children. Acquired TTP is more common and more acute and severe. It occurs mostly in females in their 30s and is rarely observed in infants and older adults. The microthrombi formation is found throughout the entire vascular system, causing damage to multiple organs. The most susceptible organs for damage include the kidney, brain, and heart. Also affected are the pancreas, spleen, and adrenal glands. The thrombi are composed of platelets with minimal fibrin and red blood cells, differentiating them from thrombi secondary to intravascular coagulation (see p. 550). Clinical manifestations Chronic relapsing TTP is a rare familial form of TTP observed in children and usually recognized and successfully treated. The acquired acute idiopathic TTP is much more common and more severe.82 TTP is clinically related to and must be distinguished from other thrombotic microangiopathic conditions, including HUS, malignant hypertension, pre-eclampsia, and pregnancy-induced HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome. Early diagnosis and treatment is essential because TTP may prove fatal within 90 days. Acute idiopathic TTP is characterized by a “pentad” of symptoms, including extreme thrombocytopenia (less than 20 × 109/L), intravascular hemolytic anemia, ischemic signs and symptoms most often involving the CNS (about 65% present with memory disturbances, behavioural irregularities, headaches, or coma), kidney failure (present in about 65%), and fever (present in about 33%). Evaluation and treatment A routine blood smear usually shows fragmented red blood cells (schizocytes) produced by shear forces when red blood cells are in contact with the fibrin mesh in clots that form in the vessels. As a result of tissue injury, serum levels of lactate dehydrogenase (LDH) may be very high, and low-density

lipoprotein (LDL) levels may be elevated. Tests for antibody on red blood cells are negative, excluding immune hemolytic anemia. Plasma exchange with fresh frozen plasma is the treatment of choice, achieving a 70 to 85% response rate. Additionally, steroids (glucocorticoids) are administered. In the absence of major organ damage, this approach may lead to complete recovery with no long-term complications. The anti-CD20 monoclonal antibody rituximab (Rituxan) has shown some success in people who are refractory to plasma exchange.20 Relapses do occur at a rate of 13 to 36%, and recurrences have been reported, sometimes delayed until 9 years after treatment. Individuals who do not respond to conventional treatment may be candidates for splenectomy; however, postoperative hemorrhage remains a dangerous complication. Immunosuppression therapy has been successful in some individuals.

Thrombocythemia Thrombocythemia (also called thrombocytosis) is characterized by a platelet count greater than 400 × 109/L of blood.83 Thrombocythemia may be primary or secondary (reactive) and is usually asymptomatic until the count exceeds 1 000 × 109/L. Then intravascular clot formation (thrombosis), hemorrhage, or other abnormalities can occur. Pathophysiology Essential (primary) thrombocythemia (ET) is a myeloproliferative neoplasm characterized by an increase in platelet production (or thrombocytosis) and often an increase in red blood cell production (or erythrocytosis).84 Other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, itching (or pruritus), and risk for leukemic or bone marrow fibrotic transformation.84 Myeloproliferative neoplasms (MPNs) are one of five categories of myeloid malignancies. ET is characterized by stem cell–derived clonal bone marrow proliferation (myeloproliferation) with a unique “gain-of-function” mutation that induces overactivity in cell signalling from JAK2. JAK2, a tyrosine kinase, is an essential player downstream of cytokine receptors, such as the thrombopoietin (affects platelet proliferation) and erythropoietin (affects erythrocyte proliferation) receptors, and a gain-of-function mutation contributes to the development of MPN. More simply, both erythropoietin and thrombopoietin convey their signals and consequent proliferation through JAK2. The alteration is a valine-to-phenylalanine (V617F) mutation that causes constant activation of the JAK2 gene, leading to an increased responsiveness or production of platelets and other cells in the bone marrow. Along with increased platelets, there may be a concomitant increase in the number of red blood cells, indicating a myeloproliferative disorder; however, the increase in red blood cells is not to the extent seen in PV (see p. 526). Red blood cells in ET tend to aggregate and adhere to the endothelium and contribute to the blockage of flow in the microvasculature and altered interactions between platelets and the vascular endothelium.85 The JAK2 (V617F) mutation is present in 50 to 60% of persons with ET. Other mutually exclusive mutations found include calreticulin (CALR) or myeloproliferative leukemia virus oncogene (MPL) mutation. In Canada, the annual incidence rate for ET has been estimated to range from 0.1 to 1.5 per 100 000. The prevalence of ET has been estimated to be 24 per 100 000 people.44 The overall incidence rate of ET is 0.8 per 100 000 in the United Kingdom, 2.53 per 100 000 in the United States, and 0.59 per 100 000 in Denmark. It is more common in middle-aged individuals, with the majority of cases occurring between ages 50 and 60 years. There is no known gender preference. There also is a rare hereditary type of ET called familial essential thrombocythemia (FET) that is inherited in an autosomal dominant pattern. Secondary thrombocythemia may occur after splenectomy because platelets that normally would be stored in the spleen remain in circulating blood. The increase in platelets may be gradual, with thrombocythemia not occurring for up to 3 weeks after splenectomy. Reactive thrombocythemia may occur during some inflammatory conditions, such as rheumatoid arthritis and cancers. In these conditions, excessive production of some cytokines (e.g., IL-6, IL-11) may induce increased production of thrombopoietin in the liver, resulting in increased megakaryocyte proliferation. Reactive thrombocythemia also may occur during a variety of physiological conditions, such as after exercise. Clinical manifestations

Clinical manifestations vary among individuals. Those with ET are at risk for large-vessel arterial or venous thrombosis, although the most common complication is microvasculature thrombosis leading to ischemia in the fingers, toes, or cerebrovascular regions.85 The primary presenting symptoms of microvasculature thrombosis are erythromyalgia, headache, and paresthesias. Erythromyalgia is characterized by unilateral or bilateral warm, congested, red hands and feet with painful burning sensations, particularly in the forefoot sole and one or more toes. The lower extremities are affected more often and only one side may be involved. The pain is initiated by standing, exercise, or warmth and relieved by elevation and cooling. In extreme situations, acrocyanosis and gangrene may result. Arterial thrombosis is more common than venous thrombosis and may involve the coronary and renal arteries. Deep venous thrombosis of the lower extremities and pulmonary embolism are the major sites for venous involvement. Other common venous sites include intra-abdominal venous thrombosis (portal and hepatic). People older than 60 years of age or those with prior history of thrombotic events have as much as a 25% chance of developing a cerebral, cardiac, or peripheral arterial thrombus and, less often, developing a pulmonary embolism or deep venous thrombosis.86,87 Conversion to acute leukemia is found in less than 10%.88 Symptoms related to microvascular thrombosis in the CNS include headache, dizziness with paresthesias, transient ischemic attacks, strokes, visual disturbances, and seizures. Major thrombotic events, not directly related to the platelet count, occur in about 20 to 30% of individuals with ET. Prior history of thrombotic events, advanced age, and duration of thrombocytosis are predictors of future thrombotic complications. Individuals older than age 60 are at greatest risk. Although thrombosis is the more common symptom, hemorrhage can also occur. Sites for bleeding include the GI tract, skin, mucous membranes, urinary tract, gums, teeth sockets after extraction, joints, eyes, and brain. GI bleeding may be mistaken for a duodenal ulcer. Hemorrhage is not severe and generally occurs in the presence of very high platelet counts; transfusions are required only occasionally. Bleeding and clotting may occur simultaneously, and individuals will not necessarily be “bleeders” or “clotters.” Evaluation and treatment Initial diagnosis is not difficult; as many as two-thirds of cases are diagnosed from a routine CBC. Secondary thrombocytosis also may occur as a moderate rise in the platelet count that resolves with treatment or resolution of the underlying condition. The World Health Organization requires that the following four criteria be met for a diagnosis of ET: (1) sustained platelet count of at least 450 × 109/L; (2) bone marrow biopsy showing proliferation of enlarged mature megakaryocytes and no increase of granulocyte or erythrocyte precursors; (3) failure to meet the criteria of PV, myelofibrosis, CML, or other myelodysplastic syndrome; and (4) presence of JAK2 617F or another clonal marker or evidence of reactive thrombocytosis.89 Since ET can be mistaken for CML, careful differentiation is necessary because treatment varies significantly. Treatment of ET is directed toward preventing thrombosis or hemorrhage.90 Reducing the platelet count remains a significant treatment issue. Hydroxyurea (Hydrea), a nonalkylating myelosuppressive agent, has been the medication of choice to suppress platelet production; however, long-term use may cause progression to other myeloplastic disorders, particularly AML or myelofibrosis.90 Another medication used to treat ET is interferon (IFN). IFN has a response rate of 80% but may not be effective for everyone because of side effects. Anagrelide (Agrylin) is now the medication of choice. Anagrelide interferes with platelet maturation rather than production, thus not interfering with red and white blood cell growth and development. Low-dose Aspirin may be effective to alleviate erthromyalgia and transient neurological manifestations. ET is not necessarily considered life-threatening, but in those older than age 60 and who have had previous incidences of thrombosis, complications are more common and associated with a higher risk of mortality.

Alterations of Platelet Function Qualitative alterations in platelet function are characterized by an increased bleeding time in the presence of a normal platelet count. Associated clinical manifestations include spontaneous petechiae and purpura, and bleeding from the GI tract, genitourinary tract, pulmonary mucosa, and gums. Congenital alterations

in platelet function (thrombocytopathies) are quite rare.91 Acquired disorders of platelet function are more common than congenital disorders and may be categorized into three principal causes: (1) medications, (2) systemic inflammatory conditions, and (3) hematological alterations. Multiple medications are known to interfere with platelet function in several ways: inhibition of platelet membrane receptors, inhibition of prostaglandin pathways, and inhibition of phosphodiesterase activity. Aspirin is the most commonly used medication that affects platelets. It irreversibly inhibits cyclooxygenase function for several days after administration. NSAIDs also affect cyclo-oxygenase, although in a reversible fashion. Systemic disorders that affect platelet function are chronic renal disease, liver disease, cardiopulmonary bypass surgery, and severe deficiencies of iron or folate and antiplatelet antibodies associated with autoimmune disorders. Hematological disorders associated with platelet dysfunction include chronic myeloproliferative disorders, MM, leukemias, and myelodysplastic syndromes and dysproteinemias.

Disorders of Coagulation Disorders of coagulation are usually caused by defects or deficiencies in one or more of the clotting factors. (The normal function of clotting factors is described in Chapter 20.) Qualitative or quantitative abnormalities interfere with or prevent the enzymatic reactions that transform clotting factors, circulating as plasma proteins, into a stable fibrin clot (see Figure 20-17). Some clotting factor defects are inherited and involve a deficiency in a single factor, such as the hemophilias and von Willebrand's disease. Other coagulation defects are acquired and tend to result from deficient synthesis of clotting factors by the liver. Causes include liver disease and dietary deficiency of vitamin K. Other coagulation disorders are attributed to pathological conditions that trigger coagulation inappropriately, engaging the clotting factors and causing detrimental clotting within blood vessels. For example, any cardiovascular abnormality that alters normal blood flow by acceleration, deceleration, or obstruction can create conditions in which coagulation proceeds within the vessels. An example of cardiovascular-related coagulation pathology is thromboembolic disease, in which blood clots obstruct blood vessels. Coagulation is also stimulated by the presence of tissue factor (TF) that is released by damaged or dead tissues. Vasculitis, or inflammation of the blood vessels, along with vessel damage activates platelets, which in turn activates the coagulation cascade. In extensive or prolonged vasculitis, blood clot formation can suppress mechanisms that normally control clot formation and dissolution, leading to clogging of the vessels. In each of these acquired conditions, normal hemostatic function proves detrimental to the body by consuming coagulation factors excessively or by overwhelming normal control of clot formation and breakdown (fibrinolysis) (see Figure 20-19).

Impaired Hemostasis Impaired hemostasis, or the inability to promote coagulation and the development of a stable fibrin clot, is commonly associated with liver dysfunction, which may be caused by either specific liver disorders or lack of vitamin K.

Vitamin K deficiency. Vitamin K, a fat-soluble vitamin, is required for the synthesis and regulation of prothrombin; the procoagulant factors (VII, IX, X); and the anticoagulant factors within the liver (proteins C and S).92 Unknown is the contribution of vitamin K to the overall supply by the intestinal flora. The primary source of vitamin K is found in green leafy vegetables. The most common cause of vitamin deficiency is parenteral nutrition in combination with antibiotics that destroy normal gut flora. Rarely is the deficiency caused by a lack of dietary intake; however, bulimia can suppress vitamin K–dependent activity. Parenteral administration of vitamin K is the treatment of choice and usually results in correction of the deficiency within 8 to 12 hours. Fresh frozen plasma also may be administered but is usually reserved for individuals with life-threatening hemorrhages or those who require emergency surgery.

Liver disease. Individuals who have liver disease (e.g., acute or chronic hepatocellular diseases, cirrhosis, vitamin K deficiency, or liver surgery) present with a broad range of hemostatic derangements that may be characterized by defects in the clotting or fibrinolytic systems and by platelet function. The hepatic parenchyma cells produce most of the factors involved in hemostasis; therefore, damage to the liver frequently results in diminished production of factors involved in clotting. Factor VII level is the first to decline after liver damage because of its rapid turnover. Factor IX levels are less affected and do not decline until the liver destruction is well advanced. The liver also is a major site for production of plasminogen and α2-antiplasmin of the fibrinolytic system, as well as thrombopoietin and the metalloprotease ADAMTS13. Diminished thrombopoietin may lead to thrombocytopenia from decreased platelet production. Decreased production of ADAMTS13 results in increased levels of large precursor molecules of von Willebrand factor, which leads to the formation of large aggregates of platelets. With severe liver disease, such as cirrhosis, most clotting factors are significantly depressed. Levels of clotting system regulators, such as antithrombin, protein C, protein S, and fibrinogen, also are diminished. The fibrolytic system is commonly active because of plasmin inhibitor and unaffected other activators. Thrombocytopenia occurs in affected individuals because of diminished thrombopoietin and ADAMTS13, as well as increased sequestration (pooling) of platelets in the spleen, which is frequently enlarged in cirrhosis and is associated with portal hypertension. Thus, these individuals may appear to have a condition similar to DIC (see “Consumptive Thrombohemorrhagic Disorders”). Treatment of hemostasis alterations in liver disease must be comprehensive to cover all aspects of dysfunctions. Fresh frozen plasma administration is the treatment of choice; however, not all individuals tolerate the volume needed to adequately replace all deficient factors. Alternative modalities include the addition of exchange transfusions and platelet concentration to plasma administration.

Consumptive Thrombohemorrhagic Disorders Consumptive thrombohemorrhagic disorders are a heterogeneous group of conditions that demonstrate the entire spectrum of hemorrhagic and thrombotic pathological findings. Symptoms range from the subtle to the devastating and generally are considered to be intermediary disease processes that complicate a vast number of primary disease states. These disorders are also characterized by confusion and controversy related to their diagnosis, treatment, and management. No one definition can cover all possible varieties of these disorders; however, in the clinical setting, DIC is most commonly used to describe a pathological condition that is associated with hemorrhage and thrombosis.

Disseminated intravascular coagulation. Disseminated intravascular coagulation (DIC) is an acquired clinical syndrome characterized by widespread activation of coagulation resulting in formation of fibrin clots in medium and small vessels or microvasculature throughout the body.93 Widespread clotting may lead to blockage of blood flow to organs, resulting in multiple organ failure. The magnitude of clotting may result in consumption of platelets and clotting factors, leading to a tendency to bleed despite widespread clots. The clinical course of DIC is largely determined by the stimulus intensity, host response, and comorbidities, and ranges from an acute, severe, life-threatening process that is characterized by massive hemorrhage and thrombosis to a chronic, low-grade condition. The chronic condition is characterized by subacute hemorrhage and diffuse microcirculatory thrombosis. DIC may be localized to one specific organ or generalized, involving multiple organs. The diagnosis of DIC has been confusing and difficult because of the complexity and wide variations in clinical manifestations. Minimally acceptable diagnostic criteria have been established and include a systemic thrombohemorrhagic disorder with laboratory evidence of (1) clotting activation, (2) fibrinolytic activation, (3) coagulation inhibitor consumption, and (4) biochemical evidence of end-organ damage or failure. DIC is secondary to a wide variety of well-defined clinical conditions, specifically those capable of activating the clotting cascade. Sepsis is the most common condition associated with DIC. Gram-negative microorganisms, as well as some Gram-positive microorganisms, fungi, protozoa (malaria), and viruses

(influenza, herpes), are capable of precipitating DIC by causing damage to the vascular endothelium. Gram-negative endotoxins are the primary cause of endothelial damage; DIC may occur in up to 50% of individuals with Gram-negative sepsis. DIC occurs in approximately 10 to 20% of individuals with metastatic cancer or acute leukemia. The adenocarcinomas most frequently associated with DIC include the lung, pancreas, colon, and stomach.36 Direct tissue damage (e.g., massive trauma, extensive surgery, severe burns) also results in release of TF, an initiator of DIC, by the endothelium. Severe trauma, especially to the brain, can induce DIC. DIC occurs in about two-thirds of individuals with a systemic inflammatory response to trauma. Some complications of pregnancy also are associated with DIC; incidences range from 50% for women with placental abruptions to less than 10% for severe preeclampsia. Other causes of DIC have been identified, most notably blood transfusion. Transfused blood dilutes the clotting factors, as well as circulating naturally occurring antithrombins. In hemolytic transfusion reactions, the endothelium is damaged by complement-mediated reactions. Pathophysiology The coagulation system is designed to function at local areas of vascular damage, resulting in cessation of bleeding and activation of repair to the vessels. The function of clotting is to prevent excessive blood loss, and the function of fibrinolysis is to ensure easy circulation within the vasculature (see Chapter 20). DIC results from abnormally widespread and ongoing activation of clotting—coagulopathy—in small and mid-size vessels that alters the microcirculation, leading to ischemic necrosis in various organs, particularly the kidney and lung. Concomitantly, DIC can be caused by the imbalance between the coagulant system and the fibrinolytic system (which generates plasmin) to maintain normal circulation. DIC can cause widespread deposition of fibrin in the microcirculation that leads to ischemia, microvascular thrombotic obstruction, and organ failure (Figure 21-19).

FIGURE 21-19

Pathophysiology of Disseminated Intravascular Coagulation. See text.

Seemingly paradoxical, DIC involves both widespread clotting and bleeding because of simultaneous procoagulant activation, fibrinolytic activation, and consumption of platelets and coagulation factors, which results directly in serious bleeding (see Figure 21-19). DIC is not a disease but is secondary to a variety of conditions (Box 21-2) because of activation of the

clotting cascade. The common pathway for DIC appears to be excessive and widespread exposure to TF. This may occur by several mechanisms: (1) damage to the vascular endothelium results in exposure to TF; (2) when stimulated by inflammatory cytokines, endothelial cells and monocytes express surface TF; (3) endotoxin triggers the release of many cytokines that can both promote and cause progression of DIC; (4) sepsis is associated with many cytokines, interleukins, and platelet-activating factor that promote DIC as well as activate endothelial cells that stimulate thrombi development; and (5) TF may be released directly into the bloodstream from circulating white blood cells.

Box 21-2

Conditions Associated With DIC Malignancy: acute myelocytic leukemia, metastatic solid tumours (pancreas, prostate) Infections: bacterial (Gram-negative endotoxin, Gram-positive mucopolysaccharides), viral (hepatitis, CMV, dengue, HIV), fungal, parasitic, rickettsial Pregnancy complications: eclampsia/pre-eclampsia, placental abruption, amniotic fluid embolism, dead fetus syndrome Severe trauma: head injury, burns, crush injuries, tissue necrosis, severe hypo- or hyperthermia Liver disease: obstructive jaundice, acute liver failure, fatty liver of pregnancy Intravascular hemolysis: transfusion reactions, medication-induced hemolysis, viper snake bites, graft versus host disease Medical devices: aortic balloon, prosthetic devices Hypoxia and low blood flow states: arterial hypotension secondary to shock, cardiopulmonary arrest Vascular disorders: Giant hemangiomas (Kasabach-Merritt syndrome), aortic aneurysms CMV, cytomegalovirus; DIC, disseminated intravascular coagulation; HIV, human immunodeficiency virus. TF binds clotting factor VII, which leads to conversion of prothrombin to thrombin and formation of fibrin clots (see Figure 20-19). This pathway appears to be the primary route by which DIC is initiated. Not only is the clotting system extensively activated in DIC, but also the activities of the predominant natural anticoagulants (TF pathway inhibitor, antithrombin III, protein C) are greatly diminished. During DIC, the activation of clotting is prolonged and is a result of certain conditions (e.g., bacteremia or endotoxemia); thrombin generation is increased and is insufficiently balanced by impaired anticoagulant systems, such as antithrombin and protein C.94 The overall result is fibrin generation and deposition in the vascular system. In early DIC, plasmin (naturally occurring clot busting or fibrinolytic agent) produced from endothelial cells causes fibrinolysis to maintain circulation. Bleeding can occur with excess fibrinolytic activity. However, fibrinolysis becomes blunted by high levels of plasminogen activator inhibitor-1 (PAI-1), a fibrinolytic inhibitor.94 Over time the activity of plasmin is diminished by PAI-1. Although some fibrinolytic activity remains, the level is inadequate to control the systemic deposition of fibrin. The slow breakdown of fibrin by plasmin produces fibrin split products (FSPs) (also known as fibrin degradation products [FDPs]). These products are powerful anticoagulants that are normally removed from blood by fibronectin and macrophages. FSPs, along with thrombin, induce further cytokine release from monocytes, contributing to endothelial damage and TF release. During DIC, the presence of FSPs is prolonged possibly because of diminished production of fibronectin. Fibronectin is a glycoprotein with adhesive properties that mediates removal of particulate matter, such as fibrin clumps. Low levels of fibronectin suggest a poor prognosis. Although thrombosis is generalized and widespread, individuals with DIC are paradoxically at risk for hemorrhage. Hemorrhage is secondary to the abnormally high consumption of clotting factors and platelets, as well as the anticoagulant properties of FSPs, which interfere with fibrin mesh formation or polymerization. Both thrombin and FSPs have a high affinity for platelets and cause platelet activation

and aggregation—an event that occurs early in the development of DIC—which facilitates microcirculatory coagulation and obstruction in the initial phase. However, platelet consumption exceeds production, resulting in a thrombocytopenia that increases bleeding. Activation of clotting also leads to activation of other inflammatory pathways, including the kallikrein– kinin and complement systems (see Chapter 6). Factor XIIa, generated in DIC, converts prekallikrein to kallikrein, which then activates the vasoactive peptides bradykinin and kallidin. Activation of these systems contributes to increased vascular permeability, hypotension, and shock. Activated complement components also induce platelet destruction, which initially contributes to the thrombosis and later to the thrombocytopenia. The deposition of fibrin clots in the circulation interferes with blood flow, causing widespread organ hypoperfusion. This condition may lead to ischemia, infarction, and necrosis, further potentiating and complicating the existing DIC process by causing further release of TF and eventually organ failure. Manifestations of multisystem organ dysfunction and failure ultimately result. In addition to initiation of clotting by TF, DIC may be precipitated by direct proteolytic activation of factor X. The proteolytic activation of factor X has been described as “thrombin mimicry” and is the result of proteases directly converting fibrinogen to fibrin. These proteases may come from snake venom, some tumour cells, or the pancreas and liver, where they are respectively released during episodes of pancreatitis and various stages of liver disease. Direct proteolytic activity appears to be independent of any type of damage to the endothelium or tissue. Whatever initiates the process of DIC, the cycle of thrombosis and hemorrhage persists until the underlying cause of the DIC is removed or appropriate therapeutic interventions are used. Clinical manifestations Clinical signs and symptoms of DIC present a wide spectrum of possibilities, depending on the underlying disease process that initiates DIC and whether the DIC is acute or chronic in nature (Box 213). Most symptoms are the result of either bleeding or thrombosis. Acute DIC presents with rapid development of hemorrhaging (oozing) from venipuncture sites, arterial lines, or surgical wounds or development of ecchymotic lesions (purpura, petechiae) and hematomas. Other sites of bleeding include the eyes (sclera, conjunctiva), the nose, and the gums. Most individuals with DIC demonstrate bleeding at three or more unrelated sites, and any combination may be observed. Shock of variable intensity, out of proportion to the amount of blood loss, also may be observed. Hemorrhaging into closed compartments of the body also can occur and may precede the development of shock.

Box 21-3

Clinical Manifestations Associated With DIC Integumentary System Widespread hemorrhage and vascular lesions Oozing from puncture sites, incisions, mucous membranes Acrocyanosis (irregular-shaped cyanotic patches) Gangrene

Central Nervous System Subarachnoid hemorrhage Altered state of consciousness (slight confusion to convulsions and coma)

Gastro-Intestinal System

Occult bleeding to massive gastro-intestinal bleeding Abdominal distension Malaise Weakness

Pulmonary System Pulmonary infarctions ARDS Cyanosis Tachypnea Hypoxemia

Renal System Hematuria Oliguria Renal failure ARDS, acute respiratory distress syndrome; DIC, disseminated intravascular coagulation. Manifestations of thrombosis are not always as evident, even though it is often the first pathological alteration to occur. The initial observations may be bleeding and sometimes very extensive hemorrhage. Several organ systems are susceptible to microvascular thrombosis associated with dysfunction: cardiovascular, pulmonary, central nervous, renal, and hepatic systems. Acute and accurate clinical interpretations are critical to preventing progression of DIC that may lead to multisystem organ dysfunction and failure. (Multiple organ dysfunction syndrome is discussed further in Chapter 24.) Indicators of multisystem dysfunction include changes in level of consciousness or behaviour, confusion, seizure activity, oliguria, hematuria, hypoxia, hypotension, hemoptysis, chest pain, and tachycardia. Symmetrical cyanosis of fingers and toes (blue finger/toe syndrome), nose, and breast may be observed and indicates macrovascular thrombosis. This may lead to infarction and gangrene that may require amputation. Jaundice also is observed and most likely results from red blood cell destruction rather than liver dysfunction. Individuals with chronic or low-grade DIC do not present with the overt manifestations of hemorrhaging and thrombosis but instead have subacute bleeding and diffuse thrombosis; these individuals are described as having compensated DIC, or nonovert DIC. The major characteristic of this state is an increased turnover and decreased survival time of the components of hemostasis: platelets and clotting factors. Occasionally, diffuse or localized thrombosis develops, but this outcome is infrequent. Evaluation and treatment No single laboratory test can be used to effectively diagnose DIC. Diagnosis is based primarily on clinical symptoms and confirmed by a combination of laboratory tests. The person must present with a clinical condition that is known to be associated with DIC. The most commonly used combination of laboratory tests usually confirms thrombocytopenia or a rapidly decreasing platelet count on repeated testing, prolongation of clotting times, the presence of FSPs, and decreased levels of coagulation inhibitors. Platelet counts below 100 × 109/L or a progressive decrease in platelet counts is very sensitive for DIC, although not highly specific. These changes usually indicate consumption of platelets. The standard coagulation tests (e.g., prothrombin time [PT], activated partial thromboplastin time [aPTT]) also have a high degree of sensitivity, but they are not highly specific for DIC. As a result of consumption of circulating clotting factors, these tests are usually abnormal, ranging from shortened to prolonged times. However, conditions other than DIC may prolong clotting times. Detection of FSPs is more specific for DIC. Detection of D-dimers is a widely used test for DIC. A D-

dimer is a molecule produced by plasmin degradation of cross-linked fibrin in clots. D-dimers in the blood can be quantified using ELISA tests that include commercially available and highly specific monoclonal antibody against the D-dimer. Agglutination tests for other FSPs are available. Levels of FSPs are elevated in the plasma in 95 to 100% of cases; however, they are less specific and only document the presence of plasmin and its action on fibrin. ELISAs for markers of thrombin activity are sometimes used. Levels of coagulation inhibitors (e.g., antithrombin III [AT-III], protein C) can be measured by assays that rely on function or by ELISAs that quantify the amount of the specific inhibitor. AT-III levels can provide key information for diagnosing and monitoring therapy of DIC. Initial levels of functional AT-III are low in DIC because thrombin is irreversibly complexed with activated clotting factors and AT-III. Treatment of DIC is directed toward (1) eliminating the underlying pathological condition, (2) controlling ongoing thrombosis, and (3) maintaining organ function. Elimination of the underlying pathological condition is the initial intervention in the treatment phase to remove the trigger for activation of clotting. Once the stimulus is gone, production of coagulation factors in the liver leads to restoration of normal plasma levels within 24 to 48 hours. Control of thrombosis is more difficult to attain. Heparin has been used for this purpose; however, its use is controversial because its mechanism of action is binding to and activating AT-III, which is deficient in many types of DIC. Currently, heparin is only indicated in certain types of situations related to DIC. For instance, heparin seems to be effective in DIC caused by a retained dead fetus or associated with acute promyelocytic leukemia. Organ function is compromised by microthrombi, and there is a risk of losing an extremity because of vascular occlusion; thus heparin is also indicated in these conditions. However heparin's usefulness for DIC that is precipitated by septic shock has not been established and so is contraindicated in that instance; heparin is also contraindicated when there is evidence of postoperative bleeding, peptic ulcer, or CNS bleeding. Replacement of deficient coagulation factors, platelets, and other coagulation elements is gaining recognition as an effective treatment modality. This treatment modality is not without controversy, however, because a major concern with replacement therapy is the possible risk of adding components that will increase the rate of thrombosis. Clinical judgement is the key factor in determining whether replacement is to be used as a treatment modality. Several clinical trials are evaluating replacement of anticoagulants (i.e., AT-III, protein C). Replacement of AT-III appears to be effective in DIC caused by sepsis. Low levels of AT-III correlate with sepsisinitiated DIC, which makes a case for its use. AT-III inactivates thrombin, factor Xa, factor IXa, and other activated components of the clotting system. Heparin augments AT-III, but the effectiveness of the combination of heparin with AT-III replacement has not been established. Antifibrinolytic medications also are used in treatment but are limited to instances of life-threatening bleeding that have not been controlled by blood component replacement therapy. Maintenance of organ function is achieved by fluid replacement to sustain adequate circulating blood volume and maintain optimal tissue and organ perfusion. Fluids may be required to restore blood pressure, cardiac output, and urine output to normal parameters.

Thromboembolic Disorders Certain conditions within the blood vessels predispose an individual to develop clots spontaneously. A stationary clot attached to the vessel wall is called a thrombus (Figure 21-20). A thrombus is composed of fibrin and blood cells and can develop in either the arterial or the venous system. Arterial thrombi form under conditions of high blood flow and are composed mostly of platelet aggregates held together by fibrin strands. Venous thrombi form under conditions of low flow and are composed mostly of red blood cells with larger amounts of fibrin and few platelets.

FIGURE 21-20

Thrombus. Thrombus arising in valve pocket at upper end of superficial femoral vein (arrow). Postmortem clot on the right is shown for comparison. (From McLachlin, J., & Paterson, J.C. [1951]. Surg Gynecol Obstet, 93[1], 1–8.)

A thrombus eventually reduces or obstructs blood flow to tissues or organs, such as the heart, brain, or lungs, depriving them of essential nutrients critical to survival. A thrombus also has the potential of detaching from the vessel wall and circulating within the bloodstream (referred to as an embolus). The embolus may become lodged in smaller blood vessels, blocking blood flow into the local tissue or organ and leading to ischemia. Whether episodes of thromboembolism are life-threatening depends on the site of vessel occlusion. Therapy consists of removal or dissolution of the clot and supportive measures. Anticoagulant therapy is effective in treating or preventing venous thrombosis; it is not as useful in treating or preventing arterial thrombosis. Parenteral heparin is the major anticoagulant used to treat thromboembolism. Oral warfarin (Coumadin) medications also are widely used, including a newer direct factor Xa inhibitor (rivaroxaban [Xarelto]). More aggressive therapy may be indicated for such conditions as pulmonary embolism, coronary thrombosis, or thrombophlebitis. Streptokinase (Kabikinase), tissue plasminogen activator (Alteplase) (t-PA), and urokinase (Kinlytic) activate the fibrinolytic system and are administered to accelerate the lysis of known thrombi. These medications are known as fibrinolytic or thrombolytic therapy and are prescribed with a high degree of caution because they can cause hemorrhagic complications. The risk of developing spontaneous thrombi is related to several factors, referred to as the Virchow triad: (1) injury to the blood vessel endothelium, (2) abnormalities of blood flow, and (3) hypercoagulability of the blood. The role of estrogens as a cause of thrombi has received much attention. Endothelial injury to blood vessels can result from atherosclerosis (plaque deposits on arterial walls) (see Chapter 24). Atherosclerosis initiates platelet adhesion and aggregation, promoting the development of atherosclerotic plaques that enlarge, causing further damage and occlusion. Other causes of vessel endothelial injury may be related to hemodynamic alterations associated with hypertension and turbulent blood flow. Injury also is caused by radiation injury, exogenous chemical agents (e.g., toxins from cigarette smoke), endogenous agents (e.g., cholesterol), bacterial toxins or endotoxins, or immunological mechanisms. Sites of turbulent blood flow in the arteries and stasis of blood flow in the veins are at risk for thrombus formation. In areas of turbulence, platelets and endothelial cells may be activated, leading to thrombosis. In sites of stasis, platelets may remain in contact with the endothelium for prolonged lengths of time, and clotting factors that would normally be diluted with fresh flowing blood are not diluted and may become activated. The most common clinical conditions that predispose to venous stasis and subsequent thromboembolic phenomena are major surgery (e.g., orthopedic surgery), acute myocardial infarction, heart failure, limb paralysis, spinal injury, malignancy, advanced age, the postpartum period, and bed rest longer than 1 week. Turbulence and stasis occur with ulcerated atherosclerotic plaques (myocardial infarction), hyperviscosity (polycythemia), and conditions with deformed red blood cells (sickle cell

anemia). Hypercoagulability, or thrombophilia, is the condition in which an individual is at risk for thrombosis, but by itself it is a rare cause of thrombosis. Hypercoagulability is differentiated according to whether it results from primary (hereditary) or secondary (acquired) causes.

Hereditary thrombophilias. Thrombophilias can result from both inherited conditions and, more commonly, acquired conditions.95 Several inherited conditions increase the risk of developing thrombosis, and most are autosomal dominant. Thus individuals who are homozygous for the mutation are at greatest risk for thrombosis. These inherited conditions include mutations in platelet receptors, coagulation proteins, fibrinolytic proteins, and other factors. The particular mutations that have been most strongly linked as risk factors for venous thrombosis or for arterial thrombosis leading to coronary artery disease or stroke include those that affect fibrinogen, prothrombin (G20210A variant), factor V (factor V Leiden) of the coagulation system, PAI-1 of the fibrinolytic system, the platelet receptor GPIIIa, and methylenetetrahydrofolate reductase (MTHFR), as well as mutations that result in excessive levels of homocysteine (hyperhomocysteinemia). Other inherited thrombophilias are risk factors mostly for venous thrombosis and include deficiencies in protein C, protein S, and AT-III.95,96 Factor V Leiden results from a single nucleotide mutation that confers partial resistance to inactivation by activated protein C, resulting in prolonged high levels of activated factor V (factor Va) and overproduction of thrombin. Although this mutation increases the risk for thrombosis, most individuals with factor V Leiden do not have clinically relevant thrombotic events. It is the most common hereditary thrombophilia and is primarily observed in individuals of European ancestry. It is observed in about 5% of the White population and in about 30% of individuals presenting with deep venous thrombosis or pulmonary embolism. Other hereditary thrombophilias are less common. Prothrombin mutation, which leads to high levels of circulating prothrombin, is observed in about 2 to 5% of individuals of European ancestry. It is, however, found in 5 to 10% of individuals presenting with thrombosis. MTHFR mutation leads to alterations in the metabolism of the amino acid homocysteine into methionine and abnormally elevated levels of that amino acid in the blood (hyperhomocysteinemia). Acquired hyperhomocysteinemia may result from deficiencies in vitamins B6 or B12, endocrine diseases (e.g., diabetes mellitus, hypothyroidism), PA, inflammatory bowel disease, renal failure, and therapy with some medications. Individuals with homocysteine levels greater than the 95th percentile are 2.5 times more likely to experience an episode of deep venous thrombosis. More than 100 different known mutations lead to defects of proteins C, protein S, and AT-III and increase the risk for venous thrombosis. Mutations may lead to either quantitative (low levels of protein) or qualitative (production of defective protein) changes. Tests to diagnose inherited thrombophilias include PT; PTT; and levels of protein C, protein S, and ATIII. More elaborate tests to detect precise mutations in factor V, prothrombin, or MTHFR may be indicated.

Acquired hypercoagulability. Deficiencies in proteins S and C and AT-III may be acquired and contribute to a hypercoagulable state.97 Conditions associated with an acquired protein deficiency include DIC, liver disease, infection, deep venous thrombosis, acute respiratory distress syndrome, L-asparaginase therapy, HUS, and TTP. The postoperative state also predisposes an individual to protein C or S deficiency; however, its role in contributing to deep venous thrombosis remains unclear. Acquired hypercoagulable states include antiphospholipid syndrome (APS).98 APS is an autoimmune syndrome characterized by autoantibodies against plasma membrane phospholipids and phospholipidbinding proteins. As with most autoimmune diseases, the predominantly affected individual is female and of reproductive age. Those with APS are at risk for both arterial and venous thrombosis and a variety of obstetrical complications, including pregnancy loss and pre-eclampsia/eclampsia. In severe cases the individual may die from recurrent major thrombus formation.99 The pathophysiology is related to autoantibodies directly reacting with platelets or endothelial cells (increasing the risk for thrombosis) or the placental surface (resulting in damage to the placenta). The predominant diagnostic tests measure

prolongation of laboratory blood coagulation tests related to an antibody inhibitor (lupus anticoagulant) and specific ELISAs for antibodies against phospholipids (e.g., anticardiolipin antibody) or proteins that bind to phospholipids (e.g., β2-glycoprotein I). Highly effective therapy (i.e., unfractionated or lowmolecular-weight heparin with low-dose Aspirin) is available to prevent the obstetrical complications.100

Quick Check 21-6 1. Compare and contrast thrombocytopenia with thrombocytosis. 2. Why does vitamin K deficiency predispose an individual to a coagulation disorder? 3. Identify three pathological causes of DIC, and describe the manifestations associated with DIC. 4. Compare and contrast a thrombus with an embolus.

Did You Understand? Alterations of Erythrocyte Function 1. Anemia is defined as a reduction in the number or volume of circulating red blood cells or a decrease in the quality or quantity of hemoglobin. 2. The most common classification of anemias is based on changes in the cell size—represented by the cell suffix -cytic—and changes in the cell's hemoglobin content—represented by the suffix chromic. 3. Clinical manifestations of anemia can be found in all organs and tissues throughout the body. Decreased oxygen delivery to tissues causes fatigue, dyspnea, syncope, angina, compensatory tachycardia, and organ dysfunction. 4. Macrocytic (megaloblastic) anemias are characterized by unusually large stem cells in the marrow that mature into very large erythrocytes. Macrocytic anemias are caused most commonly by deficiencies of vitamin B12 or folate. Pernicious anemia, the most common type of macrocytic anemia, can be fatal unless vitamin B12 replacement is given (lifelong replacement is required). 5. Microcytic-hypochromic anemias are characterized by abnormally small red blood cells with insufficient hemoglobin content. The most common cause is iron deficiency. 6. Iron deficiency anemia (IDA) is the most common type of anemia worldwide and usually develops slowly, with a gradual, insidious onset of symptoms, including fatigue, weakness, dyspnea, alteration of various epithelial tissues, and vague neuromuscular complaints. 7. IDA is usually a result of a chronic blood loss or decreased iron intake. Once the source of blood loss is identified and corrected, iron replacement therapy can be initiated. 8. Sideroblastic anemias (SAs) are a heterogeneous group of inherited and acquired disorders. SAs have various causes, but all share altered heme synthesis. 9. Normocytic-normochromic anemias are characterized by insufficient numbers of normal erythrocytes. Included in this category are aplastic, posthemorrhagic, hemolytic, and anemia of chronic inflammation.

Myeloproliferative Red Blood Cell Disorders 1. Polycythemia vera (PV) is a stem cell disorder with hyperplastic and neoplastic bone marrow alterations. It is characterized by excessive proliferation of erythrocyte precursors (frequently with increased white blood cells and platelets) in the bone marrow. Polycythemia is responsible for most of the clinical symptoms, including increased blood volume and viscosity. Frequent phlebotomies reduce iron levels, and hydroxyurea is the medication of choice for myelosuppression. Use of radioactive phosphorus has been helpful in decreasing the excessive red blood cell pool. 2. PV may spontaneously convert to acute myeloid (or myelogenous) leukemia.

Alterations of Leukocyte Function 1. Quantitative alterations of leukocytes (too many or too few) can be caused by bone marrow dysfunction or premature destruction of cells in the circulation. Many quantitative changes in leukocytes occur in response to invasion by microorganisms. 2. Leukocytosis is a condition in which the leukocyte count is higher than normal; it is usually a response to physiological stressors and invasion of microorganisms. 3. Leukopenia is present when the leukocyte count is lower than normal; it is caused by pathological conditions, such as malignancies and hematological disorders. 4. Granulocytosis (particularly as a result of an increase in neutrophils, eosinophils, or basophils)

occurs in response to infection and inflammation. 5. Granulocytopenia, a significant decrease in the number of neutrophils, can be a life-threatening condition if sepsis occurs; it is often caused by chemotherapeutic agents, severe infection, and radiation. 6. Eosinophilia results most commonly from allergic disorders, parasitic invasion, and ingestion or inhalation of toxic foreign particles. 7. Basophilia is rare and generally is a response to inflammation and immediate hypersensitivity reactions. Basopenia is a decrease in circulating numbers of basophils. 8. Monocytosis is an increase in the number of circulating monocytes and is often transient. It occurs during the late or recuperative phase of infection. Monocytopenia is a decrease in the number of circulating monocytes. 9. Lymphocytopenia is a decrease in the number of circulating lymphocytes in the blood. It is associated with neoplasias, immune deficiencies, and destruction by medications, viruses, or radiation. 10. Infectious mononucleosis (IM) is an acute infection of B cells most commonly (85% of IM cases) associated with the Epstein-Barr virus (EBV). The classic symptoms are pharyngitis, lymphadenopathy, and fever. The proliferation of infected B cells may be uncontrolled and lead to B-cell lymphomas. 11. Transmission of EBV is usually through saliva from close personal contact. IM is self-limiting, and treatment consists of rest and symptomatic treatment. 12. The common pathological feature of all forms of leukemia is an uncontrolled proliferation of malignant leukocytes, causing an overcrowding of bone marrow and decreased production and function of normal hematopoietic cells. 13. The classification of leukemias is based on the cell type involved—myeloid or lymphoid—and the rate of progression—acute or chronic. There are four major types of leukemia: (a) acute lymphocytic leukemia (ALL), (b) acute myeloid (or myelogenous) leukemia (AML), (c) chronic lymphocytic leukemia (CLL), and (d) chronic myeloid (or myelogenous) leukemia (CML). 14. Although the exact cause of leukemia is unknown, several risk factors and related genetic aberrations are associated with the onset of malignancy. The leukemias are clonal disorders driven by genetically abnormal stem-like cancer cells. 15. Abnormal immature white blood cells, called blasts, fill the bone marrow and spill into the blood. The blasts overcrowd the marrow and cause cellular proliferation of the other cell lines to cease. 16. The major clinical manifestations of leukemia include fatigue caused by anemia, bleeding caused by thrombocytopenia, fever secondary to infection, anorexia, and weight loss. 17. Treatment varies depending on the type of leukemia and includes observation, steroids, chemotherapy, monoclonal antibodies, and transplant options. 18. Chronic leukemias progress slowly and insidiously, different from acute leukemias (which can have an abrupt stormy onset).

Alterations of Lymphoid Function 1. Lymphadenopathy is characterized by enlarged lymph nodes. 2. Lymphomas consist of a diverse group of neoplasms that develop from the proliferation of malignant lymphocytes in the lymphoid system. There are three major categories of lymphomas: (a) B-cell neoplasms, (b) T-cell and natural killer (NK)–cell neoplasms, and (c) the two general categories of Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). 3. In general, lymphomas are the result of genetic mutations or viral infection. Malignant transformation produces a cell with uncontrolled and excessive growth that accumulates in the lymph nodes and other sites, producing tumour masses. 4. HL is characterized by the presence of B cells called the Reed-Sternberg cells. 5. The pathogenesis of HL may be linked to infection with EBV. 6. An enlarged, painless mass or swelling, most commonly in the neck, is an initial sign of HL; however, asymptomatic lymphadenopathy can progress undetected for years.

7. Treatment of HL includes chemotherapy, radiation therapy, and surgery. Treatment with chemotherapy or radiation therapy, or both, may increase the risk for secondary cancers, cardiovascular disease, and other health problems for many months or years after treatment. 8. NHL is not a single disease, but a heterogeneous group of proliferative lymphoid tissue neoplasms. Clonal expansion of B cells accounts for the majority of NHLs. Oncogenes may be activated by chromosomal translocation (most common alteration) or by deletion of tumoursuppressor genes. Certain subtypes may have altered genomes by oncogenic viruses. 9. Generally, with NHL, the swelling of lymph nodes is painless and the nodes enlarge and transform over a period of months or years. 10. Standard treatment for NHL includes radiation therapy, chemotherapy, target therapy (monoclonal antibody therapy, proteasome inhibitor therapy), plasmapheresis, biological therapy, and watchful waiting. 11. Burkitt lymphoma is a B-cell tumour and involves the jaw and facial bones and sometimes the abdomen. Although more common in Africa, it is documented in Canada, the United States, Latin America, and other Western countries. Burkitt lymphoma is heterogeneous and may involve infection with EBV and suppression of the immune system by other illnesses. 12. Treatment for Burkitt lymphoma is intensive chemotherapy. 13. Multiple myeloma (MM) is a neoplasm of plasma cells in the bone marrow and usually not found in the peripheral blood. It is characterized by multiple malignant tumour masses of plasma cells scattered throughout the skeletal system (lytic bone lesions) and sometimes found in soft tissue. 14. MM tumours are highly heterogeneous and involve mutations in different signalling pathways. Chromosomal translocations are common. The exact cause of MM is unknown, but risk factors include radiation, certain chemicals, and a history of monoclonal gammopathy of undetermined significance (MGUS). 15. The common presentation of MM is characterized by elevated levels of calcium in the blood, renal failure, anemia, and bone (lytic) lesions. 16. Treatment includes chemotherapy, radiation therapy, plasmapheresis, and stem cell transplant.

Alterations of Splenic Function 1. Splenomegaly (enlargement of the spleen) may be considered normal in certain individuals, but its presence is associated with various diseases. 2. Splenomegaly results from (a) acute inflammatory or infectious processes, (b) congestive disorders, (c) infiltrative processes, and (d) tumours or cysts. 3. Hypersplenism (overactivity of the spleen) results from splenomegaly. Hypersplenism results in sequestering of the blood cells, causing increased destruction of red blood cells, leukopenia, and thrombocytopenia.

Hemorrhagic Disorders and Alterations of Platelets and Coagulation 1. The arrest of bleeding is called hemostasis. 2. Thrombocytopenia is characterized by a platelet count below 150 × 109/L of blood; the most significant count is less than 100 × 109/L, and a count less than 50 × 109/L increases the potential for hemorrhage associated with minor trauma. 3. Thrombocytopenia exists in primary or secondary forms and is associated with autoimmune diseases, viral infections, medications, nutritional deficiencies, chronic renal failure, cancer, radiation therapy, bone marrow hypoplasia, and disseminated intravascular coagulation (DIC). 4. Immune thrombocytopenic purpura (ITP) is the most common cause of thrombocytopenia, secondary to increased platelet destruction. 5. Thrombocythemia is characterized by a platelet count greater than 400 × 109/L of blood and is symptomatic when the count exceeds 1 000 × 109/L, at which time the risk for intravascular clot formation (thrombosis), hemorrhage, or other abnormalities can occur.

6. Essential (primary) thrombocythemia is a myeloproliferative neoplasm characterized by an increase in platelet production and often an increase in red blood cell production. 7. Qualitative alterations in normal platelet function prevent platelet plug formation and may result in prolonged bleeding times. Acquired disorders of platelet function are more common than congenital disorders. 8. Disorders of coagulation are usually caused by defects or deficiencies in one or more of the clotting factors. Coagulation is stimulated by the presence of tissue factor that is released by damaged or dead tissues. 9. Coagulation is impaired when there is a deficiency of vitamin K because of insufficient production of prothrombin and synthesis of clotting factors VII, IX, and X, often associated with liver diseases. 10. DIC is an acquired clinical syndrome characterized by widespread activation of coagulation, resulting in formation of fibrin clots in medium and small vessels or microvasculature throughout the body. Widespread clotting may lead to blockage of blood flow to organs, resulting in multiple organ failure. The magnitude of clotting may result in consumption of platelets and clotting factors, leading to a tendency to bleed despite widespread clots. 11. DIC is secondary to a wide variety of clinical conditions; sepsis is the most common condition associated with DIC. 12. For a diagnosis of DIC, the person must present with a clinical condition that is known to be associated with DIC. The most commonly used combination of laboratory tests usually confirms thrombocytopenia or a rapidly decreasing platelet count on repeated testing, prolongation of clotting times, the presence of fibrin split products, and decreased levels of coagulation inhibitors. 13. Treatment of DIC is directed toward (a) eliminating the underlying pathological condition, (b) controlling ongoing thrombosis, and (c) maintaining organ function. 14. Thromboembolic disorders result from a fixed (thrombus) or moving (embolus) clot that blocks flow within a vessel, denying nutrients to tissues distal to the occlusion; death can result when clots obstruct blood flow to the heart, brain, or lungs. 15. The term Virchow triad refers to three factors that can cause thrombus formation: (a) injury to the blood vessel endothelium, (b) abnormalities of blood flow, and (c) hypercoagulability of the blood. 16. Hypercoagulability, or thrombophilia, is a condition in which an individual is at risk for thrombosis.

Key Terms Absolute lymphocytosis, 531 Absolute polycythemia, 526 Acquired sideroblastic anemia (ASA), 525 Acute idiopathic TTP, 548 Acute leukemia, 533 Acute lymphocytic leukemia (ALL), 534 Acute myeloid (or myelogenous) leukemia (AML), 534 Agranulocytosis, 531 Amyloidosis, 544 Anemia, 520 Anisocytosis, 520 Arterial thrombus (pl. thrombi), 553 Basopenia, 531 Basophilia, 531 B-cell neoplasm, 540 Bence Jones protein, 543 β2-Microglobulin, 545 Blast cell, 533 Burkitt lymphoma, 541 Chronic leukemia, 533 Chronic lymphocytic leukemia (CLL), 536 Chronic myeloid (or myelogenous) leukemia (CML), 536 Chronic relapsing TTP, 548 Congestive splenomegaly, 545 Consumptive thrombohemorrhagic disorder, 550 D-dimer, 553 Disseminated intravascular coagulation (DIC), 550 Ecchymoses, 546 Embolus, 553 Eosinopenia, 531 Eosinophilia, 531 Epistaxis, 546 Eryptosis, 522 Erythromyalgia, 549 Essential (primary) thrombocythemia (ET), 549 Fibrin degranulation product (FDP), 552 Fibrin split product (FSP), 552 Folate (folic acid), 523 Granulocytopenia, 531 Granulocytosis, 530 Hematoma, 546 Hemochromatosis, 529 Hemolysis, 522 Hemostasis, 546 Heparin-induced thrombocytopenia (HIT), 547 Hereditary (congenital) sideroblastic anemia, 525 Hereditary hemochromatosis (HH), 529 Heterophilic antibody, 532 Hodgkin's lymphoma (HL), 539

Hypercoagulability (thrombophilia), 554 Hypersplenism, 545 Hypoplastic anemia, 526 Hypoxemia, 522 Immune thrombocytopenic purpura (ITP), 547 Impaired hemostasis, 550 Infectious mononucleosis (IM), 531 Infiltrative splenomegaly, 546 Intrinsic factor (IF), 523 Iron deficiency anemia (IDA), 524 Janus kinase 2 gene (JAK2 gene), 527 Koilonychia, 525 Leukemia, 532 Leukocytosis, 529 Leukopenia, 529 Lymphadenopathy, 538 Lymphoblastic lymphoma (LL), 542 Lymphocytopenia, 531 Lymphocytosis, 531 M protein, 543 Macrocytic (megaloblastic) anemia, 522 Microcytic-hypochromic anemia, 524 Microvasculature thrombosis, 549 Monoclonal gammopathy of undetermined significance (MGUS), 544 Monocytopenia, 531 Monocytosis, 531 Multiple myeloma (MM), 542 Myelodysplastic syndrome (MDS), 525 Myeloproliferative disorder, 536 Neutropenia, 531 Neutrophilia, 530 NK-cell neoplasm, 540 Non-Hodgkin's lymphoma (NHL), 540 Normocytic-normochromic anemia (NNA), 526 Palpable purpura, 546 Pancytopenia, 533 Pernicious anemia (PA), 522 Petechia, 546 Philadelphia chromosome, 533 Phlebotomy, 526 Poikilocytosis, 520 Polycythemia, 526 Polycythemia vera (PV; also primary polycythemia), 526 Purpura, 546 Reed-Sternberg (RS) cell, 539 Relative polycythemia, 526 Reversible sideroblastic anemia (reversible SA), 525 Ringed sideroblast, 525 Secondary thrombocythemia, 549 Shift to the left (leukemoid reaction), 530 Shift to the right, 531 Sideroblastic anemia (SA), 525 Small lymphocytic lymphoma (SLL; also CLL/SLL), 536

Smouldering myeloma, 544 Splenomegaly, 545 T-cell neoplasm, 540 Thrombocythemia (thrombocytosis), 548 Thrombocytopenia, 547 Thromboembolic disease, 546 Thrombosis, 546 Thrombotic thrombocytopenic purpura (TTP), 548 Thrombus, 553 Vasculitis, 550 Venus thrombus (pl. thrombi), 553 Virchow triad, 554

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22

Alterations of Hematological Function in Children Joan Shea, Nancy E. Kline, Anna E. Roche, Kathryn L. McCance, Kelly Power-Kean

CHAPTER OUTLINE Disorders of Erythrocytes, 560 Acquired Disorders, 560 Inherited Disorders, 564 Disorders of Coagulation and Platelets, 569 Inherited Hemorrhagic Disease, 569 Antibody-Mediated Hemorrhagic Disease, 569 Neoplastic Disorders, 570 Leukemia, 570 Lymphomas, 571

Among the diseases that affect erythrocytes in children are acquired disorders, such as iron deficiency anemia and hemolytic disease of the newborn, and inherited disorders, such as glucose-6-phosphate dehydrogenase deficiency, sickle cell disease, and the thalassemias. Childhood disorders that involve the coagulation process and platelets include inherited hemorrhagic diseases, such as the hemophilias, and antibody-mediated hemorrhagic diseases, including immune thrombocytopenic purpura. Finally, leukocyte disorders, such as leukemia and the lymphomas (both Hodgkin's lymphoma [HL] and non-Hodgkin's lymphoma [NHL]), are discussed in this chapter.

Disorders of Erythrocytes Anemia is the most common blood disorder in children. Like the anemias of adulthood, the anemias of childhood are caused by ineffective erythropoiesis or premature destruction of erythrocytes. The most common cause of insufficient erythropoiesis is iron deficiency, which may result from insufficient dietary intake or chronic loss of iron caused by bleeding. The hemolytic anemias of childhood may be divided into (1) disorders that result from premature destruction caused by intrinsic abnormalities of the erythrocytes and (2) disorders that result from damaging extraerythrocytic factors. The hemolytic anemias are either inherited or acquired. The most dramatic form of acquired congenital hemolytic anemia is hemolytic disease of the newborn (HDN), also termed erythroblastosis fetalis. HDN is an alloimmunity (isoimmunity) disease in which maternal blood and fetal blood are incompatible, causing the mother's immune system to produce antibodies against fetal erythrocytes. Fetal erythrocytes attacked by (i.e., bound to) maternal antibodies are recognized as foreign or defective by the fetal mononuclear phagocyte system and are removed from the circulation by phagocytosis, usually in the fetal spleen. (For a complete examination of HDN, see the discussion in “Hemolytic Disease of the Newborn.”) Other acquired hemolytic anemias—some of which begin in utero—include those caused by infections or the presence of toxic chemicals. The inherited forms of hemolytic anemia result from intrinsic defects of the child's erythrocytes, any of which can lead to erythrocyte removal by the mononuclear phagocyte system. Structural defects include abnormal cellular size or shape and abnormalities of plasma membrane structure (spherocytosis). Intracellular defects include enzyme deficiencies, the most common of which is glucose-6-phosphate dehydrogenase (G6PD) deficiency, and defects of hemoglobin synthesis, which manifest as sickle cell disease or thalassemia, depending on which component of hemoglobin is defective. These and other causes of childhood anemia are listed in Table 22-1. TABLE 22-1 Anemias of Childhood Cause Deficient Erythropoiesis or Hemoglobin Synthesis Decreased stem cell population in marrow (congenital or acquired pure red cell aplasia) Decreased erythropoiesis despite normal stem cell population in marrow (infection, inflammation, cancer, chronic renal disease, congenital dyserythropoiesis) Deficiency of a factor or nutrient needed for erythropoiesis Cobalamin (vitamin B12), folate Iron Increased or Premature Hemolysis Alloimmune disease (maternal–fetal Rh, ABO, or minor blood group incompatibility) Autoimmune disease (idiopathic autoimmune hemolytic anemia, symptomatic systemic lupus erythematosus, lymphoma, medication-induced autoimmune processes) Inherited defects of plasma membrane structure (spherocytosis, elliptocytosis, stomatocytosis) or cellular size or both (pyknocytosis) Infection (bacterial sepsis, congenital syphilis, malaria, cytomegalovirus infection, rubella, toxoplasmosis, disseminated herpes) Intrinsic and inherited enzymatic defects (deficiencies) of glucose-6-phosphate dehydrogenase, pyruvate kinase, 5′-nucleotidase, glucose phosphate isomerase Inherited defects of hemoglobin synthesis Disseminated intravascular coagulation (see Chapter 21) Galactosemia Prolonged or recurrent respiratory or metabolic acidosis Blood vessel disorders (cavernous hemangiomas, large vessel thrombus, renal artery stenosis, severe coarctation of aorta)

Anemic Condition Normocytic-normochromic anemia Normocytic-normochromic anemia Megaloblastic anemia Microcytic-hypochromic anemia Autoimmune hemolytic anemia Autoimmune hemolytic anemia Hemolytic anemia Hemolytic anemia Hemolytic anemia Sickle cell anemia Thalassemia Hemolytic anemia Hemolytic anemia Hemolytic anemia Hemolytic anemia

Acquired Disorders Iron Deficiency Anemia Iron is critical to the developing child, especially for normal brain development. Without it the damage from the periods of iron deficiency anemia (IDA) in children is irreversible. The prevalence of IDA in Canadian children among the general population is low (3.5 to 10.5%); however, there are certain Indigenous populations in Canada in whom the prevalence is very high (14 to 50%). IDA is the most common nutritional disorder worldwide, with the highest incidence occurring between 6 months and 2

years of age. IDA is common in Canada with prevalence higher in toddlers, adolescent girls, and women of childbearing age.1 IDA causes clinical manifestations mostly related to inadequate hemoglobin synthesis.2 IDA can result from (1) dietary lack of iron, (2) problems with iron absorption, (3) blood loss, and (4) increased requirement for iron. Inadequate intake of iron is the most common cause of IDA during the first few years of life. Blood loss is the most common cause during childhood and adolescence, and for adults in the Western world. Chronic IDA from occult (hidden) blood loss may be caused by a gastrointestinal lesion, parasitic infestation, or hemorrhagic disease. A reasonable hypothesis for infants and young children who develop IDA is that it occurs because of chronic intestinal blood loss induced by exposure to a heat-labile protein in cow's milk. Such exposure causes an inflammatory gastro-intestinal reaction that damages the mucosa and results in diffuse microhemorrhage. Growing evidence indicates that cellular components of both innate and adaptive immunity play significant roles during the pathogenesis of cow's milk allergy.3 Dietary lack of iron is not common in developed countries, where iron is in the readily absorbed form from heme found in meat. IDA was recently found in Israel, mainly in children 1.5 to 3 years old, and was associated with low red meat intake.4 In developing countries, food may be less available and the iron found in plants is in the poorly absorbable inorganic form.1 Infants are at increased risk for IDA because of very small amounts of iron in milk. Bioavailability of iron from breast milk is higher than that from cow's milk. Impaired absorption is found in chronic diarrhea, fat malabsorption, and sprue (see Health Promotion: Prevention of Iron Deficiency Anemia in Infants and Children).

Health Promotion Prevention of Iron Deficiency Anemia in Infants and Children Studies have indicated that iron deficiency in infants and children is a public health concern within several Canadian populations. Certain Indigenous populations in Canada are affected by very high percentages of IDA, as are children of low socioeconomic status, children of Chinese background, lowbirthweight infants, and children who consume whole cow's milk prior to 12 months of age. Risk factors associated with severe iron deficiency include high consumption of evaporated milk and cow's milk after 6 months of age, prolonged exclusive breastfeeding, and Helicobacter pylori infection. Chronic severe IDA in the first years of life increases the risk for irreversible cognition problems as well as affective and motor development issues. IDA is a preventable disease that can be addressed through primary prevention efforts, including the promotion of breastfeeding or, alternatively, using fortified formula and infant cereal. It is recommended that healthy exclusively breastfed infants be supplemented with 1 mg/kg/day of oral iron beginning at 4 months of age until iron-containing foods are introduced. Whole milk should not be introduced before 12 months of age. In addition, the early introduction of red meat and higher iron content vegetables is recommended. Preterm infants who are fed human milk should receive an iron supplement of 2 mg/kg/day by 1 month of age until weaned to iron-fortified formula or beginning iron-containing foods. Data from Canadian Pediatric Surveillance Program. (2011). Iron deficiency anemia in children. Retrieved from http://www.cpsp.cps.ca/uploads/publications/RA-iron-deficiency-anemia.pdf.

Children in developing countries are often affected by chronic parasite infestations that result in blood and iron loss greater than dietary intake. Treatment of helminth (parasitic worm) infections results in improvement in both appetite and growth, as well as reduction of anemia. The association between IDA and lead poisoning is controversial. Newer areas of investigation include iron deficiency in overweight children and the association of Helicobacter pylori infection with IDA.5 Pathophysiology No matter the cause, a deficiency of iron produces a hypochromic-microcytic anemia.2 Progressive

depletion of blood and low serum levels of ferritin and transferrin saturation eventually lead to a lowering of hemoglobin and hematocrit levels. In the early stages, an adaptive increase in red blood cell activity in the bone marrow may prevent the development of anemia. When the iron stores are depleted, with accompanying important laboratory indicators, anemia develops. Clinical manifestations The symptoms of mild anemia—listlessness and fatigue—usually are not present or are undetectable in infants and young children, who are unable to describe these symptoms. Therefore, parents generally do not note any change in the child's behaviour or appearance until moderate anemia has developed. General irritability, decreased activity tolerance, weakness, and lack of interest in play are nonspecific indications of anemia. When hemoglobin levels fall below 50 mmol/L, pallor, anorexia, tachycardia, and systolic murmurs may occur. Other symptoms and signs of chronic IDA include splenomegaly, widened skull sutures, decreased physical growth, developmental delays, pica (a behaviour in which nonfood substances, such as clay, are eaten), and altered neurological and intellectual functions, especially those involving attention span, alertness, and learning ability. Evaluation and treatment The diagnosis of IDA is confirmed by laboratory tests. These tests include measurement of hemoglobin, hematocrit, serum iron, and ferritin levels and determination of the total iron binding capacity. Most essential is obtaining a thorough history of present illness and dietary history in addition to performing a complete physical examination. Evaluation and treatment of iron deficiency anemia in children is similar to that used for adults with IDA (see Chapter 21). Oral administration of a simple ferrous salt is usually satisfactory and additional vitamin C helps promote absorption.6 Iron in a liquid form should be administered through a straw because it can stain teeth. Dietary modification is required to prevent recurrences of IDA. Intake of iron-rich foods is increased, and the intake of cow's milk may be restricted.

Hemolytic Disease of the Newborn The most common cause of hemolytic anemia in newborns is alloimmune disease. Hemolytic disease of the newborn (HDN) (erythroblastosis fetalis) can occur only if antigens on fetal erythrocytes differ from antigens on maternal erythrocytes. Maternal–fetal incompatibility exists if mother and fetus differ in ABO blood type or if the fetus is Rh-positive and the mother is Rh-negative. Some minor blood antigens also may be involved (see Chapter 7). ABO incompatibility occurs in about 20 to 25% of all pregnancies, but only 1 in 10 cases of ABO incompatibility results in HDN. Rh incompatibility occurs in less than 10% of pregnancies and rarely causes HDN in the first incompatible fetus. Even after five or more pregnancies, only 5% of women have babies with hemolytic disease. Usually erythrocytes from the first incompatible fetus cause the mother's immune system to produce antibodies that affect the fetuses of subsequent incompatible pregnancies. Only one in three cases of HDN is caused by Rh incompatibility; most cases are caused by ABO incompatibility. Pathophysiology HDN will result (1) if the mother's blood contains preformed antibodies against fetal erythrocytes or produces them on exposure to fetal erythrocytes, (2) if sufficient amounts of antibody (usually immunoglobulin G [IgG]) cross the placenta and enter fetal blood, and (3) if IgG binds with sufficient numbers of fetal erythrocytes to cause widespread antibody-mediated hemolysis or splenic removal. (Antibody-mediated cellular destruction is described in Chapter 8.) Maternal antibodies may be formed against type B erythrocytes if the mother is type A or against type A erythrocytes if the mother is type B. Usually, however, the mother is type O and the fetus is A or B. ABO incompatibility can cause HDN even if fetal erythrocytes do not escape into the maternal circulation during pregnancy. HDN occurs because the blood of most adults already contains anti-A or anti-B antibodies, which are produced on exposure to certain foods or infection by Gram-negative bacteria. (Anti-O antibodies do not exist because type O erythrocytes are not antigenic.) Therefore, IgG against

type A or B erythrocytes is usually preformed in maternal blood and can enter the fetal circulation throughout the first incompatible pregnancy. Anti-Rh antibodies, on the other hand, are formed only in response to the presence of incompatible (Rh-positive) erythrocytes from the fetus in the blood of an Rh-negative mother. Sources of exposure include fetal blood that is mixed with the mother's blood at the time of delivery, transfused blood, and, rarely, previous sensitization of the mother by her own mother's incompatible blood (Figure 22-1).

FIGURE 22-1 Hemolytic Disease of the Newborn. A, Before or during delivery, Rh-positive erythrocytes from the fetus enter the blood of an Rh-negative woman through a tear in the placenta. B, The mother is sensitized to the Rh antigen and produces Rh antibodies. Because this sensitization usually happens after delivery, there is no effect on the fetus in the first pregnancy. C, During a subsequent pregnancy with an Rh-positive fetus, Rh-positive erythrocytes cross the placenta, enter the maternal circulation, and (D) stimulate the mother to produce antibodies against the Rh antigen. (Modified from Seeley, R.R., Stephens, T.D., Tate, P., et al. [1995]. Anatomy and physiology [3rd ed.]. St. Louis: Mosby.)

The first Rh-incompatible pregnancy generally presents no difficulties because few fetal erythrocytes cross the placental barrier during gestation. When the placenta detaches at birth, however, a large number of fetal erythrocytes usually enter the mother's bloodstream. If the mother is Rh-negative and the fetus is Rh-positive, the mother produces anti-Rh antibodies. Anti-Rh antibodies persist in the bloodstream for a long time, and if the next offspring is Rh-positive, the mother's anti-Rh antibodies can enter the bloodstream of the fetus and destroy the erythrocytes. Antibodies against Rh antigen D are of the IgG class and easily cross the placenta. IgG-coated fetal erythrocytes usually are destroyed in the spleen. As hemolysis proceeds, the fetus becomes anemic. Erythropoiesis accelerates, particularly in the liver and spleen, and immature nucleated cells (erythroblasts) are released into the bloodstream (hence the name erythroblastosis fetalis). The degree of anemia depends on the length of time the antibody has been in the fetal circulation, the concentration of the antibody, and the ability of the fetus to compensate for increased hemolysis. Unconjugated (indirect) bilirubin, which is formed during breakdown of hemoglobin, is transported across the placental barrier into the maternal circulation and is excreted by the mother. Hyperbilirubinemia occurs in the neonate after birth because excretion of lipid-soluble unconjugated bilirubin through the placenta is no longer possible. The pathophysiological effects of HDN are more severe in Rh incompatibility than in ABO

incompatibility. ABO incompatibility may resolve after birth without life-threatening complications. Maternal–fetal incompatibility in which a mother with type O blood has a child with type A or B blood usually is so mild that it does not require treatment. Rh incompatibility is more likely than ABO incompatibility to cause severe or even life-threatening anemia, death in utero, or damage to the central nervous system. Severe anemia alone can cause death as a result of cardiovascular complications. Extensive hemolysis also results in increased levels of unconjugated bilirubin in the neonate's circulation. If bilirubin levels exceed the liver's ability to conjugate and excrete bilirubin, some of it is deposited in the brain, causing cellular damage and, eventually, death if the neonate does not receive exchange transfusions. Fetuses that do not survive anemia in utero usually are stillborn, with gross edema in the entire body, a condition called hydrops fetalis. Death can occur as early as 17 weeks' gestation and results in spontaneous abortion. Clinical manifestations Neonates with mild HDN may appear healthy or slightly pale, with slight enlargement of the liver or spleen. Pronounced pallor, splenomegaly, and hepatomegaly indicate severe anemia, which predisposes the neonate to cardiovascular failure and shock. Life-threatening Rh incompatibility is rare today, largely because of the routine use of Rh immunoglobulin. Because the maternal antibodies remain in the neonate's circulatory system after birth, erythrocyte destruction can continue. This destruction causes hyperbilirubinemia and icterus neonatorum (neonatal jaundice) shortly after birth. Without replacement transfusions, in which the child receives Rh-negative erythrocytes, the bilirubin is deposited in the brain, a condition termed kernicterus. Kernicterus produces cerebral damage and usually causes death (icterus gravis neonatorum). Infants who do not die may have intellectual disabilities, cerebral palsy, or high-frequency deafness. Evaluation and treatment Routine evaluation of fetuses at risk for HDN (i.e., fetuses resulting from Rh- or ABO-incompatible matings) includes the Coombs test. The indirect Coombs test measures antibodies in the mother's circulation and indicates whether the fetus is at risk for HDN. The direct Coombs test measures antibodies already bound to the surfaces of fetal erythrocytes and is used primarily to confirm the diagnosis of antibody-mediated HDN. With a prior history of fetal hemolytic disease, diagnostic tests are done to determine risk with the current pregnancy. These tests include maternal antibody titres, fetal blood sampling, amniotic fluid spectrophotometry, and ultrasound fetal assessment. The key to treatment of HDN resulting from Rh incompatibility lies in prevention (immunoprophylaxis).7,8 One of the success stories of immunology has been the result obtained with Rh immune globulin (RhoGAM), a preparation of antibodies against Rh antigen D (anti-D Ig). If an Rhnegative woman is given Rh immune globulin within 72 hours of exposure to Rh-positive erythrocytes, she will not produce antibodies against the D antigen, and the next Rh-positive baby she conceives will be protected. Updated recommendations also state that if anti-D Ig is not given within 72 hours, every effort should still be made to administer the anti-D Ig within 10 days. The newer updates on the use of anti-D Ig as prophylaxis to prevent sensitization to the D antigen during pregnancy or at delivery for the prevention of HDN can be found at the Canadian Blood Services website at https://professionaleducation.blood.ca/en/transfusion/clinical-guide/hemolytic-disease-fetus-andnewborn-and-perinatal-immune-thrombocytopenia. The British Society for Haematology (BSH) Guideline (previously known as BCSH Guidelines) also provides guidance on the use of anti-D Ig for Rh D prophylaxis.8

Inherited Disorders Sickle Cell Disease Sickle cell disease is a group of disorders characterized by the production of abnormal hemoglobin S (Hb S) within the erythrocytes. Hb S is formed by a genetic mutation in which one amino acid (valine) replaces another (glutamic acid) (Figure 22-2). Hb S, the so-called sickle hemoglobin, reacts to

deoxygenation and dehydration by solidifying and stretching the erythrocyte into an elongated sickle shape, producing hemolytic anemia (see Figure 22-2).

FIGURE 22-2 Sickle Cell Hemoglobin. A, Sickle cell hemoglobin is produced by a recessive allele of the gene encoding the β-chain of the protein hemoglobin. It represents a single amino acid change—from glutamic acid to valine at the sixth position of the chain. In this model of a hemoglobin molecule, the position of the mutation can be seen near the end of the upper arm. B, Colour-enhanced electron micrograph shows normal erythrocytes and sickled blood cell. C, Brief summary of sickle cell. (A, from Raven, P.H., & Johnson, G.B. [1992]. Biology [3rd ed.]. St. Louis: Mosby; B, Dennis Kunkel Microscopy/Science Source; C, from Kierszenbaum, A., & Tres, L. [2012]. Histology and cell biology: An introduction to pathology [3rd ed.]. St. Louis: Mosby.)

Sickle cell disease is an inherited, autosomal recessive disorder expressed as sickle cell anemia, sickle cell–thalassemia disease, or sickle cell–hemoglobin C disease, depending on mode of inheritance (Table 22-2). (See Chapter 2 for a discussion of genetic inheritance of disease.) Sickle cell anemia, a homozygous form, is the most severe. Sickle cell–thalassemia disease and sickle cell–hemoglobin C disease are heterozygous forms in which the child simultaneously inherits another type of abnormal hemoglobin from one parent. Sickle cell trait, in which the child inherits Hb S from one parent and normal hemoglobin (Hb A) from the other, is a heterozygous carrier state that rarely has clinical manifestations. All forms of sickle cell disease are lifelong conditions. TABLE 22-2

Inheritance of Sickle Cell Disease Hemoglobin Inherited From First Parent

Hemoglobin Inherited From Second Parent

Hemoglobin (Hb) S (an abnormal hemoglobin) Hb S

Hb S

Hb S Hb S

Form of Sickle Cell Disease in Child

Sickle cell anemia: homozygous inheritance in which child's hemoglobin is mostly Hb S, with remainder Hb F (fetal hemoglobin) Defective or insufficient α- or β-chains of Hb A (α- Sickle cell–thalassemia disease (heterozygous inheritance of Hb S and α- or β-thalassemia) or β-thalassemia) Hb C or D (both abnormal hemoglobins) Sickle cell–hemoglobin C (or D) disease (heterozygous inheritance of hemoglobin S and either C or D) Normal hemoglobins (mostly Hb A) Sickle cell trait, carrier state (heterozygous inheritance of Hb S and normal hemoglobin)

Sickle cell disease is a genetically linked disease that tends to occur in persons with ancestors from parts of Africa, the Mediterranean, the Caribbean, and India. In Canada, it is estimated that 3 000 to 7 000 people have been diagnosed with the disease.9 The number of Canadian patients with sickle cell disease will continue to increase, related to high rates of immigration from countries with high prevalence. Improved outcomes for those affected by sickle cell disease are expected with advances in medical care. Sickle cell–hemoglobin C disease is less common (1 in 800 births), and sickle cell–thalassemia disease occurs in 1 in 1 700 births. Sickle cell trait occurs in 7 to 13% of Blacks, whereas its incidence among East Africans may be as high as 45%. The sickle cell trait may provide protection against lethal forms of malaria, a genetic advantage to carriers who reside in endemic regions for malaria (Mediterranean and African zones), but it provides no advantage to carriers living in North America. Pathophysiology Hb S is soluble and usually causes no problem when properly oxygenated. When oxygen tension decreases, the single amino acid substitution in the β-globin chain of Hb S polymerizes, forming abnormal fluid polymers. As these polymers realign, they cause the red blood cell to deform into the sickle shape. Sickling depends on the degree of oxygenation, pH, and dehydration of the individual. A decrease in oxygenation (hypoxemia) and pH, as well as dehydration, increases sickling. Deoxygenation is probably the most important variable in determining the occurrence of sickling.10 Sickle-trait cells sickle at oxygen tensions of about 15 mm Hg, whereas those from an individual with sickle cell disease begin to sickle at about 40 mm Hg. Sickled erythrocytes tend to plug the blood vessels, increasing the viscosity of the blood, which slows circulation and causes vascular occlusion, pain, and organ infarction. Viscosity increases the time of exposure to less oxygenation, promoting further sickling. Sickled cells undergo hemolysis in the spleen or become sequestered there, causing blood pooling and infarction of splenic vessels. The anemia that follows triggers erythropoiesis in the marrow and, in extreme cases, in the liver (Figure 22-3).

FIGURE 22-3

Sickling of Erythrocytes. Hb S, hemoglobin S; O2, oxygen; PO2, partial pressure of oxygen.

Sickling usually is not permanent; most sickled erythrocytes regain a normal shape after reoxygenation and rehydration. Irreversible sickling is caused by irreversible plasma membrane damage caused by sickling. In persons with sickle cell anemia, in which the erythrocytes contain a high percentage of Hb S (75 to 95%), up to 30% of the erythrocytes can become irreversibly sickled. Occasionally, irreversible sickling occurs in sickle cell disease but not in the carrier state (sickle cell trait). Sickling also can be triggered by increased plasma osmolality, decreased plasma volume, and low environmental temperature. Clinical manifestations There is much variation in the clinical manifestations of sickle cell disease. Some individuals have mild symptoms, and others suffer from repeated vaso-occlusive crises.2 When sickling occurs, the general manifestations of hemolytic anemia—pallor, fatigue, jaundice, and irritability—sometimes are accompanied by acute manifestations called crises. Extensive sickling can precipitate the following four types of crises: 1. Vaso-occlusive crisis (thrombotic crisis). This crisis begins with sickling in the microcirculation. As blood flow is obstructed by sickled cells, vasospasm occurs and a “logjam” effect blocks all blood flow through the vessel. Unless the process is reversed, thrombosis and infarction of local tissue follow. Vaso-occlusive crisis is extremely painful and may last for days or even weeks, with an average duration of 4 to 6 days. The frequency of this type of crisis is variable and unpredictable. Vaso-occlusion in vessels to the brain can result in stroke. Chronic vaso-occlusion in vessels to the kidneys results in end-stage renal disease. 2. Sequestration crisis. Large amounts of blood become acutely pooled in the liver and spleen. This type of crisis is seen only in the young child. Because the spleen can hold as much as one-fifth of the body's blood supply at one time, up to 50% mortality has been reported, with death being caused by cardiovascular collapse. 3. Aplastic crisis. Profound anemia is caused by diminished erythropoiesis despite an increased need for new erythrocytes. In sickle cell anemia, erythrocyte survival is only 10 to 20 days. Normally a compensatory increase in erythropoiesis (five to eight times normal) replaces the cells lost through premature hemolysis. If this compensatory response is compromised, aplastic crisis develops in a very short time. 4. Hyperhemolytic crisis. Although unusual, this crisis may occur in association with certain medications or infections. The clinical manifestations of sickle cell disease usually do not appear until the infant is at least 6 months old, at which time the postnatal decrease in concentrations of Hb F causes concentrations of Hb S to rise (Figure 22-4). Infection is the most common cause of death related to sickle cell disease. Sepsis and meningitis develop in as many as 10% of children with sickle cell anemia during the first 5 years of life. Survival time is unpredictable and has improved over the past decades.

FIGURE 22-4 Differences Between Effects of (A) Normal and (B) Sickled Red Blood Cells on Blood Circulation, and Selected Consequences in a Child. C, Tissue Effects of Sickle Cell Anemia. CVA, cerebrovascular accident. (A and B, adapted from Hockenberry, M.J., & Wilson, D. [Eds.]. [2015]. Wong's nursing care of infants and children [10th ed.]. St. Louis: Mosby.)

Sickle cell–hemoglobin C disease is usually milder than sickle cell anemia. The main clinical problems are related to vaso-occlusive crises and are thought to result from higher hematocrit values and viscosity. In older children, sickle cell retinopathy, renal necrosis, and aseptic necrosis of the femoral heads occur along with obstructive crises. Sickle cell–thalassemia disease has the mildest clinical manifestations of all the sickle cell diseases. The normal hemoglobins, particularly Hb F, inhibit sickling. In addition, the erythrocytes tend to be small (microcytic) and to contain relatively little hemoglobin (hypochromic), making them less likely to occlude the microcirculation, even when in a sickled state. Evaluation and treatment The sickle cell trait does not affect life expectancy or interfere with daily activities. However, on rare occasions, severe hypoxia caused by shock, vigorous exercising at high altitudes, flying at high altitudes in unpressurized aircraft, or undergoing anaesthesia is associated with vaso-occlusive episodes in persons with sickle cell trait. These cells form an ivy shape instead of a sickle shape. The parents' hematological history and clinical manifestations may suggest that a child has sickle cell disease, but hematological tests are necessary for diagnosis. If the sickle solubility test confirms the presence of Hb S in peripheral blood, hemoglobin electrophoresis provides information about the amount of Hb S in erythrocytes. Prenatal diagnosis can be made after chorionic villus sampling as early as 8 to 10 weeks' gestation or by amniotic fluid analysis at 15 weeks' gestation (Figure 22-5). Newborn screening for sickle cell disease should be performed according to provincial recommendations.

FIGURE 22-5 Prepregnancy Sickle Cell Test. This technique has potential for detection of other inherited diseases.1, Fertilization produces several embryos. 2, The embryos are tested for the presence of the gene. 3, The embryos without the gene are implanted. 4, Amniocentesis confirms whether the fetus (or fetuses) has the sickle cell gene. 5, Woman has a normal child.

The main treatment for sickle cell disease is hydroxyurea; it inhibits DNA synthesis, causes an increase in Hb F concentration, and results in an anti-inflammatory effect (decreases leukocyte production). These outcomes are thought to decrease crises. Treatment of sickle cell disease consists of supportive care aimed at preventing consequences of anemia and avoiding crises, including adequate hydration and pain management. Debate about transfusion therapy exists because of iron overload that can cause liver damage and fibrosis, delayed physical and sexual development, and heart disease; in addition, transfusion therapy requires chelation therapy to remove excess iron.11 Genetic counselling and psychological support are important for the child and family.

Thalassemias The α- and β-thalassemias are inherited autosomal recessive disorders that cause an impaired rate of synthesis of one of the two chains—α or β—of adult hemoglobin (Hb A). The disorder was named thalassemia, which is derived from the Greek word for sea, because it was discovered initially in persons with origins near the Mediterranean Sea. β-Thalassemia, in which synthesis of the β-globin chain is slowed or defective, is prevalent among Greeks, Italians, and some Arabs and Sephardic Jews. αThalassemia, in which the α-globin chain is affected, is most common among Chinese, Vietnamese, Cambodians, and Laotians. Both α- and β-thalassemias are common among Blacks. Both α- and β-thalassemias are referred to as major or minor, depending on how many of the genes that control α- or β-chain synthesis are defective and whether the defects are inherited homozygously (thalassemia major) or heterozygously (thalassemia minor). Pathophysiological effects range from mild microcytosis to death in utero, depending on the number of defective genes and mode of inheritance. The anemic manifestation of thalassemia is microcytic-hypochromic hemolytic anemia. Pathophysiology The β-thalassemias are caused by mutations that decrease the synthesis of β-globin chains, leading to anemia, tissue hypoxia, and red blood cell hemolysis. β-Chain production is depressed—moderately in the heterozygous form, β-thalassemia minor, and severely in the homozygous form, β-thalassemia major (also called Cooley's anemia). This depressed production results in erythrocytes with a reduced amount of hemoglobin and an accumulation of free α-chains (Figure 22-6). The free α-chains are unstable and easily precipitate in the cell. Most erythroblasts that contain precipitates are destroyed by mononuclear phagocytes in the marrow, resulting in ineffective erythropoiesis and anemia. Some of the precipitate-carrying cells do mature and enter the bloodstream, but they are destroyed prematurely in the spleen, resulting in mild hemolytic anemia.

FIGURE 22-6 Pathogenesis of β-Thalassemia Major. The aggregates of unpaired α-globin chains are a hallmark of the disease. Blood transfusions can diminish the anemia, but they add to the systemic iron overload. Hb A, hemoglobin A. (From Kumar, V., Abbas, A.K., & Aster, J.C. [Eds.]. [2015]. Robbins and Cotran pathologic basis of disease [9th ed.]. Philadelphia: Saunders.)

There are four forms of α-thalassemia: (1) α-thalassemia trait (the carrier state), in which a single αchain–forming gene is defective; (2) α-thalassemia minor, in which two genes are defective; (3) hemoglobin H disease, in which three genes are defective; and (4) α-thalassemia major, a fatal condition in which all four α-forming genes are defective. Death is inevitable because α-chains are absent and oxygen cannot be released to the tissues. Clinical manifestations β-Thalassemia occurs more commonly than does α-thalassemia. Occasionally, synthesis of γ- or δpolypeptide chains is defective, resulting in γ- or δ-thalassemia. (Hemoglobin chains are described in Chapter 20.) β-Thalassemia minor causes mild to moderate microcytic-hypochromic anemia, mild splenomegaly, bronze colouring of the skin, and hyperplasia of the bone marrow. The degree of reticulocytosis depends on the severity of the anemia and results in skeletal changes. Hemolysis of immature (and therefore fragile) erythrocytes may cause a slight elevation in serum iron and indirect bilirubin levels. Persons with β-thalassemia minor are usually asymptomatic. Persons with β-thalassemia major may become quite ill. Anemia is severe and results in a significant cardiovascular burden with high-output heart failure. In the past, death resulted from heart failure. Today, blood transfusions can increase lifespan by one to two decades, and death usually is caused by hemochromatosis (from transfusions). Liver enlargement occurs as a result of progressive hemosiderosis, whereas enlargement of the spleen is caused by extramedullary hemopoiesis and increased destruction of red blood cells. Growth and maturation are developmentally delayed, and a characteristic chipmunk deformity develops on the face, caused by expansion of bones to accommodate hyperplastic marrow. Persons who inherit the mildest form of α-thalassemia (the α-thalassemia trait) usually are symptomfree or have mild microcytosis. α-Thalassemia minor has clinical manifestations that are virtually identical to those of β-thalassemia minor: mild microcytic-hypochromic reticulocytosis, bone marrow

hyperplasia, increased serum iron concentrations, and moderate splenomegaly. Signs and symptoms of α-thalassemia major are similar to those of β-thalassemia major, but milder. Moderate microcytic-hypochromic anemia, enlargement of the liver and spleen, and bone marrow hyperplasia are evident. α-Thalassemia major causes hydrops fetalis, the most severe form of α-thalassemia, caused by deletion of all four α-globin genes. The infant suffers from severe tissue anoxia and may develop fulminant intrauterine heart failure. Signs of fetal distress became evident by the third trimester of pregnancy. In the past, severe tissue anoxia led to death in utero; now many such infants are saved by intrauterine transfusions. Both α- and β-thalassemia major are life-threatening. Children with thalassemia major generally are weak, fail to thrive, show poor development, and experience cardiovascular compromise with highoutput failure secondary to anemia. Untreated, they will die by 5 to 6 years of age. Evaluation and treatment Evaluation of thalassemia is based on familial disease history, clinical manifestations, and blood tests. Peripheral blood smears that show microcytosis and hemoglobin electrophoresis that demonstrates diminished amounts of α- or β-chains are used to make the diagnosis. Analysis of fetal DNA from withdrawn amniotic fluid is used as a screening test to detect hydrops fetalis (α-thalassemia major). Newborn screening for thalassemia should be done according to provincial recommendations. Persons who are silent carriers or have thalassemia minor generally have few if any symptoms and require no specific treatment. However, therapies to support and prolong life are necessary for thalassemia major and include chronic blood transfusion therapy and management of resultant iron overload (see Figure 22-6). Allogeneic hematopoietic stem cell transplantation (HSCT) is the only cure. For both symptom-free carriers and those with the disease, prenatal diagnosis and genetic counselling may be the most important therapeutic measures that can be offered.

Quick Check 22-1 1. Why is Rh incompatibility rare today? 2. Why do clinical manifestations of sickle cell disease not appear until the infant is at least 6 months old? 3. Why do children with thalassemia major develop cardiovascular complications?

Disorders of Coagulation and Platelets Inherited Hemorrhagic Disease Hemophilias Hemophilia A is defined as factor VIII deficiency and is the most common hereditary disease associated with life-threatening bleeding. It is caused by a mutation in factor VIII, an essential cofactor for factor IX in the coagulation cascade. Factor IX deficiency is most often called hemophilia B (Christmas disease, after the first person identified and not the holiday) but is clinically indistinguishable from factor VIII deficiency because factors VIII and IX function together to activate factor X. Both hemophilia A and hemophilia B are inherited as X-linked recessive traits, thus affecting mainly males and homozygous females.2 Excessive bleeding rarely occurs in heterozygous females. New mutations, not family history, are the cause of about 30% of cases. The incidence of hemophilia A is approximately 1 in 5 000 male births, whereas hemophilia B is five times less common, with an incidence of approximately 1 in 30 000 male births. The incidence worldwide of hemophilia is not well known, but it is estimated to be at more than 400 000 people.12 Races are affected equally for both disorders. Only hemophilias A and B will be discussed in this chapter. Of note is a third, less common hemophilia, called hemophilia C, which results from a deficiency of factor XI. Table 22-3 lists the coagulation factors and deficiencies associated with clinical bleeding. TABLE 22-3 The Coagulation Factors and Associated Disorders Clotting Factors

Synonym

Disorder

I II V VII VIII IX X XI XII XIII

Fibrinogen Prothrombin Labile factor or proaccelerin Stable factor or proconvertin Antihemophilic factor Christmas factor Stuart-Prower factor Plasma thromboplastin antecedent Hageman factor Fibrin-stabilizing factor

Congenital deficiency (afibrinogenemia) and dysfunction (dysfibrinogenemia) Congenital deficiency or dysfunction Congenital deficiency (parahemophilia) Congenital deficiency Congenital deficiency is hemophilia A (classic hemophilia) Congenital deficiency is hemophilia B Congenital deficiency Congenital deficiency, sometimes referred to as hemophilia C Congenital deficiency is not associated with clinical symptoms Congenital deficiency

Pathophysiology Hemophilia may be inherited or caused by a spontaneous mutation of the factor gene. The genetic instructions for both factor VIII and factor IX lie on the long arm of the X chromosome. Deficiencies of factor VIII and factor IX are clinically manifested almost exclusively in males. Because a male's DNA contains only one X chromosome, hemophilia affects mostly males. Women have two X chromosomes, and if one X chromosome has a defective gene, the other X chromosome has the information needed to create clotting factors. A female can have hemophilia because of X-inactivation or lyonization (see Chapter 2). It is possible for one X chromosome to not express itself. If the X chromosome with the hemophilia gene is the active chromosome, the woman will have lower levels of clotting factors. Fifty percent of carriers have low clotting factor levels. There is a known family history of hemophilia A and B in about two-thirds of cases; the remaining third are new genetic mutations, either in the individual with hemophilia or in his unaffected carrier mother. Numerous gene mutations and deletions have been identified at the molecular level in factor VIII and IX deficiency. The molecular defect that leads to hemophilia is identical among members of a given family; however, the deletion mutation has been unique in each family studied.13 Clinical manifestations The clinical manifestations and severity of hemophilia depend largely on the level of factor VIII and IX activity. The severity designation of an individual's hemophilia will determine the characteristics of the resulting disorder and will direct treatment strategies.14 Joint bleeding is the most characteristic type of bleeding in hemophilia. Bleeding into muscles, usually from trauma, also occurs with both hemophilia A

and hemophilia B. Oral bleeding is common in the setting of dental surgery. Spontaneous painless hematuria, which is relatively common in hemophilia, generally does not result in significant blood loss but requires evaluation. Hematuria accompanied by pain requires prompt evaluation and treatment. Intracranial bleeds, bleeding of internal organs, and bleeding into the tissues of the neck, chest, or abdomen are all life-threatening. Delayed or suboptimal treatment of these bleeds may lead to permanent brain injury, loss of organ function, or death. Evaluation and treatment Because hemophilia is most often an inherited disease, a positive family history may expedite a diagnosis of hemophilia. When a suspected carrier mother is pregnant, genetic testing in utero through amniocentesis or chorionic villus sampling (CVS) may reveal a hemophilia diagnosis before childbirth. In the absence of a positive family history, when a bleeding disorder is suspected, personal bleed history, laboratory testing, family history, and physical assessment contribute to a thorough evaluation and accurate diagnosis. In general, those with hemophilia A or B will have a prolonged partial thromboplastin time (PTT), and the prothrombin time (PT) will be normal. Measurement of factor VIII (hemophilia A) and factor IX (hemophilia B) levels is necessary for diagnosis. The majority of children with hemophilia A (factor VIII deficiency) can be treated with recombinant factor VIII, and the majority of children with hemophilia B (factor IX deficiency) can be treated with recombinant factor IX. Recombinant factor is reconstituted in a small volume of diluent, administered by slow intravenous push, and raises the factor level almost immediately.

Antibody-Mediated Hemorrhagic Disease The antibody-mediated hemorrhagic diseases are a group of disorders caused by the immune response. Antibody-mediated destruction of platelets or antibody-mediated inflammatory reactions to allergens damage blood vessels and cause seepage into tissues. The thrombocytopenic purpuras may be intrinsic or idiopathic, or they may be transient phenomena transmitted from mother to fetus. The inflammatory, or “allergic,” purpuras, although rare, occur in response to allergens in the blood. All of these disorders first appear during infancy or childhood.

Immune Thrombocytopenic Purpura Acute immune thrombocytopenic purpura (ITP; autoimmune [primary] thrombocytopenic purpura) is the most common disorder of platelet consumption. Autoantibodies bind to the plasma membranes of platelets, causing platelet sequestration and destruction by mononuclear phagocytes in the spleen and other lymphoid tissues at a rate that exceeds the ability of the bone marrow to produce them. The destruction of platelets is triggered by medications, infections, lymphomas, or an unknown cause. Pathophysiology The autoantibodies that produce the destruction are often of the IgG class and are usually against the platelet membrane glycoproteins (IIb-IIIa or Ib-IX). In approximately 70% of cases of ITP, there is an antecedent viral disease (e.g., cytomegalovirus [CMV], Epstein-Barr virus [EBV], parvovirus, or respiratory tract infection) that precedes the eruption of petechiae or purpura by 1 to 3 weeks. Clinical manifestations Bruising and a generalized petechial rash often occur with acute onset. Petechiae can develop into ecchymoses. Asymmetrical bruising is typical and is found most often on the legs and trunk. Hemorrhagic bullae of the gums, lips, and other mucous membranes may be prominent, and epistaxis (nose bleeding) may be severe and difficult to control. Otherwise, the child appears well. The principal changes are found in the spleen, bone marrow, and blood.2 The acute phase lasts 1 to 2 weeks, but thrombocytopenia often persists. Although the incidence is less than 1%, intracranial hemorrhage is the most serious complication of ITP. In some cases, the onset is more gradual, and clinical manifestations consist of moderate bruising and a few petechiae.

Evaluation and treatment Laboratory examination reveals an isolated low platelet count, and the few platelets observed on a smear are large, reflecting increased bone marrow production. The Ivy test (a bleeding time test) is prolonged. Bone marrow aspiration is not recommended for children with typical features of ITP. The primary treatment for children with ITP is observation regardless of platelet count. When bleeding is present, primary treatment is with an infusion of intravenous immune globulin (IVIg) or a short course of corticosteroids. Even without treatment, the prognosis for children with ITP is excellent: 75% recover completely within 3 months. After the initial acute phase, spontaneous clinical manifestations subside. By 6 months after onset, 80% of affected children have regained normal platelet counts.15 ITP that persists longer than 12 months in children is considered chronic, and immunosuppressive therapies are utilized.16,17

Quick Check 22-2 1. List the major disorders of coagulation and platelets found in children. 2. How do gene deletions differ from gene mutations? 3. Why are persons with hemophilia at risk of developing degenerative joint changes? 4. What is the major abnormality in immune thrombocytopenic purpura?

Neoplastic Disorders Leukemia Leukemia is cancer of the blood-forming tissues, such as the bone marrow, that most often produces abnormal white blood cells called leukemic cells. Once in the blood, leukemic cells can spread to other organs, such as the lymph nodes, spleen, and brain. Leukemia is the most common malignancy in children and teens. Among children and teens, about 75% of leukemias are acute lymphoblastic leukemia (ALL); the remaining cases are acute myeloid (or myelogenous) leukemia (AML). ALL is most common in early childhood, peaking between 2 and 4 years of age.18 AML is slightly more common during the first 2 years of life and during the teenage years, and it occurs about equally among boys and girls of all races. ALL is more common in boys than girls and among Latin American and White children.18 The cause of most childhood cancer is unknown. About 5% of all childhood cancers are caused by inherited mutations. Genetic mutations can occur during fetal development. Other genetic conditions associated with leukemia include Down syndrome, neurofibromatosis, Shwachman-Diamond syndrome, Bloom's syndrome, and ataxia-telangiectasia. Many studies have shown that exposure to ionizing radiation (prenatal exposure to X-rays and postnatal exposure to high doses) can lead to the development of childhood leukemia and possibly other cancers.19 There is recent concern for performing computed tomography (CT) scans in children because increased use combined with wide variability in radiation doses has resulted in many children receiving a high dose of radiation.20 Studies of other possible environmental risk factors, including parental exposure to cancer-causing chemicals, prenatal exposure to pesticides, childhood exposure to common infectious agents, and living near a nuclear power plant, have so far produced inconsistent results. Higher risks of cancer have not been seen in children of individuals treated for sporadic cancer (cancer not caused by an inherited mutation).21,22 Pathophysiology ALL is composed of immature B (pre-B) or T (pre-T) cells called lymphoblasts. The bone marrow is dense with lymphoblasts, considered hypercellular, that replace the normal marrow and disrupt normal function. Many of the chromosomal abnormalities documented in ALL cause dysregulation of the expression and function of transcription factors required for normal B-cell and T-cell development.2 The mutations can include both gain of function and loss of function that are required for normal development. AML is caused by acquired oncogenic mutations that impair differentiation, resulting in the accumulation of immature myeloid blasts in the marrow and other organs. Epigenetic alterations are frequent in AML and have a central role. The bone marrow crowding by blasts produces marrow failure and complications, including anemia, thrombocytopenia, and neutropenia. AML is very heterogeneous because myeloid cell differentiation is very complex. To be called acute, the bone marrow usually must include greater than 20% leukemic blasts. Clinical manifestations The onset of leukemia may be abrupt or insidious, but the most common symptoms reflect the consequences of bone marrow failure: decreased levels of both red blood cells and platelets and changes in white blood cells. Pallor, fatigue, petechiae, purpura, bleeding, and fever generally are present. Approximately 45% of children have a hemoglobin level below 70 mmol/L. If acute blood loss occurs, characteristic symptoms of tachycardia, air hunger, restlessness, and thirst may be present. Epistaxis often occurs in children with severe thrombocytopenia. Fever is usually present as a result of (1) infection associated with the decrease in functional neutrophils and (2) hypermetabolism associated with the ongoing rapid growth and destruction of leukemic cells. White blood cell counts greater than 200 × 109/L can cause leukostasis, an intravascular clumping of cells that results in infarction and hemorrhage, usually in the brain and lung. Renal failure as a result of hyperuremia (high uric acid levels) can be associated with ALL, particularly

at diagnosis or during active treatment. Extramedullary invasion with leukemic cells can occur in nearly all body tissue. The central nervous system (CNS) is a common site of infiltration of extramedullary leukemias, although less than 10% of children with ALL have CNS involvement at diagnosis. The most common symptoms of CNS involvement relate to increased intracranial pressure, causing early morning headaches, nausea, vomiting, irritability, and lethargy. Gonadal involvement can occur, and leukemic infiltration into bones and joints is common. Reports of bone or joint pain actually lead to the diagnosis of leukemia in some children. In most children, bone pain is characterized as migratory, vague, and without areas of swelling or inflammation. However, if joint pain is the primary symptom and some swelling is associated with the pain, misdiagnoses of rheumatoid arthritis and rheumatic fever have occurred. Other organs reported to be sites of leukemic invasion include the kidneys, heart, lungs, thymus, eyes, skin, and gastro-intestinal tract. Children with leukemia can show symptoms only 1 week before diagnosis. Evaluation and treatment The diagnosis of leukemia is made from blood tests and examination of peripheral blood smears. A bone marrow aspiration is usually performed to further characterize the leukemia. The blast cell is the hallmark of acute leukemia (Figure 22-7). Healthy children have less than 5% blast cells in the bone marrow and none in the peripheral blood. In ALL, the bone marrow often is replaced by 80 to 100% blast cells, with a reduction in normal developing red blood cells and granulocytes. Occasionally, the marrow appears hypocellular, making the diagnosis difficult to differentiate from aplastic anemia. When this difficulty occurs, bone marrow biopsy or biopsy of extramedullary sites is necessary to confirm the diagnosis.

FIGURE 22-7 Monoblasts From Acute Monoblastic Leukemia. Monoblasts in a marrow smear from an individual with acute monoblastic leukemia. The monoblasts are larger than myeloblasts and usually have abundant cytoplasm, often with delicate scattered azurophilic granules (an element that stains well with blue aniline dyes). (From Damjanov, I., & Linder, J. [Eds.]. [1996]. Anderson's pathology [10th ed.]. St. Louis: Mosby.)

Remarkable success has occurred with treatment of ALL in children. Chemotherapy is the treatment of choice for acute leukemia. Radiation has special considerations for use. In ALL, identification of various risk groups has led to the development of different intensities of medication protocols. Thus treatment is tailored specifically for a particular risk group. Chronic myeloid (or myelogenous) leukemia (CML) accounts for less than 5% of childhood leukemias. In the past, it was treated with high-dose chemotherapy followed by allogeneic stem cell transplant, resulting in significant treatment-related mortality. However, targeted medications, known as tyrosine kinase inhibitors (TKIs), have revolutionized the treatment of CML. Several TKIs are now approved for use in children; treatment requires continued adherence to an oral regimen and the health impact of longterm TKI therapy is not yet known.23

Lymphomas Lymphoma (HL and NHL) develops from the proliferation of malignant lymphocytes (immune cells) in

the lymphoid system (see Chapters 12 and 21). The four most common types of leukemia are (1) ALL, (2) AML, (3) chronic lymphocytic leukemia (CLL), and (4) CML (see Chapter 21). Most childhood leukemias are ALL. Chronic leukemias are rare in children.24 Lymphomas are malignant proliferations that arise from discrete tissue masses.2 Lymphoid neoplasms involve some recognizable stage of lymphocyte B- or T-cell differentiation. With time and better understanding, it is clear that some lymphomas occasionally have leukemic presentations, and evolution to “leukemia” is not unusual during the progression of incurable “lymphomas.” The terms, therefore, merely reflect the usual tissue distribution.2 Much controversy has surrounded the classifications of lymphoma, and a consensus has been reached with the current World Health Organization classification scheme found at https://www.lymphoma.ca/lymphoma/lymphoma-101/types-lymphoma/classifying-nhl. NHL and HL constitute approximately 11% of all cases of childhood cancer. Approximately 100 children younger than 14 years of age are diagnosed with lymphoma in Canada each year.25 NHL (including Burkitt lymphoma) occurs more often than HL (for newborns to children age 14 years, 5 to 6% versus 4%; and for ages 15 to 19 years, 8% versus 15% of all pediatric malignancies). Either group of diseases is rare before the age of 5 years, and the relative incidence increases throughout childhood. Boys are more likely to be diagnosed with a malignant lymphoma than are girls. At particular risk are children with inherited or acquired immune deficiency syndrome, who have increased rates of lymphoreticular cancers that range between 100 and 10 000 times the rate of normal children.

Non-Hodgkin's Lymphoma Non-Hodgkin's lymphomas (NHLs) are neoplasms of immune cells. NHLs are a large and diverse group of tumours; some tumours have a slow-growing (indolent) course, whereas others have a fast-growing (aggressive) course. Almost without exception, childhood NHL becomes evident as a diffuse disease and can be further subdivided into four major types: (1) B-cell NHL (Burkitt and Burkitt-like lymphoma, and Burkitt leukemia); (2) diffuse large B-cell lymphoma; (3) lymphoblastic lymphoma; and (4) anaplastic large cell lymphoma.26 The common types of NHL in children are different than those in adults. The most common types of NHL in children are Burkitt lymphoma (40%), lymphoblastic lymphoma (25 to 30%), and large cell lymphoma (10%). Pathophysiology Burkitt lymphoma will be discussed as an example of pathogenesis of NHL in children. All forms of Burkitt lymphoma are associated with translocations of the MYC gene on chromosome 8 that lead to increased MYC protein levels.2 MYC is a transcriptional regulator that increases the expression of genes required for aerobic glycolysis, called the Warburg effect (see Chapter 10). Most Burkitt lymphomas are latently infected with EBV.2 EBV is also present in about 25% of HIV-associated tumours and 15 to 20% of sporadic cases.2 There is increased evidence of NHL in children with congenital immunodeficiency syndromes, such as Wiskott-Aldrich syndrome, ataxia-telangiectasia, and Bloom's syndrome. Clinical manifestations NHL has been found to arise from any lymphoid tissue. Signs and symptoms therefore are specific for the site involved. Associated signs of NHL include swelling of the lymph nodes in the neck, underarm, stomach, or groin; trouble swallowing; painless lump or swelling in a testicle; weight loss for unknown reason; night sweats; and possibly trouble breathing. Involvement of facial bones, particularly the jaw, is common in African Burkitt lymphoma. Evaluation and treatment Diagnosis is made by physical examination and health history, followed by biopsy of disease sites— usually the involved lymph nodes, tonsils, bone marrow, spleen, liver, bowel, or skin. Burkitt lymphoma is very aggressive and responds well to treatment. With intensive chemotherapy, most children and young adults can be cured.

Hodgkin's Lymphoma Hodgkin's lymphoma (HL) is a group of lymphoid neoplasms that, unlike NHL, arises in a single chain

of lymph nodes and spreads first in a contiguous way to lymphoid tissue. NHL frequently arises at extranodal sites and spreads in a noncontiguous or unpredictable way. HL is characterized by the presence of Reed-Sternberg cells, which are large cells derived from the germinal centre of B cells (Figure 22-8). The World Health Organization has identified five types of HL: (1) nodular sclerosis, (2) mixed cellularity, (3) lymphocyte rich, (4) lymphocyte depletion, and (5) lymphocyte predominance. The first four types are considered the classic types of HL with similar expression of Reed-Sternberg cells. In the lymphocyte predominance type, the Reed-Sternberg cell is distinctive but different than the others. HL is a common type of cancer in young adults and adolescents but rare in childhood. The average age at diagnosis is 32 years of age.

FIGURE 22-8

Diagnostic Reed-Sternberg Cell. A large multinucleated or multilobated cell with inclusion body–like nucleoli (arrow) surrounded by a halo of clear nucleoplasm. (From Damjanov, I., & Linder, J. [2000]. Pathology: A color atlas. St. Louis: Mosby.)

Pathophysiology The Reed-Sternberg cells fail to express most of the B-cell normal genes, including the Ig genes. The causes of the genetic rearrangements or reprogramming are not fully known but are thought to be the result of widespread epigenetic changes. Activation of the transcription factor NF-κB, which controls transcription of DNA, is a very common event in classic HL.2 NF-κB may be activated by EBV infection. EBV-infected B cells, resembling Reed-Sternberg cells, are found in lymph nodes in individuals with infectious mononucleosis, suggesting that the EBV proteins may have a role in changes of the B cells into Reed-Sternberg cells.2 NF-κB is involved in many biological processes, including inflammation, immunity, cell growth, differentiation, and apoptosis. The cytoplasm is abundant with Reed-Sternberg cells and tissue is reactive with many inflammatory type cells and immune cells. These reactive cells crosstalk with Reed-Sternberg cells and support the growth and survival of the tumour cells. Clinical manifestations Painless lymphadenopathy in the lower cervical chain, with or without fever, is the most common symptom in children. Other lymph nodes and organs also may be involved (Figure 22-9). Mediastinal involvement can cause pressure on the trachea or bronchi, leading to airway obstruction. Extranodal primary sites in HL are rare. Initial symptoms consist of anorexia, malaise, and lassitude. Intermittent fever is present in 30% of children, and weight loss also may accompany these symptoms. HL has a welldefined staging system that considers the extent and location of disease and the presence of fever, weight loss, or night sweats at diagnosis.

FIGURE 22-9

Main Areas of Lymphadenopathy and Organ Involvement in Hodgkin's Lymphoma. (From Hockenberry, M.J., & Wilson, D. [Eds.]. [2015]. Wong's nursing care of infants and children [10th ed.]. St. Louis: Mosby.)

Evaluation and treatment Treatment for HL includes chemotherapy and radiation therapy. Long-term survivors treated with radiotherapy had a much higher incidence of secondary cancers, including lung cancer, melanoma, and breast cancer. Individuals previously treated with chemotherapy alkylating agents also had a high incidence of secondary tumours. These results have changed the treatment protocols to minimize the use of radiotherapy and use less toxic chemotherapy. A promising target therapy is anti-CD30.

Quick Check 22-3 1. List the childhood leukemias in order of rate of incidence. 2. Why do children with leukemia experience bone or joint pain? 3. What are the common types of non-Hodgkin's lymphoma in children?

Did You Understand? Disorders of Erythrocytes 1. Anemia is the most common blood disorder in children. Like the anemias of adulthood, the anemias of childhood are caused by ineffective erythropoiesis or premature destruction of erythrocytes. 2. Iron deficiency anemia (IDA) is the most common nutritional disorder worldwide. IDA has the highest incidence occurring between 6 months and 2 years of age. Iron is critical for the developing child. Without it the damage from the periods of IDA is irreversible. 3. No matter the cause of IDA, it produces a hypochromic-microcytic anemia, eventually lowering hemoglobin and hematocrit. 4. Hemolytic disease of the newborn (HDN) results from incompatibility between the maternal and the fetal blood, which may involve differences in Rh factors or blood type (ABO). Maternal antibodies (anti-Rh antibodies) form in response to the presence of fetal incompatible (Rhpositive) erythrocytes in the blood of an Rh-negative mother. The maternal antibodies then enter the fetal circulation and cause hemolysis of fetal erythrocytes. However, ABO incompatibility can cause HDN even if fetal erythrocytes do not escape into the maternal circulation during pregnancy. 5. The key to treatment of HDN resulting from Rh incompatibilities lies in prevention or immunoprophylaxis. 6. Sickle cell disease is a group of disorders characterized by the production of abnormal hemoglobin S (Hb S) within the erythrocytes. 7. Sickle cell disease is an inherited, autosomal recessive disorder expressed as sickle cell anemia, sickle cell–thalassemia disease, or sickle cell–hemoglobin C disease, depending on mode of inheritance. Sickle cell anemia, a homozygous form, is the most severe. 8. Sickle cell–thalassemia disease and sickle cell–hemoglobin C disease are heterozygous forms in which the child simultaneously inherits another type of abnormal hemoglobin from one parent. Sickle cell trait, in which the child inherits Hb S from one parent and normal hemoglobin (Hb A) from the other, is a heterozygous carrier state that rarely has clinical manifestations. All forms of sickle cell disease are lifelong conditions. 9. Sickle cell disease causes a change in the shape of red blood cells, resulting in deoxygenation or dehydration. It is most common among Blacks and those of Mediterranean descent. 10. The α- and β-thalassemias are inherited autosomal recessive disorders that cause an impaired rate of synthesis of one of the two chains—α or β—of adult hemoglobin (Hb A).

Disorders of Coagulation and Platelets 1. Hemophilia A is defined as factor VIII deficiency and is the most common hereditary disease associated with life-threatening bleeding. It is caused by a mutation in factor VIII, an essential cofactor for factor IX in the coagulation cascade. Factor IX deficiency is most often called hemophilia B. 2. Hemophilia may be inherited or caused by a spontaneous mutation of the factor gene. 3. The antibody-mediated hemorrhagic diseases are a group of disorders caused by the immune response. Antibody-mediated destruction of platelets or antibody-mediated inflammatory reactions to allergens damage blood vessels and cause seepage into tissues. 4. Immune thrombocytopenic purpura, the most common of the childhood thrombocytopenic purpuras, is a disorder of platelet consumption in which antiplatelet antibodies bind to the plasma membranes of platelets. This binding results in platelet sequestration and destruction by mononuclear phagocytes at a rate that exceeds the ability of the bone marrow to produce them.

Neoplastic Disorders 1. Leukemia is cancer of the blood-forming tissues, such as the bone marrow, that most often produces abnormal white blood cells called leukemic cells. 2. Among children and teens, about 75% of leukemias are acute lymphoblastic leukemia (ALL); the remaining cases are acute myeloid (or myelogenous) leukemia (AML). Chronic leukemias are rare in children. 3. The cause of childhood leukemia is unknown. About 5% of all childhood cancers are caused by inherited mutations. Genetic mutations can occur during fetal development. 4. Studies have shown that exposure to ionizing radiation can lead to the development of childhood leukemia and possibly other cancers. 5. ALL causes dysregulation of the expression and function of transcription factors required for normal B-cell and T-cell development. 6. Epigenetic alterations are frequent in AML and have a central role. 7. The onset of leukemia may be abrupt or insidious, but the most common symptoms reflect the consequences of bone marrow failure. These changes can include decreased levels of red blood cells and platelets and changes in white blood cells. 8. Lymphomas are malignant proliferations that arise from discrete tissue masses. Lymphoid neoplasms involve some recognizable stage of lymphocyte B- or T-cell differentiation. 9. With time and better understanding, it is now clear that some lymphomas occasionally have leukemic presentations. 10. The lymphomas of childhood are Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). 11. NHL are neoplasms of immune cells. The most common types of NHL in children are Burkitt lymphoma (40%), lymphoblastic lymphoma (25 to 30%), and large cell lymphoma (10%). 12. Most Burkitt lymphomas are latently infected with the Epstein-Barr virus (EBV). There is increased evidence of NHL in children with congenital immunodeficiency syndromes. 13. Unlike NHL, HL arises in a single chain of lymph nodes and spreads first in a contiguous way to lymphoid tissue. 14. HL is characterized by the presence of Reed-Sternberg cells, which are large cells derived from the germinal centre of B cells.

Key Terms α-Thalassemia major, 567 α-Thalassemia minor, 567 α-Thalassemia trait, 567 Aplastic crisis, 566 β-Thalassemia major (Cooley's anemia), 567 β-Thalassemia minor, 567 Blast cell, 571 Glucose-6-phosphate dehydrogenase (G6PD) deficiency, 560 Hemoglobin H disease, 567 Hemoglobin S (Hb S), 564 Hemolytic anemia, 560 Hemolytic disease of the newborn (HDN) (erythroblastosis fetalis), 562 Hemophilia A, 569 Hemophilia B, 569 Hodgkin's lymphoma (HL), 572 Hydrops fetalis, 562 Hyperbilirubinemia, 563 Hyperhemolytic crisis, 566 Icterus gravis neonatorum, 563 Icterus neonatorum (neonatal jaundice), 563 Immune thrombocytopenic purpura (ITP), 569 Kernicterus, 563 Leukemia, 570 Leukemic cell, 570 Lymphoblast, 570 Lymphoma, 571 Non-Hodgkin's lymphoma (NHL), 571 Sequestration crisis, 566 Sickle cell anemia, 564 Sickle cell disease, 564 Sickle cell–hemoglobin C disease, 565 Sickle cell–thalassemia disease, 564 Sickle cell trait, 565 Thalassemia, 567 Vaso-occlusive crisis (thrombotic crisis), 565

References 1. Christofides A, Schauer C, Zlotkin SH. Iron deficiency anemia among children: Addressing a global public health problem within a Canadian context. Paediatrics & Child Health. 2005;10(10):597–601. 2. Kumar V, Abbas AK, Aster JC. Robbins and Cotran pathologic basis of disease. 9th ed. Saunders: Philadelphia; 2015. 3. Jo J, Garssen J, Knippels L, et al. Role of cellular immunity in cow's milk allergy: Pathogenesis, tolerance induction, and beyond. Mediators of Inflammation. 2014;2014:249784; 10.1155/2014/249784. 4. Moshe G, Amitai Y, Korchia G, et al. Anemia and iron deficiency in children: Association with red meat and poultry consumption. Journal of Pediatric Gastroenrology and Nutrition. 2013;57(6):722– 727; 10.1097/MPG.0b013e3182a80c42. 5. Gheibi SH, Farrokh-Eslamlou HR, Noroozi M, et al. Refractory iron deficiency anemia and Helicobacter pylori infection in pediatrics: A review. Iranian Journal of Pediatric Hematology and Oncology. 2015;5(1):50–64. 6. Shah M, Griffin IJ, Lifschitz CH, et al. Effect of orange and apple juice on iron absorption in children. Archives of Pediatrics and Adolescent Medicine. 2003;157(12):1232–1236; 10.1001/archpedi.157.12.1232. 7. Crowther CA, Middleton P, McBain RD. Anti-D administration in pregnancy for preventing Rhesus alloimmunization. Cochrane Database of Systematic Reviews. 2013;(2); 10.1002/14651858.CD000020.pub2 [CD000020]. 8. Qureshi H, Massey E, Kirwan D, et al. BCSH guideline for the use of anti-D immunoglobulin for the prevention of haemolytic disease of the fetus and newborn. Transfusion Medicine (Oxford, England). 2014;24(1):8–20. 9. Canadian Haemoglobinopathy Association. Consensus statement on the care of patients with sickle cell disease in Canada. [Retrieved from] https://emergencymedicinecases.com/wpcontent/uploads/filebase/pdf/Canadian%20Sickle%20Cell%20Guidelines%202014.pdf; 2014. 10. Kyung P. Sickle cell disease and other hemoglobinopathies. International Anesthesiology Clinics. 2004;42(3):77–93. 11. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease summary of the 2014 evidence-based report by Expert Panel Members. JAMA: The Journal of the American Medical Association. 2014;312(10):1033–1048; 10.1001/jama.2014.10517. 12. National Hemophilia Foundation. National hemophilia foundation's information resource center. Author: New York; 2015. 13. Mariani G, Bernardi F. Factor II deficiency. Seminars in Thrombosis and Hemostasis. 2009;35(4):400– 406; 10.1055/s-0029-1225762. 14. Blanchette VS, Breakey VR, Revel-Vilk S. SickKids handbook of pediatric thrombosis and hemostasis. Karger: Basel, Switzerland; 2013:59–78. 15. Gupta V, Tilak V, Bhatia BD. Immune thrombocytopenic purpura. Indian Journal of Pediatrics. 2008;75(7):723–728; 10.1007/s12098-008-0137-z. 16. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117:4190–4207; 10.1182/blood-201008-302984. 17. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115(2):168–186; 10.1182/blood2009-06-225565. 18. American Cancer Society. What are the key statistics for childhood leukemia?. Author: Atlanta, GA; 2015. 19. National Cancer Institute. Childhood acute lymphoblastic leukemia treatment PDQ®—Health professional version. Author.: Bethesda, MD; 2015 [Retrieved from] https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq#link/_67_toc. 20. Miglioretti DL, Johnson E, Williams A, et al. The use of computed tomography in pediatrics and

the associated radiation exposure and estimated cancer risk. JAMA Pediatrics. 2013;167(8):700–707; 10.1001/jamapediatrics.2013.311. 21. Hudson MM. Reproductive outcomes for survivors of childhood cancer. Obstetrics and Gynecology. 2010;116(5):1171–1183; 10.1097/AOG.0b013e3181f87c4b. 22. National Cancer Institute. Cancer in children and adolescents. Author: Bethesda, MD; 2014. 23. National Cancer Institute. PDQ® childhood acute myeloid leukemia/other myeloid malignancies treatment. Author.: Bethesda, MD; 2015 [Retrieved from] http://cancer.gov/cancertopics/pdq/treatment/childAML/HealthProfessional. 24. American Cancer Society. What you need to know about leukemia. National Cancer Institute: Bethesda, MD; 2015. 25. Statistics Canada. Health at a glance: Childhood cancer incidence and mortality in Canada. Author.: Ottawa; 2015 [Retrieved from] http://www.statcan.gc.ca/pub/82-624-x/2015001/article/14213eng.pdf. 26. National Cancer Institute. PDQ® childhood non-Hodgkin lymphoma treatment. [Bethesda, MD: Author; Retrieved from] http://cancer.gov/cancertopics/pdq/treatment/child-nonhodgkins/Patient.

UNIT 7

The Cardiovascular and Lymphatic Systems OUTLINE 23 Structure and Function of the Cardiovascular and Lymphatic Systems 24 Alterations of Cardiovascular Function 25 Alterations of Cardiovascular Function in Children

23

Structure and Function of the Cardiovascular and Lymphatic Systems Susanna G. Cunningham, Valentina L. Brashers, Kathryn L. McCance, Mohamed El-Hussein

CHAPTER OUTLINE The Circulatory System, 575 The Heart, 575 Structures That Direct Circulation Through the Heart, 576 Structures That Support Cardiac Metabolism: The Coronary Vessels, 578 Structures That Control Heart Action, 580 Factors Affecting Cardiac Output, 587 The Systemic Circulation, 589 Structure of Blood Vessels, 589 Factors Affecting Blood Flow, 593 Regulation of Blood Pressure, 595 Regulation of the Coronary Circulation, 598 The Lymphatic System, 599

The functions of the circulatory system include delivery of oxygen, nutrients, hormones, immune system components, and other substances to body tissues and removal of the waste products of metabolism. Delivery and removal are achieved by an extensive array of tubes—the blood and lymphatic vessels— connected to a pump, the heart. The heart continuously pumps blood through the blood vessels in collaboration with other systems, particularly the nervous and endocrine systems, which regulate the heart and blood vessels. Immune system components, nutrients, and oxygen are supplied by the immune, digestive, and respiratory systems; gaseous wastes of metabolism are expired through the lungs; and other wastes are removed by the kidneys and digestive tract. The vascular endothelium also is a key component of the circulatory system and is sometimes considered a separate endocrine organ. This endothelium is a multifunctional tissue whose health is essential to normal vascular, immune, and hemostatic system function. Endothelial dysfunction is a critical factor in the development of vascular and other diseases.1

The Circulatory System The heart is composed of two conjoined pumps moving blood through two separate circulatory systems in sequence: one pump supplies blood to the lungs, whereas the second pump delivers blood to the rest of the body. Structures on the right side, or right heart, pump blood through the lungs. This system is termed the pulmonary circulation and is described in Chapter 26. The left side, or left heart, sends blood throughout the systemic circulation, which supplies all of the body except the lungs (Figure 23-1). These two systems are serially connected; thus the output of one becomes the input of the other.

FIGURE 23-1 Diagram of the Pulmonary and Systemic Circulatory Systems. The right heart pumps unoxygenated blood (blue) through the pulmonary circulation, where oxygen enters the blood and carbon dioxide is exhaled, and the left heart pumps oxygenated (red) blood to and from all the other organ systems in the body. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. (From Patton, K.T., Thibodeau, G.A., & Douglas, M.M. [2012]. Essentials of anatomy & physiology. St. Louis: Elsevier.)

Arteries carry blood from the heart to all parts of the body, where they branch into arterioles and even smaller vessels, ultimately becoming a fine meshwork of capillaries. Capillaries allow the closest contact and exchange between the blood and the interstitial space, or interstitium—the environment in which cells live. Venules and then veins next carry blood from the capillaries back to the heart. Some of the plasma or liquid part of the blood passes through the walls of the capillaries into the interstitial space. This fluid, lymph, is returned to the cardiovascular system by vessels of the lymphatic system. The lymphatic system is a critical component of the immune system as described in Chapters 6 and 7.

The Heart Adult hearts weigh between 200 and 350 grams and are about fist-sized. The heart lies obliquely (diagonally) in the mediastinum, the area above the diaphragm and between the lungs. Heart structures can be categorized by three functions: 1. Structural support of heart tissues and circulation of pulmonary and systemic blood through the heart. This category includes the heart wall and fibrous skeleton enclosing and supporting the heart and dividing it into four chambers: the valves directing flow through the chambers and the great vessels conducting blood to and from the heart. 2. Maintenance of heart cells. This category includes all the vessels of the coronary circulation—the arteries and veins that serve the metabolic needs of all the heart cells—and the heart's lymphatic vessels. 3. Stimulation and control of heart action. Among these structures are the nerves and specialized muscle cells that direct the rhythmic contraction and relaxation of the heart muscles, propelling blood throughout the pulmonary and systemic circulatory systems.

Structures That Direct Circulation Through the Heart The Heart Wall The three layers of the heart wall—the epicardium, myocardium, and endocardium—are enclosed in a double-walled membranous sac, the pericardium (Figure 23-2). The pericardial sac has three main functions: (1) it prevents displacement of the heart during gravitational acceleration or deceleration, (2) it serves as a physical barrier to protect the heart against infection and inflammation coming from the lungs and pleural space, and (3) it contains pain receptors and mechanoreceptors that can cause reflex changes in blood pressure and heart rate. The two layers of the pericardium, the parietal and the visceral pericardia (see Figure 23-2), are separated by a fluid-containing space called the pericardial cavity (also referred to as pericardial space). The pericardial fluid (about 20 mL) is secreted by cells of the mesothelial layer of the pericardium and lubricates the membranes that line the pericardial cavity, enabling them to slide smoothly over one another with minimal friction as the heart beats. The amount and character of the pericardial fluid are altered if the pericardium is inflamed (see Chapter 24).

FIGURE 23-2 Wall of the Heart. This section of the heart wall shows the fibrous pericardium, the parietal and visceral layers of the serous pericardium (with the pericardial space between them), the myocardium, and the endocardium. Note the fatty connective tissue between the visceral layer of the serous pericardium (epicardium) and the myocardium. Note also that the endocardium covers tubular projections of myocardial muscle tissue called trabeculae. (Revised from Applegate, E. [2011]. The anatomy and physiology learning system [4th ed.]. St. Louis: Saunders.)

The smoothness of the outer layer of the heart, the epicardium, also minimizes the friction between the heart wall and the pericardial sac. The thickest layer of the heart wall, the myocardium, is composed of cardiac muscle and is anchored to the heart's fibrous skeleton. The heart muscle cells, cardiomyocytes, provide the contractile force needed for blood to flow through the heart and into the pulmonary and systemic circulations. About 0.5 to 1% of the cardiomyocytes are replaced annually; thus over a lifetime about half of these muscle cells are replaced.2 There is great interest in finding therapies that will increase the rate of cardiomyocyte replacement for persons who have suffered a myocardial infarction or have heart failure from another cause. The internal lining of the myocardium, the endocardium, is composed of connective tissue and squamous cells (see Figure 23-2). This lining is continuous with the endothelium that lines all the arteries, veins, and capillaries of the body, creating a continuous, closed circulatory system.

Chambers of the Heart The heart has four chambers: the left atrium, the right atrium, the right ventricle, and the left ventricle. These chambers form two pumps in series: the right heart is a low-pressure system pumping blood through the lungs, and the left heart is a high-pressure system pumping blood to the rest of the body (Figure 23-3). The atria are smaller than the ventricles and have thinner walls. The ventricles have a thicker myocardial layer and constitute much of the bulk of the heart. The ventricles are formed by a continuum of muscle fibres originating from the fibrous skeleton at the base of the heart.

FIGURE 23-3

Structures That Direct Blood Flow Through the Heart. The blue and red arrows indicate the pathways of unoxygenated and oxygenated blood flow through chambers, valves, and major vessels.

The wall thickness of each cardiac chamber depends on the amount of pressure or resistance it must overcome to eject blood. The two atria have the thinnest walls because they are low-pressure chambers that serve as storage units and channels for blood that is emptied into the ventricles. Normally, there is little resistance to flow from the atria to the ventricles. The ventricles, on the other hand, must propel the blood all the way through the pulmonary or systemic vessels. The mean pulmonary artery pressure, the force the right ventricle must overcome, is only 15 mm Hg, whereas the mean arterial pressure the left ventricle must pump against is about 92 mm Hg. Because the pressure is markedly higher in the systemic circulation, the wall of the left ventricle is about three times thicker than that of the right ventricle. The right ventricle is shaped like a crescent or triangle, enabling a bellowslike action that efficiently ejects large volumes of blood through the pulmonary semilunar valve into the low-pressure pulmonary system. The larger left ventricle is bullet shaped, which allows it to generate enough pressure to eject blood through a relatively larger aortic semilunar valve into the high-pressure systemic circulation. The septal membrane separates the right and left sides of the heart and prevents blood from crossing between the two circulatory systems. The atria are separated by the interatrial septum, and the ventricles are separated by the interventricular septum. Because the fetus does not depend on the lungs for oxygenation, there is an opening before birth between the right and left atria called the foramen ovale that facilitates circulation. This opening closes functionally at the time of birth as the higher pressure in the left atrium pushes a flap, the septum primum, over the hole. In 75 to 80% of infants, these septa are permanently fused within the first year of life3,4 (see Chapter 25).

Fibrous Skeleton of the Heart Four rings of dense fibrous connective tissue provide a firm anchorage for the attachments of the atrial and ventricular musculature, as well as the valvular tissue (Figure 23-4). The fibrous rings are adjacent and form a central, fibrous supporting structure collectively termed the annuli fibrosi cordis.

FIGURE 23-4 Transverse Section of the Heart Showing the Atrioventricular (Mitral and Tricuspid) and Semilunar (Aortic and Pulmonary) Valves. Superior view with the atria and vessels removed. Arrows indicate direction of blood flow. A, When the heart is filling with blood, the AV valves are open and the semilunar valves are closed. B, When blood is leaving the heart, the semilunar valves are open and the AV valves are closed. AV, atrioventricular. (From Naish, J. [2015]. Medical sciences [2nd ed.]. London: Saunders.)

Valves of the Heart Four heart valves and the pressure gradients they maintain ensure that blood only flows one way through the heart. When the ventricles are relaxed, the two atrioventricular valves (AV valves) open and blood flows from the relatively higher pressure in the atria to the lower pressure in the ventricles. As the ventricles contract, ventricular pressure increases and causes these valves to close and prevent backflow into the atria. The semilunar valves of the heart open when intraventricular pressure exceeds aortic and pulmonary pressures, and blood flows out of the ventricles and into the pulmonary and systemic circulations. After ventricular contraction and ejection, intraventricular pressure falls and the pulmonic semilunar valve and aortic semilunar valve close when the pressure in the vessels is greater than the pressure in the ventricles, thus preventing backflow into the right and left ventricles, respectively. The actions of the heart valves are shown in Figures 23-3 and 23-4. The AV (tricuspid and mitral) valve openings are composed of tissue flaps called leaflets or cusps, which are attached at the upper margin to a ring in the heart's fibrous skeleton and by the chordae tendineae at the lower end to the papillary muscles (see Figure 23-3). The papillary muscles, extensions of the myocardium, help hold the cusps together and downward at the onset of ventricular contraction, thus preventing their backward expulsion or prolapse into the atria. The AV valve in the right heart is called the tricuspid valve because it has three cusps. The left AV valve is a bicuspid (two-cusp) valve called the mitral valve (left atrioventricular valve, bicuspid valve). The tricuspid and mitral valves function as a unit because the atria, fibrous rings, valvular tissue, chordae tendineae, papillary muscles, and ventricular walls are connected. Collectively, these six structures are known as the mitral and tricuspid complex. Damage to any one of the six components of this complex can alter function significantly and contribute to heart failure. Blood leaves the right ventricle through the pulmonic semilunar valve, and it leaves the left ventricle through the aortic semilunar valve (see Figures 23-3 and 23-4). Both the pulmonic and aortic semilunar valves have three cup-shaped cusps that arise from the fibrous skeleton.

The Great Vessels Blood moves in and out of the heart through several large veins and arteries (see Figure 23-3). The right heart receives venous blood from the systemic circulation through the superior vena cava and inferior vena cava, which join and then enter the right atrium. Blood leaving the right ventricle enters the pulmonary circulation through the pulmonary artery, which divides into right and left branches to transport unoxygenated blood from the right heart to the lungs. The pulmonary arteries branch further

into the pulmonary capillary beds, where oxygen and carbon dioxide exchange occurs. Four pulmonary veins, two from the right lung and two from the left lung, carry oxygenated blood from the lungs to the left side of the heart. The oxygenated blood moves through the left atrium and ventricle, out into the aorta that subsequently branches into the systemic arteries that supply the body.

Blood Flow During the Cardiac Cycle The pumping action of the heart consists of contraction and relaxation of the heart muscle, or myocardium. Each ventricular contraction and the relaxation that follows it constitute one cardiac cycle. (Blood flow through the heart during a single cardiac cycle is illustrated in Figure 23-5.) During the period of relaxation, termed diastole, blood fills the ventricles. The ventricular contraction that follows, termed systole, propels the blood out of the ventricles and into the pulmonary and systemic circulations. Contraction of the left ventricle occurs slightly earlier than contraction of the right ventricle.

FIGURE 23-5 Blood Flow Through the Heart During a Single Cardiac Cycle. A, During diastole, blood flows into atria, atrioventricular valves are pushed open, and blood begins to fill ventricles. Atrial systole squeezes blood remaining in the atria into the ventricles. B, During ventricular systole, the ventricles contract, pushing blood out through semilunar valves into the pulmonary artery (right ventricle) and the aorta (left ventricle). (From Patton, K.T., & Thibodeau, G.A. [2016]. Structure & function of the body [15th ed.]. St. Louis: Elsevier.)

The five phases of the cardiac cycle are said to begin with the opening of the mitral and tricuspid valves and atrial contraction (Figures 23-6 and 23-7). Closing of the mitral and tricuspid valves as passive ventricular filling begins marks the end of one cardiac cycle.

FIGURE 23-6 Composite Chart of Heart Function. This chart is a composite of several diagrams of heart function (cardiac pumping cycle, blood pressure, blood flow, volume, heart sounds, venous pulse, and electrocardiogram [ECG]), all on the same time scale.

FIGURE 23-7 The Five Phases of the Cardiac Cycle. 1, Atrial systole: Atria contract, pushing blood through the open tricuspid and mitral valves into the ventricles. Semilunar valves are closed. 2, Beginning of ventricular systole. Ventricles contract, increasing pressure within the ventricles. The tricuspid and mitral valves close, causing the first heart sound. 3, Period of rising pressure: semilunar valves open when pressure in the ventricle exceeds that in the arteries. Blood spurts into the aorta and pulmonary arteries. 4, Beginning of ventricular diastole: pressure in the relaxing ventricles drops below that in the arteries. Semilunar valves snap shut, causing the second heart sound. 5, Period of falling pressure: blood flows from veins into the relaxed atria. Tricuspid and mitral valves open when pressure in the ventricles falls below that in the atria. (Adapted from Solomon, E. [2016]. Introduction to human anatomy and physiology [4th ed.]. St. Louis: Saunders.)

Normal Intracardiac Pressures Normal intracardiac pressures are shown in Table 23-1. TABLE 23-1 Normal Intracardiac Pressures Right atrium Right ventricle Systolic End-diastolic Left atrium Left ventricle Systolic End-diastolic

Mean (mm Hg)

Range (mm Hg)

4

0–8

24 4 7

15–28 0–8 4–12

130 7

90–140 4–12

Quick Check 23-1 1. Why are the two separate circulatory systems said to be “serially connected”? 2. What are the functions of the pericardial sac? 3. Why is the thickness of the myocardium different in the right and left ventricles? 4. Trace the flow of blood through the heart during one cardiac cycle.

Structures That Support Cardiac Metabolism: The Coronary Vessels

The myocardium and other heart structures are supplied with oxygen and nutrients by the coronary circulation, which is part of the systemic circulation. The coronary arteries originate at the upper edge of the aortic semilunar valve cusps (Figure 23-8, B) and receive blood through openings in the aorta called the coronary ostia. The cardiac veins empty into the right atrium through another ostium, the opening of a large vein called the coronary sinus (Figure 23-8, C). (Regulation of the coronary circulation, which is similar to regulation of flow through systemic and pulmonary vessels, is described in “Regulation of the Coronary Circulation,” p. 598.)

FIGURE 23-8 Coronary Circulation. A, Arteries. B, Coronary artery openings from the aorta. C, Veins. Both A and C are anterior views of the heart. Vessels near the anterior surface are more darkly coloured than vessels of the posterior surface seen through the heart. B, Placement of the coronary artery opening behind the leaflets of the aortic valve allows the coronary arteries to fill during ventricular relaxation. (A and C, from Patton, K.T., & Thibodeau, G.A. [2010]. Anatomy & physiology [7th ed.]. St. Louis: Mosby. B, Patton, K.T., & Thibodeau, G.A. [2014]. The human body in health & disease [6th ed.]. St. Louis: Mosby.)

Coronary Arteries The major coronary arteries, the right coronary artery (RCA) and the left coronary artery (LCA) (Figure 23-8, A), traverse the epicardium, myocardium, and endocardium and branch to become arterioles and then capillaries. Their main branches are outlined in Box 23-1. The coronary arteries are smaller in women than in men because women's hearts weigh proportionately less than men's hearts.

Box 23-1

Main Branches of the Coronary Arteries

Left coronary artery. Arises from single ostium behind left cusp of aortic semilunar valve; ranges from a few millimetres to a few centimetres long; passes between left arterial appendage and pulmonary artery and generally divides into two branches: the left anterior descending artery and the circumflex artery; other branches are distributed diagonally across the free wall of the left ventricle. Left anterior descending artery (or anterior interventricular artery). Delivers blood to portions of left and right ventricles and much of interventricular septum; travels down the anterior surface of the interventricular septum toward apex of the heart. Circumflex artery. Travels in a groove (coronary sulcus) that separates left atrium from left ventricle and extends to left border of heart; supplies blood to left atrium and lateral wall of left ventricle; often branches to posterior surfaces of left atrium and left ventricle. Right coronary artery. Originates from an ostium behind the right aortic cusp, travels from behind the pulmonary artery, and extends around the right heart to the heart's posterior surface, where it branches to atrium and ventricle; three major branches are conus (supplies blood to upper right ventricle), right marginal branch (supplies right ventricle to the apex), and posterior descending branch (lies in posterior interventricular sulcus and supplies smaller branches to both ventricles).

Collateral Arteries Collateral arteries are anastomoses or connections between branches of the same coronary artery or connections of branches of the RCA with branches of the left. The epicardium contains more collateral vessels than the endocardium. New collateral vessels are formed through two processes: arteriogenesis (new artery growth branching from pre-existing arteries) and angiogenesis (growth of new capillaries within a tissue).5 This collateral growth is stimulated by shear stress that results from increased blood flow speed within and just beyond areas of stenosis, as well as the production of growth factors and cytokines, including monocyte chemoattractant protein-1 (MCP-1) and vascular endothelial growth factor (VEGF).6 The collateral circulation assists in supplying blood and oxygen to myocardium that has become ischemic following gradual narrowing, or stenosis, of one or more major coronary arteries (coronary artery disease). Unfortunately, diabetes, which predisposes to coronary artery disease, also impedes collateral formation because of increased production of antiangiogenic factors, such as endostatin and angiostatin. Current research is focused on identifying whether some factors that stimulate collateral growth might be useful treatments for myocardial ischemia; so far, none have been demonstrated to be effective.6

Coronary Capillaries The heart requires an extensive capillary network to function. Blood travels from the arteries to the arterioles and then into the capillaries, where oxygen and other nutrients enter the myocardium while waste products enter the blood. At rest, the heart extracts 50 to 80% of the oxygen delivered to it, and coronary blood flow is directly correlated with myocardial oxygen consumption.7 Any alteration of the cardiac muscles dramatically affects blood flow in the capillaries.

Coronary Veins and Lymphatic Vessels After passing through the capillary network, blood from the coronary arteries drains into the cardiac veins located alongside the arteries. Most of the venous drainage of the heart occurs through veins in the visceral pericardium. The veins then feed into the great cardiac vein (see Figure 23-8, C) and coronary sinus on the posterior surface of the heart, between the atria and ventricles, in the coronary sulcus. The myocardium has an extensive system of lymphatic capillaries and collecting vessels within the layers of the myocardium and the valves. With cardiac contraction, the lymphatic vessels drain fluid to lymph nodes in the anterior mediastinum that empty into the superior vena cava. The lymphatics are important for protecting the myocardium against infection and injury.

Structures That Control Heart Action Life depends on continuous repetition of the cardiac cycle (systole and diastole), which requires the

transmission of electrical impulses, termed cardiac action potentials, through the myocardium.7 (Action potentials are described in Chapters 1 and 5.) The muscle fibres of the myocardium are electrically coupled so that action potentials pass from cell to cell rapidly and efficiently. The myocardium contains its own pacemakers and conduction system—specialized cells that enable it to generate and transmit action potentials without input from the nervous system (Figure 23-9). The pacemaker cells are concentrated at two sites, or nodes, in the myocardium. The cardiac cycle is stimulated by these nodes of specialized cells. Although the heart is innervated by the autonomic nervous system (both sympathetic and parasympathetic fibres), neural impulses are not needed to maintain the cardiac cycle. Thus the heart will beat in the absence of any innervation, one of the many factors that allow heart transplantation to be successful.

FIGURE 23-9 The Cardiac Conduction System. Specialized cardiac muscle cells in the heart wall rapidly conduct an electrical impulse throughout the myocardium. The signal is initiated by the sinoatrial node (pacemaker) and spreads through the atrial myocardium to the atrioventricular node. The atrioventricular node then initiates a signal that is conducted through the ventricular myocardium by way of the atrioventricular bundle (of His) and Purkinje fibres. (From Koeppen, B.M. [Ed.]. [2010]. Berne & Levy physiology [6th ed.]. St. Louis: Mosby.)

Heart action is also influenced by substances delivered to the myocardium in coronary blood. Nutrients and oxygen are needed for cellular survival and normal function. Hormones and biochemical substances, including medications, can affect the strength and duration of myocardial contraction and the degree and duration of myocardial relaxation. Normal or appropriate function depends on the supply of these substances, which is why coronary artery disease can seriously disrupt heart function.

The Conduction System Normally, electrical impulses arise in the sinoatrial node (SA node, sinus node), the usual pacemaker of the heart. The SA node is located at the junction of the right atrium and superior vena cava, just superior to the tricuspid valve. The SA node is heavily innervated by both sympathetic and parasympathetic nerve fibres.8 In the resting adult, the SA node generates about 60 to 100 action potentials per minute, depending on age and physical condition. Each action potential travels rapidly from cell to cell and through the atrial myocardium, carrying the action potential onward to the atrioventricular node (AV node), as well as causing both atria to contract, beginning systole.8 The AV node, located in the right atrial wall superior to the tricuspid valve and anterior to the ostium of the coronary sinus, conducts the action potentials onward to the ventricles. It is innervated by nerves from the autonomic parasympathetic ganglia that serve as receptors for the vagus nerve and cause slowing of impulse conduction through the AV node. Conducting fibres from the AV node converge to form the bundle of His (atrioventricular bundle [AV bundle]), within the posterior border of the interventricular septum. The bundle of His then gives rise to the right and left bundle branches. The right bundle branch (RBB) is thin and travels without much branching to the right ventricular apex. Because of its thinness and relative lack of branches, the RBB is susceptible to interruption of impulse conduction by damage to the endocardium. The left bundle

branch (LBB) in some hearts divides into two branches, or fascicles. The left anterior bundle branch (LABB) passes the left anterior papillary muscle and the base of the left ventricle and crosses the aortic outflow tract. Damage to the aortic valve or the left ventricle can interrupt this branch. The left posterior bundle branch (LPBB) travels posteriorly, crossing the left ventricular inflow tract to the base of the left posterior papillary muscle. This branch spreads diffusely through the posterior inferior left ventricular wall. Blood flow through this portion of the left ventricle is relatively nonturbulent, so the LBB is somewhat protected from injury caused by wear and tear. The Purkinje fibres are the terminal branches of the RBB and LBB. They extend from the ventricular apexes to the fibrous rings and penetrate the heart wall to the outer myocardium. The first areas of the ventricles to be excited are portions of the interventricular septum. The septum is activated from both the RBB and the LBB. The extensive network of Purkinje fibres promotes the rapid spread of the impulse to the ventricular apexes. The basal and posterior portions of the ventricles are the last to be activated.

Quick Check 23-2 1. Draw a diagram of the conduction system of the heart. 2. Why are the left and right coronary vessels considered the major coronary vessels?

Propagation of cardiac action potentials. Electrical activation of the muscle cells, termed depolarization, is caused by the movement of ions, including sodium, potassium, calcium, and chloride, across cardiac cell membranes. Deactivation, called repolarization, occurs the same way. (Movement of ions across cell membranes is described in Chapter 1; electrical activation of muscle cells is described in Chapter 38.) Movement of ions into and out of the cell creates an electrical (voltage) difference across the cell membrane, called the membrane potential. The resting membrane potential of myocardial cells is between −80 and −90 mV, whereas that of the SA node is between −50 and −60 mV and that of the AV node is between −60 and −70 mV.8 During depolarization, the inside of the cell becomes less negatively charged. In cardiac cells, as in other excitable cells, when the resting membrane potential (in millivolts) becomes more negative with depolarization and reaches the threshold potential for cardiac cells, a cardiac action potential is fired. Table 23-2 summarizes the intracellular and extracellular ionic concentrations of cardiac muscle. Medications that alter the movement of these ions (e.g., calcium) have profound effects on the action potential and can alter heart rate. The various phases of the cardiac action potential are related to changes in the permeability of the cell membrane to sodium, potassium, chloride, and calcium. Threshold is the point at which the cell membrane's selective permeability to these ions is temporarily disrupted, leading to an “all or nothing” depolarization. If the resting membrane potential becomes more negative because of a decrease in extracellular potassium concentration (hypokalemia), it is termed hyperpolarization. TABLE 23-2 Intracellular and Extracellular Ion Concentrations in the Myocardium Sodium (Na+) Potassium (K+) Chloride (Cl−) Calcium (Ca++)

Intracellular Concentration (mmol/L)

Extracellular Concentration (mmol/L)

5 150 5 10−7

135–145 3.5–5.0 98–106 Total Ca: 2.25–2.75 Ionized: 1.05–1.30

A refractory period, during which no new cardiac action potential can be initiated by a stimulus, follows depolarization. This effective or absolute refractory period corresponds to the time needed for the reopening of channels that permit sodium and calcium influx into the cells. A relative refractory period occurs near the end of repolarization, following the effective refractory period. During this time, the membrane can be depolarized again but only by a greater-than-normal stimulus. Abnormal refractory

periods as a result of disease can cause abnormal heart rhythms or dysrhythmias, including ventricular fibrillation and cardiac arrest (see Chapter 24). The electrocardiogram. An electrocardiogram originates from myocardial cell electrical activity as recorded by skin electrodes and is the summation of all the cardiac action potentials (Figure 23-10). The P wave represents atrial depolarization. The PR interval is a measure of time from the onset of atrial activation to the onset of ventricular activation (normally 0.12 to 0.20 second). The PR interval represents the time necessary for electrical activity to travel from the sinus node through the atrium, AV node, and His–Purkinje system to activate ventricular myocardial cells. The QRS complex represents the sum of all ventricular muscle cell depolarization. The configuration and amplitude of the QRS complex may vary considerably among individuals. The duration is normally between 0.06 and 0.10 second. During the ST interval, the entire ventricular myocardium is depolarized. The QT interval is sometimes called the “electrical systole” of the ventricles. It lasts about 0.4 second but varies inversely with the heart rate. The T wave represents ventricular repolarization.

FIGURE 23-10 Electrocardiogram, and Cardiac Electrical Activity. A, Normal ECG. Depolarization and repolarization. B, ECG intervals among P, QRS, and T waves. C, Schematic representation of ECG and its relationship to cardiac electrical activity. AV, atrioventricular; ECG, electrocardiogram; LA, left atrium; LBB, left bundle branch; LV, left ventricle; RA, right atrium; RBB, right bundle branch; RV, right ventricle.

Automaticity. Automaticity, or the property of generating spontaneous depolarization to threshold, enables the SA and AV nodes to generate cardiac action potentials without any external stimulus. Cells capable of spontaneous depolarization are called automatic cells. The automatic cells of the cardiac conduction

system can stimulate the heart to beat even when it is transplanted and thus has no innervation. Spontaneous depolarization is possible in automatic cells because the membrane potential of these special cells does not actually “rest” during return to the resting membrane potential. Instead, it slowly depolarizes toward threshold during the diastolic phase of the cardiac cycle. Because threshold is approached during diastole, return to the resting membrane potential in automatic cells is called diastolic depolarization. The electrical impulse normally begins in the SA node because its cells depolarize more rapidly than other automatic cells. Rhythmicity. Rhythmicity is the regular generation of an action potential by the heart's conduction system. The SA node sets the pace because normally it has the fastest rate. The SA node depolarizes spontaneously 60 to 100 times per minute. If the SA node is damaged, the AV node can become the heart's pacemaker at a rate of about 40 to 60 spontaneous depolarizations per minute. Eventually, however, conduction cells in the atria usually take over from the AV node. Purkinje fibres are capable of spontaneous depolarization but at an even slower rate than the AV node.

Quick Check 23-3 1. What are the pathways of conduction through the heart? 2. What does each of the electrocardiogram waves (P, Q, R, S, T) represent? 3. Define automaticity and rhythmicity.

Cardiac Innervation Although the heart's nodes and conduction system are able to generate action potentials independently, the autonomic nervous system influences both the rate of impulse generation (firing), depolarization, and repolarization of the myocardium, and the strength of atrial and ventricular contraction. Autonomic neural transmission produces changes in the heart and circulatory system faster than metabolic or humoral agents. Speed is important, for example, in stimulating the heart to increase its pumping action during times of stress and fear—the so-called fight-or-flight response—or with increased physical activity. Although increased delivery of oxygen, glucose, hormones, and other bloodborne factors sustains increased cardiac activity, the rapid initiation of increased activity depends on the sympathetic and parasympathetic fibres of the autonomic nervous system.

Sympathetic and parasympathetic nerves. Sympathetic and parasympathetic nerve fibres innervate all parts of the atria and ventricles and the SA and AV nodes. In general, sympathetic stimulation increases electrical conductivity and the strength of myocardial contraction, and vagal parasympathetic nerve activity does the opposite, slowing the conduction of action potentials through the heart and reducing the strength of contraction. Thus the sympathetic and parasympathetic nerves affect the speed of the cardiac cycle (heart rate, or beats per minute), and the sympathetic nerves also influence the diameter of the coronary vessels (Figure 23-11). Sympathetic nervous activity enhances myocardial performance. Stimulation of the SA node by the sympathetic nervous system rapidly increases heart rate. Furthermore, neurally released norepinephrine or circulating catecholamines interact with β-adrenergic receptors on the cardiac cell membranes. The overall effect is an increased influx of calcium (Ca++), which increases the contractile strength of the heart and increases the speed of electrical impulses through the heart muscle and the nodes.8 Finally, increased sympathetic discharge dilates the coronary vessels by causing the release of vasodilating metabolites resulting from increased myocardial contraction.7

FIGURE 23-11

Autonomic Innervation of Cardiovascular System. Inhibition (−); activation (+).

The parasympathetic nervous system affects the heart through the vagus nerve, which releases acetylcholine. Acetylcholine causes decreased heart rate and slows conduction through the AV node.

Myocardial Cells Cardiomyocytes are composed of long, narrow fibres that contain bundles of longitudinally arranged myofibrils; a nucleus (cardiac muscle); mitochondria; an internal membrane system (the sarcoplasmic reticulum); cytoplasm (sarcoplasm); and a plasma membrane (the sarcolemma), which encloses the cell. Cardiac and skeletal muscle cells also have an “external” membrane system made up of transverse tubules (T tubules) formed by inward pouching of the sarcolemma. The sarcoplasmic reticulum forms a network of channels that surrounds the muscle fibre. Because the myofibrils in both cardiac and skeletal fibres consist of alternating light and dark bands of protein, the fibres appear striped, or striated. The dark and light bands of the myofibrils create repeating longitudinal units, called sarcomeres, which are between 1.6 and 2.2 µm long (Figures 23-12 and 23-13). The length of these sarcomeres determines the limits of myocardial stretch at the end of diastole and subsequently the force of contraction during systole. Alterations in sarcomere size are seen in both physiological and pathological myocardial hypertrophy.

FIGURE 23-12 Cardiac Muscle Fibre. Unlike other types of muscle fibres, cardiac muscle fibres are typically branched with junctions, called intercalated discs, between adjacent myocytes. Like skeletal muscle cells, cardiac muscle cells contain sarcoplasmic reticula and T tubules, although these structures are not as highly organized as in skeletal muscle fibres.

FIGURE 23-13 Structure of a Sarcomere. The sarcomere is the basic contractile unit of a muscle cell. The Z disc is the anchor for the contractile elements actin and myosin. Actin attaches directly to the Z disc, whereas myosin is attached to it by elastic titin filaments. The myosin filaments are connected to each other by M-protein at the M line. The A, H, and I bands refer to parts of the sarcomere as they were originally seen by light microscopy.

Hypertrophy, or enlargement, of the heart may occur through growth in either the length or the width of the sarcomeres in both normal and disease conditions. When normal stimuli, such as physical activity or pregnancy, cause hypertrophy, myocardial contractility is increased; and when the stimulus is removed, regression of the hypertrophy occurs. Conversely, disease-related hypertrophy caused by conditions such as hypertension or myocardial infarction results in reduced contractility and often heart failure. It has long been thought that this pathological hypertrophy was not reversible, but new research has shown that reversal may be possible.

When patients with hypertrophic heart failure awaiting a heart transplant were treated by the placement of a left ventricular assist device, regression of the ventricular hypertrophy was observed, occasionally to the point that heart transplant was not required. Research on the mechanisms involved in regression has shown that gene activation, several signalling pathways, angiogenesis, and autophagy are all involved. The hope is that identification of these mechanisms will lead to new and more effective pharmaceutical treatments for heart failure that currently is associated with a poor long-term prognosis.911

Differences between cardiac and skeletal muscle reflect heart function. Cardiac cells are arranged in branching networks throughout the myocardium, whereas skeletal muscle cells tend to be arranged in parallel units throughout the length of the muscle. Cardiac fibres have only one nucleus, whereas skeletal muscle cells have many nuclei. Other differences enable cardiac fibres to do the following:

• Transmit action potentials quickly from cell to cell. Electrical impulses are transmitted rapidly from cardiac fibre to cardiac fibre because the network of fibres connects at intercalated discs, which are thickened portions of the sarcolemma. The intercalated discs contain three junctions: desmosomes or macula adherens; fascia adherens, which mechanically attach one cell to another; and gap junctions, also known as tight junctions, which allow the electrical impulse to spread from cell to cell through a low-resistance pathway (see Chapter 1). Changes in the function of these junctional elements may cause an increased risk for arrhythmias.8 • Maintain high levels of energy synthesis. Unlike skeletal muscle, the heart cannot rest and is in constant need of energy, which is supplied by molecules such as adenosine triphosphate (ATP). Therefore, the cytoplasm surrounding the bundles of myofibrils in each cardiomyocyte contains a large number of mitochondria (25 to 33% of cell volume). Cardiac muscle cells have more mitochondria than do skeletal muscle cells to provide the necessary respiratory enzymes for aerobic metabolism and supply quantities of ATP sufficient for the constant action of the myocardium.12 • Gain access to more ions, particularly sodium and potassium, in the extracellular environment. Cardiac fibres contain more T tubules than do skeletal muscle fibres (see Figure 23-12). This increased closeness to the T tubules gives each myofibril in the myocardium faster access to molecules needed for the transmission of action potentials, a process that involves transport of sodium and potassium through the walls of the T tubules. Because the T tubule system is continuous with the extracellular space and the interstitial fluid, it facilitates the rapid transmission of the electrical impulses from the surface of the sarcolemma to the myofibrils inside the fibre. This rapid transmission activates all the myofibrils of one fibre simultaneously. The

sarcoplasmic reticulum is located around the myofibrils. As an action potential is transmitted through the T tubules, it induces the sarcoplasmic reticulum to release its stored calcium, thus activating the contractile proteins actin and myosin. Actin, myosin, and the troponin–tropomyosin complex. Within each myocardial sarcomere are myosin molecules that resemble golf clubs with two large, ovoid heads at one end of the shaft (Figure 23-14, B). The two heads contain an actin binding site and a site of adenosinetriphosphatase (ATPase) activity. Thick filaments of myosin overlapping with thinner actin molecules form the central dark band of the sarcomere called the anisotropic band, or A band (see Figures 23-13 and 23-14). A thick filament has about 200 myosin molecules bundled together with their outward-facing heads named cross-bridges because they can form force-generating bridges by binding with exposed actin molecules, resulting in contraction (Figure 23-14, A). Actin molecules are part of the thin filaments (see Figures 23-13 and 23-14). The light bands, called isotropic bands (or I bands), of the sarcomere contain only actin molecules and no myosin (see Figure 23-13). Thin filaments of actin extend from each side of the Z line, a dense fibrous structure at the centre of each I band. The area from one dark Z line to the next Z line defines one sarcomere. The centre of the sarcomere is the H zone, a less dense region with a central thin, dark M line.12

FIGURE 23-14

Structure of Myofilaments. A, Thin myofilament. B, Thick myofilament.

A single tropomyosin molecule (a relaxing protein) lies alongside seven actin molecules. Troponin, another relaxing protein, associates with the tropomyosin molecule, forming the troponin–tropomyosin complex (see Figures 23-14, A, and 23-15). The troponin complex itself has three components. Troponin T aids in the binding of the troponin complex to actin and tropomyosin; troponin I inhibits the ATPase of actomyosin; and troponin C contains binding sites for the calcium ions involved in contraction. Troponin T and I molecules are released into the bloodstream during myocardial injury and are measured to evaluate if a myocardial infarction or other damage has occurred. When troponin and tropomyosin cover

the myosin binding sites on actin, the cross-bridges release calcium and the myocardium relaxes. The sarcomere also contains a giant elastic protein, titin, which attaches myosin to the Z line, acts as a spring, and influences myocardial stiffness.12 Titin structure impacts myocardial diastolic filling and has been found to play a role in heart failure.13

FIGURE 23-15 Cross-Bridge Theory of Muscle Contraction. A, Each myosin cross-bridge in the thick filament moves into a resting position after an adenosine triphosphate (ATP) molecule binds and transfers its energy. B, Calcium ions (Ca+) released from the sarcoplasmic reticulum bind to troponin in the thin filament, allowing tropomyosin to shift from its position blocking the active sites of actin molecules. C, Each myosin cross-bridge then binds to an active site on a thin filament, displacing the remnants of ATP hydrolysis— adenosine diphosphate and inorganic phosphate (Pi). D, The release of stored energy from step A provides the force needed for each cross-bridge to move back to its original position, pulling actin along with it. Each cross-bridge will remain bound to actin until another ATP molecule binds to it and pulls it back into its resting position (A). (Adapted from Thibodeau, G.A., & Patton, K.T. [1999]. Anatomy & physiology [4th ed.]. St. Louis: Mosby.)

Myocardial metabolism. Cardiomyocytes depend on the constant production of ATP, which is synthesized within the mitochondria mainly from glucose, fatty acids, and lactate. If the myocardium is underperfused because of coronary artery disease, anaerobic metabolism must be used for energy (see Chapter 1). Energy produced by metabolic processes fuels muscle contraction and relaxation, electrical excitation, membrane transport, and synthesis of large molecules. Normally, the amount of ATP produced supplies sufficient energy to pump blood throughout the system. Cardiac work is expressed as myocardial oxygen consumption (MV̇O2), which is closely correlated with total cardiac energy requirements. MV̇O2 is determined by three major factors: (1) amount of wall stress during systole, estimated by measuring the systolic blood pressure; (2) duration of systolic wall tension, measured indirectly by the heart rate; and (3) contractile state of the myocardium, which is not measured clinically. The coronary arteries deliver oxygen to the myocardium. Approximately 70 to 75% of this oxygen is used immediately by cardiac muscle, leaving little oxygen in reserve. Since the oxygen content of the blood and the amount of oxygen extracted from the blood cannot be increased under normal circumstances, any increased energy needs can be met only by increasing coronary blood flow. MV̇O2 increases with exercise and decreases with hypotension and hypothermia. As myocardial metabolism and consumption of oxygen increase, the local concentration of local vasoactive metabolic factors increases. Some of these factors—such as adenosine, nitric oxide, and prostaglandins—dilate coronary arterioles, thus increasing coronary blood flow.14

Myocardial Contraction and Relaxation Myocardial contractility is a change in developed tension at a given resting fibre length, which basically is the ability of the heart muscle to shorten. At the molecular level, thin filaments of actin slide over thick filaments of myosin, called the cross-bridge theory of muscle contraction. Anatomically, contraction occurs when the sarcomere shortens, so adjacent Z lines move closer together (see Figure 23-13). The degree of shortening depends on the amount of overlap between the thick and thin filaments.

Calcium and excitation–contraction coupling. Excitation–contraction coupling is the process by which an action potential arriving at the muscle fibre

plasma membrane triggers the cycle, leading to cross-bridge formation and contraction. Cycle activation depends on calcium availability, and the amount of force developed is regulated by how much the concentration of calcium ions increases within the cardiomyocytes. Calcium enters the myocardial cell from the interstitial fluid after electrical excitation that increases membrane calcium permeability. Two types of calcium channels (L-type, T-type) are found in cardiac tissues.12 The L-type, or long-lasting, channels predominate and are the channels blocked by calcium channel–blocking medications (verapamil [Isoptin], nifedipine [Adalat], diltiazem [Cardizem]).12 The T-type, or transient, channels are much less abundant in the heart. T-type channels are not blocked by currently available calcium channel–blocking medications; therefore T-type channel blockers are being investigated.15 Calcium entering the cell triggers the release of additional calcium from the two storage sites within the sarcomere—the sarcoplasmic reticulum and tubule system. Calcium ions then diffuse toward the myofibrils, where they bind with troponin. The calcium–troponin complex interaction facilitates the contraction process. In the resting state, troponin I is bound to actin and the tropomyosin molecule covers the sites where the myosin heads bind to actin, thereby preventing interaction between actin and myosin. Calcium binds to troponin C, which ultimately results in tropomyosin moving troponin I, thus uncovering the binding sites on the myosin heads. Myosin and actin can now form cross-bridges, and ATP can be dephosphorylated to adenosine diphosphate (ADP). Under these circumstances, sliding of the thick and thin filaments can occur, and the muscle contracts.12

Myocardial relaxation. Relaxation is as vital to optimal cardiac function as contraction; and calcium, troponin, and tropomyosin also facilitate relaxation. After contraction, free calcium ions are actively pumped out of the cell back into the interstitial fluid or taken back into storage by the sarcoplasmic reticulum and tubule system. As the concentration of calcium within the sarcomere decreases, troponin releases its bound calcium. The tropomyosin complex moves and blocks the active sites on the actin molecule, preventing cross-bridge formation with the myosin heads. If the ability of the myocardium to relax is impaired, it can lead to increased diastolic filling pressures and eventually heart failure.16

Quick Check 23-4 1. What features distinguish myocardial cells from skeletal cells? 2. Describe the interactions of actin, myosin, and the troponin–tropomyosin complex in controlling heart function. 3. Define excitation–contraction coupling.

Factors Affecting Cardiac Output Cardiac performance can be evaluated by measuring the cardiac output. Cardiac output is calculated by multiplying heart rate in beats per minute (beats/min) by stroke volume in litres per beat. Normal adult cardiac output is about 5 L/min at rest given a heart rate of about 70 beats/min and a normal stroke volume of about 70 mL.7 With each heartbeat, the ventricles eject much of their blood volume, and the amount ejected per beat is called the ejection fraction. The ejection fraction is estimated by echocardiography, computed tomography (CT) scan, nuclear medicine scan, or cardiac catheterization and is calculated by dividing stroke volume by end-diastolic volume. The end-diastolic volume of the normal ventricle is about 70 to 80 mL/m2, and the normal ejection fraction of the resting heart measured with gated myocardial perfusion imaging is 66% ± 8% for women and 58% ± 8% for men.17 The ejection fraction is increased by factors that increase contractility, such as increased sympathetic nervous system activity. A decrease in ejection fraction may indicate ventricular failure. The effects of aging on cardiovascular function are summarized in Table 23-3.

TABLE 23-3 Cardiovascular Function in Older Adults Determinant

Resting Cardiac Performance

Exercise Cardiac Performancea

Cardiac output Heart rate Stroke volume Ejection fraction Afterload End-diastolic volume End-systolic volume Contraction Myocardial wall stiffness Maximum oxygen consumption Plasma catecholamines

Unchanged Slight decrease Slight increase Unchanged Increased Unchanged Unchanged Decreased velocity Increased Not applicable —

Decreases because of a decrease in maximum heart rate Increases less than in younger people No change Decreased Increased Increased Increased Decreased Increased Decreased Increased

a

Changes in healthy men and women up to age 80 years as compared with those who are 20 years of age.

Data from Lakatta, E.G., Najjar, S.S., Schulman, S.P., et al. (2011). Aging and cardiovascular disease in the elderly. In V. Fuster, R.A. Walsh, R.A. Harrington, et al. (Eds.), Hurst's the heart (13th ed., pp. 2196–2225). Philadelphia: McGraw-Hill.

The factors that determine cardiac output are (1) preload, (2) afterload, (3) myocardial contractility, and (4) heart rate. Preload, afterload, and contractility all affect stroke volume.

Preload Preload is the volume and pressure inside the ventricle at the end of diastole (ventricular end-diastolic volume [VEDV] and ventricular end-diastolic pressure [VEDP]). Preload is determined by two primary factors: (1) the amount of venous blood returning to the ventricle during diastole and (2) the amount of blood left in the ventricle after systole (end-systolic volume). Venous return is dependent on blood volume and flow through the venous system and the AV valves. End-systolic volume is dependent on the strength of ventricular contraction and the resistance to ventricular emptying. Clinically, preload is estimated by measuring the central venous pressure (CVP) for the right side of the heart and the pulmonary artery wedge pressure for the left side. Normal values for these two estimates are 1 to 5 mm Hg and 4 to 12 mm Hg, respectively.18 Laplace's law states that wall tension generated in the wall of the ventricle (or any chamber or vessel) to produce a given intraventricular pressure depends directly on ventricular size or internal radius and inversely on ventricular wall thickness. VEDV, which determines the size of the ventricle and the stretch of the cardiac muscle fibres, therefore affects the tension (or force) for contraction. Starling's law of the heart indicates that the volume of blood in the heart at the end of diastole determines the length of its muscle fibres and is directly related to the force of contraction during the next systole. Muscle fibres have an optimal resting length from which to generate the maximum amount of contractile strength. Within a physiological range of muscle stretching, increased preload increases stroke volume (and therefore cardiac output and stroke work) (Figure 23-16, curve B). Excessive ventricular filling and preload (increased VEDV) stretches the heart muscle beyond optimal length and stroke volume begins to fall. Factors that increase contractility cause the heart to operate on a higher length-tension curve (see Figure 23-16, curve A). Factors that decrease contractility (see Figure 23-16, curve C) cause the heart to operate at a lower length-tension curve. Figure 23-17 illustrates the relationship between VEDV and stroke volume, cardiac output, and stroke work.

FIGURE 23-16 Starling's Law of the Heart. The relationship between length and tension in the heart. End-diastolic volume determines end-diastolic length of ventricular muscle fibres and is proportional to tension generated during systole, as well as to cardiac output, stroke volume, and stroke work. A change in myocardial contractility causes the heart to perform on a different length-tension curve. A, Increased contractility; B, normal contractility; C, heart failure or decreased contractility. (See text for further explanation.)

FIGURE 23-17 Factors Affecting Cardiac Performance. Cardiac output, the amount of blood (in litres) ejected by the heart per minute, depends on heart rate (beats per minute) and stroke volume (millilitres of blood ejected during ventricular systole).

Increases in preload (VEDV) may not only cause a decline in stroke volume but also result in increases in VEDP. These changes can lead to heart failure (see Chapter 24). Increased VEDP causes pressures to increase or “back up” into the pulmonary or systemic venous circulation, thus increasing the movement of plasma out through vessel walls, causing fluid to accumulate in lung tissues (pulmonary edema; see Chapter 27) or in peripheral tissues (peripheral edema).

Afterload Left ventricular afterload is the resistance to ejection of blood from the left ventricle. It is the load the muscle must move during contraction (see Figure 23-17). Aortic systolic pressure is an index of afterload. Pressure in the ventricle must exceed aortic pressure before blood can be pumped out during systole. Low aortic pressures (decreased afterload) enable the heart to contract more rapidly and efficiently, whereas high aortic pressures (increased afterload) slow contraction and cause higher workloads against which the heart must function to eject blood. Increased aortic pressure is usually the result of increased systemic vascular resistance (SVR), sometimes referred to as total peripheral resistance (TPR). In individuals with hypertension, increased TPR means that afterload is chronically elevated, resulting in increased ventricular workload and hypertrophy of the myocardium. In some individuals, changes in afterload are the result of aortic valvular disease. SVR is calculated by dividing mean arterial pressure by cardiac output; the normal range is 700 dyne/sec/cm−5.7,18

Myocardial Contractility Stroke volume, or the volume of blood ejected per beat during systole, also depends on the force of contraction, myocardial contractility, or the degree of myocardial fibre shortening. Three major factors determine the force of contraction (see Figure 23-17): 1. Changes in the stretching of the ventricular myocardium caused by changes in VEDV (preload). As discussed previously, increased venous return to the heart distends the ventricle, thus increasing preload, which increases the stroke volume and, subsequently, cardiac output, up to a certain point. However, an excessive increase in preload leads to decreased stroke volume. 2. Alterations in the inotropic stimuli of the ventricles. Hormones, neurotransmitters, or medications that affect contractility are called inotropic agents. The most important endogenous positive inotropic agents are epinephrine and norepinephrine released from the sympathetic nervous system. Other positive inotropes include thyroid hormone and dopamine. The most important negative inotropic agent is acetylcholine released from the vagus nerve. Many medications have positive or

negative inotropic properties that can have profound effects on cardiac function. In sepsis, a variety of cytokines, including tumour necrosis factor-alpha (TNF-α) and interleukin-1β, have been shown to impair myocardial contractility.19 3. Adequacy of myocardial oxygen supply. Oxygen and carbon dioxide levels (tensions) in the coronary blood also influence contractility. With severe hypoxemia (arterial oxygen saturation of less than 50%), contractility is decreased. With less severe hypoxemia (arterial oxygen saturation of more than 50%), contractility is stimulated. Moderate degrees of hypoxemia may increase contractility by enhancing the myocardial response to circulating catecholamines.20 Preload, afterload, and contractility all interact with one another to determine stroke volume and cardiac output. Changes in any one of these factors can result in deleterious effects on the others, resulting in heart failure (see Chapter 24).

Heart Rate As described previously, SA node activity is the primary determinant of the heart rate. The average heart rate in healthy adults is about 70 beats/min. This rate diminishes by 10 to 20 beats/min during sleep and can accelerate to more than 100 beats/min during muscular activity or emotional excitement. In wellconditioned athletes, resting heart rate is normally about 50 to 60 beats/min. In highly trained or elite athletes, the resting heart rate can be below 50 beats/min; these athletes also have a greater stroke volume and lower peripheral resistance in active muscles than they had before training. The control of heart rate includes activity of the central nervous system, autonomic nervous system, neural reflexes, atrial receptors, and hormones (see Figure 23-17).

Cardiovascular control centres in the brain. The cardiovascular vasomotor control centre is in the medulla and pons areas of the brainstem, with additional areas in the hypothalamus, cerebral cortex, and thalamus.21 The hypothalamic centres regulate cardiovascular responses to changes in temperature, the cerebral cortex centres adjust cardiac reaction to a variety of emotional states, and the brainstem control centre regulates heart rate and blood pressure (see Figure 23-11). The nerve fibres from the cardiovascular control centre synapse with autonomic neurons that influence the rate of firing of the SA node. As previously discussed, increased heart rate occurs with sympathetic (adrenergic) stimulation. When the parasympathetic nerves to the heart are stimulated (primarily via the vagus nerve), heart rate slows and the sympathetic nerves to the heart, arterioles, and veins are inhibited.8 At rest, the heart rate in healthy individuals is primarily under the control of parasympathetic stimulation. Administration of medications that block parasympathetic function (anticholinergic) or physical interruption of the vagus nerve causes significant tachycardia (abnormally fast heart rate) because this inhibitory parasympathetic influence is lost.

Neural reflexes. Output from the baroreceptor reflexes influences short-term regulation of the vascular smooth muscle of resistance arteries, myocardial contractility, and heart rate, all components of blood pressure control. The baroreceptors or pressoreceptors are located in the aortic arch and carotid arteries. If blood pressure decreases, the baroreceptor reflex accelerates heart rate, increases myocardial contractility, and increases vascular smooth muscle contraction in the arterioles, thus raising blood pressure. This reflex is critical to maintaining adequate tissue perfusion. When blood pressure increases, the baroreceptors increase their rate of discharge, sending neural impulses over a branch of the glossopharyngeal nerve (ninth cranial nerve) and through the vagus nerve to the cardiovascular control centres in the medulla. These reflexes increase parasympathetic activity and decrease sympathetic activity, causing the resistance arteries to dilate, decreasing myocardial contractility and heart rate. The role of baroreceptors in influencing blood pressure is discussed in more detail in “Baroreceptors” later in this chapter.

Atrial receptors.

Mechanoreceptors that influence heart rate exist in both atria.21 They are located where the veins, venae cavae, and pulmonary veins enter their respective atria. Bainbridge reflex is the name for the changes in the heart rate that may occur after intravenous infusions of blood or other fluid. The change in heart rate is thought to be caused by a reflex mediated by these atrial volume receptors that are innervated by the vagus nerve (volume receptors are thought to respond to increased plasma volume). Although this reflex can be elicited in humans, its relevance is uncertain at this time.22 Stimulation of these atrial receptors also increases urine volume, presumably because of a neurally mediated reduction in antidiuretic hormone. In addition, peptides of the atrial natriuretic family are released from atrial tissue in response to the increases in blood volume. These peptides have diuretic and natriuretic (salt excretion) properties, resulting in decreased blood volume and pressure. The atrial natriuretic peptides also have been shown to relax vascular smooth muscle and oppose myocardial hypertrophy, leading to measurement of blood levels to evaluate clinical status and raising interest in their use as therapeutic agents.23

Hormones and biochemicals. Hormones and other biochemically active substances affect the arteries, arterioles, venules, capillaries, and contractility of the myocardium. Norepinephrine, mainly released as a neurotransmitter from the adrenal medulla, dilates vessels of the liver and skeletal muscle and also causes an increase in myocardial contractility. Some adrenocortical hormones, such as hydrocortisone, potentiate the effects of the catecholamines—norepinephrine and epinephrine. Thyroid hormones enhance sympathetic activity and increase cardiac output. Growth hormone, working together with insulinlike growth factor 1 (IGF-1), also has been shown to increase myocardial contractility.24 Decreases in levels of growth hormone or thyroid hormone may result in bradycardia (heart rate below 60 beats/min), reduced cardiac output, and low blood pressure. (Other hormones are discussed in “Regulation of Blood Pressure,” later in this chapter.)

Quick Check 23-5 1. Explain four ways that aging impacts the cardiovascular system. 2. Why is Starling's law of the heart important to the understanding of heart failure? 3. Discuss the baroreceptor reflex and explain its influence on blood pressure and heart rate.

The Systemic Circulation The arteries and veins of the systemic circulation are illustrated in Figure 23-18. Oxygenated blood leaves the left side of the heart through the aorta and flows into the systemic arteries. These arteries branch into small arterioles, which branch into the smallest vessels, the capillaries, where nutrient and waste product exchange between the blood and tissues occurs. Blood from the capillaries then enters tiny venules that join to form the larger veins, which return venous blood to the right heart. Peripheral vascular system is the term used to describe the part of the systemic circulation that supplies the skin and the extremities, particularly the legs and feet.

FIGURE 23-18

Circulatory System. A, Principal arteries of the body. B, Principal veins of the body. (From Patton, K.T., Thibodeau, G.A., & Douglas, M.M. [2012]. Essentials of anatomy & physiology. St. Louis: Elsevier.)

Structure of Blood Vessels Blood vessel walls are composed of three layers: (1) the tunica intima (innermost, or intimal, layer); (2) the tunica media (middle, or medial, layer); and (3) the tunica externa or adventitia (outermost, or external, layer), which also contains nerves and lymphatic vessels. These layers are illustrated in Figure 23-19. Blood vessel walls vary in thickness depending on the thickness or absence of one or more of these three layers. Cells of the larger vessel walls are nourished by the vasa vasorum, small vessels located in the tunica externa.

FIGURE 23-19

Structure of the Blood Vessels. The tunica externa of the veins is colour-coded blue and the arteries red. (From Patton, K.T., & Thibodeau, G.A. [2016]. Structure & function of the body [15th ed.]. St. Louis: Elsevier.)

Arterial Vessels An artery is a thick-walled pulsating blood vessel transporting blood away from the heart. In the systemic circulation, arteries carry oxygenated blood. Arterial walls are composed of elastic connective tissue, fibrous connective tissue, and smooth muscle. Elastic arteries, such as the aorta, the branches of the aorta, and the trunk of the pulmonary artery, have a thick tunica media with more elastic fibres than smooth muscle fibres. Elasticity allows the vessel to absorb energy and stretch as blood is ejected from the heart during systole. During diastole, elasticity promotes recoil of the arteries, maintaining blood pressure within the vessels. Muscular arteries, medium- and small-sized arteries, are farther from the heart than the elastic arteries. They contain more muscle fibres and fewer elastic fibres than the elastic arteries and they function to distribute blood to arterioles throughout the body. Because their smooth muscle can contract or relax, they play a role in blood flow control and in directing flow to body parts with the highest need at any point in time. Contraction narrows the vessel lumen (the internal cavity of the vessel), which diminishes flow through the vessel (vasoconstriction). When the smooth muscle layer relaxes, more blood flows through the vessel lumen (vasodilation). An artery becomes an arteriole where the diameter of its lumen narrows to less than 0.5 mm. Arterioles are mainly composed of smooth muscle and regulate the flow of blood into the capillaries by constricting or dilating to either slow or increase the flow of blood into the capillaries (Figure 23-20). The thick smooth muscle layer of the arterioles is a major determinant of the resistance blood encounters as it flows through the systemic circulation.

FIGURE 23-20 Microcirculation. Control of local blood flow through a capillary network is regulated by altering the tone of precapillary sphincters surrounding arterioles and metarterioles. In the diagram, the sphincters are relaxed, permitting blood flow to enter the capillary bed. (From Patton, K.T., Thibodeau, G.A., & Douglas, M.M. [2012]. Essentials of anatomy & physiology. St. Louis: Elsevier.)

The capillary network is composed of connective channels called metarterioles, and “true” capillaries (see Figure 23-20). Metarterioles have discontinuous smooth muscle cells in their tunica media, whereas capillaries have no smooth muscle cells. There is a ring of smooth muscle called the precapillary sphincter at the point where capillaries branch from metarterioles. As the sphincters contract and relax, they regulate blood flow through the capillary beds. The precapillary sphincters help to maintain arterial pressure and regulate selective flow to vascular beds. Capillaries are composed solely of a layer of endothelial cells surrounded by a basement membrane. Their thin walls and unique structure make possible the rapid exchange of water; small (low molecular weight) soluble molecules; some larger molecules, such as albumin; and cells of the innate and adaptive components of the immune system between the blood and the interstitial fluid. In some capillaries, the endothelial cells contain oval windows or pores termed fenestrations covered by a thin diaphragm. Substances pass between the capillary lumen and the interstitial fluid (1) through junctions between endothelial cells, (2) through fenestrations in endothelial cells, (3) in vesicles moved by active transport across the endothelial cell membrane, or (4) by diffusion through the endothelial cell membrane. A single capillary may be only 0.5 to 1 mm in length and 0.01 mm in diameter, but the capillaries are so numerous their total surface area may be more than 600 m2 (about 100 football fields).

Endothelium The vascular endothelium is important to several body functions and is sometimes considered a separate endocrine organ. All tissues depend on a blood supply, and the blood supply depends on endothelial cells, which form the lining (or endothelium) of the blood vessel (Figure 23-21). In addition to substance transport, the vascular endothelium has important roles in coagulation, antithrombogenesis, and fibrinolysis; immune system function; tissue and vessel growth and wound healing; and vasomotion, the contraction and relaxation of vessels.25 Table 23-4 summarizes some of the more important endothelial functions. Endothelial injury and dysfunction are central processes in many of the most common and serious cardiovascular disorders, including hypertension and atherosclerosis (see Chapter 24).

FIGURE 23-21

Vascular Endothelium. The endothelial cells arrange themselves as a single-layer lining that has numerous critical functions (see Table 23-4).

TABLE 23-4 Functions of the Endothelium Function

Actions Involved

Filtration and permeability

Facilitates transport of large molecules via vesicular transport movement through intercellular junctions

Vasomotion

Hemostatic balance

Inflammation/immunity Angiogenesis/vessel growth Lipid metabolism

Facilitates transport of small molecules via movement of vesicles, through opening of tight junctions, and across cytoplasm Stimulates vascular relaxation through production of nitric oxide, prostacyclin, and other vasodilators Stimulates vascular constriction through production of endothelin-1 and of angiotensin II by the action of endothelial angiotensin-converting enzyme on angiotensin I Maintains a balance between procoagulant and anticoagulant factors, as well as profibrinolytic and antifibrinolytic factors; endothelial surface is normally antithrombotic Counteracts coagulation through anticoagulant factors, including prostacyclin, nitric oxide, antithrombin, thrombomodulin, tissue factor pathway inhibitor, and heparins Activates coagulation through procoagulant factors, including tissue factor (factor VII), factor VIII, factor V, and plasminogen activator inhibitor-1 (PAI-1) Controls coagulation through profibrinolytic factors: tissue- and urokinase-type plasminogen activating factor and plasminogen activator inhibitor-1 (PAI-1) Breaks down blood clots through antifibrinolytic factor: tissue plasminogen activator Expresses chemotactic agents and adhesion molecules that support white blood cells (including monocytes, neutrophils, and lymphocytes) moving into tissues Expresses receptors for oxidized lipoproteins, allowing them to enter vascular intima Releases growth factors such as endothelin-1 and heparins for vascular smooth muscle cells Expresses receptors for lipoprotein lipase and low-density lipoproteins

From Griendling, K.K., Harrison, D.G., & Alexander, R.W. (2011). Biology of the vessel wall. In V. Fuster, R.A. Walsh, R.A. Harrington, et al. (Eds.), Hurst's the heart (13th ed., pp. 153–171). Philadelphia: McGraw-Hill; Rajendran, P., Rengarajan, T., Thangavel, J., et al. (2013). Int J Biol Sci, 9(10), 1057–1069.

Veins Compared with arteries, veins are thin walled with more fibrous connective tissue and have a larger diameter (see Figure 23-19). Veins also are more numerous than arteries. The smallest venules downstream from the capillaries have an endothelial lining and are surrounded by connective tissue. The largest venules have some smooth muscle fibres in their thin tunica media. The venous tunica externa has less elastic tissue than that in arteries, so veins do not recoil as much or as rapidly after distension. Like arteries, veins receive nourishment from tiny vasa vasorum. Veins contain valves to facilitate the one-way flow of blood toward the heart (Figure 23-22). These valves are folds of the tunica intima and resemble the semilunar valves of the heart. When a person stands up, contraction of the skeletal muscles of the legs compresses the deep veins of the legs and assists the flow of blood toward the heart. This important mechanism of venous return is called the muscle pump (Figure 23-22, B).

FIGURE 23-22 Venous Valves and the Muscle Pump. In veins, one-way valves aid circulation by preventing backflow of venous blood when pressure in a local area is low. A, Blood is moved toward the heart as valves in the veins are forced open by pressure from volume of blood downstream and the neighbouring muscles are relaxed. B, When pressure below the valve drops, blood begins to flow backward but fills the “pockets” formed by the valve flaps, pushing the flaps together and thus blocking further backward flow. Contraction in the adjacent muscles and the valves of the systemic veins assist in the return of unoxygenated blood to the right heart.

Factors Affecting Blood Flow Blood flow, the amount of fluid moved per unit of time, is usually expressed as litres or millilitres per minute (L/min or mL/min). Factors that influence blood flow include pressure, resistance, velocity, turbulent versus laminar flow, and compliance, with the most important of these being pressure and resistance.

Pressure and Resistance Pressure in a liquid system is the force exerted on the liquid per unit area and is expressed clinically as millimetres of mercury (mm Hg), or torr (1 torr = 1 mm Hg). Blood flow to an organ depends partly on the pressure difference between the arterial and venous vessels supplying that organ. Fluid moves from the arterial “side” of the capillaries where the pressure is higher to the venous side where the pressure is lower. Resistance is the opposition to blood flow. Most opposition to blood flow results from the diameter and length of the vessels. Changes in blood flow through an organ result from changes in the vascular resistance within the organ because of increases or decreases in vessel diameter and the opening or closing of vascular channels. Resistance in a vessel is inversely related to blood flow—that is, increased resistance leads to decreased blood flow. Poiseuille's law indicates that resistance is directly related to tube length and blood viscosity and inversely related to the radius of the tube to the fourth power (r4). Because blood flow is inversely related to resistance, the greater the resistance the lower the blood flow will be. Resistance to flow cannot be measured directly, but it can be calculated if the pressure difference and flow volumes are known. Resistance to blood flow in a single vessel is determined by the radius and length of the blood vessel and by the blood viscosity. Clinically, the most important factor determining resistance in a single vessel is the radius or diameter of the vessel's lumen. Small changes in the lumen's radius or diameter lead to large changes in vascular resistance. Clinically, vasoconstriction will contribute to an increase in resistance whereas vasodilation will cause a decrease in resistance that may be reflected by a fall in blood pressure. Because vessel length is relatively constant, whereas lumen size is quite variable, length is not as important as lumen size in determining flow through a single vessel. Because viscosity is relatively constant, blood vessel radius is usually the key factor in determining TPR. An exception to this rule is when red blood cell volume, measured as hematocrit, is elevated, which is relatively rare. Conditions with elevated hematocrits include a lack of body water, cyanotic congenital heart disease (see Chapter 25), or polycythemia (see Chapter 21), and can lead to increased cardiac work as a result of increased vascular resistance. Resistance to flow through a system of vessels, or total resistance, depends not only on characteristics of individual vessels but also on whether the vessels are arranged in series or in parallel and on the total cross-sectional area of the system. Vessels arranged in parallel provide less resistance than vessels

arranged in series. Blood flowing through the distributing arteries, beginning with branches off the aorta and ending at arterioles in the capillary bed, encounters more resistance than blood flowing through the capillary bed itself, where flow is distributed among many short, tiny branches arranged in parallel (Figure 23-23). The total cross-sectional area of the arteriolar system is greater than that of the arterial system, yet the greater number of arterioles arranged in series leads to great resistance to flow in the arteriolar system. In contrast, the capillary system has a larger number of vessels arranged in parallel than the arteriolar system, and the total cross-sectional area is much greater; thus there is lower resistance overall through the capillary system. The resulting slow velocity of flow in each capillary is optimal for capillary–tissue exchange.

FIGURE 23-23 Relationship Between Cross-Sectional Area and Velocity of Blood Flow. Blood flows with great speed in the large arteries. However, branching of arterial vessels increases the total cross-sectional area of the arterioles and capillaries, reducing the flow rate. When capillaries merge into venules and venules merge into veins, the total cross-sectional area decreases, causing the flow rate to increase. (From Patton, K.T., & Thibodeau, G.A. [2016]. Anatomy & physiology [9th ed.]. St. Louis: Elsevier.)

Velocity Blood velocity or speed is the distance blood travels in a unit of time, usually centimetres per second. It is directly related to blood flow (amount of blood moved per unit of time) and inversely related to the crosssectional area of the vessel in which the blood is flowing (see Figure 23-23). As blood moves from the aorta to the capillaries, the total cross-sectional area of the vessels increases and the velocity decreases.

Laminar Versus Turbulent Flow Flow through a tubular system can be either laminar or turbulent. Blood flow through the vessels, except where vessels split or branch, is usually laminar. In laminar flow, concentric layers of molecules move “straight ahead,” with each layer flowing at a slightly different velocity (Figure 23-24). The cohesive attraction between the fluid and the vessel wall prevents the molecules of blood that are in contact with the wall from moving at all. The next thin layer of blood is able to slide slowly past the stationary layer

and so on until, at the centre, the blood velocity is greatest. Large vessels have room for a large centre layer; therefore, they have less resistance to flow and greater flow and velocity than smaller vessels.

FIGURE 23-24 Laminar and Turbulent Blood Flow. A, Laminar flow. Fluid flows in long, smooth-walled tubes as if it were composed of a large number of concentric layers. B, Turbulent flow. Turbulent flow is caused by numerous small currents flowing cross-wise or oblique to the long axis of the vessel, resulting in flowing whorls and eddy currents.

Where flow is obstructed, the vessel turns, or blood flows over rough surfaces, the flow becomes turbulent with whorls or eddy currents that produce noise, causing a murmur to be heard on auscultation. Resistance increases with turbulence, which frequently occurs in areas with atherosclerotic plaque (see Chapter 24).

Vascular Compliance Vascular compliance is the increase in volume a vessel can accommodate for a given increase in pressure. Compliance depends on factors related to the nature of a vessel wall, such as the ratio of elastic fibres to muscle fibres in the wall. Elastic arteries are more compliant than muscular arteries. The veins are more compliant than either type of artery, and they can serve as storage areas for the circulatory system. Compliance determines a vessel's response to pressure changes. For example, a large volume of blood can be accommodated by the venous system with only a small increase in pressure. In the less compliant arterial system, where smaller volumes and higher pressures are normal, even small changes in blood volume can cause significant changes in arterial pressure. Stiffness is the opposite of compliance. Several conditions and disorders can cause stiffness, with the most common being aging and atherosclerosis (see Chapter 24).

Quick Check 23-6 1. What is the function of the arterioles? 2. Identify the functions of the endothelium. 3. Why does the total cross-sectional area in the capillary system lower the resistance to flow?

Regulation of Blood Pressure Arterial Pressure Arterial blood pressure is determined by the cardiac output multiplied by the peripheral resistance (Figure 23-25). The systolic blood pressure is the highest arterial blood pressure following ventricular contraction or systole. The diastolic blood pressure is the lowest arterial blood pressure that occurs during ventricular filling or diastole. The mean arterial pressure (MAP), which is the average pressure in the arteries throughout the cardiac cycle, depends on the elastic properties of the arterial walls and the mean volume of blood in the arterial system. MAP can be approximated from the measured values of the systolic (Ps) and diastolic (Pd) pressures as follows:

FIGURE 23-25

Factors and Relationships Regulating Blood Pressure. CO2, carbon dioxide; H, hydrogen; K+, potassium; O2, oxygen.

The normal range for MAP is 70 to 110 mm Hg.26 The difference between the systolic pressure and diastolic pressure (Ps − Pd) is called the pulse pressure and typically is between 40 and 50 mm Hg.7 Pulse pressure is directly related to arterial wall stiffness and stroke volume. During a wide range of physiological conditions, including changes in body position, muscular activity, and circulating blood volume, arterial pressure is regulated within a fairly narrow range to maintain tissue perfusion, or blood supply to the capillary beds. The major factors and relationships that regulate arterial blood pressure are summarized in Figure 23-25.

Effects of Cardiac Output The cardiac output (minute volume) of the heart can be changed by alterations in heart rate, stroke volume (volume of blood ejected during each ventricular contraction), or both. An increase in cardiac output without a decrease in peripheral resistance will cause MAP and flow rate to increase. The higher arterial pressure increases blood flow through the arterioles. On the other hand, a decrease in the cardiac output causes a drop in the mean arterial blood pressure and arteriolar flow if peripheral resistance stays

constant.

Effects of Total Peripheral Resistance Total resistance in the systemic circulation, known as either SVR or TPR, is primarily a function of arteriolar diameter. If cardiac output remains constant, arteriolar constriction raises MAP by reducing the flow of blood into the capillaries, whereas arteriolar dilation has the opposite effect. Reflex control of total cardiac output and peripheral resistance includes (1) sympathetic stimulation of heart, arterioles, and veins; and (2) parasympathetic stimulation of the heart (Figure 23-26). The cardiovascular centre in the medulla receives input from arterial baroreceptors and chemoreceptors throughout the vascular system and then modifies vagal and sympathetic output to control heart rate and contractility, plus vascular diameter. Vasoconstriction is regulated by an area of the brainstem that maintains a constant (tonic) output of norepinephrine from sympathetic fibres in the peripheral arterioles. This tonic activity is essential for maintenance of blood pressure.

FIGURE 23-26 Baroreceptors and Chemoreceptor Reflex Control of Blood Pressure. A, Baroreceptor reflexes. B, Vasomotor chemoreflexes. CN, cranial nerve; CO2, carbon dioxide; H+, hydrogen; O2, oxygen. (Modified from Patton, K.T., & Thibodeau, G.A. [2016]. Anatomy & physiology [9th ed.]. St. Louis: Elsevier.)

Baroreceptors. As discussed previously, baroreceptors are stretch receptors located predominantly in the aorta and in the carotid sinus (Figure 23-26, A). They respond to changes in smooth muscle fibre length by altering

their rate of discharge and supplying sensory information to the cardiovascular centre in the brainstem. When activated (stretched), the baroreceptors decrease cardiac output (by lowering heart rate and stroke volume) and peripheral resistance, and thus lower blood pressure. (Postural changes and the baroreceptor reflex are discussed in Chapter 24.)

Arterial chemoreceptors. Specialized areas within the aortic arch and carotid arteries are sensitive to concentrations of oxygen, carbon dioxide, and hydrogen ions (pH) in the blood (Figure 23-26, B). Although these chemoreceptors are most important for respiratory control, they also transmit impulses to the medullary cardiovascular centres that regulate blood pressure. A decrease in arterial oxygen concentration or an increase in carbon dioxide concentration contributes to an increase in heart rate, stroke volume, and blood pressure, whereas an increase in carbon dioxide concentration causes decreases in these variables. The major chemoreceptive reflex is caused by alterations in arterial oxygen concentration. The effects of altered pH or carbon dioxide levels are minor.21

Effect of Hormones Hormones influence blood pressure regulation through their effects on vascular smooth muscle and blood volume. By constricting or dilating the arterioles in organs, hormones can (1) increase or decrease the flow in response to the body's needs, (2) redistribute blood volume during hemorrhage or shock, and (3) regulate heat loss. The key vasoconstrictor hormones include angiotensin II, vasopressin (or antidiuretic hormone), epinephrine, and norepinephrine. The main vasodilator hormones are the atrial natriuretic hormones. By causing fluid retention or loss, aldosterone, vasopressin, and the natriuretic hormones can influence stroke volume and thus blood pressure. A variety of other factors, including adipokines and insulin, may be related to the hypertension that occurs with chronic conditions, such as adiposity and diabetes mellitus; but these factors have not been clearly demonstrated to play a role in blood pressure regulation in healthy individuals.27 Some research has suggested that the risk for cardiovascular disease and hypertension that often co-occurs with diabetes mellitus is more closely related to insulin resistance than to insulin levels.28 Adrenomedullin (ADM) is a vasodilating peptide present in cardiovascular, pulmonary, renal, and other tissues. Because increases in ADM levels are associated with heart failure and myocardial infarction, ADM levels may be useful for risk categorization in people with these conditions.29

Vasoconstrictor hormones. The vasoconstrictor hormones include epinephrine; norepinephrine; angiotensin II, which is part of the renin-angiotensin-aldosterone system; and vasopressin (also known as antidiuretic hormone). Epinephrine, the catecholamine hormone released from the adrenal medulla, causes vasoconstriction in most vascular beds except the coronary, liver, and skeletal muscle circulations. Norepinephrine mainly acts as a neurotransmitter; however, some norepinephrine also is released from the adrenal medulla. When released into the circulation, it is a more potent vasoconstrictor than epinephrine. Although angiotensin II and vasopressin are vasoconstrictors, they are not thought to have a major role in blood pressure control in normal circumstances. Vasopressin and aldosterone also affect blood pressure by increasing blood volume through their influence on fluid reabsorption in the kidney and by stimulating thirst. Vasopressin causes the reabsorption of water from tubular fluid in the distal tubule and collecting duct of the nephron. Aldosterone, the end product of the renin-angiotensin-aldosterone system, stimulates the reabsorption of sodium, chloride, and water from the same locations in the kidney (Figure 23-27; also see Chapters 5 and 18).

FIGURE 23-27 Three Mechanisms That Influence Total Plasma Volume. The antidiuretic hormone (ADH) mechanism and reninangiotensin-aldosterone system (RAAS) tend to increase water, sodium, and chloride retention and thus increase total plasma volume. The atrial natriuretic hormone (ANH) mechanism antagonizes these mechanisms by promoting water, sodium, and chloride loss, thus promoting a decrease in total plasma volume. ACE, angiotensin-converting enzyme. (Modified from Patton, K.T., & Thibodeau, G.A. [2016]. Anatomy & physiology [9th ed.]. St. Louis: Elsevier.)

Vasodilator hormones. The natriuretic peptides (NPs) or hormones (see Figure 23-27), including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and urodilatin, function as both vasodilators and regulators of sodium and water excretion (natriuresis and diuresis). Increased pressure or diastolic volume in the heart stimulates the release of these peptide hormones. Increased levels of BNP predict increased risk for a poor outcome in heart failure (see Health Promotion: B-type Natriuretic Peptide and Heart Failure), pulmonary embolism, valvular heart disease, and chronic coronary artery disease.30

Health Promotion B-type Natriuretic Peptide and Heart Failure Heart failure occurs due to chronic and progressive loss of functioning cardiac myocytes and a disruption of the ability of the myocardium to contract normally, which triggers a variety of compensatory mechanisms. Compensatory mechanisms such as an increase in adrenergic nervous system activity and excessive activation of the renin-angiotensin-aldosterone system will initially restore cardiovascular contractility. However, over time, continual activation of these systems can lead to detrimental dysfunction in myocardial pumping ability, left ventricular remodelling, and subsequent cardiac decompensation. B-type natriuretic peptide (BNP) is a hormone that was initially identified in the brain but is now recognized as being released primarily from the heart, particularly the ventricles. The normal reference range for BNP is less than 100 ng/L. Values increase with age and weight, and are higher in women than men. The production of BNP increases in response to ventricular volume expansion and pressure overload. It also increases to counteract the possible deleterious effects of the compensatory mechanisms. BNP has diuretic, natriuretic, and vasodilator actions. It also inhibits the renin-angiotensin-aldosterone

system, the secretion of endothelin, and systemic and renal sympathetic activity. BNP may protect against collagen formation and accumulation, and the pathological cardiac remodelling that contributes to the worsening of heart failure. As such, elevated BNP serum levels is a marker of ventricular distress and useful in diagnosing and monitoring the severity of heart failure. BNP levels higher than 400 correlate with heart failure. The severity of heart failure is directly correlated with the level of BNP. That is, the higher the BNP level, the greater the severity of heart failure. In 2015, Lourenço, Ribeiro, Pintalhão, and colleagues established that BNP is the gold standard for heart failure prognostic prediction. They also concluded that a decrease in BNP levels independently predicts better survival and lower mortality. For example, patients in whom BNP decreased by greater than 30% had a hazard ratio of death of 0.57 (0.37 to 0.89). Also in 2015, Egom suggested that a linear relationship exists between plasma BNP levels and cardiovascular mortality. It should be noted that elevated BNP does not differentiate between ventricular systolic or ventricular diastolic dysfunction. Studies reveal that BNP is a marker that is highly sensitive and specific. The greater value of BNP is in repeated measurement to monitor the progression of disease and in evaluating the response to medical therapy. As a marker, BNP is particularly useful in the emergency department setting for patients who present with acute dyspnea. BNP measurement is also a valuable tool in differentiating cardiac from noncardiac causes of respiratory distress. Several studies have shown that concentrations of BNP are substantially higher in patients with acute heart failure when compared with those with dyspnea due to other causes. Data from Egom, E.E. (2015). J Cardiovasc Transl Res, 8(3), 149–157. doi:10.1007/s12265-015-9619-3; Kessenich, C.R. (2011). Nurse Pract, 36(1), 13–14. doi:10.1097/01.npr.0000391180.55502.18; Lourenço, P., Ribeiro, A., Pintalhão, M., et al. (2015). Am J Cardiol, 116(5), 744–748. doi:10.1016/j.amjcard.2015.05.046.

Effects of Other Mediators A variety of other mediators have been demonstrated to cause arteriolar vasodilation or vasoconstriction. Some of the vasodilating mediators include nitric oxide, ADM, the endothelins, and prostacyclin. These mediators are being investigated to determine whether they or their inhibitors might be useful medications for the treatment of cardiovascular diseases or whether their levels might be useful in determining the prognosis of persons with known disease. Nitric oxide (NO), an intercellular and intracellular signalling molecule produced in endothelial cells, has a variety of roles in vascular function, including acting as a vasodilator and inhibitor of smooth muscle proliferation. Nitric oxide also has been referred to as endothelium-derived relaxing factor (EDRF). One way that diabetes may contribute to hypertension is through inhibition of nitric oxide production by impeding a family of enzymes—the nitric oxide synthases.31 Understanding the role of nitric oxide in producing vasodilation explains why sublingual nitroglycerine has been a useful treatment for coronary artery spasm.32 ADM, a peptide with powerful vasodilatory activity, is present in numerous tissues. It is a member of the calcitonin gene–related peptide family. Although it has been found to have numerous cardiovascular effects, including a role in fetal cardiovascular system development and vasodilation, its exact role in adult human cardiovascular function and disease is unclear. Some research indicates that elevated ADM levels may be useful disease indicators.33 The endothelins are a family of three peptides (ET-1, ET-2, and ET-3) and four receptors produced in cells in the vascular smooth muscle, the endothelium, the kidneys, and other organs. Understanding the physiological and pathological roles of these peptides has been complicated by the fact that endothelin binding to the type-A receptor causes vasodilation and natriuresis, whereas binding to type-B receptor causes the opposite response—vasoconstriction plus sodium and water retention.34 Inhibitors to ET-1 have been approved for the treatment of pulmonary hypertension.35 Prostacyclin is a vasodilator that is produced by the actions of cyclo-oxygenases (COX-1 and COX-2) on arachidonic acid. It also has the additional properties of opposing clot formation (antithrombotic), decreasing platelet activity, and inhibiting the release of growth factors from macrophages and the endothelial cells.32 Nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit these cyclo-oxygenases have been associated with cardiovascular disease risk in healthy people and in those with a known cardiovascular disease.36,37

Venous Pressure The main determinants of venous blood pressure are (1) the volume of fluid within the veins and (2) the compliance (distensibility) of the vessel walls. The venous system typically accommodates about 66% of the total blood volume at any time, with venous pressure averaging less than 10 mm Hg. The systemic arteries accommodate about 11% of the total blood volume, with an average arterial pressure (blood pressure) of about 100 mm Hg; the remainder of the blood volume is within the heart, capillaries, and pulmonary circulation.26 The sympathetic nervous system controls venous compliance. The walls of the veins are highly innervated by sympathetic fibres that control venous smooth muscle. Rather than constriction that would occur in the arteries, smooth muscle contraction in the veins results in stiffening of the vessel walls. This stiffening reduces venous distensibility and increases venous blood pressure, thus forcing more blood through the veins and into the right heart. Two other mechanisms that increase venous pressure and venous return to the heart are (1) the skeletal muscle pump and (2) the respiratory pump. During skeletal muscle contraction, the veins within the muscles are partially compressed, causing decreased venous capacity and increased return to the heart (see Figure 23-26). The respiratory pump acts during inspiration, when the veins of the abdomen are partially compressed by the downward movement of the diaphragm. Increased abdominal pressure moves blood toward the heart.

Regulation of the Coronary Circulation Coronary blood flow is directly proportional to the perfusion pressure and inversely proportional to the vascular resistance of the coronary bed. Coronary perfusion pressure is the difference between pressure in the aorta and pressure in the coronary vessels. Thus, aortic pressure is the driving pressure for the arteries and arterioles that perfuse the myocardium. Vasodilation and vasoconstriction maintain coronary blood flow despite stresses imposed by the constant contraction and relaxation of the heart muscle and despite shifts (within a physiological range) of coronary perfusion pressure. Several unique anatomical factors influence coronary blood flow. Because of their anatomical location, the aortic valve cusps can obstruct coronary blood flow by occluding the openings of the coronary arteries during systole. Also during systole, the coronary arteries are compressed by ventricular contraction. The resulting systolic compressive effect is particularly evident in the subendocardial layers of the left ventricular wall and can greatly increase resistance to coronary blood flow with the result that most left ventricular coronary blood flow occurs during diastole. During the period of systolic compression, when flow is slowed or stopped, myoglobin, a protein in heart muscle that binds oxygen, provides the supply of oxygen to the myocardium. Myoglobin's oxygen levels are replenished during diastole.

Autoregulation Autoregulation (automatic self-regulation) enables organs to regulate blood flow by altering the resistance (diameter) in their arterioles. Autoregulation in the coronary circulation maintains the blood flow at a nearly constant rate at perfusion pressures (MAP) between 60 and 140 mm Hg when other influencing factors are held constant.21 Thus autoregulation helps to ensure constant coronary blood flow despite shifts in the perfusion pressure within the stated range. Given that blood flow is directly related to pressure and inversely related to resistance, for flow to stay constant as pressure decreases resistance also has to decrease; therefore, the mechanisms underlying autoregulation must be related to control of smooth muscle contraction in the arteriolar walls. Although the exact mechanisms underlying autoregulation are unknown, research has indicated that factors influencing calcium release with the myocardium are involved and perhaps also the accumulation of vasodilatory products of metabolism, such as adenosine.21,38

Autonomic Regulation Although the coronary vessels, themselves, contain sympathetic (α- and β-adrenergic) and parasympathetic neural receptors, coronary blood flow during regular activity is regulated locally by the

factors that cause autoregulation. During exercise, however, the vasodilating effects of β2-receptors on the smaller coronary resistance arteries are responsible for about 25% of any increase in blood flow. At the same time, α-adrenergic receptors in larger arteries cause vasoconstriction to direct the blood flow to the inner layers of the myocardium.21

Quick Check 23-7 1. Identify the factors and relationships regulating blood pressure. 2. Why is capillary flow increased with increased mean arterial pressure? 3. Why is angiotensin significant in blood flow? 4. Define natriuretic peptides and adrenomedullin.

The Lymphatic System The lymphatic system is a one-way network of lymphatic vessels and the lymph nodes (Figures 23-28 and 23-29) that is important for immune function, fluid balance, and transport of lipids, hormones, and cytokines. Every day about 3 litres of fluid filters out of venous capillaries in body tissues and is not reabsorbed. This fluid becomes the lymph that is carried by the lymphatic vessels to the chest, where it enters the venous circulation. The lymphatic vessels run in the same sheaths with the arteries and veins. (Lymph nodes and lymphoid tissues are described in Chapters 6 and 8.) In this pumpless system, a series of valves ensures one-way flow of the excess interstitial fluid (now called lymph) toward the heart. The lymphatic capillaries are closed at the distal ends, as shown in Figure 23-30.

FIGURE 23-28 Role of the Lymphatic System in Fluid Balance. Fluid from plasma flowing through the capillaries moves into interstitial spaces. Although most of this interstitial fluid is either absorbed by tissue cells or reabsorbed by blood capillaries, some of the fluid tends to accumulate in the interstitial spaces. This lymph then diffuses into the lymphatic vessels that carry it to the lymph nodes and then into the systemic venous blood. Green is used to diagram the lymphatic vessels, although the lymphatic vessels, particularly the smaller ones, are almost transparent. (Modified from Thibodeau, G.A., & Patton, K.T. [2008]. Structure & function of the body [13th ed.]. St. Louis: Elsevier.)

FIGURE 23-29

Principle Organs of the Lymphatic System. (From VanMeter, K.C., & Hubert, R.J. [2010]. Microbiology for the healthcare professional. St. Louis: Mosby.)

FIGURE 23-30

Lymphatic Capillaries. A, Schematic representation of lymphatic capillaries. B, Anatomical components of microcirculation.

Lymph consists primarily of water and small amounts of dissolved proteins, mostly albumin, that are

too large to be reabsorbed into the less permeable blood capillaries. Lymph also carries two types of immune system cells: lymphocytes and antigen-presenting cells. The antigen-presenting cells are carried to the next lymph node in the system while lymphocytes traffic between lymph nodes. Once within the lymphatic system, lymph travels through lymphatic venules and lymphatic veins that drain into one of two large ducts in the thorax: the right lymphatic duct and the thoracic duct. The right lymphatic duct drains lymph from the right arm and the right side of the head and thorax, whereas the larger thoracic duct receives lymph from the rest of the body (see Figure 23-29). The right lymphatic duct and the thoracic duct drain lymph into the right and left subclavian veins, respectively. Lymphatic veins are thin walled like the veins of the cardiovascular system. In larger lymphatic veins, endothelial flaps form valves similar to those in blood-carrying veins (see Figure 23-30). The valves allow lymph to flow in only one direction as lymphatic vessels are compressed intermittently by skeletal muscle contraction, pulsatile expansion of the artery in the same sheath, and contraction of the smooth muscles in the walls of the lymphatic vessels. As lymph is transported toward the heart, it is filtered through thousands of bean-shaped lymph nodes clustered along the lymphatic vessels (see Figure 23-29). Lymph enters the nodes through afferent lymphatic vessels, filters through the sinuses in the node, and leaves by way of efferent lymphatic vessels. Lymph flows slowly through a node, allowing phagocytosis of foreign substances within the node and delivery of lymphocytes. (Phagocytosis is described in Chapter 7.)

Quick Check 23-8 1. Why is the lymphatic system considered a circulatory system? 2. What happens to lymph in lymph nodes?

Did You Understand? Overview 1. The circulatory system is part of the body's transport and communication systems. It delivers oxygen, nutrients, metabolites, hormones, neurochemicals, proteins, and blood cells including lymphocytes and leukocytes throughout the body and carries metabolic wastes to the kidneys, lungs, and liver for excretion.

The Circulatory System 1. The circulatory system consists of the heart and the blood and lymphatic vessels and is made up of two separate, but conjoined serially connected pump systems: the pulmonary circulation and the systemic circulation. The lymphatic system is a one-way network consisting of lymphatic vessels and lymph nodes. 2. The low-pressure pulmonary circulation is driven by the right side of the heart; its function is to deliver blood to the lungs for oxygenation. 3. The higher pressure systemic circulation is driven by the left side of the heart and functions to provide oxygenated blood, nutrients, and other key substances to body tissues and transport waste products to the lungs, kidneys, and liver for excretion. 4. The lymphatic vessels collect fluids from the interstitium and return the fluids to the circulatory system; lymphatic vessels also deliver antigens, microorganisms, and cells to the lymph nodes.

The Heart 1. The heart consists of four chambers (two atria and two ventricles), four valves (two atrioventricular valves [AV valves] and two semilunar valves), a muscular wall, a fibrous skeleton, a conduction system, nerve fibres, systemic vessels (the coronary circulation), and openings where the great vessels enter the atria and ventricles. 2. The heart wall, which encloses the heart and divides it into chambers, is made up of three layers: the epicardium (outer layer), the myocardium (muscular layer), and the endocardium (inner lining). The heart lies within the pericardium, a double-walled membranous sac. 3. The myocardial layer of the two atria, which receive blood entering the heart, is thinner than the myocardial layer of the ventricles, which have to be stronger to squeeze blood out of the heart. 4. The right and left sides of the heart are separated by portions of the heart wall called the interatrial septum and the interventricular septum. 5. Deoxygenated (venous) blood from the systemic circulation enters the right atrium through the superior and inferior venae cavae. From the right atrium, the blood passes through the right AV (tricuspid) valve into the right ventricle. In the ventricle, the blood flows from the inflow tract to the outflow tract and then through the pulmonary semilunar valve (pulmonary valve) into the pulmonary artery, which delivers it to the lungs for oxygenation. 6. Oxygenated blood from the lungs enters the left atrium through the four pulmonary veins (two from the left lung and two from the right lung). From the left atrium, the blood passes through the left AV valve (mitral valve) into the left ventricle. In the ventricle, the blood flows from the inflow tract to the outflow tract and then through the aortic semilunar valve (aortic valve) into the aorta, which delivers it to systemic arteries of the entire body. 7. There are four heart valves. The AV valves ensure one-way flow of blood from the atria to the ventricles. The semilunar valves ensure one-way blood flow from the right ventricle to the pulmonary artery and from the left ventricle to the aorta. 8. Oxygenated blood enters the coronary arteries through openings from the aorta, and

deoxygenated blood from the coronary veins enters the right atrium through the coronary sinus. 9. The pumping action of the heart consists of two phases: diastole, during which the myocardium relaxes and the ventricles fill with blood; and systole, during which the myocardium contracts, forcing blood out of the ventricles. A cardiac cycle includes one systolic contraction and the diastolic relaxation that follows it. Each cardiac cycle represents one heartbeat. 10. The conduction system of the heart generates and transmits electrical impulses (cardiac action potentials) that stimulate systolic contractions. The autonomic nerves (sympathetic and parasympathetic fibres) can adjust heart rate and force of contraction, but they do not originate the heartbeat. 11. Each cardiac action potential travels from the SA node to the AV node to the bundle of His (atrioventricular bundle [AV bundle]), through the bundle branches, and finally to the Purkinje fibres and ventricular myocardium, where the impulse stops. It is prevented from reversing its path by the refractory period of cells that have just been polarized. The refractory period ensures that diastole (relaxation) will occur, thereby completing the cardiac cycle. 12. The normal electrocardiogram is the sum of all cardiac action potentials. The P wave represents atrial depolarization; the QRS complex is the sum of all ventricular cell depolarizations. The ST interval occurs when the entire ventricular myocardium is depolarized. 13. Cells of the cardiac conduction system possess the properties of automaticity and rhythmicity. Automatic cells return to threshold and depolarize rhythmically without an outside stimulus. The cells of the SA node depolarize faster than other automatic cells, making it the natural pacemaker of the heart. If the SA node is disabled, the next fastest pacemaker, the atrioventricular node (AV node), takes over. 14. Cardiac action potentials are generated by the sinoatrial node (SA node) at a rate of 60 to 100 impulses per minute. The impulses can travel through the conduction system of the heart, stimulating myocardial contraction as they go. 15. Adrenergic receptor number, type, and function govern autonomic (sympathetic) regulation of heart rate, contractile strength, and the dilation or constriction of coronary arteries. The presence of specific receptors on the myocardium and coronary vessels determines the effects of the neurotransmitters norepinephrine and epinephrine. 16. Unique features that distinguish myocardial cells from skeletal cells enable myocardial cells to transmit action potentials faster (through intercalated discs), synthesize more adenosine triphosphate (because of a large number of mitochondria), and have readier access to ions in the interstitium (because of an abundance of transverse tubules). These combined differences enable the myocardium to work constantly, which is not required by skeletal muscle. 17. Cross-bridges between actin and myosin enable contraction. Calcium ions interacting with the troponin complex help initiate the contraction process. Subsequently, myocardial relaxation begins as troponin releases calcium ions. 18. Cardiac performance is affected by preload, afterload, myocardial contractility, and heart rate. 19. Preload, or pressure generated in the ventricles at the end of diastole, depends on the amount of blood in the ventricle. Afterload is the resistance to ejection of the blood from the ventricle. Afterload depends on pressure in the aorta. 20. Myocardial stretch determines the force of myocardial contraction; thus the greater the stretch, the stronger the contraction up to a certain point. This relationship is known as Starling's law of the heart. 21. Contractility is the potential for myocardial fibre shortening during systole. It is determined by the amount of stretch during diastole (i.e., preload) and by sympathetic stimulation of the ventricles. 22. Heart rate is determined by the SA node and by components of the autonomic nervous system, including cardiovascular control centres in the brain, receptors in the aorta and carotid arteries, and hormones, including catecholamines (epinephrine, norepinephrine).

The Systemic Circulation

1. Blood flows from the left ventricle into the aorta and from the aorta into arteries that eventually branch into arterioles and capillaries, the smallest of the arterial vessels. Oxygen, nutrients, and other substances needed for cellular metabolism pass from the capillaries into the interstitium, where they are taken up by the cells. Capillaries also absorb metabolic waste products from the interstitium. 2. Venules, the smallest veins, receive capillary blood. From the venules, the venous blood flows into larger and larger veins until it reaches the venae cavae, through which it enters the right atrium. 3. Blood vessel walls have three layers: (1) the tunica intima (inner layer), (2) the tunica media (middle layer), and (3) the tunica externa (the outer layer). 4. Layers of the blood vessel wall differ in thickness and composition from vessel to vessel, depending on the vessel's size and location within the circulatory system. In general, the tunica media of arteries close to the heart has more elastic fibres because these arteries must be able to distend during systole and recoil during diastole. Distributing arteries farther from the heart contain more smooth muscle fibres because they constrict and dilate to control blood pressure and volume within specific capillary beds. 5. Blood flow into the capillary beds is controlled by the contraction and relaxation of smooth muscle bands (precapillary sphincters) at junctions between metarterioles and capillaries. 6. Endothelial cells line the blood vessels. The endothelium is a life-support tissue; it functions as a filter (altering permeability), changes in vasomotion (constriction and dilation), and is involved in clotting and inflammation. 7. Blood flow through the veins is assisted by the contraction of skeletal muscles (the muscle pump), and backward flow is prevented by one-way valves, which are particularly important in the deep veins of the legs. 8. Blood flow is affected by blood pressure, resistance to flow within the vessels, blood consistency (which affects velocity), anatomical features that may cause turbulent or laminar flow, and compliance (distensibility) of the vessels. 9. Poiseuille's law describes the relationship of blood flow, pressure, and resistance as the difference between pressure at the inflow end of the vessel and pressure at the outflow end divided by resistance within the vessel. 10. The greater a vessel's length and the blood's viscosity and the narrower the radius of the vessel's lumen, the greater the resistance within the vessel. 11. Total peripheral resistance, or the resistance to flow within the entire systemic circulatory system, depends on the combined lengths and radii of all the vessels within the system and on whether the vessels are arranged in series (greater resistance) or in parallel (lesser resistance). 12. Blood flow is also influenced by neural stimulation (vasoconstriction or vasodilation) and by autonomic features that cause turbulence within the vascular lumen (e.g., protrusions from the vessel wall, twists and turns, vessel branching). 13. Arterial blood pressure is influenced and regulated by factors that affect cardiac output (heart rate, stroke volume), total resistance within the system, and blood volume. 14. Antidiuretic hormone, the renin-angiotensin-aldosterone system, and natriuretic peptides can all alter blood volume and thus blood pressure. 15. Venous blood pressure is influenced by blood volume within the venous system and compliance of the venous walls. 16. Blood flow through the coronary circulation is governed by the same principles as flow through other vascular beds plus two adaptations dictated by cardiac dynamics. First, blood flows into the coronary arteries during diastole rather than systole, because during systole the cusps of the aortic semilunar valve block the openings of the coronary arteries. Second, systolic contraction inhibits coronary artery flow by compressing the coronary arteries. 17. Myoglobin in heart muscle stores oxygen for use during the systolic phase of the cardiac cycle. 18. Autoregulation enables the coronary vessels to maintain optimal perfusion pressure despite systolic compression.

The Lymphatic System

1. The vessels of the lymphatic system run in the same sheaths as the arteries and veins. 2. Lymph (interstitial fluid) is absorbed by lymphatic venules in the capillary beds and travels through ever larger lymphatic veins until it empties through the right lymphatic duct or thoracic duct into the right or left subclavian veins, respectively. 3. As lymph travels toward the thoracic ducts, it passes through thousands of lymph nodes clustered around the lymphatic veins. The lymph nodes are sites of immune function and are ideally placed to sample antigens and cells carried by the lymph from the periphery of the body into the central circulation.

Key Terms Actin, 585 Adrenomedullin (ADM), 597 Afferent lymphatic vessel, 599 Afterload, 588 Angiogenesis, 579 Anisotropic band (A band), 585 Aorta, 577 Aortic semilunar valve, 577 Arteriogenesis, 579 Arteriole, 589 Artery, 589 Atrioventricular node (AV node), 581 Atrioventricular valve (AV valve), 577 Automatic cell, 583 Automaticity, 583 Autoregulation, 598 Bainbridge reflex, 589 Baroreceptor reflex, 589 Blood flow, 593 Blood velocity, 594 Bundle of His (atrioventricular bundle [AV bundle]), 582 Capillary, 589 Cardiac action potential, 580 Cardiac cycle, 578 Cardiac output, 587 Cardiac vein, 578 Cardiomyocyte, 576 Cardiovascular vasomotor control centre, 588 Chordae tendineae, 577 Collateral artery, 578 Conduction system, 580 Coronary artery, 578 Coronary ostium (pl., ostia), 578 Coronary perfusion pressure, 598 Coronary sinus, 578 Cross-bridge theory of muscle contraction, 586 Depolarization, 582 Diastole, 578 Diastolic blood pressure, 595 Diastolic depolarization, 583 Efferent lymphatic vessel, 599 Ejection fraction, 587 Elastic artery, 589 Endocardium, 576 Endothelial cell, 590 Endothelium, 590 Epinephrine, 588 Excitation–contraction coupling, 586 Fenestration, 590

Great cardiac vein, 580 Heart rate, 576 Inferior vena cava, 577 Inotropic agent, 588 Intercalated disc, 584 Isotropic band (I band), 585 Laminar flow, 594 Laplace's law, 587 Left atrium, 577 Left bundle branch (LBB), 582 Left coronary artery (LCA), 578 Left heart, 575 Left ventricle, 577 Lumen, 589 Lymph, 599 Lymph node, 599 Lymphatic vein, 599 Lymphatic venule, 599 Mean arterial pressure (MAP), 595 Mediastinum, 575 Metarteriole, 589 Mitral and tricuspid complex, 577 Mitral valve (left atrioventricular valve, bicuspid valve), 577 M line, 585 Muscle pump, 593 Muscular artery, 589 Myocardial contractility, 586 Myocardial oxygen consumption (MV̇O2), 586 Myocardium, 576 Myoglobin, 598 Myosin, 585 Natriuretic peptide (NP), 597 Nitric oxide (NO), 597 Papillary muscle, 577 Perfusion, 595 Pericardial cavity, 576 Pericardial fluid, 576 Pericardial sac, 576 Pericardium, 576 Peripheral vascular system, 589 Poiseuille's law, 593 PR interval, 582 Precapillary sphincter, 590 Preload, 587 Pressure, 593 Prolapse, 577 Pulmonary artery, 577 Pulmonary circulation, 575 Pulmonary vein, 577 Pulmonic semilunar valve, 577 Pulse pressure, 595 Purkinje fibre, 582 P wave, 582

QRS complex, 582 QT interval, 583 Radius (diameter), 593 Refractory period, 582 Repolarization, 582 Resistance, 593 Rhythmicity, 583 Right atrium, 577 Right bundle branch (RBB), 582 Right coronary artery (RCA), 578 Right heart, 575 Right lymphatic duct, 599 Right ventricle, 577 Semilunar valve, 577 Shear stress, 579 Sinoatrial node (SA node, sinus node), 581 Starling's law of the heart, 587 Stenosis, 579 ST interval, 583 Stroke volume, 587 Superior vena cava, 577 Systemic circulation, 575 Systemic vascular resistance (SVR), 588 Systole, 578 Systolic blood pressure, 595 Systolic compressive effect, 598 Thoracic duct, 599 Titin, 586 Total peripheral resistance (TPR), 588 Total resistance, 594 Tricuspid valve, 577 Tropomyosin, 585 Troponin C, 585 Troponin I, 585 Troponin T, 585 Troponin–tropomyosin complex, 585 Tunica externa (adventitia), 589 Tunica intima, 589 Tunica media, 589 Turbulent (flow), 594 T wave, 583 Vasa vasorum, 589 Vascular compliance, 595 Vasoconstriction, 589 Vasodilation, 589 Vein, 591 Ventricular end-diastolic pressure (VEDP), 587 Ventricular end-diastolic volume (VEDV), 587 Venule, 589 Z line, 585

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21. Hoit BD, Walsh RA. Normal physiology of the cardiovascular system. Fuster V, Walsh RA, Harrington RA, et al. Hurst's the heart. 13th ed. McGraw-Hill: Philadelphia; 2011. 22. Crystal GJ, Salem MR. The Bainbridge and the “reverse” Bainbridge reflexes: History, physiology, and clinical relevance. Anesthesia and Analgesia. 2012;114(3):520–532; 10.1213/ANE.0b013e3182312e21. 23. Volpe M, Rubattu S, Burnett J Jr. Natriuretic peptides in cardiovascular diseases: Current use and perspectives. European Heart Journal. 2014;35(7):419–425; 10.1093/eurheartj/eht466. 24. Perkel D, Naghi J, Agarwal M, et al. The potential effects of IGF-1 and GH on patients with chronic heart failure. Journal of Cardiovascular Pharmacology and Therapeutics. 2012;17(1):72–78; 10.1177/1074248411402078. 25. Girard J-P, Moussion C, Förster R. HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nature Reviews. Immunology. 2012;12(11):762–773; 10.1038/nri3298. 26. Patton KT, Thibodeau GA. Anatomy & physiology online package. 9th ed. Elsevier: St. Louis; 2016. 27. Kim DH, Kim C, Ding EL, et al. Adiponectin levels and the risk of hypertension: A systematic review and meta-analysis. Hypertension. 2013;62(1):27–32; 10.1161/HYPERTENSIONAHA.113.01453. 28. Younk LM, Lamos EM, Davis SN. The cardiovascular effects of insulin. Expert Opinion on Drug Safety. 2014;13(7):955–966; 10.1517/14740338.2014.919256. 29. Yuyun MF, Narayan HK, Ng LL. Prognostic significance of adrenomedullin in patients with heart failure and with myocardial infarction. American Journal of Cardiology. 2015;115(7):986–991; 10.1016/j.amjcard.2015.01.027. 30. Bergler-Klein J, Gyöngyösi M, Maurer G. The role of biomarkers in valvular heart disease: Focus on natriuretic peptides. Canadian Journal of Cardiology. 2014;30(9):1027–1034; 10.1016/j.cjca.2014.07.014. 31. Lei J, Vodovotz Y, Tzeng E, et al. Nitric oxide, a protective molecule in the cardiovascular system. Nitric Oxide: Biology and Chemistry. 2013;35:175–185; 10.1016/j.niox.2013.09.004. 32. Griendling KK, Harrison DG, Alexander RW. Biology of the vessel wall. Fuster V, Walsh RA, Harrington RA, et al. Hurst's the heart. 13th ed. McGraw-Hill: Philadelphia; 2011:153–171. 33. Nishikimi T, Kuwahara K, Nakagawa Y, et al. Adrenomedullin in cardiovascular disease: A useful biomarker, its pathological roles and therapeutic application. Current Protein and Peptide Science. 2013;14(4):256–267; 10.2174/13892037113149990045. 34. Kohan DE, Rossi NF, Inscho EW, et al. Regulation of blood pressure and salt homeostasis by endothelin. Physiological Reviews. 2011;91(1):1–77; 10.1152/physrev.00060.2009. 35. Nasser SA, El-Mas MM. Endothelin ETA receptor antagonism in cardiovascular disease. European Journal of Pharmacology. 2014;737:210–213; 10.1016/j.ejphar.2014.05.046. 36. Schjerning Olsen AM, Fosbøl EL, Gislason GH. The impact of NSAID treatment on cardiovascular risk—Insight from Danish observational data. Basic and Clinical Pharmacology and Toxicology. 2014;115(2):179–184; 10.1111/bcpt.12244. 37. Singh BK, Haque SE, Pillai KK. Assessment of nonsteroidal anti-inflammatory drug-induced cardiotoxicity. Expert Opinion on Drug Metabolism and Toxicology. 2014;10(2):143–156; 10.1517/17425255.2014.856881. 38. Izzard AS, Haegerty AM. Myogenic properties of brain and cardiac vessels and their relation to disease. Current Vascular Pharmacology. 2014;12(6):829–835; 10.2174/15701611113116660150.

24

Alterations of Cardiovascular Function Valentina L. Brashers, Mohamed El-Hussein

CHAPTER OUTLINE Diseases of the Veins, 604 Varicose Veins and Chronic Venous Insufficiency, 604 Thrombus Formation in Veins, 605 Superior Vena Cava Syndrome, 605 Diseases of the Arteries, 606 Hypertension, 606 Orthostatic (Postural) Hypotension, 611 Aneurysm, 611 Thrombus Formation, 612 Embolism, 613 Peripheral Vascular Disease, 613 Atherosclerosis, 614 Peripheral Artery Disease, 617 Coronary Artery Disease, Myocardial Ischemia, and Acute Coronary Syndromes, 617 Disorders of the Heart Wall, 629 Disorders of the Pericardium, 629 Disorders of the Myocardium: The Cardiomyopathies, 630 Disorders of the Endocardium, 632 Cardiac Complications in AIDS, 638 Manifestations of Heart Disease, 638 Heart Failure, 638 Dysrhythmias, 643 Shock, 643 Impairment of Cellular Metabolism, 643 Clinical Manifestations of Shock, 648 Treatment for Shock, 648 Types of Shock, 648 Multiple Organ Dysfunction Syndrome, 653

Our understanding of the pathophysiology of cardiovascular diseases is evolving rapidly. Neurohumoral, genetic, inflammatory, and metabolic factors are now the focus. This new information is leading to improvements in prevention and treatment.

Diseases of the Veins Varicose Veins and Chronic Venous Insufficiency A varicose vein is a vein in which blood has pooled, producing distended, tortuous, and palpable vessels (Figure 24-1). Veins are thin-walled, highly distensible vessels with valves to prevent backflow and pooling of blood (see Figure 23-26). Varicose veins typically involve the saphenous veins of the leg and are caused by (1) trauma to the saphenous veins that damages one or more valves or (2) gradual venous distension caused by the action of gravity on blood in the legs.

FIGURE 24-1

Varicose Veins of the Leg. (Solarisys/Shutterstock.com.)

If a valve is damaged, a section of the vein is subjected to the pressure of a larger volume of blood under the influence of gravity. Altered connective tissue proteins and proteolytic enzyme activity also play a role in remodelling of the vessel wall.1 The vein swells as it becomes engorged and surrounding tissue becomes edematous because increased hydrostatic pressure pushes plasma through the stretched vessel wall. Venous distension can develop over time in individuals who habitually stand for long periods, wear constricting garments, or cross the legs at the knees, which diminishes the action of the muscle pump (see Figure 23-27). Risk factors also include age, female gender, a family history of varicose veins, obesity, pregnancy, deep venous thrombosis (DVT), and previous leg injury. Eventually the pressure in the vein damages venous valves, rendering them incompetent and unable to maintain normal venous pressure. Varicose veins and valvular incompetence can progress to chronic venous insufficiency, especially in obese individuals. Chronic venous insufficiency (CVI) is inadequate venous return over a long period. Venous hypertension, circulatory stasis, and tissue hypoxia cause an inflammatory reaction in vessels and tissue leading to fibrosclerotic remodelling of the skin and then to ulceration. Symptoms include edema of the lower extremities and hyperpigmentation of the skin of the feet and ankles. Edema in these areas may extend to the knees. Circulation to the extremities can become so sluggish that the metabolic demands of the cells to obtain oxygen and nutrients and to remove wastes are barely met. Any trauma or pressure can therefore lower the oxygen supply and cause cell death and necrosis (venous stasis ulcers) (Figure 24-2). Infection can occur because poor circulation impairs the delivery of the cells and biochemicals necessary for the immune and inflammatory responses. This same sluggish circulation makes infection following reparative surgery a significant risk.

FIGURE 24-2

Venous Stasis Ulcer. (From Rosai, J. [1989]. Ackerman's surgical pathology [7th ed., vol. 2]. St. Louis: Mosby.)

Treatment of varicose veins and CVI begins conservatively, and excellent wound healing results have followed noninvasive treatments such as elevating the legs, wearing compression stockings, and performing physical exercise.2 Invasive management includes endovenous ablation, sclerotherapy or surgical ligation, conservative vein resection, and vein stripping.3

Thrombus Formation in Veins A thrombus is a blood clot that remains attached to a vessel wall (see Figure 21-20). A detached thrombus is a thromboembolus. Venous thrombi are more common than arterial thrombi because flow and pressure are lower in the veins than in the arteries. Deep venous thrombosis (DVT) occurs primarily in the lower extremity. Three factors (Virchow triad) promote venous thrombosis: (1) venous stasis (e.g., immobility, age, heart failure), (2) venous endothelial damage (e.g., trauma, intravenous medications), and (3) hypercoagulable states (e.g., inherited disorders, malignancy, pregnancy, use of oral contraceptives or hormone replacement therapy). Orthopedic trauma or surgery, spinal cord injury, and obstetric/gynecological conditions can be associated with up to a 100% likelihood of DVT. Numerous genetic abnormalities are associated with an increased risk for venous thrombosis primarily related to states of hypercoagulability. These inherited abnormalities include factor V Leiden mutation, prothrombin mutations, and deficiencies of protein C, protein S, and antithrombin; these abnormalities are commonly found in individuals who develop thrombi in the absence of the usual risk factors.4 Accumulation of clotting factors and platelets leads to thrombus formation in the vein, often near a venous valve. Inflammation around the thrombus promotes further platelet aggregation, and the thrombus propagates or grows proximally. This inflammation may cause pain and redness, but because the vein is deep in the leg, it is usually not accompanied by clinical symptoms or signs. If the thrombus creates significant obstruction to venous blood flow, increased pressure in the vein behind the clot may lead to edema of the extremity. Most thrombi will eventually dissolve without treatment; however, untreated DVT is associated with a high risk for embolization of a part of the clot to the lung (pulmonary embolism) (see Chapter 27). Persistent venous obstruction may lead to CVI and post-thrombotic syndrome with associated pain, edema, and ulceration of the affected limb.5 Because DVT is usually asymptomatic and difficult to detect clinically, prevention is important in atrisk individuals and includes early ambulation, pneumatic devices, and prophylactic anticoagulation. If thrombosis does occur, diagnosis is confirmed by a combination of serum D-dimer measurement and Doppler ultrasonography. Management most often consists of anticoagulation therapy using heparin (low-molecular-weight heparin) and warfarin (Coumadin).6 New oral anticoagulant therapies, such as factor Xa inhibitors and direct thrombin inhibitors, have been shown to have a more favourable benefitto-risk ratio and are rapidly becoming the treatments of choice.7 Thrombolytic therapy or placement of an inferior vena cava filter may be indicated in selected individuals.4,6

Superior Vena Cava Syndrome Superior vena cava syndrome (SVCS) is a progressive occlusion of the superior vena cava (SVC) that leads to venous distension in the upper extremities and head. Causes include bronchogenic cancer (75%

of cases) followed by lymphomas and metastasis of other cancers.8 Other less common causes include tuberculosis, mediastinal fibrosis, and cystic fibrosis. Invasive therapies (pacemaker wires, central venous catheters, and pulmonary artery catheters) with associated thrombosis now account for nearly 40% of cases.9 The SVC is a relatively low-pressure vessel that lies in the closed thoracic compartment; therefore, tissue expansion can easily compress the SVC. The right mainstem bronchus abuts the SVC so that cancers occurring in this bronchus may exert pressure on the SVC. Additionally, the SVC is surrounded by lymph nodes and lymph chains that commonly become involved in thoracic cancers and compress the SVC during tumour growth. Because onset of SVCS is most often slow, collateral venous drainage to the azygos vein usually has time to develop. Clinical manifestations of SVCS are edema and venous distension in the upper extremities and face, including the ocular beds. Affected persons complain of a feeling of fullness in the head or tightness of shirt collars, necklaces, and rings. Cerebral edema may cause headache, visual disturbance, and impaired consciousness. The skin of the face and arms may become purple and taut, and capillary refill time is prolonged. Respiratory distress may be present because of edema of bronchial structures or compression of the bronchus by a carcinoma. In infants, SVCS can lead to hydrocephalus. Diagnosis is made by chest X-ray, Doppler studies, computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound. Because of its slow onset and the development of collateral venous drainage, SVCS is generally not a vascular emergency, but it is an oncological emergency. Treatment for malignant disorders can include radiation therapy, surgery, chemotherapy, and the administration of diuretics, steroids, and anticoagulants, as necessary. Treatment for nonmalignant causes may include bypass surgery using various grafts, thrombolysis (both locally and systemically), balloon angioplasty, and placement of intravascular stents.8

Quick Check 24-1 1. What is chronic venous insufficiency, and how does it present clinically? 2. What are the major risk factors for deep venous thrombosis? 3. Name three causes of superior vena cava syndrome.

Diseases of the Arteries Hypertension Hypertension is consistent elevation of systemic arterial blood pressure.10 Approximately 7.5 million Canadians have hypertension. Hypertension is considered to be the main factor contributing to mortality, disability-adjusted life years (DALYs), and years of life lost (YLL) in Canada. About 90% of Canadians are expected to develop hypertension if they live an average lifespan.11 The chance of developing primary hypertension increases with age. Although hypertension is usually considered an adult health problem, it is important to remember that hypertension does occur in children and is being diagnosed with increasing frequency (see Chapter 25). The prevalence of hypertension is higher in those of African descent and in those with diabetes. Hypertension is defined by Hypertension Canada as a mean systolic blood pressure greater than or equal to 140 mm Hg or diastolic blood pressure greater than or equal to 90 mm Hg when a nonautomated office blood pressure measurement is used (Table 24-1). Alternately, hypertension is also defined as a mean systolic blood pressure greater than or equal to 135 mm Hg or diastolic blood pressure greater than or equal to 85 mm Hg when an automated office blood pressure measurement is used.12 Figure 24-3 presents a hypertension diagnostic algorithm for adults. TABLE 24-1 Classification of Blood Pressure for Adults Age 18 Years and Older Category

Systolic (mm Hg)

Normal Prehypertension Stage 1 hypertension Stage 2 hypertension

0.11 and rate 20 or less

Decreased mean arterial pressure

Same as atrial flutter

Same as atrial tachycardia

Decreased cardiac output from loss of atrial contribution to ventricular preload Same as idiojunctional rhythm

Atrial and sinus bradycardia, standstill, or Same as sinus bradycardia block

Decreased cardiac output from loss of atrial contribution to ventricular preload for that beat Decreased cardiac output from loss of atrial contribution to ventricular preload Decreased cardiac output from loss of atrial contribution to ventricular preload Increased myocardial demand because of tachycardia Same as idiojunctional rhythm Same as idiojunctional rhythm

Absent or barely present cardiac output and pulse Not compatible with life

Ventricular standstill or asystoleb Premature ventricular contractions (PVCs) or depolarizationsa

P absent or independent QRS absent Early beats with P waves QRS occasionally opposite in deflection from usual QRS

No cardiac output Not compatible with life Same as premature junctional contractions

Accelerated ventricular rhythm

P absent or independent QRS >0.11 and rate of 41– 99 P absent or independent QRS >0.11 and rate 100 or more P absent QRS >300 and usually not observable

Same as accelerated junctional rhythm

Ventricular tachycardiab Ventricular fibrillationb

Same as atrial tachycardia

Same as idiojunctional rhythm Vagal hyperactivity Hyperkalemia (5.4–6 mmol/L) Hypercalcemia, hypoxia, and elevated preload (see PACs) Same as PJCs

Same as sinus bradycardia

Same as PJCs

Same as PAC

Sinus, atrial, and junctional bradycardia, standstill, or block Same as idiojunctional rhythm

Same as sinus bradycardia

Depolarization and contraction not coupled: electrical activity present with little or no mechanical activity Usually caused by profound hypoxia Profound ischemia, hyperkalemia, acidosis

Vigorous pharmacological treatment aimed at restoring rate and force Usually ineffective May attempt to use pacemaker Same as agonal rhythm, plus electrical defibrillation Pharmacological interventions to change thresholds, refractory periods; reduce myocardial demand, increase supply

Same as PJCs, aging and induction of anaesthesia Impulse originates in cell outside normal conduction system and spreads through intercalated disks Same as PVCs

Same as PAC

Same as PAC

Same as sinus bradycardia

Removal of cause Same as PVCs

Same as junctional tachycardia

Same as PVCs

Same as PVCs, plus electrical cardioversion

Same as ventricular standstill

Same as PVCs Rapid infusion of potassium

Same as PVCs, plus electrical cardioversion

a

Most common in adults.

b

Life-threatening in adults.

TABLE 24-10 Disorders of Impulse Conduction Type

Electrocardiogram

Effect

Pathophysiology

Treatment

Sinus block

Occasionally absent P, with loss of QRS for that beat

Occasional decrease in cardiac output Increase in preload for following beat

Local hypoxia, scarring of intra-atrial conduction pathways, electrolyte imbalances Increased atrial preload

First-degree blocka

PRI >0.2 sec

None

Second-degree block, Mobitz I, or Wenckebacha

Progressive prolongation of PRI Same as sinus block until one QRS is dropped Pattern of prolongation resumes

Second-degree block or Mobitz II

Same as sinus block

Same as sinus block

Third-degree blockb

P waves present and independent of QRS No observed relationship between P and QRS Always AV dissociation P waves present and independent of QRS, but not always because of block (e.g., ventricular tachycardia) AV dissociation not always third-degree block

Same as idiojunctional rhythm

Same as sinus block Hyperkalemia (>7 mmol/L) Hypokalemia (25% Increased creatinine × 2 or GFR decrease >50% Increased creatinine × 3 or GFR decrease >75% Persistent ARF = complete loss of kidney function >4 weeks End-stage kidney disease (>3 months)

UO 3 cm in diameter), circumscribed, and encapsulated, glistening appearance, varies in colour; two types: pure and mixed; pure tumour is surrounded by mucin; infrequent; found in lateral half of breast; tends to occur in women after age 70 years Medullary Encapsulated and grows very large (7–8 cm in diameter); commonly surrounded by lymphocytic inflammatory infiltrate; occurs after age 50 years Tubular Well-differentiated with orderly tubules in centre (stroma) of mass; can be associated with noninfiltrating ductal carcinoma; occurs in women about 50 years of age; nodal metastasis infrequent; occurrence rare Adenoid cystic Very rare; well-circumscribed, painless mass arising from nipple and areola Metaplastic Involves cartilage or bone, mixed tumours or osteogenic sarcomas Squamous cell Frequent in Blacks; originates in ductal epithelium Carcinoma of Mammary Lobules Lobular Found in individuals with fibrocystic disease; localized to upper breast quadrants; 15–35% risk of becoming invasive; occurs frequently in mid-40s; infiltrating variety occurs carcinoma in in early 50s situ Infiltrating Infiltrates from duct; firm mass with chalky streaks lobular Paget's disease Eczema of nipple that extends to areola; cancer usually found underneath nipple; poorly circumscribed; large Paget cells arise from duct and directly invade nipple; history of scaly, red rash spreading from nipple; lesion palpable beneath nipple, often bilateral; occurs in middle age Inflammatory Not a histological type; fairly diffuse within breast tissue, diffuse edema of overlying skin; extremely undifferentiated, very rare; most metastasize to axilla carcinoma Sarcoma of the Breast Cystosarcoma Usually large (>17 cm in diameter); mostly localized but can rupture through skin; rarely metastasizes to lymph nodes; history of painless nodule present for years before it phyllodes forms a large mass; ulceration and bleeding of skin often present; occurs in wide age range (13–77 years) Fibrosarcoma Well-circumscribed, firm, and usually does not involve skin or nipple; well-differentiated to extremely undifferentiated; arises from connective tissue; extremely rare (e.g., liposarcoma, angiosarcoma)

The many genetic and epigenetic changes drive the sequential expansion of progressively more and more malignant cell populations.206 Breast tissue stem cells are thought to be the cell of origin for all breast cancers. Gene expression profiling studies have identified at least four major subtypes classified as luminal A, luminal B, HER2+, and basal-like.207 Mounting evidence shows that there are “subtypes within subtypes,” and emerging evidence suggests that the biology of specific subtypes reflects contributions from the microenvironment.208 Many models of breast carcinogenesis have been suggested, and three interrelated themes related to breast cancer initiation also have emerged: (1) gene addiction, (2) phenotype plasticity, and (3) cancer stem cells. Cancer gene addiction includes oncogene addiction, whereby these driver genes play key roles in breast cancer development and progression, and nononcogene addiction, whereby these genes may not initiate cancer but play roles in cancer development and progression.209 Examples of key driver genes include HER2 and MYC, and examples of tumour-suppressor genes are TP53, BRCA1, and BRCA2. Once a founding tumour clone is established, genomic instability may assist through the establishment of other subclones and contribute to both tumour progression and therapy resistance.97 Phenotypic plasticity is

exemplified by a distinctive phenotype called epithelial–mesenchymal transition (EMT) (see Chapter 10). EMT is involved in the generation of tissues and organs during embryogenesis, is essential for driving tissue plasticity during development, and is an unintentional process during cancer progression. The EMT-associated reprogramming is involved in many cancer cell characteristics, including suppression of cell death or apoptosis and senescence, is reactivated during wound healing, and is resistant to chemotherapy and radiation therapy.210 Remodelling or reprogramming of the breast during postpregnancy involution is important because it involves inflammatory and “wound healing–like” tissue reactions known as reactive stroma. These tissue reactions increase the risk for tumour invasion and may facilitate the transition of carcinoma in situ to invasive carcinoma. Activation of an EMT program during cancer development often requires signalling between cancer cells and neighbouring stromal cells.211 In advanced primary carcinomas, cancer cells recruit a variety of cell types into the surrounding stroma, including fibroblasts, myofibroblasts, granulocytes, macrophages, mesenchymal stem cells, and lymphocytes (Figure 33-30). Overall, increasing evidence suggests that interactions of cancer cells with adjacent tumour-associated stromal cells induce malignant cell phenotypes (Figure 33-31).

FIGURE 33-30 Cells of the Tumour Microenvironment. A, Distinct cell types constitute most solid tumours including breast tumours. Both the main cellular tissue, called parenchyma, and the surrounding tissue, or stroma, of tumours contain cell types that enable tumour growth and progression. For example, the immune-inflammatory cells present in tumours can include both tumour-promoting and tumour-killing subclasses of cells. B, The microenvironment of tumours. Multiple stromal cell types create a succession of tumour microenvironments that change as tumours invade normal tissue, eventually seeding and colonizing distant tissues. The organization, numbers, and phenotypic characteristics of the stromal cell types and the extracellular matrix (hatched background) evolve during progression and enable primary, invasive, and metastatic growth.(Not shown are the premalignant stages.) (Data from Hanahan, D., & Weinberg, R. [2011]. Cell, 144, 646–674.)

FIGURE 33-31 Signalling Interactions in the Tumour Microenvironment During Malignant Progression. Upper panel: Numerous cell types constitute the tumour microenvironment and are orchestrated and maintained by reciprocal interactions. Lower panel: The reciprocal interactions between the breast main tissue or parenchyma and the surrounding stroma are important for cancer progression and growth. Certain organ sites of “fertile soil” or “metastasis niches” facilitate metastatic seeding and colonization. Cancer stem cells are involved in some or all stages of tumour development and progression. CSC, cancer stem cell. (Adapted from Hanahan, D., & Weinberg, R. [2011]. Cell, 144, 646–674.)

Research is ongoing to define cancer stem cells in breast carcinogenesis, including cancer stem cell origin and renewability properties. Studies have begun to identify the role of MaSCs and to describe how they drive development of the gland and maintain homeostasis, maintain the many cycles of proliferation and apoptosis needed to expand and maintain the breast during pregnancy, and return it to a quiet (quiescent) state after involution.212 EMT generates multiple epithelial cell subsets with different states of stemness relative to more differentiated cells.213 The ECM and the basement membrane, in particular, are no longer just considered the “bricks and mortar” of a tissue but now a place where stem cells reside; and correct tissue architecture, together with the reservoir of growth factors, cytokines, and proteinases, is critical for mammary tissue to develop and function properly.212 Many of the biological traits of highgrade malignancy—motility, invasiveness, and self-renewal—have been traced to subpopulations of stem cells within carcinomas.214,215 Hormones may act as accelerators as well as initiators, delay involution, and influence the susceptibility of the breast epithelium to environmental carcinogens because hormones

control the differentiation of the mammary gland epithelium and, thereby, regulate the rate of stem cell division. Two new concepts being investigated as important to metastases are tumour dormancy and vascular mimicry. Tumour dormancy has been noted in the care of people with cancer, whereby microscopic and occult cancerous lesions enter a latent or dormant phase in various stages of tumour progression. In fact, these microscopic and occult cancerous lesions are often found in healthy people.216 Ironically, in healthy people these are the slow-growing tumours (some called “pseudodisease”) detected by present screening methods that would not advance to routine clinical presentation over the individual's lifetime.216 Current debates surround the concern that individuals often undergo unnecessary treatment for a disease they were never destined to experience.216 Evidence exists that organ-specific molecular signalling can determine whether a metastatic lesion will expand or remain dormant. Significant to different signalling profiles that may determine this outcome are stress-activated kinases, transcription factors (such as p53), and cell cycle inhibitors. Thus, cell stress–activated signalling may be increased, for example, with certain treatment modalities such as surgery. Evidence has been accumulating that removal of a malignant tumour from a host is curative for many but—in some circumstances—is insufficient to prevent the cancer from recurring and can lead to rapid cancer recurrence.217,218 Immune cells in the ECM or stroma and the overall immune response have been recognized for their role in regulating tumour growth and are being investigated for their role in tumour dormancy. Cancer metastases require that primary tumour cells evolve the ability to intravasate into the lymphatic system or vasculature, and extravasate into and colonize secondary sites.201 Investigators developed a mouse model of breast tumour heterogeneity and isolated a distinct clone of specialized cells that efficiently enter the vasculature and express two proteins, Serpine2 and SLPI, which were necessary and sufficient to program these cells for vascular mimicry. Vascular mimicry is a blood supply pathway in tumours that is formed by tumour cells and is independent of endothelial cell–lined blood vessels—thus it mimics real blood vessels (Figure 33-32). This blood supply pathway facilitates perfusion of the primary tumours and correlates with poor clinical outcome. The increase in these blood supply pathways was associated with an increase in CTCs and a subsequent increase in lung metastases. Additionally, treatment with the anticoagulant warfarin (Coumadin) increased the number of CTCs and lung metastases, suggesting that the anticoagulant function of Serpine2 and SLPI both maintains blood flow through the extravascular network and promotes intravasation. These remarkable findings identify Serpine2- and SLPI-driven vascular mimicry as a critical mechanism or driver of metastatic progression in cancer.201

FIGURE 33-32 Vascular Mimicry Drives Metastasis. The steps to accomplish metastasis include intravasation, in which tumour cells escape from the primary tumour into the vasculature and move through the bloodstream; or extravasation, in which tumour cells escape from the vasculature to colonize in distant tissue. Metastasis is promoted by vascular mimicry, whereby tumour cells adopt characteristics similar to those of the endothelial cells that line blood vessels, and mimic vascularlike networks within tumours and between tumours and blood vessels. Wagenblast and colleagues found that two proteins, Serpine2 and SLPI, promoted metastasis by stimulating vascular mimicry. Tumour cells expressing these proteins (green) form the vascularlike network that allows other tumour cells (purple, blue) to move to secondary sites. (Adapted from Hendrix, M.J.C. [2015]. Nature, 520, 300–302; Wagenblast, E., Soto, M., Gutiérrez-Ángel, C.A., et al. [2015]. Nature, 520, 358–362.)

Ductal and Lobular Carcinoma in Situ Ductal carcinoma in situ (DCIS) is a heterogeneous group of proliferations limited to breast ducts and lobules without invasion of the basement membrane. About 84% of all in situ disease is DCIS; the remainder is mostly lobular carcinoma in situ (LCIS). DCIS occurs predominantly in females but can occur in males. Since 1980, the widespread adoption of screening mammography has led to an epidemic of diagnoses of DCIS.219 DCIS presents as microcalcifications (low grade) (Figure 33-33, B) or rod-shaped branching (high grade) on a mammogram (Figure 33-33, A).

FIGURE 33-33 Ductal Carcinoma in Situ. A, Malignant microcalcifications. Extensive area of pleomorphic microcalcifications; granular, rod-shaped, and branching microcalcifications can be identified. The appearances are typical of high-grade ductal carcinoma in situ (DCIS). B, Craniocaudal mammography reveals fine and coarse granular calcifications. Histopathological analysis revealed low-grade DCIS. (A, from O'Malley, F.P., Pinder, S.E., & Mulligan, A.M. [Eds.]. [2011]. Breast pathology [2nd ed.]. Philadelphia: Saunders; B, from Donegan, W.L., & Spratt, J.S. [2002]. Cancer of the breast [5th ed.]. Philadelphia: Saunders.)

Still controversial, DCIS does not appear to progress from sequential steps of low grade or risk types to higher grade or risk types during its route to cancer or cancer recurrence.205,220 This property, therefore, suggests a stable population.205 Because of these findings, some argue that the term is misleading and should be replaced by ductal intraepithelial neoplasia, similar to the term used in prostate cancer, and that breast cancer statistics should exclude these DCIS cases with invasive breast cancer statistics.221 DCIS is a very common type of noninvasive cancer, with one in five breast cancers diagnosed as DCIS.222 Because of the large numbers of cases diagnosed yearly in Canada, the debate is whether mammography is causing the overdiagnosis of potential pseudodisease; for example, the Canadian National Breast Screening Study-2 of women aged 50 to 59 years found a fourfold increase in DCIS cases in those screened by clinical breast examination (CBE) plus mammography compared with those screened by CBE alone, with no difference in breast cancer mortality.219,222 The difficulty for this clinical dilemma is that the natural history of DCIS is poorly understood because nearly all cases are treated. More directed research is needed on DCIS with genetic expression profiling, best treatment to achieve disease regression, and studies of tumour characteristics and risk profiling. An important, newer mission of the DCIS Discovery Enterprise at MD Anderson Cancer Center in Houston, Texas, is to prevent invasive disease while also reducing unnecessary surgery or radiation. Key to understanding the progression of breast cancer after treatment of DCIS are the characteristics of the lesion and the delivered treatment. According to the US National Cancer Institute, the best evidence indicates that most lesions of DCIS will not evolve to invasive cancer, and those that do can be managed successfully, even after that transition.221 The detection and treatment of nonpalpable DCIS often represents overdiagnosis and overtreatment.221 Surprisingly, the overall death rate for women with DCIS is lower than that for women in the population as a whole.97,221 This favourable outcome may reflect the benign nature of the condition or the benefits of treatment, or it may be a marker for socioeconomic factors associated with longevity.97,221 Attempts to define low-risk DCIS cases that can be managed with fewer therapies are critical.221

Lobular carcinoma in situ (LCIS) originates from the TDLU. Unlike DCIS, LCIS has a uniform appearance—the cells expand but do not distort involved spaces; thus the lobular structure is preserved. The cells grow in a noncohesive (discohesive) fashion usually because of a loss of the tumour-suppressive adhesion protein E-cadherin.97 LCIS is found as an incidental lesion from a biopsy and not from mammography because it is not associated with calcifications or stromal reactions that produce mammographic densities. LCIS has an incidence of about 1 to 6% of all carcinomas and did not increase with mammographic screening.97 With biopsies in both breasts, LCIS is bilateral in 20 to 40% of cases, compared with 10 to 20% of cases of DCIS.97 The cells of AH, LCIS, and invasive lobular carcinoma are structurally identical.97 Loss of cellular adhesion because of dysfunction of E-cadherin results in a rounded shape without attachment to adjacent cells, increasing the risk for invasion. E-cadherin functions as a tumour-suppressor protein and may be lost in neoplastic proliferations from various mechanisms, including mutation. LCIS is a risk factor for invasive carcinoma and develops in 25 to 35% of women over a period of 20 to 30 years. Unlike DCIS, the risk is almost as high in the contralateral breast as in the ipsilateral breast. Treatments include close clinical follow-up and mammographic screening, tamoxifen, and bilateral prophylactic mastectomy. Clinical manifestations The majority of carcinomas of the breast occur in the upper outer quadrant, where most of the glandular tissue of the breast is located. The lymphatic spread of cancer to the opposite breast, to lymph nodes in the base of the neck, and to the abdominal cavity is caused by obstruction of the normal lymphatic pathways or destruction of lymphatic vessels by surgery or radiotherapy (see Figure 32-11). The less common inner quadrant tumours may spread to mediastinal nodes or Rotter nodes, which are located between the pectoral muscles (see Figure 32-11). Internal mammary chain nodes also are common sites of metastasis. Metastases from the vertebral veins can involve the vertebrae, pelvic bones, ribs, and skull. The lungs, kidneys, liver, adrenal glands, ovaries, and pituitary gland are also sites of metastasis. The first sign of breast cancer is usually a painless lump. Lumps caused by breast tumours do not have any classic characteristics. Other presenting signs include palpable nodes in the axilla, retraction of tissue (dimpling) (Figure 33-34), or bone pain caused by metastasis to the vertebrae. Table 33-12 summarizes the clinical manifestations of breast cancer. Manifestations vary according to the type of tumour and stage of disease.

FIGURE 33-34

Retraction of Nipple Caused by Carcinoma. (From Ackerman, L.V., del Regato, J.A., Spjut, H.J., et al. [1985]. Cancer: Diagnosis, treatment, and prognosis [6th ed.]. St. Louis: Mosby.)

TABLE 33-12

Clinical Manifestations of Breast Cancer Clinical Manifestation

Pathophysiology

Local pain Dimpling of skin Nipple retraction Skin retraction Edema Nipple/areolar eczema Pitting of skin (similar to surface of an orange [peau d'orange]) Reddened skin, local tenderness, and warmth Dilated blood vessels Nipple discharge in a nonlactating woman Ulceration Hemorrhage Edema of arm Chest pain

Local obstruction caused by tumour Can occur with invasion of dermal lymphatics because of retraction of Cooper ligament or involvement of pectoralis fascia Shortening of mammary ducts Involvement of suspensory ligament Local inflammation or lymphatic obstruction Paget's disease Obstruction of subcutaneous lymphatics, resulting in accumulation of fluid Inflammation Obstruction of venous return by a fast-growing tumour; obstruction dilates superficial veins Spontaneous and intermittent discharge caused by tumour obstruction Tumour necrosis Erosion of blood vessels Obstruction of lymphatic drainage in axilla Metastasis to lung

Evaluation and treatment CBE, mammography, ultrasound, thermography, MRI, biopsy, hormone receptor assays, and gene expression profiling are used in evaluating breast alterations and cancer. Treatment is based on the extent or stage of the cancer. The extent of the tumour at the primary site, the presence and extent of lymph node metastases, and the presence of distant metastases are all evaluated to determine the stage of disease. Treatment includes surgery, radiation, chemotherapy, hormone therapy, and biological therapy.

Quick Check 33-5 1. What types of fibrocystic breast changes increase the risk for breast cancer? 2. What is the role of hormones and growth factors in the pathophysiology of breast cancer? 3. Why are reproductive factors, such as early menarche and late menopause, important for the pathogenesis of breast cancer? 4. Why is complete breast involution important for reducing risk for breast cancer? 5. Discuss the role of the microenvironment or stromal tissue on breast cancer development.

Did You Understand? Abnormalities of the Female Reproductive Tract 1. Normal development of the female reproductive tract requires absence of testosterone during embryonic and fetal life. 2. Alterations in the normal process include errors in cellular sensitivity to testosterone (androgen insensitivity) or failures of cell line migration resulting in changes in the structure of the reproductive organs. 3. Androgen insensitivity syndrome is a disorder of hormone resistance characterized by a female phenotype in an individual with an XY karyotype or male genotype. 4. Other abnormalities of the uterus, cervix, and fallopian/uterine tubes have multifactorial origins and are often the result of an interaction between genetic predisposition and environmental factors.

Alterations of Sexual Maturation 1. Sexual maturation, or puberty, is marked by the development of secondary sex characteristics, rapid growth, and, ultimately, the ability to reproduce. The normal range for the onset of puberty is now 8 to 13 years of age but can vary geographically. 2. Delayed puberty is the onset of sexual maturation after these ages; precocious puberty is the onset before these ages. Treatment for delayed and precocious puberty depends on the cause.

Disorders of the Female Reproductive System 1. The female reproductive system can be altered by hormonal imbalances, infectious microorganisms, inflammation, structural abnormalities, and benign or malignant proliferative conditions. 2. Primary dysmenorrhea is painful menstruation not associated with pelvic disease. It results from excessive synthesis of prostaglandin F2α. Secondary dysmenorrhea results from endometriosis, pelvic adhesions, inflammatory disease, uterine fibroids, or adenomyosis. 3. Primary amenorrhea is the continued absence of menarche and menstrual function by 13 years of age without the development of secondary sex characteristics or by 15 years of age if these changes have occurred. 4. Secondary amenorrhea is the absence of menstruation for a time equivalent to three or more cycles in women who have previously menstruated. Secondary amenorrhea is associated with many disorders and physiological conditions. 5. Dysfunctional uterine bleeding is heavy or irregular bleeding in the absence of organic disease. 6. Polycystic ovary syndrome is a condition in which excessive androgen production is triggered by inappropriate secretion of gonadotropins. This hormonal imbalance prevents ovulation and causes enlargement and cyst formation in the ovaries, excessive endometrial proliferation, and often hirsutism. Insulin resistance and hyperinsulinemia play a key role in androgen excess. 7. Premenstrual syndrome is the cyclic recurrence of physical, psychological, or behavioural changes distressing enough to disrupt normal activities or interpersonal relationships. Emotional symptoms, particularly depression, anger, irritability, and fatigue, are reported as the most distressing symptoms; physical symptoms tend to be less problematic. Treatment is symptomatic and includes stress reduction, exercise, biofeedback, lifestyle changes, counselling, and medication. 8. Infection and inflammation of the female genitalia can result from microorganisms that are present in the environment and often sexually transmitted or from overproliferation of microorganisms

that normally populate the genital tract. 9. Pelvic inflammatory disease (PID) is an acute inflammatory process caused by infection. Many infections are sexually transmitted and microorganisms that comprise the vaginal flora are implicated. PID is a substantial health risk to women, and untreated PID can lead to infertility. 10. Vaginitis is irritation or inflammation of the vagina, typically caused by infection. It is usually caused by sexually transmitted pathogens or Candida albicans, which causes candidiasis. 11. Cervicitis, which is infection of the cervix, can be acute (mucopurulent cervicitis) or chronic. Its most common cause is a sexually transmitted pathogen. 12. Vulvodyniavestibulitis (VV) is chronic vulvar pain lasting 3 months or longer without visible dermatosis. The cause of VV is unknown and theories include embryonic factors, chronic inflammation, genetic immune factors, nerve pathways, increased sensitivity to environmental factors, human papillomavirus (HPV), and hormonal changes. 13. Bartholinitis, also called Bartholin cyst, is an infection of the ducts that lead from the Bartholin glands to the surface of the vulva. Infection blocks the glands, preventing the outflow of glandular secretions. 14. The pelvic relaxation disorders—uterine displacement, uterine prolapse, cystocele, rectocele, and urethrocele—are caused by the relaxation of muscles and fascial supports, usually a result of advancing age or following childbirth or other trauma, and are more likely to occur in women with a familial or genetic predisposition. 15. Benign ovarian cysts develop from mature ovarian follicles that do not release their ova (follicular cysts) or from a corpus luteum that persists abnormally instead of degenerating (corpus luteum cyst). Cysts usually regress spontaneously. 16. Endometrial polyps consist of benign overgrowths of endometrial tissue and often cause abnormal bleeding in the premenopausal woman. 17. Leiomyomas, also called myomas or uterine fibroids, are benign tumours arising from the smooth muscle layer of the uterus, the myometrium. 18. Adenomyosis is the presence of endometrial glands and stroma within the uterine myometrium. 19. Endometriosis is the presence of functional endometrial tissue (i.e., tissue that responds to hormonal stimulation) at sites outside the uterus. Endometriosis causes an inflammatory reaction at the site of implantation and is a cause of infertility. Emerging is the relationship between endometriosis and ovarian cancer. 20. Cancers of the female genitalia involve the uterus (particularly the endometrium), the cervix, and the ovaries. Cancer of the vagina is rare. 21. Cervical cancer arises from the cervical epithelium and is triggered by HPV. The cellular transformational zone is called the squamous-columnar junction. The progressively serious neoplastic alterations are cervical intraepithelial neoplasia (CIN) (cervical dysplasia), cervical carcinoma in situ, and invasive cervical carcinoma. Cocarcinogens include immune responses, hormonal responses, and other environmental factors that determine regression or persistence of the HPV infection. 22. Primary cancer of the vagina is rare. Risk factors include being 60 or older, diethylstilbestrol exposure in utero, HPV-16, human immunodeficiency virus (HIV), genital warts, and previous carcinoma of the cervix or vulva. The relationship between cancer of the vagina and developing precancerous cell changes called vaginal intra-epithelial neoplasia is controversial. 23. Risk factors for vulvar cancer include HPV-16 (cause), HIV, HPV-18 (probable cause), increasing age, previous cancer (untreated high-grade vulvar intraepithelial neoplasia), cervical cancer survivor, previous CIN, certain autoimmune conditions, organ transplant recipient (perhaps because of immunosuppression to clear HPV), and tobacco use (may relate to inability to clear HPV infection). 24. Carcinoma of the endometrium is the most common type of uterine cancer and the most prevalent gynecological malignancy. Primary risk factors for endometrial cancer include exposure to unopposed estrogen (e.g., estrogen-only hormone replacement therapy [HRT], tamoxifen, early menarche, late menopause, nulliparity, failure to ovulate), chronic hyperinsulinemia, hyperglycemia, body fatness and adult weight gain, chronic inflammation, and lack of physical

exercise. 25. Risk factors for ovarian cancer include advancing age, genetic factors, family history, overweight and obesity, height, reproductive or hormonal factors, HRT, endometriosis, diabetes, previous cancer, smoking, asbestos, talc-based powder, and ionizing radiation. Ovarian cancer causes more deaths than any other genital cancer in women. 26. The biology of ovarian cancer is changing, and ovarian cancer is heterogeneous. 27. Sexual dysfunction is the lack of satisfaction with sexual function resulting from pain or a deficiency in sexual desire, arousal, or orgasm/climax. 28. Sexual function and dysfunction result from a complex set of personal and biological factors that interact with culture. Both organic and psychosocial disorders can be implicated in sexual dysfunction. 29. Infertility, or the inability to conceive after 1 year of unprotected intercourse, affects approximately 16% of all couples. Fertility can be impaired by factors in the male, female, or both partners. 30. Female infertility results from dysfunction of the normal reproductive process: menses and ovulation, fallopian tube function (transport of the egg to the uterus and as a site of fertilization), ovarian dysfunction, and implantation of the fertilized egg into a receptive endometrium.

Disorders of the Female Breast 1. Most disorders of the breast are disorders of the mammary gland—that is, the female breast. 2. Galactorrhea, or inappropriate lactation, is the persistent secretion of a milky substance by the breasts of a woman who is not in the postpartum state or nursing an infant. Its most common cause is nonpuerperal hyperprolactinemia—a rise in serum prolactin levels. 3. Benign breast conditions are numerous and involve both ducts and lobules. Benign epithelial lesions can be broadly classified according to their future risk of developing breast cancer as (a) nonproliferative breast lesions, (b) proliferative breast disease, and (c) atypical (atypia) hyperplasia. 4. Nonproliferative breast lesions include simple breast cysts, papillary apocrine change, and mild hyperplasia of the usual type. 5. Proliferative breast lesions without atypia are diverse and include usual ductal hyperplasia, intraductal papillomas, sclerosing adenosis, radial scar, and simple fibroadenoma. 6. Proliferative breast lesions with atypia include atypical ductal hyperplasia and atypical lobular hyperplasia. 7. Ductal carcinoma in situ (DCIS) refers to a heterogeneous group of proliferations limited to breast ducts and lobules without invasion of the basement membrane. Lobular carcinoma in situ (LCIS) originates from the duct lobular unit. 8. Breast cancer is the most common form of cancer in women and second to lung cancer as the most common cause of cancer death. However, the inclusion of DCIS with invasive breast cancer statistics is controversial. Breast cancer is a heterogeneous disease with diverse molecular, phenotypic, and pathological changes. 9. The major risk factors for breast cancer are reproductive factors, such as nulliparity; hormonal factors and growth factors, such as excessive estradiol and insulinlike growth factor 1; familial factors, such as a family history of breast cancer; and environmental factors, such as ionizing radiation. Two factors emerging as important are delayed involution of the mammary gland and breast density. Physical activity and lack of postmenopausal weight gain may be risk-reducing factors. 10. A dominating movement in the field of cancer research is that epithelial function depends on the entire tissue including the stroma or microenvironment. Breast cancer is now known as a tissuebased disease with a possible abnormal, aberrant wound healing and inflammatory stromal (reactive stroma) component. 11. Models of breast carcinogenesis include three interrelated themes: gene addiction, phenotype plasticity, and cancer stem cells. The exact molecular events leading to breast cancer invasion are

complex and not completely understood. These events involve genetic and epigenetic alterations and cancer cell and stromal interactions. New concepts for breast cancer metastases include tumour dormancy and vascular mimicry. 12. Most breast cancers arise from the ductal epithelium and then may metastasize to the lymphatics, opposite breast, abdominal cavity, lungs, bones, kidneys, liver, adrenal glands, ovaries, and pituitary glands. 13. The first clinical manifestation of breast cancer is usually a small, painless lump in the breast. Other manifestations include palpable lymph nodes in the axilla, dimpling of the skin, nipple and skin retraction, nipple discharge, ulcerations, reddened skin, and bone pain associated with bony metastases.

Key Terms Adenomyosis, 831 Amenorrhea, 819 Androgen insensitivity syndrome (AIS), 816 Anorgasmia (orgasmic dysfunction), 842 Atypia, 844 Atypical ductal hyperplasia (ADH), 845 Atypical hyperplasia (AH), 845 Atypical lobular hyperplasia (ALH), 845 Bartholinitis (Bartholin cyst), 827 Benign breast disease (BBD), 844 Carcinoma in situ, 855 Cervicitis, 826 Complete precocious puberty, 818 Corpus luteum cyst, 830 Cyst, 844 Cystocele, 828 Delayed puberty, 818 Dermoid cyst, 830 Diffuse papillomatosis, 844 Disorder of desire (hypoactive sexual desire, decreased libido), 842 Ductal carcinoma in situ (DCIS), 857 Dysfunctional uterine bleeding (DUB), 820 Dyspareunia (painful intercourse), 842 E-cadherin, 859 Endometrial polyp, 830 Endometriosis, 832 Enterocele, 828 Epithelial–mesenchymal transition (EMT), 855 Fibrocystic change (FCC), 844 Follicular cyst, 829 Functional cyst, 829 Galactorrhea (inappropriate lactation), 843 Genetic heterogeneity, 855 Hirsutism, 820 Infertility, 843 Intraductal papilloma, 844 Leiomyoma (myoma, uterine fibroid), 831 Lobular carcinoma in situ (LCIS), 859 Lobular involution, 849 Mammographic density (MD), 852 Menopausal hormone therapy (MHT), 850 Mild hyperplasia of the usual type, 844 Mucopurulent cervicitis (MPC), 826 Nonpuerperal hyperprolactinemia, 843 Ovarian torsion, 830 Papillary apocrine change, 844 Pelvic inflammatory disease (PID), 824 Pelvic organ prolapse (POP), 828 Pessary, 828

Polycystic ovary syndrome (PCOS), 822 Precocious puberty, 818 Pregnancy-associated breast cancer (PABC), 849 Premenstrual dysphoric disorder (PMDD), 822 Premenstrual syndrome (PMS), 822 Primary amenorrhea, 819 Primary dysmenorrhea, 819 Prolactin-inhibiting factor (PIF), 843 Puberty, 817 Radial scar (RS), 844 Rectocele, 828 Salpingitis, 825 Sclerosing adenosis, 844 Secondary amenorrhea, 819 Secondary dysmenorrhea, 819 Sexual dysfunction, 842 Simple fibroadenoma, 845 Terminal duct lobular unit (TDLU), 849 Thelarche, 818 Tumour dormancy, 856 Usual ductal hyperplasia (UDH), 844 Uterine prolapse, 828 Vaginismus, 842 Vaginitis, 826 Vaginosis, 826 Vascular mimicry, 857 Vulvodyniavestibulitis (VV), 827 Xenoestrogen, 855

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34

Alterations of the Male Reproductive System George W. Rodway, Kathryn L. McCance, Kelly Power-Kean

CHAPTER OUTLINE Alterations of Sexual Maturation, 868 Delayed or Absent Puberty, 868 Precocious Puberty, 868 Disorders of the Male Reproductive System, 869 Disorders of the Urethra, 869 Disorders of the Penis, 869 Disorders of the Scrotum, Testis, and Epididymis, 872 Disorders of the Prostate Gland, 876 Sexual Dysfunction, 888 Disorders of the Male Breast, 890 Gynecomastia, 890 Carcinoma, 891 Sexually Transmitted Infections, 891

Alterations of the reproductive system span a wide range of concerns, from delayed sexual development and suboptimal sexual performance to structural and functional abnormalities. Many common male reproductive disorders carry potentially serious physiological or psychological consequences. For example, sexual or reproductive dysfunction, such as erectile dysfunction or infertility, can dramatically affect self-concept, relationships, and overall quality of life. Conversely, organic and psychosocial problems, such as alcoholism, depression, situational stressors, chronic illness, and medications, can affect sexual performance and may be risk factors for the development of some types of reproductive tract cancers. Aside from skin cancer, prostate cancer is the second leading cause of cancer deaths and is the most frequently diagnosed cancer in men. Incidence rates for prostate cancer changed substantially between the mid-1980s and mid-1990s and have since fluctuated widely from year to year, in large part reflecting changes in prostate cancer screening with the prostate-specific antigen (PSA) blood test.1 Diagnosis and treatment of male reproductive system disorders are, like female reproductive system

disorders, often complicated by the stigma and symbolism associated with the reproductive organs and emotion-laden beliefs and behaviours related to reproductive health. Treatment or diagnosis for any problem may be delayed because of embarrassment, guilt, fear, or denial.

Alterations of Sexual Maturation The process of sexual maturation, or puberty, is marked by the development of secondary sex characteristics, rapid growth, and, ultimately, the ability to reproduce. A variety of congenital and endocrine disorders can disrupt the timing of puberty. Puberty that occurs too late (delayed puberty) or too early (precocious puberty) is caused by the inappropriate onset of sex hormone production. While the mean age of pubertal onset appears to be decreasing for girls, the age of pubertal onset has remained essentially unchanged for boys.

Delayed or Absent Puberty About 3% of children living in North America experience delayed development of secondary sex characteristics.2 Normally, boys tend to mature later than girls, around 14 to 14.5 years of age. In boys, the first sign of maturity is the enlargement of testes and thinning of the scrotal skin. In delayed puberty, these secondary sex characteristics develop later. In about 95% of cases, delayed puberty is a normal physiological event. Hormonal levels are normal, the hypothalamic-pituitary-gonadal axis is intact, and maturation is slowly occurring. Treatment is seldom needed unless the delayed puberty is causing psychosocial problems.3 The other 5% of cases are caused by the disruption of the hypothalamic-pituitary-gonadal axis or by the outcomes of a systemic disease. Treatment depends on the cause (Box 34-1), and referral to a pediatric endocrinologist is necessary.4

Box 34-1

Causes of Delayed Puberty Hypergonadotropic Hypogonadism (Low Testosterone, Increased Follicle-Stimulating Hormone [FSH] and Luteinizing Hormone [LH]) 1. Gonadal dysgenesis, most commonly Turner syndrome (45,X/46,XX; structural X or Y abnormalities, or mosaicism) 2. Klinefelter's syndrome (47,XXY) 3. Bilateral gonadal failure a. Traumatic or infectious b. Postsurgical, postirradiation, or postchemotherapy c. Autoimmune d. Idiopathic empty-scrotum or vanishing-testes syndrome (congenital anorchia)

Hypogonadotropic Hypogonadism (Low Testosterone, Decreased LH, Depressed FSH) 1. Reversible a. Physiological delay b. Weight loss/anorexia c. Strenuous exercise d. Severe obesity e. Illegal drug use, especially marihuana f. Primary hypothyroidism g. Congenital adrenal hyperplasia h. Cushing's syndrome i. Prolactinomas

2. Irreversible a. Gonadotropin-releasing hormone (GnRH) deficiency (Kallmann's syndrome) or idiopathic hypogonadotropic hypogonadism (IHH) b. Hypopituitarism c. Congenital central nervous system defects d. Other pituitary adenomas e. Craniopharyngioma f. Malignant pituitary tumours

Precocious Puberty Precocious puberty is a rare event, affecting fewer than 1 in 50 000 boys. Precocious puberty for boys of all ethnic/racial groups is defined as sexual maturation occurring before age 9.5 A recent study observed that the mean ages of beginning male genital and pubic hair growth and early testicular volumes are leaning toward younger ages than earlier studies have suggested, although this seems to be dependent on race/ethnicity.6 Precocious puberty may be caused by many conditions (Box 34-2), including lethal central nervous system tumours. All cases of precocious puberty require thorough evaluation.

Box 34-2

Primary Forms of Precocious Puberty Complete Precocious Puberty Appropriate characteristics for the child's gender develop prematurely. Hypothalamic-pituitary-gonadal axis functions normally but prematurely. In about 10% of cases, lethal central nervous system tumour may be the cause.

Partial Precocious Puberty Appropriate secondary sex characteristics develop partially. Premature adrenarche (growth of axillary and pubic hair) tends to occur between 5 and 8 years of age. It can progress to complete precocious puberty; it may be caused by estrogen-secreting neoplasms or may be a variant of normal pubertal development.

Mixed Precocious Puberty It causes the child to develop some secondary sex characteristics of the opposite gender. Common causes are adrenal hyperplasia or androgen-secreting tumours. Data from Burchett, M.L.R., Hanna, C.E., & Steiner, R.D. (2009). Endocrine and metabolic diseases. In C.E. Burns, A.M. Dunn, M.A. Brady, et al. (Eds.), Pediatric primary care (4th ed.). St. Louis: Saunders; Jospe, N. (2005). Disorders of pubertal development. In L.M. Osborn, T.G. DeWitt, L.R. First, et al. (Eds.), Pediatrics. Philadelphia: Mosby.

All forms of precocious puberty are treated by identifying and removing the underlying cause or administering appropriate hormones. In many cases, precocious puberty can be reversed. However, complete precocious puberty (development consistent with the gender of the individual) is difficult to treat and can cause long bones to stop growing before the child has reached normal height.

Quick Check 34-1 1. Why does puberty occur too late or too early in some individuals? 2. Why do all forms of precocious puberty require evaluation?

Disorders of the Male Reproductive System Disorders of the Urethra Urethritis and urethral strictures are common disorders of the male urethra. Urethral carcinoma, an extremely rare form of cancer, can occur in men older than 60 years.

Urethritis Urethritis is an inflammatory process that is usually, but not always, caused by a sexually transmitted microorganism. Infectious urethritis caused by Neisseria gonorrhoeae is often called gonococcal urethritis (GU); urethritis caused by other microorganisms is called nongonococcal urethritis (NGU). Nonsexual origins of urethritis include inflammation or infection as a result of urological procedures, insertion of foreign bodies into the urethra, anatomical abnormalities, or trauma. Noninfectious urethritis is rare and is associated with the ingestion of wood or ethyl alcohol or turpentine. It is also seen with reactive arthritis.7 Symptoms of urethritis include urethral tingling or itching or a burning sensation, and frequency and urgency with urination. The individual may note a purulent or clear mucouslike discharge from the urethra. Nucleic acid detection amplification tests allow early detection of N. gonorrhoeae and Chlamydia trachomatis in urine studies.8 Treatment consists of appropriate antibiotic therapy for infectious urethritis and avoidance of future exposure or mechanical irritation.

Urethral Strictures A urethral stricture is a narrowing of the urethra caused by scarring. The scars may be congenital but can be present at any age and have a wide range of etiological factors, including untreated urethral infection, trauma, and urological instrumentation. Infections also can occur from long-term use of indwelling catheters. Prostatitis and infection secondary to urinary stasis are common complications. Severe and prolonged obstruction can result in hydronephrosis and kidney failure. The clinical manifestations of urethral stricture are caused by bladder outlet obstruction. Urethral stricture often manifests itself as lower urinary tract symptoms (LUTS) or urinary tract infections with significant impairment in the quality of life. The primary symptom is diminished force and calibre of the urinary system; other symptoms include urinary frequency and hesitancy, mild dysuria, double urinary stream or spraying, and dribbling after voiding. Urethral stricture is diagnosed on the basis of history, physical examination, flow rates, and cystoscopy. Treatment is usually surgical and may involve urethral dilation, urethrotomy, or a variety of open surgical techniques. The choice of surgical intervention depends on the age of the individual and the severity of the problem.

Disorders of the Penis Phimosis and Paraphimosis Phimosis and paraphimosis are both disorders in which the foreskin (prepuce) is “too tight” to move easily over the glans penis. Phimosis is a condition in which the foreskin cannot be retracted back over the glans, whereas paraphimosis is the opposite: the foreskin is retracted and cannot be moved forward (reduced) to cover the glans (Figure 34-1). Both conditions can cause penile pathological conditions.

FIGURE 34-1 Phimosis and Paraphimosis. A, Phimosis: the foreskin has a narrow opening that is not large enough to permit retraction over the glans. B, Lesions on the prepuce secondary to infection cause swelling, and retraction of foreskin may be impossible. Circumcision is usually required. C, Paraphimosis: the foreskin is retracted over the glans but cannot be reduced to its normal position. Here it has formed a constricting band around the penis. D, Ulcer on the retracted prepuce with edema. (A and C, from Monahan, F.D., Sands, J., Neighbors, M., et al. [2007]. Phipps' medical-surgical nursing: Health and illness perspectives [8th ed.]. St. Louis: Mosby; B, from Taylor, P.K. [1995]. Diagnostic picture tests in sexually transmitted diseases. St. Louis: Mosby; D, from Morse, S.A., Holmes, K.K., & Ballard, R.C. [2011]. Atlas of sexually transmitted diseases and AIDS [4th ed.]. London: Saunders.)

The inability to retract the foreskin is normal in infancy and is caused by congenital adhesions. During the first 3 years of life, congenital adhesions (between the foreskin and glans) separate naturally with penile erections and are not an indication for circumcision. Phimosis can occur at any age and is most commonly caused by poor hygiene and chronic infection.9 It rarely occurs with normal foreskin. Reasons for seeking treatment include edema, erythema, and tenderness of the prepuce and purulent discharge; inability to retract the foreskin is a less common complaint. Circumcision, if needed, is performed after infection has been eradicated. Complications of phimosis include inflammation of the glans (balanitis) or prepuce (posthitis) and paraphimosis. There is a higher incidence of penile carcinoma in uncircumcised males, but chronic infection and poor hygiene are usually the underlying factors in such cases. Approximately 40 to 63% of invasive penile carcinomas are attributable to human papillomavirus (HPV).10,11 Paraphimosis, in which the foreskin is retracted, can constrict the penis, causing edema of the glans. If the foreskin cannot be reduced manually, surgery must be performed to prevent necrosis of the glans caused by constricted blood vessels. Severe paraphimosis is a surgical emergency.

Peyronie Disease Peyronie disease (“bent nail syndrome”) is a fibrotic condition that causes lateral curvature of the penis during erection (Figure 34-2). Peyronie disease develops slowly and is characterized by tough, fibrous thickening of the fascia in the erectile tissue of the corpora cavernosa. A dense, fibrous plaque is usually palpable on the dorsum of the penile shaft. The problem usually affects middle-aged men and is associated with painful erection, painful intercourse (for both partners), and poor erection distal to the involved area.12 In some cases, erectile dysfunction or unsatisfactory penetration occurs. When the penis is flaccid, there is no pain.

FIGURE 34-2

Peyronie Disease. This person complained of pain and deviation of his penis to one side on erection. (From Taylor, P.K. [1995]. Diagnostic picture tests in sexually transmitted diseases. London: Mosby.)

A local vasculitislike inflammatory reaction occurs, and decreased tissue oxygenation results in fibrosis and calcification. The exact cause is unknown. Peyronie disease is associated with Dupuytren's contracture (a flexion deformity of the fingers or toes caused by shortening or fibrosis of the palmar or plantar fascia), diabetes, tendency to develop keloids, and, in rare cases, use of beta-blocker medications.9 There is no definitive treatment for Peyronie disease; however, treatment can include pharmacological agents and surgery. Spontaneous remissions occur in as many as 50% of individuals. However, men suffering with Peyronie disease and who have significant penile deformity precluding successful coitus should be appraised for surgical correction.9

Priapism Priapism is an uncommon condition of prolonged penile erection. It is usually painful and is not associated with sexual arousal (Figure 34-3). Priapism is idiopathic in 60% of cases; the remaining 40% of cases can be associated with spinal cord trauma, sickle cell disease, leukemia, pelvic tumours, infections, or penile trauma.

FIGURE 34-3

Priapism. (From Lloyd-Davies, R.W., Parkhouse, H., Crow, J., et al. [1994]. Color atlas of urology [2nd ed.]. London: Wolfe Medical.)

Priapism must be considered a urological emergency. Treatment within hours is effective and prevents erectile dysfunction. Conservative approaches include iced saline enemas, ketamine administration, and spinal anaesthesia. Needle aspiration of blood from the corpus through the dorsal glans is often effective and is followed by catheterization and pressure dressings to maintain decompression. More aggressive surgical treatments include the creation of vascular shunts to maintain blood flow. Erectile dysfunction

results in up to 50% of prolonged cases.

Balanitis Balanitis is an inflammation of the glans penis (Figure 34-4) and usually occurs in conjunction with posthitis, an inflammation of the prepuce. (Inflammation of the glans and the prepuce is called balanoposthitis.) It is associated with poor hygiene and phimosis. The accumulation under the foreskin of glandular secretions (smegma), sloughed epithelial cells, and Mycobacterium smegmatis can irritate the glans directly or lead to infection. Skin disorders (e.g., psoriasis, lichen planus, eczema) and candidiasis must be differentiated from inflammation resulting from poor hygienic practices. Balanitis is most commonly seen in men with poorly controlled diabetes mellitus and candidiasis. The infection is treated with antimicrobials. After the inflammation has subsided, circumcision can be considered to prevent recurrences.

FIGURE 34-4

Balanitis. (From Taylor, P.K. [1995]. Diagnostic picture tests in sexually transmitted diseases. London: Mosby.)

Tumours of the Penis Tumours of the penis are not common. The most frequent are the benign epithelial tumour condyloma acuminatum and penile carcinomas. Condyloma acuminatum is a benign tumour caused by HPV, a sexually transmitted infection (STI). HPV type 6 and, less often, type 11 are the most frequent types and can cause a common wart and moist surface of the external genitalia. Giant condylomata (Buschke-Löwenstein tumour) affect older men and may be 5 to 10 cm in size.13 Atypia may be evident in longstanding, giant condylomata, and assessment of other HPV subtypes may be indicated to distinguish from a noninvasive warty carcinoma.13,14

Penile Cancer Carcinoma of the penis is rare in Canada. The Canadian Cancer Society estimated that 220 Canadian men were diagnosed with penile cancer in 2013. It also estimated that 41 Canadian men died of this disease in 2013.15 It does account, however, for about 10% of cancers in African and South American men. It can affect men 40 to 70 years of age, with two-thirds of men diagnosed at 65 years of age and older. Although the exact cause is unknown, risk factors include HPV infection, smoking, low socioeconomic status, poor personal hygiene, and psoriasis (possibly autoimmune diseases linked to the lack of clearance of HPV). Circumcision at birth decreases the risk for penile cancer, and penile cancer is more common in men with phimosis and those with acquired immune deficiency syndrome (AIDS).16 Squamous cell carcinoma accounts for 95% of invasive penile cancers. Other premalignant lesions, or in situ forms of epidermal carcinoma, that occur on the penis include leukoplakia (white plaque), Paget's disease (red, inflamed areas), erythroplasia of Queyrat (raised red areas), and Buschke-Löwenstein patches (large venous areas). Recently, penile intraepithelial neoplasia (PeIN; atypical cells) has been redesignated into two subcategories: differentiated PeIN and undifferentiated PeIN, including warty

basaloid and mixed warty-basaloid subtypes.13 HPV-6 and HPV-11 associated with genital warts (condylomata acuminata) have low cancer risks.17 At times, the penis might be the site of metastatic spread of solid tumours from the bladder, prostate, rectum, or kidney. Early squamous cell carcinoma and premalignant epidermal lesions are easily treated, but delays in seeking treatment are attributed to denial, embarrassment, failure to detect lesions under a phimotic foreskin, fear, guilt, and ignorance. Squamous cell carcinoma usually begins as a small, flat, ulcerative or papillary lesion on the glans or foreskin that grows to involve the entire penile shaft. Extensive lesions are associated with metastases and a poor prognosis.18,19 The regional femoral and iliac lymph nodes are common metastatic sites; the urethra and bladder are rarely involved. Weight loss, fatigue, and malaise accompany chronic suppurative lesions. The specific diagnosis is made by biopsy after examination to document the location, size, and fixation of the lesion. After a positive biopsy, the extent of cancer spread is determined by imaging studies. Distant metastases are uncommon. Stages of carcinoma of the penis are presented in Box 34-3.

Box 34-3

Staging for Penile Cancer Stage 0: Tis or Ta, N0, M0 The cancer has not grown into tissue below the top layers of skin and has not spread to lymph nodes or distant sites.

Stage I: T1a, N0, M0 The cancer has grown into tissue just below the superficial layer of skin but has not grown into blood or lymph vessels. It is a grade 1 or 2. It has not spread to lymph nodes or distant sites.

Stage II: Any of the Following: T1b, N0, M0 The cancer has grown into tissue just below the superficial layer of skin and is high grade or has grown into blood or lymph vessels. It has not spread to lymph nodes or distant sites. Or

T2, N0, M0 The cancer has grown into one of the internal chambers of the penis (the corpus spongiosum or corpora cavernosa). The cancer has not spread to lymph nodes or distant sites. Or

T3, N0, M0 The cancer has grown into the urethra. It has not spread to lymph nodes or distant sites.

Stage IIIA: T1 to T3, N1, M0 The cancer has grown into tissue below the superficial layer of skin (T1). It also may have grown into the corpus spongiosum, the corpora cavernosa, or the urethra (T2 or T3). The cancer has spread to a single groin lymph node (N1). It has not spread to distant sites.

Stage IIIB: T1 to T3, N2, M0 The cancer has grown into the tissues of the penis and may have grown into the corpus spongiosum, the corpora cavernosa, or the urethra (T1 to T3). It has spread to two or more groin lymph nodes. It has not spread to distant sites.

Stage IV: Any of the Following: T4, any N, M0 The cancer has grown into the prostate or other nearby structures. It may or may not have spread to

groin lymph nodes. It has not spread to distant sites. Or

Any T, N3, M0 The cancer has spread to lymph nodes in the pelvis or spread in the groin lymph nodes and grown through the lymph nodes' outer covering and into surrounding tissue. The cancer has not spread to distant sites. Or

Any T, any N, M1 The cancer has spread to distant sites. T, Primary tumour size; N, regional lymph nodes; M, distant metastasis. Penile carcinoma is managed primarily with surgery. Newer, innovative surgical techniques can preserve as much penile tissue as possible without compromising cancer control. A multimodal approach with chemotherapy is under study.20,21 Palliative treatment with radiation or chemotherapy may be used when the disease is inoperable and bulky inguinal metastases have occurred. Options for individuals with carcinoma in situ include local excision, radiation, laser surgery, cryosurgery, chemosurgery, or chemotherapy with topical (5%) 5-fluorouracil (Efudex).18

Quick Check 34-2 1. Why are priapism and severe paraphimosis considered urological emergencies? 2. What are the risk factors for cancer of the penis?

Disorders of the Scrotum, Testis, and Epididymis Disorders of the Scrotum Men may seek treatment for painful or painless scrotal masses. Masses may be serious (cancer or torsion) or benign (hydrocele or cyst), and may require immediate surgical intervention or allow for careful observation. Varicocele, hydrocele, and spermatocele are common intrascrotal disorders. A varicocele is an abnormal dilation of the testicular veins and the pampiniform plexus within the scrotum, and is classically described as a “bag of worms” (Figure 34-5). Varicoceles are one of the most commonly identified scrotal abnormalities and abnormal findings among infertile men. Advancements in diagnostic techniques indicate that the incidence of varicoceles is significantly greater than previously reported.22 Most (90%) occur on the left side because of discrepancies in venous drainage and may be painful or tender. Varicocele occurs in 10 to 15% of males and is seen most often after puberty.23 Because most develop in adolescence, physiological changes in testosterone level may contribute to increasing blood flow to the testicle, causing venous dilation.24 Unilateral right-sided varicoceles are rare and result from compression or obstruction of the inferior vena cava by a tumour or thrombus. Varicoceles may be less likely to be diagnosed among obese men.25

FIGURE 34-5

Depiction of a Varicocele. Dilation of veins within the spermatic cord. (From Ball, J.W., Dains, J.E., Flynn, J.A., et al. [2015]. Seidel's guide to physical examination [8th ed.]. St. Louis: Mosby.)

The cause of varicocele is poorly understood. Blood pools in the veins rather than flowing into the venous system. Varicocele decreases blood flow through the testis, interfering with spermatogenesis and causing infertility. Varicoceles can alter testosterone and follicle-stimulating hormone (FSH) levels, cause oxidative stress, decrease sperm count, and affect sperm quality.26 Varicocele surgical repair is generally done when the male has a grade II or III varicocele and an abnormal semen analysis and the female has no known cause of infertility. If varicocele is mild and fertility is not an issue, a scrotal support is usually sufficient to relieve symptoms of scrotal heaviness or “dragging.” Colour doppler ultrasonography is used to confirm diagnosis.26 A hydrocele is a collection of fluid between the layers of the tunica vaginalis (Figure 34-6). It is the most common cause of scrotal swelling. Hydroceles occur in 6% of male newborns and are congenital malformations that often resolve spontaneously in the first year of life.27 In North America, common infectious causes include epididymitis and viruses. Worldwide, however, filariasis is a major cause, especially with recent travel to tropical countries.22 Other causes include trauma, torsion of the testicle or testicular appendage, and recent scrotal surgery. A man presenting with a hydrocele in his third or fourth decade needs careful evaluation for testicular cancer.28

FIGURE 34-6

Depiction of a Hydrocele. Accumulation of clear fluid between the visceral (inner) and parietal (outer) layers of the tunica vaginalis.

Hydroceles vary in size, and most are asymptomatic. The most important feature on physical

examination is a tense, smooth, scrotal mass that easily transilluminates. Transillumination, or holding a light behind the scrotum, can help distinguish a hydrocele from a hernia or a solid mass. Treatment includes watchful waiting in infants and for those older than 1 year; 75% of hydroceles resolve within 6 months.27,28 Symptomatic or communicating hydroceles need definitive treatment. Treatment includes surgical resection, aspiration, and sclerotherapy (injection of a sclerosing agent into the scrotal sac [cystic dilation]) to excise the tunica vaginalis.22 Spermatoceles (epididymal cysts) are benign cystic collections of fluid of the epididymis located between the head of the epididymis and the testis. Spermatoceles are filled with a milky fluid containing sperm and are usually painless (Figure 34-7). Spermatoceles that cause significant pain or discomfort are excised. Both spermatoceles and epididymal cysts present clinically as discrete, firm, freely mobile masses distinct from the testis that may be transilluminated. Usually, however, spermatoceles are asymptomatic or produce mild discomfort that is relieved by scrotal support. Neither hydroceles nor spermatoceles are associated with infertility.

FIGURE 34-7 Spermatocele. Retention cyst of the head of the epididymis or of an aberrant tubule or tubules of the rete testis. The spermatocele lies outside the tunica vaginalis; therefore, on palpation it can be readily distinguished and separated from the testis. (From Lloyd-Davies, R.W., Parkhouse, H., Crow, J., et al. [1994]. Color atlas of urology [2nd ed.]. London: Wolfe Medical.)

Cryptorchidism and Ectopy Cryptorchidism is a group of abnormalities in which the testis fails to descend completely, whereas an ectopic testis has strayed from the normal pathway of descent. Ectopy may be caused by an abnormal connection at the distal end of the gubernaculum testis that leads the gonad to an abnormal position, usually at the superficial inguinal site. In cryptorchidism, the descent of one or both testes is arrested, with unilateral arrest occurring more often than bilateral arrest. The testes may remain in the abdomen, or testicular descent may be arrested in the inguinal canal or the puboscrotal junction. Cryptorchidism is a common congenital anomaly, with an incidence of approximately 3% in full-term infants. However, this rate increases significantly with low birth weight; for instance, the rate of cryptorchidism at 3 months has been found to be 7.7% for infants with birth weights less than 2 000 grams, 2.5% for birth weights of 2 000 to 2 500 grams, and 1.41% for birth weights of 2 500 grams or more.29,30 The incidence of cryptorchidism in adults is 0.7 to 0.8%.26 Cryptorchidism is commonly associated with vasal or epididymal abnormalities. These congenital anomalies affect about 33 to 66% of newborns with cryptorchidism. Other structural anomalies include posterior urethral valves (less than 5%), upper genital tract abnormalities (less than 5%), and hypospadias. The presence of both hypospadias and cryptorchidism raises the suspicion of mixed gonadal dysgenesis (intersex infant). It has been hypothesized that cryptorchidism may result from an absence or abnormality of the gubernaculum—a cordlike structure that extends from the lower pole of the testis to the scrotum; a congenital gonadal or dysgenetic defect that makes the testis insensitive to gonadotropins (a likely explanation for unilateral cryptorchidism); or lack of maternal gonadotropins (a likely explanation for bilateral cryptorchidism of prematurity).26 Mechanical possibilities include a short spermatic cord, fibrous bands or adhesions in the normal path of the testes, or a narrowed inguinal canal. Chromosomal studies do not support a genetic component. Physiological cryptorchidism, also called retractile testis or migratory testis, is an involuntary retraction of

the testes out of the scrotum that occurs with excitement, physical activity, or exposure to cold and is caused by the small mass of prepubertal testis and the strength of the cremaster muscle. This phenomenon is common and self-limiting (descent occurs at puberty). Physical examination discloses the absence of one or both testes in the scrotum and an atrophic scrotum on the affected side. If the undescended testis is in a vulnerable position, over the pubic bone for example, an individual may complain of severe pain secondary to trauma. The adult male with bilateral cryptorchidism may be infertile. Testicular cancer also is a well-established complication of cryptorchidism. In men with a history of unilateral cryptorchidism, neoplasms also develop more commonly in the contralateral testis. This finding suggests that cryptorchidism affects the testes and is a process more significant than simply the position of the testis in childhood. The risk for testicular cancer is 35 to 50 times greater for men with cryptorchidism or a history of cryptorchidism than for the general male population. Because definite histological change occurs in the cryptorchid testis by 1 year of age, surgical correction is recommended around that age.29,31 Treatment often begins with administration of gonadotropin-releasing hormone (GnRH) or human chorionic gonadotropin (hCG), hormones that may initiate descent and make surgery unnecessary. GnRH is available as a nasal spray in Europe and may enhance germ cell counts even when the testis does not descend.31 If hormonal therapy is not successful (success rates range from 6 to 75%), the testis is located and moved surgically (orchiopexy) in young children or removed (orchiectomy) in adults and children more than 10 years of age.26 The testis that is properly placed in the scrotum provides adequate hormonal function and gives the scrotum a normal appearance. A successful operation does not ensure fertility if the testis is congenitally defective. Approximately 20% of males with unilateral undescended testis remain infertile even though orchiopexy is performed by age 1 year; most individuals with treated or untreated bilateral testicular maldescent have poor fertility.

Torsion of the Testis and Testicular Appendages In torsion of the testis, the testis rotates on its vascular pedicle, interrupting its blood supply (Figure 348). Torsion of the testis is one of several conditions that cause an acute scrotum, which is testicular pain and swelling. Testicular appendages include the appendix testis (a remnant of the müllerian duct) and the appendix epididymis (a remnant of the wolffian duct). Torsion of the appendages can also cause acute scrotum and be confused with testicular torsion, a urological emergency.

FIGURE 34-8

Torsion of the Testis. (A and B, from Kliegman, R.M., Stanton, B.F., Gemell, J.W., et al. [Eds.]. [2011]. Nelson textbook of pediatrics [19th ed.]. Philadelphia: Saunders; C, from Damjanov, I., & Linder, J. [Eds]. [1996]. Anderson's pathology [10th ed.]. St. Louis: Mosby.)

Torsion of the testis can occur at any age but is most common among neonates and adolescents, particularly at puberty.27 Onset may be spontaneous or follow physical exertion or trauma. Torsion twists the arteries and veins in the spermatic cord, reducing or stopping circulation to the testis. Vascular engorgement and ischemia develop, causing scrotal swelling and pain not relieved by rest or scrotal support. Diagnostic testing includes urinalysis (to determine infection) and colour doppler ultrasonography.26 Torsion of the testis is a surgical emergency. If it cannot be reduced manually (scrotal elevation), surgery must be performed within 6 hours after the onset of symptoms to preserve normal testicular function.

Orchitis Orchitis is an acute inflammation of the testes (Figure 34-9) and is uncommon except as a complication of systemic infection or as an extension of an associated epididymitis32. Infectious organisms may reach the

testes through the blood or the lymphatics or, most commonly, by ascent through the urethra, vas deferens, and epididymis. Most cases of orchitis are actually cases of epididymo-orchitis (inflammation of both the epididymis and testis). Occasionally in middle-aged men, a nonspecific, apparently noninfectious inflammatory process (called granulomatous orchitis) can occur, presumably a granulomatous response to spermatozoa.

FIGURE 34-9

Depiction of Orchitis. (From Ball, J.W., Dains, J.E., Flynn, J.A., et al. [2015]. Seidel's guide to physical examination [8th ed.]. St. Louis: Mosby.)

Mumps is the most common infectious cause of orchitis and usually affects postpubertal males. The onset is sudden, occurring 3 to 4 days after the onset of parotitis. Signs and symptoms include high fever, reaching 40°C (104°F), marked prostration, bilateral or unilateral erythema, edema and tenderness of the scrotum, and leukocytosis. An acute hydrocele may develop. Urinary signs and symptoms, which accompany epididymitis, are absent. Atrophy with irreversible damage to spermatogenesis may result in 30% of affected testes. Bilateral orchitis does not affect hormonal function but may cause permanent sterility. Treatment is supportive and includes bed rest, scrotal support, elevation of the scrotum, hot or cold compresses, and analgesic agents for relief of pain. If an acute hydrocele develops, it is aspirated. Testicular abscess usually requires orchiectomy (removal of the testis). Appropriate antimicrobial medications should be used for bacterial orchitis, and corticosteroids are indicated in proven cases of nonspecific granulomatous orchitis.

Cancer of the Testis Testicular cancer is a highly treatable, usually curable cancer that most often develops in young and middle-aged men. For men with seminoma (all stages combined), the cure rate exceeds 90%. For men with low-stage seminoma or nonseminoma, the cure rate approaches 100%.33 Overall, testicular cancers are uncommon, accounting for approximately 1% of all male cancers; yet they are the most common solid tumour of young adult men.33 Cancer of the testis occurs most commonly in men between the ages of 15 and 35 years. The Canadian Cancer Society estimated that 1 100 Canadian men were diagnosed with testicular cancer in 2017. It also estimated that 41 Canadian men died of this disease in 2017.34 Testicular cancer is more common in White men than in men of African or Asian ancestry, and occurs more often in men with a higher socioeconomic status.33 Testicular tumours are slightly more common on the right side than on the left, a pattern that parallels the occurrence of cryptorchidism, and they are bilateral in 1 to 3% of cases (Figure 34-10).

FIGURE 34-10

Testicular Tumour. (From Wolfe, J. [1984]. 400 self-assessment picture tests in clinical medicine. London: Wolfe Medical.)

Pathophysiology Ninety percent of testicular cancers are germ cell tumours, arising from the male gametes. Germ cell tumours include seminomas (most common), embryonal carcinomas, teratomas, and choriosarcomas. Testicular tumours also can arise from specialized cells of the gonadal stroma (Leydig, Sertoli, granulosa, theca cells). The cause of testicular neoplasms is unknown (see Risk Factors: Cancer of the Testis). A genetic predisposition is suggested by the fact that the incidence is higher among brothers, identical twins, and other close male relatives. Genetic predisposition is supported statistically, showing that the disease is relatively rare among Africans, Blacks, Asians, and native New Zealanders. Risk factors include history of cryptorchidism, abnormal testicular development, human immunodeficiency virus (HIV) and AIDS, Klinefelter's syndrome, and history of testicular cancer.33

Risk Factors Cancer of the Testis • HIV and AIDS • History of cryptorchidism • Abnormal testicular development • Klinefelter's syndrome • History of testicular cancer Clinical manifestations Painless testicular enlargement commonly is the first sign of testicular cancer. Occurring gradually, it may be accompanied by a sensation of testicular heaviness or a dull ache in the lower abdomen. Occasionally acute pain occurs because of rapid growth, resulting in hemorrhage and necrosis. Ten percent of affected men have epididymitis, 10% have hydroceles, and 5% have breast enlargement (gynecomastia). The testicular mass is usually discovered by the individual or by his sexual partner. At the time of initial diagnosis, approximately 10% of individuals already have symptoms related to metastases. Lumbar pain also may be present and usually is caused by retroperitoneal node metastasis. Signs of metastasis to the lungs include cough, dyspnea, and bloody sputum (hemoptysis).

Supraclavicular node involvement may cause difficulty swallowing (dysphagia) and neck swelling. With metastasis to the central nervous system, alterations in vision or mental status, papilledema, and seizures may be experienced. Evaluation and treatment An incorrect diagnosis at the initial examination occurs in as many as 25% of men with testicular cancer. Epididymitis and epididymo-orchitis are the most common misdiagnoses; others include hydrocele and spermatocele. Evaluation begins with careful physical examination, including palpation of the scrotal contents with the individual in the erect and supine positions. Signs of testicular cancer include abnormal consistency, induration, nodularity, or irregularity of the testis. The abdomen and lymph nodes are palpated to seek evidence of metastasis, and tumour type is identified after orchiectomy. The Canadian Cancer Society recommends that all males over the age of 15 should know how their testicles normally look and feel, and should talk to their primary health care provider if they notice any changes in their testicles.35 Testicular biopsy is not recommended because it may cause dissemination of the tumour and increase the risk for local recurrence. Primary testicular cancer can be assessed rapidly and accurately by scrotal ultrasonography. Tumour markers are higher than normal in the presence of a tumour and may help detect a tumour that is too small to be palpated during physical examination or to be visualized on imaging. Radiological imaging and measurement of serum markers are used in clinical staging of the disease. Besides surgery, treatment involves radiation and chemotherapy singly or in combination. Factors influencing the prognosis include histological studies of the tumour stage of the disease and selection of appropriate treatment. Most individuals treated for cancer of the testis can expect a normal lifespan; some have persistent paresthesias, Raynaud phenomenon, or infertility. Approximately 10% of men treated for testicular cancer will experience a relapse; if the relapse is discovered early and treated, 99% can be cured. Orchiectomy does not affect sexual function.

Epididymitis Epididymitis, or inflammation of the epididymis, generally occurs in sexually active young males (younger than 35 years) and is rare before puberty (Figure 34-11). In young men, the usual cause is a sexually transmitted microorganism, such as N. gonorrhoeae or C. trachomatis. Coliform bacteria are the common pathogens in other age groups.36 Men who practise unprotected anal intercourse may acquire sexually transmitted epididymitis that results from infection with Escherichia coli, Haemophilus influenzae, tuberculosis, or Cryptococcus or Brucella species. In men older than 35 years, Enterobacteriaceae (intestinal bacteria) and Pseudomonas aeruginosa associated with urinary tract infections and prostatitis also may cause epididymitis. Epididymitis also may result from a chemical inflammation caused by the reflux of sterile urine into the ejaculatory ducts, which is then called chemical epididymitis.36 It is associated with urethral strictures, congenital posterior valves, and excessive physical straining in which increased abdominal pressure is transmitted to the bladder. Chemical epididymitis is usually self-limiting and does not require evaluation or intervention unless it persists.

FIGURE 34-11

Epididymitis Secondary to Gonorrhea or Nongonococcal Urethritis. This infection spread to the testes, and rupture

through the scrotal wall is threatened. (From Taylor, P.K. [1995]. Diagnostic picture tests in sexually transmitted disease. London: Mosby.)

Pathophysiology The pathogenic microorganism usually reaches the epididymis by ascending the vasa deferentia from an already infected urethra or bladder. The resulting inflammatory response causes symptoms of bacterial epididymitis. Epididymitis caused by heavy lifting or straining results from reflux of urine from the bladder into the vas deferens and epididymis. Urine is extremely irritating to the epididymis and initiates the inflammatory response called chemical epididymitis. Clinical manifestations The main symptom of epididymitis is scrotal or inguinal pain caused by inflammation of the epididymis and surrounding tissues. The pain is usually acute and severe. Flank pain may occur if, as the urethra passes over the spermatic cord, edematous swelling of the cord obstructs the urethra. The individual may have pyuria, bacteriuria, and a history of urinary symptoms, including urethral discharge. The scrotum on the involved side is red and edematous. The tail of the epididymis near the lower pole of the testis usually swells first; then swelling ascends to the head of the epididymis. The spermatic cord also may be swollen and tender. Complications include abscess formation, infarction of the testis, recurrent infection, and infertility. Infarction is probably caused by thrombosis (obstruction by blood clots) of the prostatic vessels secondary to severe inflammation. Recurrent epididymitis may result from inadequate initial treatment or failure to identify or treat predisposing factors. Chronic epididymitis can cause scarring of the epididymal endothelium and infertility. Once scarring has occurred, treatment with antibiotics is ineffective because adequate antibiotic levels cannot be achieved within the epididymis. Evaluation and treatment A history of recent urinary tract infections or urethral discharge suggests the diagnosis of epididymitis. Common physical findings include a swollen, tender epididymis or testis located in the normal anatomical position with an intact same-side cremasteric reflex.37 The relief of pain when the inflamed testis and epididymis are elevated (Prehn sign) is also diagnostic. Definitive diagnosis is based on culture or Gram stain of a urethral swab. Epididymal aspiration may be necessary to obtain a specimen, especially if the individual has been taking antibiotics and has sterile urine. Treatment includes antibiotic therapy for the infection itself. Analgesics, ice, and scrotal elevation can provide symptomatic relief. If the individual does not steadily improve, he should be re-evaluated for possible complications, such as abscess formation, sepsis, or continued infection. Complete resolution of swelling and pain may take several weeks to months. The individual's sexual partner should be treated with antibiotics if the causative microorganism is a sexually transmitted pathogen.

Quick Check 34-3 1. Why is a genetic predisposition suggested for testicular cancer? 2. Why is testicular torsion considered a urological emergency? 3. Why is epididymitis rare in prepubescent males?

Disorders of the Prostate Gland Benign Prostatic Hyperplasia Benign prostatic hyperplasia (BPH), also called benign prostatic hypertrophy, is the enlargement of the prostate gland (Figure 34-12). (Because the major prostatic changes are caused by hyperplasia, not hypertrophy, benign prostatic hyperplasia is the preferred term.) This condition becomes problematic when prostatic tissue compresses the urethra, where it passes through the prostate, resulting in frequency of

LUTS. Similar to prostate cancer, BPH occurs more often in Westernized countries (e.g., Canada, the United States, and the United Kingdom). BPH appears to be more common in Black men than White men, and family history may increase the risk. Being overweight or obese with central fat distribution (i.e., around the abdomen) increases the risk of developing BPH. The global prevalence is approximately 8% for men in their 40s, 50% for men in their 60s, and 80% for men in their 90s.38 BPH is common and involves a complex pathophysiology with several endocrine and local factors and remodelled microenvironment. Its relationship to aging is well documented. At birth, the prostate is pea sized, and growth of the gland is gradual until puberty. At that time, there is a period of rapid development that continues until the third decade of life when the prostate reaches adult size (see Chapter 32). Around 40 to 45 years of age, benign hyperplasia begins and continues slowly until death. Although androgens, such as dihydrotestosterone (DHT), are necessary for normal prostatic development, their role in BPH remains unclear. Among all the androgen-metabolizing enzymes within the prostate, 5α-reductase is the most powerful. This reductase corresponds to an age-dependent DHT level. Therefore, although levels of 5αreductase and DHT in the epithelium decrease with age, they remain constant in the stroma (microenvironment) of the prostate gland.

FIGURE 34-12 Prostate Zones, Benign Prostatic Hyperplasia (BPH), and Prostate Cancer Locations. Benign prostatic hyperplasia (BPH) occurs in the peripheral zone of the prostate gland that can enlarge (not shown). BPH nodules and atrophy are associated with inflammation in the transition zone. Most cancer lesions occur in the peripheral zone. Carcinoma can involve the central zone but rarely occurs in isolation, suggesting that prostatic intraepithelial neoplasia (PIN) lesions do not easily progress to carcinoma in this region. (Adapted from De Marzo, A.M., Platz, E.A., Sutcliffe, S., et al. [2007]. Nat Rev Cancer, 7, 256–269.)

Pathogenesis Current causative theories of BPH focus on aging and levels and ratios of endocrine factors such as androgens and estrogens (androgen/estrogen ratio), the role of chronic inflammation, and the effects of autocrine/paracrine growth-stimulating and growth-inhibiting factors. These factors include insulinlike growth factors (IGFs), epidermal growth factors, fibroblast factors, and transforming growth factor-beta (TGF-β), and several others. Recent data show that human prostate stromal cells can actively contribute to the inflammatory process from the induction of inflammatory cytokines and chemokines39 (see “Cancer of the Prostate,” p. 879).

With aging, circulating androgens are associated with BPH and enlargement. Other effects related to estrogens include apoptosis, aromatase expression, and paracrine regulation that may be important for stimulating inflammation.40 BPH is a multifactorial disease and not all men respond well to currently available treatments, suggesting factors are involved other than androgens. Testosterone, the primary circulating androgen in men, also can be metabolized through aromatase cytochrome P450 (CYP19) into the potent estrogen estradiol-17β. The prostate is an estrogen target tissue, and estrogens directly and indirectly affect growth and differentiation of the prostate. The precise role of endogenous and exogenous estrogens in directly affecting prostate growth and differentiation in the context of BPH is an understudied area. Estrogens and selective estrogen receptor modulators have been shown to promote or inhibit prostate proliferation, signifying potential roles in BPH.41,42 Taken together, these interactions lead to an increase in prostate volume. The remodelled stroma promotes local inflammation with altered cytokine, reactive oxygen or nitrogen species, and chemoattractants.43 The resultant increased oxygen demands of proliferating cells cause a local hypoxia that induces angiogenesis and changes to fibroblasts. BPH begins in the periurethral glands, which are the inner glands or layers of the prostate. The prostate enlarges as nodules form and grow (nodular hyperplasia) and glandular cells enlarge (hypertrophy). The development of BPH occurs over a prolonged period of time, and changes within the urinary tract are slow and insidious. Clinical manifestations As nodular hyperplasia and cellular hypertrophy progress, tissues that surround the prostatic urethra compress it, usually, but not always, causing bladder outflow obstruction. These symptoms are sometimes called the spectrum of LUTS. Symptoms include the urge to urinate often, some delay in starting urination, and decreased force of the urinary stream. As the obstruction progresses, often over several years, the bladder cannot empty all the urine, and the increasing volume leads to long-term urine retention. The volume of urine retained may be great enough to produce uncontrolled “overflow incontinence” with any increase in intra-abdominal pressure. At this stage, the force of the urinary stream is significantly reduced, and much more time is required to initiate and complete voiding.44 Hematuria, bladder or kidney infection, bladder calculi, acute urinary retention hydroureter, hydronephrosis, and renal insufficiency are common complications.44 Progressive bladder distension causes diverticular outpouchings of the bladder wall. The ureters may be obstructed where they pass through the hypertrophied detrusor muscle, potentially causing hydroureter, hydronephrosis, and bladder or kidney infection. Evaluation and treatment Diagnosis is made from a medical history, physical examination, and laboratory tests, including urinalysis. Careful review of symptoms is necessary. Digital rectal examination (DRE) and measurement of PSA level are conducted to determine hyperplasia. PSA level alone, however, cannot confirm symptoms attributable to BPH because PSA level is elevated in both BPH and prostate cancer. Annual DREs are used to screen men older than 40 years for BPH, sooner in high-risk men.45 If marked enlargement, moderate to severe symptoms, or complications are present, transrectal ultrasound (TRUS) is used to determine bladder and prostate volume and residual urine. Urinalysis, serum creatinine and blood urea nitrogen levels, uroflowmetry, postvoid residual (PVR) urine, pressure-flow study, cystometry, and cystourethroscopy are used to determine kidney and bladder function.44 BPH has been treated successfully with medications. α1-Adrenergic blockers (prazosin [Minipress] and tamsulosin [Flomax CR]) are used to relax the smooth muscle of the bladder and prostate. Antiandrogen agents, such as finasteride (Proscar), selectively block androgens at the prostate cellular level and cause the prostate gland to shrink.46 By shrinking the prostate, these medications have been shown to improve BPH-related symptoms and reduce the risk for future urinary retention and BPH-related surgery. α1-Adrenergic blockers do not affect PSA and have no effect on prostate cancer risk; however, antiandrogen agents lower PSA by 50% after 6 months of therapy.47 Newer, minimally invasive treatments include interstitial laser treatment, transurethral radiofrequency procedures (such as transurethral needle ablation [TUNA]), and Cooled ThermoTherapy™.

Prostatitis Prostatitis is an inflammation of the prostate. The incidence and prevalence of prostatitis is not known. Inflammation is usually limited to a few of the gland's excretory ducts. Prostatitis syndromes have been classified by the US National Institutes of Health as (1) acute bacterial prostatitis (ABP), (2) chronic bacterial prostatitis (CBP), (3) chronic pelvic pain syndrome (CPPS), and (4) asymptomatic inflammatory prostatitis (Box 34-4). ABP and CBP are mostly caused by gram-negative Enterobacteriaceae and Enterococci species that originate in the gastro-intestinal flora. The most common organism is E. coli, which is identified in the majority of infections.48 Klebsiella species, P. aeruginosa, and Serratia species are common gram-negative cultured microorganisms. Nonbacterial prostatitis (chronic prostatitis/chronic pelvic pain syndrome [CP/CPPS]) syndromes are caused by a cascade of inflammatory, immunological, neuroendocrine, and neuropathic mechanisms whereby the initiating cause is unknown.

Box 34-4

NIH Classification of Prostatitis Syndrome This system, developed for clinical research purposes, can be simplified for use in primary care practice (see text). Category I, or acute bacterial prostatitis (ABP), is an acute infection of the prostate and is manifested by systemic signs of infection and positive urine culture. Category II, or chronic bacterial prostatitis (CBP), is a chronic bacterial infection in which bacteria are received in significant numbers from a purulent prostatic fluid. These bacteria are thought to be the most common cause of recurrent urinary tract infection in men. Category III, or chronic pelvic pain syndrome (CPPS), is diagnosed when no pathological bacteria can be localized to the prostate (culture of expressed prostatic fluid or postprostatic massage urine specimen) and is further divided into IIIa and IIIb. Category IIIa refers to inflammatory CPPS, where a significant number of white blood cells (WBCs) are localized to the prostate, whereas category IIIb is noninflammatory. Category IV refers to asymptomatic inflammatory prostatitis in which bacteria or WBCs are localized to the prostate, but individuals are asymptomatic.

Bacterial prostatitis. Acute bacterial prostatitis (ABP, category I) is an ascending infection of the urinary tract that tends to occur in men between the ages of 30 and 50 years but is also associated with BPH in older men. Infection stimulates an inflammatory response in which the prostate becomes enlarged, tender, firm, or boggy. The onset of prostatitis may be acute and unrelated to previous illnesses, or it may follow catheterization or cystoscopy. Clinical manifestations of ABP are those of urinary tract infection or pyelonephritis. Sudden onset of malaise, low back and perineal pain, high fever (up to 40°C [104°F]), and chills is common, as are dysuria, inability to empty the bladder, nocturia, and urinary retention. The individual also may have symptoms of lower urinary tract obstruction, such as slow, small, “narrowed” urinary stream, which may be a medical emergency. Acute inflammatory prostatic edema can compress the urethra, causing urinary obstruction. Systemic signs of infection include sudden onset of a high fever, fatigue, arthralgia, and myalgia. Prostatic pain may occur, especially when the individual is in an upright position, because the pelvic floor muscles tighten with standing and compression of the prostate gland occurs. Some individuals experience low back pain, painful ejaculation, and rectal or perineal pain. Palpation discloses an enlarged, extremely tender and swollen prostate that is firm, indurated, and warm to the touch. Because ABP is usually associated with a bladder infection caused by the same microorganism, urine cultures disclose its identity. Prostatic massage may express enough secretions from the urethra for direct bacterial examination, but massage may be painful and increases the risk that the infection will ascend to adjacent structures or enter the bloodstream and cause septicemia.

To resolve the infection and control its spread, individuals may require antibiotics. In severe cases, the individual is hospitalized and treated with intravenous antibiotics, followed by oral antibiotics. Analgesics, antipyretics, bed rest, and adequate hydration are also therapeutic. Complications include urinary retention that resolves with antibiotic therapy; prostatic abscess that may rupture into the urethra, rectum, or perineum; epididymitis; bacteremia; and septic shock. Urinary retention requiring drainage is best managed with a suprapubic catheter; Foley catheterization is contraindicated during acute infection. Chronic bacterial prostatitis (CBP, category II) is characterized by recurrent urinary tract symptoms and persistence of pathogenic bacteria (usually gram negative) in urine or prostatic fluid. This form of prostatitis is the most common recurrent urinary tract infection in men. Symptoms may be similar to those of an acute bladder infection: frequency, urgency, dysuria, perineal discomfort, low back pain, myalgia, arthralgia, and sexual dysfunction. The prostate may be only slightly enlarged or boggy, but it may be fibrotic because repeated infections can cause it to be firm and irregular in shape. When the initial urine sample is bacteria-free, prostatic massage is used to express secretions. Subsequently, the first 10 mL of voided urine is collected and examined microscopically. Prostatic secretions showing more than 10 white blood cells (WBCs) per high-power field (hpf) and macrophages containing fat are indicative of bacterial infection; diagnosis is confirmed by culture. A pelvic X-ray or transurethral ultrasound (TRUS) may show prostatic calculi. Treatment of CBP is difficult because it is often caused by prostatic calculi. Calculi are silent and are found in up to 50% of men with prostatitis, and infected calculi can serve as a source of bacterial persistence and relapsing urinary tract infection. Calculi harbour pathogens within the stone and, consequently, pathogens cannot be eradicated from the urinary tract. Permanent cure is achieved by surgical intervention.49

Chronic prostatitis/chronic pelvic pain syndrome. Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS, category III) is diagnosed when no pathogenic bacteria can be localized to the prostate, and is further subdivided into categories IIIa and IIIb (see Box 34-4). Category IIIa refers to inflammatory CPPS in which WBC count is elevated and localized to the prostate. Compared with category III, symptoms tend to be milder but are persistent and annoying. Presumably, noninfectious prostatitis or pain is caused by reflux of sterile urine into the ejaculatory ducts because of high-pressure voiding.49 Reflux may be triggered by spasms of the external or internal sphincters. Category IIIb is noninflammatory. Category IV exists when individuals are asymptomatic but have an increase in bacteria and WBCs localized to the prostate. Microorganisms suspected of causing CP/CPPS include E. coli, Enterobacter, P. aeruginosa, and, a new suspect, Helicobacter pylori.50 Men with nonbacterial prostatitis may complain of pain or a dull ache that is continuous or spasmodic in the suprapubic, infrapubic, scrotal, penile, or inguinal area. Other symptoms are pain on ejaculation and urinary symptoms, such as frequency of urination. The prostate gland generally feels normal on palpation. Nonbacterial prostatitis is a diagnosis of exclusion. Digital examination of the prostate, bacterial cultures of the urogenital tract, microscopic examination of expressed prostatic fluid, urethroscopy, and urodynamic studies are used to verify the diagnosis of nonbacterial prostatitis. There is no generally accepted treatment for nonbacterial prostatitis. Hot sitz baths, bed rest, and pharmacological therapies, including anti-inflammatory medications, can relieve symptoms.

Cancer of the Prostate Prostate cancer is the most commonly diagnosed, nonskin cancer in men in Canada, with an incidence rate of 99 per 100 000 persons.51 The incidence varies greatly worldwide (Figure 34-13), but it is still considered to be the second most frequently diagnosed cancer in men and the sixth leading cause of death worldwide.52 An estimated 1.1 million cases of prostate cancer were diagnosed worldwide in 2012, accounting for 15% of the cancers diagnosed in men. Almost 70% of diagnosed cases of prostate cancer (759 000) occurred in more developed regions.53 Importantly, incidence rates vary by more than 25-fold worldwide, with the highest rates recorded mostly in developed countries in regions such as Oceania, Europe, and North America, largely because of wide use or overuse of PSA testing. Screening with PSA

can amplify the incidence of prostate cancer by allowing detection of prostate lesions that, although meeting the pathological criteria for malignancy, may have low potential (e.g., latent, indolent, preclinical) for growth and metastasis. In countries with higher use of PSA testing, such as Canada, the United States, Australia, and the Nordic countries, trends in incidence rates follow similar patterns.53

FIGURE 34-13

Selected World Population Age-Standardized (to the World Population) Incidence Rates of Prostate Cancer. (From Jemal, A., Center, M.M., DeSantis, C., et al. [2010]. Cancer Epidemiol Biomarkers Prev, 19[8], 1893–1907.)

Different from Western countries, incidence and death rates are rising in several Asian and Central and Eastern European countries, including Japan. Death rates have been decreasing in several countries, including Australia, Canada, the United Kingdom, the United States, Italy, and Norway, in part because of improved treatment. Males of African descent in the Caribbean region have the highest mortality from prostate cancer in the world.53 Most cases of prostate cancer have a good prognosis even without treatment, but some cases are aggressive; the lifetime risk of dying of prostate cancer is 2.8%. Prostate cancer is rare before age 50 years, and very few men die from this cancer before 60 years of age. Indeed, more than 75% of all prostate cancer is diagnosed in men older than 65.51 With aging, most of the androgen-metabolizing enzymes undergo significant alteration and older age, race (Black), and family history remain the well-established risk factors.

Dietary factors. Although evidence exists for a dietary role in prostate cancer, the epidemiological evidence is inconsistent.54 The problem has been confounded by the lack of biomarkers for certain nutrients, difficulties in measuring and quantifying diet, and a limitation of clinical trials to study diet over time. Important are the effects of diet on signalling pathways, hormones, oxidative stress, and reactive oxygen species (ROS). Obesity seems to be negatively associated with more indolent prostate cancer and positively associated with more aggressive disease and a worse outcome.55 The nutrients in the epidemiology of prostate cancer that have received the most attention include carotenoids, fat, vitamin E, vitamin D, calcium, and selenium (Box 34-5).

Box 34-5

Summary of Diet for Prostate Cancer

• Lower rates of prostate cancer are found in countries whose residents consume a low-fat and highvegetable diet. When men from a low-risk country move to North America and eat a Western diet, their rates of prostate cancer increase significantly. Inconclusive are the exact culprits that increase this risk, including fat and sugar intake. • Obesity is linked to advanced and aggressive prostate cancer. • High body mass index (BMI) is associated with more aggressive disease and a worse outcome. • Calorie-dense or excessive carbohydrate intake and obesity, independent of dietary fat intake, may increase the risk of developing prostate cancer. • Dietary fat may increase levels of androgens, increase oxidative stress, and increase reactive oxygen species (ROS). • Monounsaturated fats may decrease the risk for prostate cancer. • High levels of linoleic acid (found in corn oil) act as a proinflammatory eicosanoid, which is implicated in promotion of cell proliferation and angiogenesis as well as inhibition of apoptosis. • The Western diet has increased omega-6 to omega-3 ratios and therefore is proinflammatory. Carcinogenic nitrosamines are formed after consumption of processed meat that contains nitrites and from heme iron present in large quantities of red meat. • Even given the preceding knowledge, it is important to realize that studies showing an association between meat intake and prostate cancers have been largely inconclusive. Some studies reveal red meat is positively associated with increased prostate cancer risk with an association with more aggressive disease states. Despite some studies showing a 43% elevation in prostate cancer risk with high consumption of red meat, others show no association with prostate cancer risk. • Although the role of red meat in prostate and breast cancer remains inconclusive, one explanation for the possible associations reported is the accumulation of carcinogens during the cooking process. Cooking meat at high temperatures produces heterocyclic amines and aromatic hydrocarbons that are carcinogenic. • Vitamin E has long been considered a candidate for prostate cancer prevention based on in vitro and in vivo animal studies. Vitamin E belongs to the family of tocopherols and tocotrienols that exist as α, β, γ, and δ isoforms. Among these, δ-tocopherol is the major dietary isoform, whereas supplements contain α-tocopherol. Vitamin E is a fat-soluble vitamin obtained from vegetable oils, nuts, and egg yolk. It is a potent intracellular antioxidant known to inhibit peroxidation and DNA damage. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC) showed that supplementation with vitamin E could reduce the incidence of prostate cancer among men who smoked. In vitro studies demonstrate that α-tocopherol succinate induces cell cycle arrest in human prostate cancer cells (i.e., induces apoptosis) and inhibits the androgen receptor (AR). Mouse studies show vitamin E can inhibit the growth-promoting effects of a high-fat diet; however, vitamin E in combination with selenium does not reduce the incidence of prostate cancer in Lady mice models. A prospective large clinical trial, the Selenium and Vitamin E Cancer Prevention Trial (SELECT), showed no reduction in prostate cancer period prevalence but an increased risk for prostate cancer with vitamin E alone. • Selenium is a trace mineral and exists in food as selenomethionine and selenocysteine. It is essential for the functioning of many antioxidant enzymes and proteins in the body. Humans receive selenium in their diet through plant (dependent on soil concentrations) and animal products. SELECT showed that neither selenium nor vitamin E, taken alone or together, helped to prevent prostate cancer. • Vitamin D may play an important role in prostate cancer prevention. • Soy anticancer properties include inhibition of cell proliferation and angiogenesis and reduction in prostate-specific antigen (PSA) and AR levels. Countries whose residents have a high intake of soy have much lower rates of prostate cancer. • Tomatoes or tomato products ingested daily seem to reduce prostate cancer risk. In vitro studies show lycopene found in tomatoes inhibits DNA strand breaks. Unresolved is whether lycopene itself or a metabolic product is responsible for its biological effect. In clinical studies tomato paste, which is

high in lycopene, reduced plasma PSA levels in those men with benign prostatic hyperplasia. Lycopene administration is associated with cell cycle arrest (apoptosis) and growth factor signalling. In 2007 the US Food and Drug Administration evaluated 13 available studies and found the relationship between lycopene and reduced risk for prostate cancer inadequate. • Vegetables including broccoli, cabbage, cauliflower, Brussels sprouts, Chinese cabbage, and turnips (all crucifers) may be protective (several epidemiological studies) against prostate cancer. In particular, a diet high in broccoli reduced cancer risk. By contrast, four studies revealed no cancerpreventive effects. Cruciforms have anticancer properties mediated by the phytochemicals phenethyl isothiocyanate, sulforaphane, and indole-3-carbinol. Sulforaphane is a naturally occurring isothiocyanate that was first isolated in broccoli. It protects against carcinogen-induced cancer in many rodents. Mice given 240 mg of broccoli sprouts per day showed a significant reduction in growth of prostate cancer cells. Sulforaphane treatment lowered AR protein and gene expression. • Green tea contains polyphenols, including epigallocatechin gallate (EGCG). Green tea consumption has been associated with a reduced incidence of several cancers, including prostate cancer. Green tea consumed within a balanced controlled diet in humans improved overall antioxidant potential. The potential anticancer effect of green tea from in vitro and experimental studies shows these compounds bind directly to carcinogens and induce phase II enzymes that inhibit heterocyclic amines. EGCG administration decreased NF-κβ activity. Green tea was shown to inhibit insulinlike growth factor 1 (IGF-1) and increase IGF-binding protein 3 (IGFBP3), leading to inhibition of prostate cancer development and progression. Yet, in two small randomized studies in individuals with highgrade prostatic neoplasia, it showed no effects. However, treatment with a mixture of bioactive compounds that share molecular anticarcinogenic targets may enhance the effect on these targets at low concentrations of individual compounds. • Epidemiological studies have consistently shown that regular consumption of fruits and vegetables is strongly associated with reduced risk of developing chronic diseases, such as cancer. It is now accepted that the actions of any specific phytonutrient alone do not explain the observed health benefits of diets rich in fruits and vegetables; also, clinical trials demonstrated that consumption of phytonutrients did not show consistent preventive effects. Synergistic inhibition of prostate cancer cell growth has been evident when using combinations of low concentrations of various carotenoids or carotenoids with retinoic acid and the active metabolite of vitamin D. Combinations of several carotenoids (e.g., lycopene, phytoene, and phytofluene) or carotenoids and polyphenols (e.g., carnosic acid and curcumin) and/or other compounds (e.g., vitamin E) synergistically inhibit the androgen receptor activity and activate the electrophile/antioxidant response element (EpRE/ARE) transcription system. The activation of EpRE/ARE is up to fourfold higher than the sum of activities of single ingredients. • Examples of important potential processes that can be targeted in the regulation of tumourigenesis include cholesterol synthesis and metabolites, ROS and hypoxia, macrophage activation and conversion, indoleamine 2,3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, and endoglin and Janus kinase signalling. • Curcumin has anticarcinogenic potential with well-characterized anti-inflammatory, antiangiogenic, and antioxidant properties. Recent studies report curcumin modulates the Wingless signalling pathway (Wnt) that supports its antiproliferative potential. Curcumin is characteristic of regulating multiple targets, a desirable feature in current medication design and medication development. Together with its potential in treating castration-resistant prostate cancer and its safety profile, this feature enables curcumin to serve as an ideal compound for the design and syntheses of agents with improved potential for enhancing clinical therapies used to treat prostate cancer. • Overall, multiple signalling pathways are involved in prostate cancer development and progression, many of which are affected by dietary and lifestyle factors.

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Hormones. Prostate cancer develops in an androgen-dependent epithelium and is usually androgen sensitive. Androgens are synthesized not only in the testis, accounting for 50 to 60% of the total testosterone in the prostate, but also in the prostate gland itself. In a process called intraprostatic conversion, the hormone dehydroepiandrosterone (DHEA) produced by the adrenal glands56 is converted to testosterone and then into DHT in the prostate (Figure 34-14). Additionally, prostate cancer cells have been reported to make androgens from cholesterol (i.e., de novo).57 However, these overall relative contributions from intratumoural sources remain to be determined. Population studies have not, however, provided clear and convincing patterns involving associations between circulating (e.g., not tissue concentrations) hormone concentrations and prostate cancer risk.58 Thus, there is universal agreement that androgens are important for prostatic growth, development, and maintenance of tissue balance; however, their role in cancer is controversial. Evidence in support of the involvement of androgens in prostate cancer development is derived from clinical trials with 5α-reductase inhibitors. However, the involvement of 5αreductase, which is critical in androgen activity in the prostate, is contradictory and inconsistent58,59 (see Figure 34-14). A prevention study has provided some of the strongest hormonal data with the medication finasteride (Apo-Finasteride), which inhibits 5α-reductase. The 7-year intervention study reduced prostate cancer risk in healthy men by about 25%.60 Important, however, was that more high-grade tumours were found in those men who developed prostate cancer while on the medication. In men younger than 50 years, circulating levels of androgens and estrogens appear to be higher in men of African descent than in North American men of European descent.

FIGURE 34-14 Sources of Androgens and Aromatase and Estrogen Signalling in the Prostate. A, Body sources of androgens in the prostate gland. Hypothalamic GnRH causes the release of LH from the anterior pituitary gland. LH stimulates the testes to produce testosterone, which then accumulates in the blood. Pituitary ACTH release stimulates the adrenal glands, which secrete the androgen precursor DHEA into the blood. DHEA is converted into testosterone and then into DHT in the prostate. B, Aromatase and estrogen signalling in the prostate. In normal and benign tissue, aromatase is expressed within the stroma and regulated by promoter PII. Estrogen then exerts its effects in an autocrine fashion through the stromal ERα receptor and also in a paracrine fashion through both ERα and ERβ receptors. With prostate cancer, aromatase is now expressed within the tumour cells and in stromal cells, and regulated by aromatase promoters 1.3, 1.4, and PII. Thus estrogen exerts its effects in an autocrine way through stromal and epithelial ERα and ERβ. Consequently, the increased levels of estrogen and abnormal ERα signalling promote inflammation, which increases aromatase expression and the development of a positive feedback cycle. Inflammation drives aromatase expression, thus increasing estrogen, which in turn promotes further inflammation. ACTH, Adrenocorticotropic hormone; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; ERα, estrogen receptor alpha; ERβ, estrogen receptor beta; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone. (A, adapted from Labrie, F. [2011]. Nat Rev Urol, 8, 73–80; B, from Ellem, S.J., & Risbridger, G.P. [2010]. J Steroid Biochem Mol Biol, 118[4–5], 246–251.)

Despite the well-documented importance of androgens, their pathophysiological process in prostate diseases is incomplete.61 Androgens also are metabolized to estrogens (Figure 34-14, B) through the action of the enzyme aromatase, and a growing body of evidence implicates estrogens in the etiology of prostate disease (see the following “Pathogenesis” section).

Vasectomy. Vasectomy has been identified as a possible risk factor for prostate cancer in both case-controlled studies and cohort studies.62,63 Three mechanisms by which vasectomy could increase risk are (1) elevation of circulating androgens; (2) activation of immunological mechanisms involving antisperm antibodies; and (3) reduction of seminal fluid levels of 5α-DHT, the active metabolite of testosterone in the prostate, in vasectomized men. These results suggest an elevation of circulating free testosterone level following vasectomy. However, with these combined mechanisms, it is unlikely that vasectomy plays a causal role.64

Chronic inflammation. A 5-year longitudinal study of the influence of chronic inflammation and prostate cancer was undertaken with 144 men, 33 of whom presented with chronic inflammation in their initial biopsy.65 Biopsies revealed prostatic hyperplasia and proliferative inflammatory atrophy (PIA) in those with chronic inflammation. Upon repeat biopsy, 29 new cancers were diagnosed, representing a new cancer incidence of 20%.65 In contrast, of the 33 men initially showing no inflammation, 2 (6%) were found to have adenocarcinoma. Certain metabolic comorbidities, including obesity, diabetes, sleep apnea, and erectile dysfunction, may be linked to both BPH and inflammation.66 The causes of chronic inflammation are emerging (possible causes are shown in Figure 34-15). Thus, chronic inflammation may be an important risk factor for prostatic adenocarcinoma.67 Chronic inflammation involves autocrine/paracrine growth-stimulating and

growth-inhibiting factors. These factors include IGFs, epidermal growth factors, fibroblast factors, and TGF-β, as well as several others. Recent data show that human prostate stromal cells can actively contribute to the inflammatory process from the induction of inflammatory cytokines and chemokines.39,68 Importantly, a continuous input from TGF-β and IGF in the tumour microenvironment or stroma will result in cancer progression. Understanding of these events can help prevention, diagnosis, and therapy of prostate cancer68 (Figure 34-16).

FIGURE 34-15 Possible Causes of Prostate Inflammation. A, Infection, including viruses, bacteria, fungi, and parasites. B, Hormones, for example, estrogen at key times during development. C, Physical trauma, any type of blunt physical injury. D, Urine reflex. E, Certain dietary factors (see text).

FIGURE 34-16 Working Model Stromal–Epithelial Interaction in Prostate Cancer Development and Progression. Normally, signalling events between transforming growth factor-beta (TGF-β) and insulinlike growth factor (IGF) are tightly regulated, keeping the epithelial cells under homeostatic balance. TGF-β binds to receptors on the cell surface known as receptor type I (TBR-I) and type II (TBR-II). A reduction in TBRs in the stromal cells will result in an increase in IGF production. The increase in IGF has a proliferative effect on the prostate epithelial cells (which have already undergone a cancer initiation process as a result of the hormones testosterone and estradiol). TGF-β and IGF in the stromal cells adjacent to prostate epithelial cells will perpetuate a vicious cycle to promote cancer progression. (Adapted from Lee, C., Jia, Z., Rahmatpanah, F., et al. [2014]. Biomed Res Int, 2014, 502093.)

Genetic and epigenetic factors. Other possible causes are those of genetic predisposition (familial and hereditary forms). Genetic studies suggest that strong familial predisposition may be responsible for 5 to 10% of prostate cancers.1 Compared with men with no family history, those with one first-degree relative with prostate cancer have twice the risk, and those with two first-degree relatives have five times the risk.69 Germline mutations in the breast cancer predisposition gene 2 (BRCA2) are the genetic events known to date that confer the highest risk for prostate cancer (8.6-fold in men 65 years of age and younger). Although the role of BRCA2 and BRCA1 in prostate tumourigenesis remains unrevealed, deleterious mutations in both genes have been associated with more aggressive disease and poor clinical outcomes.70,71 Men with BRCA2 (tumour suppressor) germline mutations have a 20-fold increase in risk for prostate cancer. Using previously estimated population carrier frequencies, investigators have recently found that deleterious BRCA1 mutations confer a relative risk for prostate cancer of approximately 3.75-fold, translating to 8.6% cumulative risk by age 65.72 A common type of somatic mutation that develops into chromosomal rearrangements is the ETS gene. The most common epigenetic alteration in prostate cancer is hypermethylation of the glutathione-S-transferase (GSTP1) gene located on chromosome 11. More than 30 independent, peer-reviewed studies have reported a consistently high sensitivity and specificity of GSTP1 hypermethylation in prostatectomy or biopsy tissue.73 There is no clear evidence of a causal link between BPH and prostate cancer, even though they may often occur together. Variations in several other genes related to inflammatory pathways might affect the probability of developing prostate cancer. Pathogenesis More than 95% of prostatic neoplasms are adenocarcinomas,74 and most occur in the periphery of the prostate (see Figures 34-12 and 34-17). Prostatic adenocarcinoma is a heterogeneous group of tumours with a diverse spectrum of molecular and pathological characteristics and, therefore, diverse clinical behaviours and challenges.75 The biological aggressiveness of the neoplasm appears to be related to the degree of differentiation rather than the size of the tumour (Box 34-6). Several genetic alterations have been found for prostate carcinoma, including acquired genomic structural changes, somatic mutations, and epigenetic alterations.76

FIGURE 34-17

Photomicrograph of Prostate Cancer Cells. Pink ruffled cells are prostate cancer cells. (Dr. Gopal Murti/Science Source.)

Box 34-6

Determining the Grade of Prostate Cancer With the Gleason Score Grade 1. The cancer cells closely resemble normal cells. They are small, uniform in shape, evenly spaced, and well differentiated (i.e., they remain separate from one another). Grade 2. The cancer cells are still well differentiated, but they are arranged more loosely and are irregular in shape and size. Some of the cancer cells have invaded the neighbouring prostate tissue. Grade 3. This grade is the most common. The cells are less well differentiated (some have fused into clumps) and are more variable in shape. Grade 4. The cells are poorly differentiated and highly irregular in shape. Invasion of the neighbouring prostate tissue has progressed further. Grade 5. The cells are undifferentiated. They have merged into large masses that no longer resemble normal prostate cells. Invasion of the surrounding tissue is extensive.

Hormonal factors. Just as the testicles are the male equivalent of the female ovaries, the prostate is the male equivalent of the female uterus; in both situations, they originate from the same embryonic cells. This correspondence may be important in understanding the role of the associated hormones testosterone, DHT, and estrogens in prostate cancer development. Testicular testosterone synthesis and serum testosterone levels fall as men age, but the levels of estradiol do not decline, remaining unchanged or increasing with age.77,78 The relationship between hormones and the pathophysiology of prostate carcinogenesis is incomplete and controversial.79 The main issues and controversies include (1) sources of androgen production outside of the testes, or extratesticular sources (e.g., from adrenal DHEA and from prostate tissue cholesterol [de novo] itself); (2) the role of prostatic androgen receptor (AR); (3) the role of estrogens, aromatase enzyme, and the estrogen receptors (ERα and ERβ); and (4) the role of the surrounding microenvironment or stroma. Prostate cancer is considered a hormone-dependent disease; cell growth and survival of early-stage prostate cancer can respond to androgens, which is the background evidence for androgen-deprivation therapy (ADT). However, evidence thus far is lacking to associate plasma androgens with prostate cancer progression. Prostatic tissue has the ability to produce its own steroids, including androgens and estrogens.80 Therefore, the local tissue levels of sex steroids have become a major focus of intraprostatic hormonal profiles. Prostate tissue contains many metabolizing enzymes for the local production of active androgens and estrogens. Carcinogenesis can alter these intraprostatic enzymes and alter the normal balance.

The androgenic hormone responses in the normal prostate and prostate cancer are mediated by androgen receptor (AR) signalling.81 Exactly how AR drives the growth of prostate cancer cells is not fully known. Several mechanisms have been suggested,81 and specific pathways of signalling are important because they can provide novel therapeutic targets. A recent study using animal models found that loss of AR function prevented prostatic carcinogenesis, malignant transformation, and metastasis. Tissue-specific evaluation of androgen hormone action demonstrated that epithelial AR was not necessary for prostate cancer progression, whereas the stromal AR was essential for prostate cancer progression, malignant transformation, and metastasis.82 Testicular testosterone provides the main source of androgens in the prostate (see Figure 34-14) and is the major circulating androgen, whereas DHT predominates in prostate tissue and binds to the AR with greater affinity than does testosterone.83 The adrenal cortex contributes the far less potent DHEA, which promotes synthesis of androgens in the prostate. In the target tissues and, to a lesser extent, in the testes themselves, testosterone is converted to DHT by the enzyme 5α-reductase (Figure 34-18). Thus, DHT is the most potent intraprostatic androgen.

FIGURE 34-18

Testosterone and Conversion to Dihydrotestosterone.

Normally, a small amount of estrogen is produced daily—estrone and estradiol—by the aromatization of androstenedione and testosterone, respectively. This reaction is catalyzed by the enzyme aromatase. A small quantity of estradiol is released by the testes (see Figure 34-18); the rest of the estrogens in males are produced by adipose tissue, liver, skin, brain, and other nonendocrine tissue. Thus, testosterone is a precursor of two hormones—DHT and estradiol. Recent studies show that aromatase is expressed in stromal tissue in the benign human prostate gland.78 Thus, it appears that both normal prostate and benign prostate have the capacity to locally metabolize androgens to estrogens through aromatase. This finding leads to the following question: How does aromatase gene expression contribute to the etiology and progression of prostate cancer? Investigators have demonstrated altered aromatase expression in prostate cancer78,84,85 (Figure 34-14, B). Accumulating evidence shows that estrogens participate in the pathogenesis and development of BPH and prostate cancer by activating estrogen receptor alpha (ERα). In contrast, estrogen receptor beta (ERβ) is involved in the differentiation and maturation of prostatic epithelial cells, and thus possesses antitumour effects in prostate cancer.86 The effect of estrogen is determined by the two receptors ERα and ERβ. ERα leads to abnormal proliferation, inflammation, and the development of premalignant lesions.78 In contrast, ERβ leads to antiproliferative, anti-inflammatory, and potentially anticarcinogenic effects that act in concert or balance the actions of ERα and androgens.78 Increased expression of ERα has been found to be associated with prostate cancer progression, metastasis, and the so-called castration-resistant (medical treatment that suppresses androgens) phenotype.87 A specific oncogene is regulated by ERs, and those hormones that stimulate the ERα receptorlike (i.e., agonists) endogenous estrogens can stimulate oncogene expression.88 Most of the androgen-metabolizing enzymes undergo a significant age-dependent alteration. In epithelium, both the blood levels of 5α-reductase activity and the DHT level decrease with age, whereas in stroma (prostate), not only the 5α-reductase activity but also the stromal DHT level is rather constant over the lifetime. In contrast to the relatively unaltered DHT level over time, the estrogen concentration follows an age-dependent increase. Thus, the age-dependent decrease of the DHT accumulation in epithelium and the concomitant increase of the estrogen accumulation in stroma lead to a tremendous increase with age of the estrogen/androgen ratio in the human prostate. In animal studies, chronic exposure to testosterone plus estradiol is strongly carcinogenic, whereas testosterone alone is weakly carcinogenic.59 In mice studies, elevated testosterone level in the absence of estrogen leads to the

development of hypertrophy and hyperplasia but not malignancy.78 High estrogen and low testosterone levels have been shown to lead to inflammation with aging and the emergence of precancerous lesions.78 The mechanism is not clearly understood and may involve estrogen-generated oxidative stress and DNA toxicity, and it requires androgen-mediated and estrogen receptor–mediated processes, such as changes in sex steroid metabolism and receptor status. In addition, there are changes in the balance between autocrine/paracrine growth-stimulatory and growth-inhibitory factors, such as the IGFs.59 Investigators have summarized the following key findings on hormones and prostate cancer: (1) androgens are clearly involved in the progression of prostate cancer; (2) it is only with the addition of estrogen to testosterone in rats that cancer can be reliably induced; (3) in vivo and in vitro studies have identified multiple mechanisms involving hormonal involvement with genotoxicity, epigenetic toxicity, hyperprolactinemia, chronic inflammation, and estrogen receptor–mediated changes.79

Prostate epithelial neoplasia. A precursor lesion, prostatic intraepithelial neoplasia (PIN), has been described. PIN may be more concentrated in prostates containing cancer and is noted in proximity to cancer.89 However, the final fate of PIN is unknown, including the possibilities of latency, invasion, and even regression. The current working model of prostate carcinogenesis suggests that repeated cycles of injury and cell death occur to the prostate epithelium as a result of damage (i.e., from oxidative stress) from inflammatory responses.90 The direct injury is hypothesized as a response to infections; autoimmune disease; circulating carcinogens or toxins, or both, from the diet; or urine that has refluxed into the prostate (see Figure 34-15). The resultant manifestation of this injury is focal atrophy or PIA. Biological responses cause an increase in proliferation and a massive increase in epithelial cells that possess a phenotype intermediate between basal cells and mature luminal cells90 (Figure 34-19). In a small subset of cells, some may contain “stem cell” or tumour-initiating properties and telomere shortening (see Chapter 10). A subset of PIN cells may activate telomerase enzyme, causing the cells to become immortal.91 Molecular genetic and epigenetic changes can increase genetic instability that might progress to high-grade PIN and early prostate cancer formation. This model of prostate carcinogenesis needs much more research.

FIGURE 34-19 Cellular and Molecular Model of Early Prostate Neoplasia Progression. A, This stage includes infiltration of lymphocytes, macrophages, and neutrophils caused by repeated infections, dietary factors, urine reflux, injury, onset of autoimmunity (which triggers inflammation), and wound healing. B, Epigenetic alterations mediate telomere shortening. C, Genetic instability and accumulation of genetic alterations. D, Continued proliferation of genetically unstable cells leading to cancer progression. PIN, Prostatic intraepithelial neoplasia.

Stromal environment. The prostate gland is composed of secretory luminal epithelium, basal epithelium, neuroendocrine cells, and various cell types comprising supportive tissue or stroma. Stroma, or tissue microenvironment, produces autocrine/paracrine factors as well as structural supporting molecules that help regulate normal cell behaviour and organ homeostasis.92 Stromal components in the tumour microenvironment are important contributions to tumour progression and metastasis.93 Reciprocal interactions between tumour cells and stromal components influence the metastatic, dormancy-related, and stem cell–like potential of tumour cells.94 The stromal compartment of the tumour is complex and includes inflammatory/immune cells, vascular endothelial cells, pericytes, fibroblasts, adipocytes, and components of the extracellular

matrix.93,95 Tumour-infiltrating inflammatory cells release a host of growth factors, chemokines, cytokines, and proinvasive matrix-degrading enzymes to promote tumour growth and progression.93 Angiogenesis occurs in response to factors secreted from tumour cells, resulting in continued growth and progression. Adipocytes in the tumour microenvironment produce adipokines, which are important for tumour growth.93 Fibroblasts in the tumour microenvironment provide the structural framework of the stroma; they remain quiet or dormant, but proliferate during wound healing, inflammation, and cancer.93 Tumour cells release paracrine factors that activate fibroblasts to become “cancer-associated fibroblasts” (CAFs). CAFs secrete factors that modulate tumour growth and modify the stroma to enhance metastasis and dampen responses to anticancer therapies.93 These findings suggest that alteration in the prostate microenvironment with therapeutic agents and approaches—in particular, natural products such as berberine, resveratrol, onionin A, epigallocatechin gallate, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone—warrants further investigation to target the tumour microenvironment for the treatment and prevention of cancer.95 Epithelial–mesenchymal transition (EMT) was first described in embryonic development, and it is observed in a number of solid tumours96 (see Chapter 10). Cells that undergo EMT become more migratory and invasive and gain access to vascular vessels.97 Numerous studies have shown that these transition states (EMT and mesenchymal–epithelial transition [MET]) are a consequence of tumour– stromal interactions.97,98 Investigators studying prostate cancer cells in vitro correlated EMT with increased growth, migration, and invasion.99 These investigators demonstrated that the microenvironment is a critical site for the transition of human prostate cancer cells from epithelial to mesenchymal structure, resulting in increased metastatic potential for bone and adrenal gland.99 Prostate cancer is known to be diverse and composed of multiple genetically distinct cancer cell clones. Recent studies, however, indicate that most metastatic cancers arise from a single precursor cancer cell.100 From all of these observations, the following multifactorial general hypothesis of prostate carcinogenesis emerges: (1) androgens act as strong tumour promoters through AR-mediated mechanisms to enhance the carcinogenic activity of strong endogenous DNA toxic carcinogens, including reactive estrogen metabolites and estrogen, and prostate-generated ROS; (2) reciprocal interactions between tumour cells and the stromal microenvironment promote prostate cancer pathogenesis; and (3) possibly unknown environmental–lifestyle carcinogens may contribute to prostate cancer. All of these factors are modulated by diet and genetic determinants, such as hereditary susceptibility genes and polymorphic genes, which encode receptors and enzymes involved in the metabolism and action of steroid hormones.59 The most common sites of distant metastasis are the lymph nodes, bones, lungs, liver, and adrenals. The pelvis, lumbar spine, femur, thoracic spine, and ribs are the most common sites of bone metastasis. Local extension is usually posterior, although late in the disease the tumour may invade the rectum or encroach on the prostatic urethra and cause bladder outlet obstruction (Figure 34-20). The spread of cancer through blood vessels is illustrated in Figure 34-21.

FIGURE 34-20

FIGURE 34-21

Carcinoma of Prostate. A, Schematic of carcinoma of the prostate. B, Carcinoma of the prostate extending into the rectum and urinary bladder. (B from Damjanov, I., & Linder, J. [Eds]. [2000]. Pathology: A color atlas. St. Louis: Mosby.)

Distribution of Hematogenous Metastases in Prostate Cancer. Based on an autopsy study of 1 589 patients with metastatic prostate cancer. (Adapted from Budendorf, L., Schöpfer, A., Wagner, U., et al. [2000]. Hum Pathol, 31(5), 578–583.)

Clinical manifestations Prostatic cancer often causes no symptoms until it is far advanced. The first manifestations of disease are

those of bladder outlet obstruction: slow urinary stream, hesitancy, incomplete emptying, frequency, nocturia, and dysuria. Unlike the symptoms of obstruction caused by BPH, the symptoms of obstruction caused by prostatic cancer are progressive and do not remit. Local extension of prostatic cancer can obstruct the upper urinary tract ureters as well. Rectal obstruction also may occur, causing the individual to experience large bowel obstruction or difficulty in defecation. Symptoms of late disease include bone pain at sites of bone metastasis, edema of the lower extremities, enlargement of lymph nodes, liver enlargement, pathological bone fractures, and mental confusion associated with brain metastases. Prostatic cancer and its treatment can affect sexual functioning. Evaluation and treatment Screening for prostatic cancer includes digital rectal examination (DRE) and PSA blood tests. There is lack of evidence, however, whether screening with PSA or DRE reduces mortality from prostate cancer.101 It is unclear whether detection of prostate cancer at an early stage leads to any change in the natural history or outcome.101 Observational studies in some countries show a trend toward lower mortality, but the relationship between the intensity and trends of screening is not clear and the associations with screening are inconsistent.101 The observed trends may be a result of screening or improved treatment. Two randomized trials show no effect on mortality through 7 years and are inconsistent beyond 7 to 10 years.102 Strong evidence shows implementation of PSA or DRE detects some prostate cancers that would never have caused significant clinical problems.101 These screening tests lead to some degree of overtreatment. The screening tests can harm patients; for example, they may lead to radical prostatectomy and radiation therapy that result in irreversible side effects in many men.101 The most common side effects are ED and urinary incontinence. The screening process can cause considerable anxiety, especially in men who have a prostate biopsy but no identified prostate cancer. Screening can lead to biopsies, which are associated with complications, including fever, pain, hematuria, hematospermia, positive urine cultures for bacteria, and, rarely, sepsis. About 20 to 70% of men who had no problems before radical prostatectomy or external-beam radiation therapy will have reduced sexual function or urinary problems, or both. Prostate cancer usually grows very slowly and is predominantly a tumour of older men, with the median age at diagnosis of 72 years.101 Until recently, many physicians and organizations encouraged yearly PSA screening for men beginning at age 50; however, with more understanding about the benefits and detriments, a number of organizations have cautioned men against routine population screening (Figure 34-22). Some organizations continue to recommend PSA screening. Some tumours found through PSA screening do not cause symptoms, grow slowly, and are unlikely to threaten a man's life. The PSA screening test often suggests that prostate cancer may be present when there is no cancer. This is called a “false positive” result. False-positive results lead to unnecessary follow-up tests. Detecting these benign tumours is called overdiagnosis.

FIGURE 34-22 Benefits and Harms of PSA Screening for Prostate Cancer. The US Preventive Services Task Force (PSTF) recommends against PSA-based screenings for prostate cancer (grade D recommendation). PSA, Prostate-specific antigen. (Adapted from USPSTF Recommendation Statement, Annals of Internal Medicine, 2012.)

Across age ranges, Black men and men with a family history of prostate cancer have an increased risk of developing and dying of prostate cancer. Black men are approximately twice as likely to die of prostate cancer compared with men of other races in North America, and the reason for this disparity is unknown. Black men represent a very small minority of participants in randomized clinical trials of screening, and thus no firm conclusions can be made about the balance of benefits and harms of PSA-based screening in this population. As such, it is questionable practice to selectively recommend PSA-based screening for Black men in the absence of data that support a more favourable balance of risks and benefits.103 Because of this “overtreatment” phenomenon, active surveillance with delayed intervention is gaining traction as a viable management approach in contemporary practice. Treatment of prostatic cancer depends on the stage of the neoplasm, the anticipated effects of treatment, and the age, general health, and life expectancy of the individual. Options include no treatment; surgical treatments, such as total prostatectomy, transurethral resection of the prostate (TURP), or cryotherapy; nonsurgical treatments, such as radiation therapy, hormone therapy, or chemotherapy; watchful waiting; and any combination of these treatment modalities.103 In addition, new approaches are using immunotherapy. Palliative treatment is aimed at relieving urinary, bladder outlet, or colon obstruction; spinal cord compression; and pain. Box 34-7 shows staging for prostate cancer. Prognosis and survival rates have improved steadily over the past 50 years. Over the past 25 years, the 5-year relative survival rate for all stages combined has increased from 68% to almost 100%. According to the most recent data, 10- and 15-year relative survival rates are 98% and 94%, respectively.1

Box 34-7

Staging for Prostate Cancer Stage I

In stage I, cancer is found in the prostate only. In this stage, cancer: • Is found by performing a needle biopsy (done for a high prostate-specific antigen [PSA] level) or by examining a small amount of tissue during surgery for other reasons (such as benign prostatic hyperplasia). The PSA level is lower than 10, and the Gleason score is 6 or lower; or • Is found on half or less of one lobe of the prostate. The PSA level is lower than 10, and the Gleason scores is 6 or lower; or • Cannot be felt during a digital rectal examination and cannot be seen in imaging tests. Cancer is found in half or less of one lobe of the prostate. The PSA level and the Gleason score are not known.

Stage II In stage II, cancer is more advanced than in stage I, but has not spread outside the prostate. Stage II is divided into stages IIA and IIB.

Stage IIA In stage IIA, cancer: • Is found by performing a needle biopsy (done for a high PSA level) or by examining a small amount of tissue during surgery for other reasons (such as benign prostatic hyperplasia). The PSA level is lower than 20, and the Gleason score is 7; or • Is found by performing a needle biopsy (done for a high PSA level) or by examining a small amount of tissue during surgery for other reasons (such as benign prostatic hyperplasia). The PSA level is at least 10 but lower than 20, and the Gleason score is 6 or lower; or • Is found in half or less of one lobe of the prostate. The PSA level is at least 10 but lower than 20, and the Gleason score is 6 or lower; or • Is found in half or less of one lobe of the prostate. The PSA level is lower than 20, and the Gleason score is 7; or • Is found in more than half of one lobe of the prostate.

Stage IIB

In stage IIB, cancer: • Is found on opposite sides of the prostate. The PSA can be any level, and the Gleason score can range from 2 to 10; or • Cannot be felt during a digital rectal examination (DRE) and cannot be seen in imaging tests. The PSA level is 20 or higher, and the Gleason score can range from 2 to 10; or • Cannot be felt during a DRE and cannot be seen in imaging tests. The PSA can be any level, and the Gleason score is 8 or higher.

Stage III In stage III, cancer has spread beyond the outer layer of the prostate and may have spread to the seminal vesicles. The PSA can be any level, and the Gleason score can range from 2 to 10.

Stage IV In stage IV, the PSA can be any level, and the Gleason score can range from 2 to 10. Also, in this stage, cancer: • Has spread beyond the seminal vesicles to nearby tissue or organs, such as the rectum, bladder, or pelvic wall; or • May have spread to the seminal vesicles or to nearby tissue or organs, such as the rectum, bladder, or pelvic wall. Cancer has spread to nearby lymph nodes; or • Has spread to distant parts of the body, which may include lymph nodes or bones. Prostate cancer often spreads to the bones.

Data from National Cancer Institute. (2016). Prostate cancer treatment (PDQ®)—Patient version. Retrieved from https://www.cancer.gov/types/prostate/patient/prostate-treatment-pdq. Figures © 2010 Terese Winslow; U.S. Government has certain rights.

Stress incontinence can occur after surgery and mild urge incontinence can occur after radiation therapy. Prostate cancer and its treatment can affect sexual functioning. Sensation of orgasm is not usually affected, but smaller amounts of ejaculate will be produced or men may experience a “dry” ejaculate because of retrograde ejaculation.

Sexual Dysfunction In males, the normal sexual response involves erection, emission, and ejaculation. Sexual dysfunction is the impairment of any or all of these processes and can be caused by various physiological, psychological, and emotional factors.

Until the late 1970s, most cases of male sexual dysfunction were considered psychogenic. Now there is evidence that 89 to 90% of cases involve organic factors and include (1) vascular, endocrine, and neurological disorders; (2) chronic disease, including kidney failure and diabetes mellitus; (3) penile diseases and penile trauma; and (4) iatrogenic factors, such as surgery and pharmacological therapies. Most of these disorders cause erectile dysfunction.104 Pathophysiology Sexual dysfunction can have a specific physiological cause, can be associated with many chronic diseases and their treatment, or may be related to low energy levels, stress, or depression. For example, vascular disease may cause erectile dysfunction, and endocrine disorders or conditions that cause decreased testosterone levels or testicular atrophy can diminish sexual functioning or libido. In addition, neurological disorders and spinal cord injuries can interfere with sympathetic, parasympathetic, and central nervous system mechanisms required for erection, emission, and ejaculation. Medication-induced sexual dysfunction consists of decreased desire, decreased erectile ability, or decreased ejaculatory ability. Alcohol and other central nervous system depressants, antihypertensives, antidepressants, antihistamines, and hormonal preparations are commonly used medications that affect sexual functioning. Other pharmacological agents may diminish the quality or quantity of sperm or cause priapism. Clinical manifestations and treatment Evaluation of sexual dysfunction includes a thorough history and physical examination. Particular attention is given to medication history and examination of the genitalia, prostate, and nervous system. Basic laboratory tests are used to identify the presence of endocrinopathies or other underlying disorders that can cause dysfunction. Psychological evaluation is indicated for younger men with a sudden onset of sexual dysfunction or for men of any age who can achieve but not maintain an erection. If no physiological cause is found and the condition does not improve with psychotherapy, the man is referred for further investigation of organic causes. Treatments for organic sexual dysfunction include both medical and surgical approaches. The advent of phosphodiesterase type 5 inhibitors (PDE5i) has revolutionized the erectile dysfunction treatment landscape and provided effective, minimally invasive therapies to restore male sexual function. The original PDE5i, sildenafil (Viagra), has created much enthusiasm over its ability to help a man maintain an erection. For a small percentage of men (1%), however, this improvement in sexual function is accompanied by heart attacks and death. Whether these effects are the result of sexual performance or sildenafil has been controversial. Research has shown that sildenafil increases blood concentrations of the enzyme cyclic guanosine monophosphate (cGMP)–dependent protein kinase G (PKG), which increases blood flow to the penis. PKG, however, plays a dual role: first, it increases platelet aggregation; and then, minutes later, it decreases clot size. The initial clot could cause some men with heart disease to experience cardiac arrest. Currently available PDE5i medications in Canada include sildenafil, vardenafil (Levitra), tadalafil (Cialis), and avanafil (Stendra), each of which has unique side effect profiles. For instance, sildenafil is associated with (in addition to the previously mentioned cardiac issues) an increased rate of visual changes, vardenafil with QT prolongation, and tadalafil with lower back pain.105 Nonsurgical approaches include correction of underlying disorders, particularly medication-induced dysfunction and endocrinopathy-related (e.g., reduced testosterone level associated with chronic kidney disease) dysfunction. Use of vasodilators and cessation of smoking can benefit individuals with vasculogenic ED. Surgical approaches include penile implants, penile revascularization, and correction of other anatomical defects contributing to sexual dysfunction.

Impairment of Sperm Production and Quality Spermatogenesis requires adequate secretion of FSH and luteinizing hormone (LH) by the pituitary and sufficient secretion of testosterone by the testes. Inadequate secretion of gonadotropins may be caused by numerous alterations (e.g., hypothyroidism, hyperadrenocortisolism, hyperprolactinemia, or hypogonadotropic hypogonadism). In the absence of adequate gonadotropin levels, the Leydig cells are

not stimulated to secrete testosterone, and sperm maturation is not promoted in the Sertoli cells. Spermatogenesis also depends on an appropriate response by the testes. Defects in testicular response to the gonadotropins result in decreased secretion of testosterone and inhibin B and occur as a result of normal feedback mechanisms and high levels of circulating gonadotropins. In the absence of adequate testosterone levels, spermatogenesis is impaired. Newer studies demonstrate the importance of inhibin B as a valuable marker of the competence of Sertoli cells and spermatogenesis.26,106 Impaired spermatogenesis also can be caused by testicular trauma, infection, atrophy of the testes, systemic illness involving high fever, ingestion of various medications, exposure to environmental toxins, and cryptorchidism. Fertility is adversely affected if spermatogenesis is normal but the sperm are chromosomally or morphologically abnormal or are produced in insufficient quantities. Chromosomal abnormalities are caused by genetic factors and by external variables, such as exposure to radiation or toxic substances. Because the Y chromosome plays a key role in testis determination and control of spermatogenesis, understanding how the genes interact can elucidate exact causes of infertility. The most common mutations are microdeletion of the Y chromosome (AZ [azoospermia] a, b, and c).107 Research related to mapping the critical genes and gene pathways is the current focus of male infertility. Common mechanisms may be involved in infertility and testicular cancer. In utero environmental exposure to endocrine disruptors modulates the genetic makeup of the gonad and may result in both infertility and testicular cancer.26 Sperm motility also may affect fertility. Motility appears to be affected by the characteristics of the semen. Dysfunction of the prostate, excessive viscosity of the semen, presence of medications or toxins in the semen, and presence of antisperm antibodies are associated with impaired sperm motility. However, new data show that motile density may not be a good indicator of infertility.108 Approximately 17% of infertile males have antisperm antibodies in their semen. These antibodies may be (1) cytotoxic antibodies, which attack sperm and reduce their number in the semen, or (2) sperm-immobilizing antibodies, which impair sperm motility and reduce their ability to traverse the endocervical canal. Treatment for impaired spermatogenesis involves correcting any underlying disorders, avoiding radiation and possibly electromagnetic radiation (hypothesis from cellphones) and toxins, and using hormones to enhance spermatogenesis. In addition, semen can be modified to improve sperm motility; modifications are followed by artificial insemination.

Quick Check 34-4 1. Why is the worldwide variation of prostate cancer incidence important? 2. What is the current understanding of hormones in the pathophysiology of prostate cancer? 3. Describe what is meant by prostate cancer cell and stromal interactions for carcinogenesis. 4. What causes impaired spermatogenesis?

Disorders of the Male Breast Gynecomastia Gynecomastia is the overdevelopment of breast tissue in a male. Gynecomastia accounts for approximately 85% of all masses that develop in the male breast and affects 32 to 40% of the male population. If only one breast is involved, it is typically the left. Incidence is greatest among adolescents and men older than 50 years. Gynecomastia results from hormonal alterations, which may be idiopathic or caused by systemic disorders, medications, or neoplasms. Gynecomastia usually involves an imbalance of the estrogen/testosterone ratio. The normal estrogen/testosterone ratio can be altered in one of two ways. First, estrogen levels may be excessively high, although testosterone levels are normal. This is the case in medication-induced and tumour-induced hyperestrogenism. Second, testosterone levels may be extremely low, although estrogen levels are normal, as is the case in hypergonadism. Gynecomastia also can be caused by alterations in breast tissue responsiveness to hormonal stimulation. Breast tissue may have increased responsiveness to estrogen or decreased responsiveness to androgen. Alterations of responsiveness may cause many cases of idiopathic gynecomastia. Besides puberty and aging, estrogen/testosterone imbalances are associated with hypogonadism, Klinefelter's syndrome, and testicular neoplasms. Hormone-induced gynecomastia is usually bilateral. Pubertal gynecomastia is a self-limiting phenomenon that usually disappears within 4 to 6 months. Senescent gynecomastia usually regresses spontaneously within 6 to 12 months. Systemic disorders associated with gynecomastia include cirrhosis of the liver, infectious hepatitis, chronic kidney disease, chronic obstructive lung disease, hyperthyroidism, tuberculosis, and chronic malnutrition. It may be that these disorders ultimately alter the estrogen/testosterone ratio, initiating the gynecomastia. Gynecomastia is often seen in males receiving estrogen therapy, either in preparation for a genderchange operation or in the treatment of prostatic carcinoma. Other medications that can cause gynecomastia include digitalis (Digoxin), cimetidine (Tagamet), spironolactone (Aldactone), reserpine (Serpasil), thiazide (Hydrochlorothiazide), isoniazid (Rifater), ergotamine (Bellergal Spacetabs), tricyclic antidepressants, amphetamines, vincristine (Oncovin), and busulfan (Busulfex). Gynecomastia is usually unilateral in these instances. Malignancies of the testes, adrenals, or liver can cause gynecomastia if they alter the estrogen/testosterone ratio. Pituitary adenomas and lung cancer also are associated with gynecomastia. Pathophysiology The enlargement of the breast consists of hyperplastic stroma and ductal tissue. Hyperplasia results in a firm, palpable mass that is at least 2 cm in diameter and located beneath the areola. Evaluation and treatment The diagnosis of gynecomastia is based on physical examination. Identification and treatment of the cause are likely to be followed by resolution of the gynecomastia. The man should be taught to perform breast self-examination and is re-examined at 6- and 12-month intervals if the gynecomastia persists.

Carcinoma Breast cancer in males accounts for 0.26% of all male cancers and 1.1% of all breast cancers.1 The Canadian Cancer Society estimated that 230 men were diagnosed with breast cancer in 2017. It also estimated that 60 men died of this disease in 2017.109 Global incidence rates were generally less than 1 per 100 000 man-years, in contrast to much higher rates in females.110 The highest incidence rate for male breast cancer (MBC) was reported in Israel (1.24 per 100 000), and the lowest incidence rates for males (0.16 per 100 000) and females (18.0 per 100 000) were observed in Thailand.110 MBC is seen most commonly after the age of 60 years, with the peak incidence between 60 and 69 years (men tend to be

diagnosed at an older age than women). It has, however, been reported in males as young as 6 years old and in adolescents. Klinefelter's syndrome is the strongest risk factor for developing MBC. Other risk factors include germline mutation in BRCA1 or BRCA2, but familial cases usually have BRCA2 rather than BRCA1 mutations.111-113 Obesity increases the risk for MBC. Testicular disorders, including cryptorchidism, mumps, orchitis, and orchiectomy, are related to risk.114 The relationship between these factors and the risk for disease is not clearly defined. Recent data on the most frequent molecular subtypes of MBC appear to be different than those for female breast cancers. Luminal A and luminal B are most common; and basal-like, unclassifiable triplenegative, and HER2-driven MBCs are rare.115,116 Male breast tumours often resemble carcinoma of the breast in women. The majority of MBCs express estrogen and progesterone receptors. The malignant male breast lesion is usually a unilateral solid mass located near the nipple. Because the nipple is commonly involved, crusting and nipple discharge are typical clinical manifestations. Other findings include skin retraction, ulceration of the skin over the tumour, and axillary node involvement. Patterns of metastasis are similar to those in females. The diagnosis of cancer is confirmed by biopsy. Because of delays in seeking treatment, MBC tends to be advanced at the time of diagnosis and therefore is likely to have a poor prognosis. Treatment protocols are similar to those for female breast cancer, but endocrine therapy is used more often for males because a higher percentage of male tumours are hormone dependent. The mainstay of treatment is modified mastectomy with axillary node dissection to assess stage and prognosis. Because 90% of tumours are hormonal-receptor positive, tamoxifen (Nolvadex) is standard adjuvant therapy. Orchiectomy is performed to treat metastatic disease. For metastatic disease, hormonal therapy is the main treatment, but chemotherapy also can provide palliation.111

Sexually Transmitted Infections Sexually transmitted infections (STIs) are a variety of clinical syndromes and infections caused by pathogens that can be acquired and transmitted through sexual activity.117 Trends in reportable STIs in Canada have revealed steady increases since 1998. Similar increases in reportable STI rates have been observed in Australia, England, and the United States.118 Young Canadians have the highest reported rates of STIs; however, increased rates have been reported among middle-aged and older adults118 (Table 34-1). STIs can lead to severe reproductive health problems, for example, infertility and ectopic pregnancy.119 Untreated or undertreated chlamydial infections are the primary cause of preventable infertility and ectopic pregnancy. In addition to ectopic pregnancy and infertility, other complications of STIs include pelvic inflammatory disease (PID), chronic pelvic pain, neonatal morbidity and mortality, genital cancer, and epidemiological synergy with HIV transmission (Table 34-2). Long-term sequelae of untreated or undertreated STIs may be disastrous and can affect a person's physical, emotional, and financial well-being. Treatment guidelines for STIs can be found on the Centers for Disease Control and Prevention website (http://www.cdc.gov/std/tg2015/2015-poster-press.pdf). TABLE 34-1 Currently Recognized Sexually Transmitted Infections Causal Microorganism Bacteria Campylobacter Calymmatobacterium granulomatis Chlamydia trachomatis Polymicrobial Gardnerella vaginalis interaction with anaerobes (Bacteroides and Mobiluncus spp.) and genital mycoplasmas Haemophilus ducreyi Mycoplasma Neisseria gonorrhoeae Shigella Treponema pallidum Viruses Cytomegalovirus Hepatitis B virus (HBV) Hepatitis C virus (HCV) Herpes simplex virus (HSV) Human immunodeficiency virus (HIV) Human papillomavirus (HPV) Molluscum contagiosum virus Protozoa Entamoeba histolytica Giardia lamblia Trichomonas vaginalis Ectoparasites Phthirus pubis Sarcoptes scabiei Fungus Candida albicans

Infection Campylobacter enteritis Granuloma inguinale Urogenital infections; lymphogranuloma venereum Bacterial vaginosis Chancroid Mycoplasmosis Gonorrhea Shigellosis Syphilis Cytomegalic inclusion disease Hepatitis Hepatitis Genital herpes Acquired immune deficiency syndrome (AIDS) Condylomata acuminata, cervical dysplasia, and cervical cancer Molluscum contagiosum Amebiasis; amebic dysentery Giardiasis Trichomoniasis Pediculosis pubis Scabies Candidiasis

TABLE 34-2 Photographs of Sexually Transmitted Infections and Precursors to Sexually Transmitted Infections Bacterial Sources Gonococcal Infections

Symptomatic Gonococcal Urethritis.a

Endocervical Gonorrhea.a

Skin Lesions of Disseminated Gonococcal Infection.a Bacterial Vaginosis

Vaginal Examination Showing Mild Bacterial Vaginosis.a Syphilis

Erythematous Penile Plaques of Secondary Syphilis.b

Multiple Primary Syphilitic Chancres of Labia and Perineum. Courtesy Barbara Romanowski, MD.a

Papular Secondary Syphilis.a Lymphogranuloma

“Groove Sign” in Man With Lymphogranuloma Venereum (LV).b Chlamydial Infections

Beefy Red Mucosa in Chlamydial Infection.a

Chlamydial Epididymitis. Courtesy Richard E. Berger.a

Chlamydial Ophthalmia: Erythematous Conjunctiva in Infant.a

Viral Sources Genital Herpes

Early Lesions of Primary Genital Herpes.a

Primary Vulvar Herpes. Courtesy Barbara Romanowski, MD.a

Generalized Herpes Simplex in Patient With Atopic Dermatitis. Courtesy David Mandeville and Peter Lane, MD.a Human Papillomavirus

Human Papillomavirus (HPV) Infection of the Cervix.b

Exophytic (Outward-Growing) Condyloma, Subclinical Human Papillomavirus (HPV) Infection, and High-Grade Cervical Intraepithelial Neoplasia (CIN).b Condylomata Acuminata

Condylomata Acuminata: Vulva and Perineum.a

Condylomata Acuminata: Perianal.a

Condylomata Acuminata: Penile.a Parasite Sources Trichomonisasis

“Strawberry Cervix” Seen With Trichomoniasis.a Scabies

Nodular Lesions of Scabies on Male Genitalia.b

Scabies of Palm With Secondary Pyoderma in Infant.a Pediculosis Pubis (Phthirus pubis [Crablouse])

Phthirus pubis Feeding on Its Host.a

Pubic Hair With Multiple Nits.a a

From Morse, S.A., Holmes, K.K., & Ballard, R.C. (2010). Atlas of sexually transmitted diseases and AIDS (4th ed.). London: Elsevier.

b

From Morse, S.A., Moreland, A.A., & Holmes, K.K. (1996). Atlas of sexually transmitted diseases and AIDS (2nd ed.). London: Elsevier.

Anyone can become infected with an STI, but young people and gay and bisexual men are at greatest risk.118 Young people between the ages of 20 and 24 years have the highest reported rates of chlamydia, and females between the ages of 15 and 24 years and males between the ages of 20 and 29 years account for the highest rates of gonorrhea. Both young men and women are negatively affected by STIs, but young women have the most serious long-term health consequences. Undiagnosed STIs may cause PID, which may lead to chronic abdominal pain, infertility, and ectopic pregnancy.118 In Canada, it has been suggested that recent increases in the incidence of syphilis is largely related to transmission among men who have sex with men (MSM) who engage in high-risk sexual practices. The majority (65.6%) of all reported cases of infectious syphilis were among men aged 30 years and older. Primary and secondary syphilis are the most infectious stages of the disease and, if not treated adequately, can lead to visual impairment and stroke.118 Syphilis infection raises the risk of acquiring and transmitting HIV infection and is a common and concerning occurrence.118 Individual risk behaviours, such as higher numbers of lifetime sex partners and environmental, social, and cultural factors, contribute to health disparities of MSM, for example, difficulty accessing health care. Homophobia and stigma also can make it difficult for gay and bisexual men to find culturally sensitive and appropriate care and treatment.118 STI screening is critical. It is recommended that women who are sexually active and younger than 25 years of age or have multiple sex partners be tested annually for chlamydia and gonorrhea. A woman should request syphilis, HIV, chlamydia, and hepatitis B testing early in her pregnancy. These tests also should be requested if a woman has a new partner or multiple sex partners.118 Recommended tests include syphilis, chlamydia, gonorrhea, and HIV once a year for gay, bisexual, or other MSM. More frequent testing is recommended for men at high risk.

Quick Check 34-5 1. What is the cause of male gynecomastia?

2. What are the risk factors for male breast cancer? 3. What factors increase the incidence of sexually transmitted infections (STIs)? 4. What are the serious long-term health consequences of STIs for young women? 5. What are the long-term health consequences of acquiring syphilis for men who have sex with men?

Did You Understand? Alterations of Sexual Maturation 1. Sexual maturation, or puberty, begins in boys between the ages of 9 and 14.5 years. 2. Delayed puberty is the onset of sexual maturation after 14.5 years; precocious puberty is sexual maturation occurring before age 9. Treatment for delayed, precocious, or absent puberty depends on the cause.

Disorders of the Male Reproductive System 1. Disorders of the urethra include urethritis (infection of the urethra) and urethral strictures (narrowing or obstruction of the urethral lumen caused by scarring). 2. Most cases of urethritis result from sexually transmitted pathogens. Urological instrumentation, foreign body insertion, trauma, or an anatomical abnormality can cause urethral inflammation with or without infection. 3. Urethritis causes urinary symptoms, including a burning sensation during urination (dysuria), frequency, urgency, urethral tingling or itching, and clear or purulent discharge. 4. The scarring that causes urethral stricture can be attributed to trauma or severe untreated urethritis. 5. Manifestations of urethral stricture include those of bladder outlet obstruction: urinary frequency and hesitancy, diminished force and calibre of the urinary stream, dribbling after voiding, and nocturia. 6. Phimosis and paraphimosis are penile disorders involving the foreskin (prepuce). In phimosis, the foreskin cannot be retracted over the glans. In paraphimosis, the foreskin is retracted and cannot be reduced (returned to its normal anatomical position over the glans). Phimosis is caused by poor hygiene and chronic infection and can lead to paraphimosis. Paraphimosis can constrict the penile blood vessels, preventing circulation to the glans. 7. Peyronie disease consists of fibrosis affecting the corpora cavernosa, which causes penile curvature during erection. Fibrosis prevents engorgement on the affected side, causing a lateral curvature that can prevent intercourse. 8. Priapism is a prolonged, painful erection that is not stimulated by sexual arousal. The corpora cavernosa (but not the corpus spongiosum) fill with blood that will not drain from the area, probably because of venous obstruction. Priapism is associated with spinal cord trauma, sickle cell disease, leukemia, and pelvic tumours. It can also be idiopathic. 9. Balanitis is an inflammation of the glans penis. It is associated with phimosis, inadequate cleansing under the foreskin, skin disorders, and pathogens (e.g., Candida albicans). 10. Carcinoma of the penis is rare in Canada. Penile carcinoma in situ tends to involve the glans; invasive carcinoma of the penis involves the shaft as well. 11. A varicocele is an abnormal dilation of the testicular veins within the spermatic cord caused either by congenital absence of valves in the internal spermatic vein or by acquired valvular incompetence. 12. A hydrocele is a collection of fluid between the testicular and scrotal layers of the tunica vaginalis. Hydroceles can be idiopathic or caused by trauma or infection of the testes. 13. A spermatocele is a cyst located between the testis and epididymis that is filled with fluid and sperm. 14. Cryptorchidism is a congenital condition in which one or both testes fail to descend into the scrotum. Uncorrected cryptorchidism is associated with infertility and significantly increased risk for testicular cancer. 15. Testicular torsion is the rotation of a testis, which twists blood vessels in the spermatic cord. This rotation interrupts the blood supply to the testis, resulting in edema and, if not corrected within 6

hours, necrosis and atrophy of testicular tissues. 16. Orchitis is an acute inflammation of the testes. Complications of orchitis include hydrocele and abscess formation. 17. Testicular cancer is the most common malignancy in males 15 to 35 years of age. Although its cause is unknown, high androgen levels, genetic predisposition, and history of cryptorchidism, trauma, or infection may contribute to tumourigenesis. 18. Epididymitis, an inflammation of the epididymis, is usually caused by a sexually transmitted pathogen that ascends through the vasa deferentia from an already infected urethra or bladder. 19. Benign prostatic hyperplasia (BPH), also called benign prostatic hypertrophy, is the enlargement of the prostate gland. This condition becomes symptomatic as the enlarging prostate compresses the urethra, causing symptoms of bladder outlet obstruction and urine retention. 20. Prostatitis is an inflammation of the prostate. Prostatitis syndromes have been classified by the US National Institutes of Health as (a) acute bacterial prostatitis (ABP), (b) chronic bacterial prostatitis (CBP), (c) chronic pelvic pain syndrome (CPPS), and (d) asymptomatic inflammatory prostatitis. 21. Prostate cancer is the most commonly diagnosed nonskin cancer in men in Canada. Its incidence varies greatly worldwide. Possible causes include genetic predisposition, environmental and dietary factors, inflammation, and alterations in levels of hormones (testosterone, dihydrotestosterone, and estradiol) and growth factors. Incidence is greatest in men in developed countries in regions such as Oceania, Europe, and North America, men older than 65 years, and Black men. 22. Most cancers of the prostate are adenocarcinomas that develop at the periphery of the gland. 23. Sexual dysfunction in males can be caused by any physical or psychological factor that impairs erection, emission, or ejaculation. 24. Spermatogenesis (sperm production by the testes) can be impaired by disruptions of the hypothalamic-pituitary-testicular axis that reduce testosterone secretion and by testicular trauma, infection, or atrophy from any cause. Sperm production is also impaired by neoplastic disease, cryptorchidism, or any factor that causes testicular temperature to rise (e.g., circulatory impairment, wearing tight clothing).

Disorders of the Male Breast 1. Gynecomastia is the overdevelopment (hyperplasia) of breast tissue in a male. It is first seen as a firm, palpable mass at least 2 cm in diameter and is located in the subareolar area. 2. Gynecomastia affects 32 to 40% of the male population. The incidence is greatest among adolescents and men older than 50 years of age. 3. Gynecomastia is caused by hormonal or breast tissue alterations that cause estrogen to dominate. These alterations can result from systemic disorders, medications, neoplasms, or idiopathic causes. 4. Breast cancer is relatively uncommon in males, but it has a poor prognosis because men tend to delay seeking treatment until the disease is advanced. The incidence is greatest in men in their 60s. 5. Most breast cancers in men are estrogen-receptor positive.

Sexually Transmitted Infections 1. Sexually transmitted infections (STIs) are contracted through intimate as well as sexual contact and include systemic infections, such as tuberculosis and hepatitis, which can spread to a sexual partner. 2. The etiology of an STI may be bacterial, viral, protozoan, parasitic, or fungal.

Key Terms Acute bacterial prostatitis (ABP, category I), 878 Androgen receptor (AR) signalling, 885 Balanitis, 871 Benign prostatic hyperplasia (BPH, benign prostatic hypertrophy), 876 Bladder outflow obstruction, 878 Chemical epididymitis, 876 Chronic bacterial prostatitis (CBP, category II), 879 Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS, category III), 879 Complete precocious puberty, 869 Condyloma acuminatum, 871 Cryptorchidism, 873 Delayed puberty, 868 Ectopic testis, 873 Epididymitis, 876 Fibroblast, 886 Gynecomastia, 890 Hydrocele, 873 Intraprostatic conversion, 882 Nonbacterial prostatitis, 879 Orchitis, 874 Paraphimosis, 870 Penile intraepithelial neoplasm (PeIN), 872 Peyronie disease (“bent nail syndrome”), 870 Phimosis, 869 Precocious puberty, 868 Priapism, 871 Prostatic intraepithelial neoplasia (PIN), 885 Prostatitis, 878 Sexual dysfunction, 888 Sexual transmitted infections (STIs), 891 Spermatocele (epididymal cyst), 873 Stroma, 885 Testicular appendage, 874 Torsion of the testis, 874 Urethral stricture, 869 Urethritis, 869 Varicocele, 872

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U N I T 11

The Digestive System OUTLINE 35 Structure and Function of the Digestive System 36 Alterations of Digestive Function 37 Alterations of Digestive Function in Children

35

Structure and Function of the Digestive System Sue E. Huether, Mohamed El-Hussein

CHAPTER OUTLINE The Gastro-Intestinal Tract, 899 Mouth and Esophagus, 899 Stomach, 902 Small Intestine, 905 Large Intestine, 909 Intestinal Microbiome, 910 Splanchnic Blood Flow, 910 Accessory Organs of Digestion, 910 Liver, 911 Gallbladder, 914 Exocrine Pancreas, 915 GERIATRIC CONSIDERATIONS: Aging and the Gastro-Intestinal System, 918

The digestive system includes the gastro-intestinal (GI) tract and accessory organs of digestion: the salivary glands, liver, gallbladder, and exocrine pancreas (Figure 35-1). The digestive system breaks down ingested food, prepares it for uptake by the body's cells, absorbs fluid, and eliminates wastes. Food breakdown begins in the mouth with chewing and continues in the stomach, where food is churned and mixed with acid, mucus, enzymes, and other secretions. From the stomach, the fluid and partially digested food pass into the small intestine, where biochemical agents and enzymes secreted by the intestinal cells, liver, gallbladder, and exocrine pancreas break it down into absorbable components of proteins, carbohydrates, and fats. These nutrients pass through the walls of the small intestine into blood vessels and lymphatics that carry them to the liver for storage or further processing.

FIGURE 35-1

Structures of the Digestive System. (From Patton, K.T., & Thibodeau, G.A. [2014]. The human body in health & disease [6th ed.]. St. Louis: Mosby.)

Ingested substances and secretions that are not absorbed in the small intestine pass into the large intestine, where fluid continues to be absorbed. Fluid wastes travel to the kidneys and are eliminated in the urine. Solid wastes pass into the rectum and are eliminated from the body through the anus. Except for chewing, swallowing, and defecation of solid wastes, the movements of the digestive system (peristalsis) are all controlled by hormones and the autonomic nervous system. The autonomic innervation, both sympathetic and parasympathetic, is controlled by centres in the brain and by local stimuli that are mediated at plexuses (networks of nerve fibres) within the GI walls. The GI tract and gut microbiome provide important immune and protective functions. Aging can alter the structure and function of the GI tract (see Geriatric Considerations: Aging and the Gastro-Intestinal System).

The Gastro-Intestinal Tract The gastro-intestinal (GI) tract (alimentary canal) consists of the mouth, esophagus, stomach, small intestine, large intestine, rectum, and anus (see Figure 35-1). It carries out the following digestive processes:

• Ingestion of food • Propulsion of food and wastes from the mouth to the anus • Secretion of mucus, water, and enzymes • Mechanical digestion of food particles • Chemical digestion of food particles • Absorption of digested food • Elimination of waste products by defecation • Immune and microbial protection against infection Histologically, the GI tract consists of four layers. From the inside out they are the mucosa, submucosa, muscularis, and serosa (or adventitia). These concentric layers vary in thickness, and each layer has sublayers (Figure 35-2). A network of intrinsic nerves that controls mobility, secretion, sensation, and blood flow is located solely within the GI tract and controlled by local and autonomic nervous system stimuli through the enteric (intramural) plexus located in different layers of the GI walls (see Figure 352).

FIGURE 35-2 Wall of the Gastro-Intestinal Tract. The wall of the gastro-intestinal (GI) tract is made up of four layers with a network of nerves between the layers. This generalized diagram shows a segment of the GI tract. Note that the serosa is continuous with a fold of serous membrane called the mesentery. Note also that digestive glands may empty their products into the lumen of the GI tract by way of ducts. (From Patton, K.T., & Thibodeau, G.A. [2016]. Anatomy & physiology [9th ed.]. St. Louis: Mosby.)

Mouth and Esophagus The mouth is a reservoir for the chewing and mixing of food with saliva. There are 32 permanent teeth in the adult mouth, and they are important for speech and mastication. As food particles become smaller and move around in the mouth, the taste buds and olfactory nerves are continuously stimulated, adding to the satisfaction of eating. The tongue's surface contains thousands of chemoreceptors, or taste buds, which can distinguish salty, sour, bitter, sweet, and savoury (umami) tastes. Tastes and food odours help to initiate salivation and the secretion of gastric juice in the stomach.

Salivation The three pairs of salivary glands—the submandibular, sublingual, and parotid glands (Figure 35-3)— secrete about 1 L of saliva per day. Saliva consists mostly of water with mucus, sodium, bicarbonate, chloride, potassium, and salivary α-amylase (ptyalin), an enzyme that initiates carbohydrate digestion in the mouth and stomach.

FIGURE 35-3

Salivary Glands. (From Gerdin, J. [2012]. Health careers today [5th ed.]. St. Louis: Mosby.)

Both sympathetic and parasympathetic divisions of the autonomic nervous system control salivation. Cholinergic parasympathetic fibres stimulate the salivary glands, and atropine (an anticholinergic agent) inhibits salivation and makes the mouth dry. β-Adrenergic stimulation from sympathetic fibres also increases salivary secretion. The salivary gland secretion is not regulated by hormones. The composition of saliva depends on the rate of secretion (Figure 35-4). Aldosterone can increase epithelial exchange of sodium for potassium, increasing sodium conservation and potassium excretion. The bicarbonate concentration of saliva sustains a pH of about 7.4, which neutralizes bacterial acids and prevents tooth decay. Saliva also contains mucin, immunoglobulin A (IgA), and other antimicrobial substances, which help prevent infection. Mucin provides lubrication. Exogenous fluoride (e.g., fluoride in drinking water) is also secreted in the saliva, providing additional protection against tooth decay.

FIGURE 35-4

Salivary Electrolyte Concentrations and Flow Rate. Changes in concentrations of sodium (Na+), potassium (K+), chloride

−

(Cl ), and bicarbonate ( ) increase flow rate of saliva. Green line, sodium; orange line, bicarbonate; red line, chloride; blue line, potassium. At low rates of salivary flow (i.e., between meals), sodium, chloride, and bicarbonate are reabsorbed in the collecting ducts of the salivary glands, and the saliva contains fewer of these electrolytes (i.e., is more hypotonic). At higher flow rates (i.e., stimulated by food), reabsorption decreases and saliva is hypertonic. By this mechanism, sodium, chloride, and bicarbonate are recycled until they are released to help with digestion and absorption.

Swallowing The esophagus is a hollow, muscular tube approximately 25 cm long that conducts substances from the oropharynx to the stomach (see Figure 35-1). Swallowed food is moved to the stomach by peristalsis, the coordinated sequential contraction and relaxation of outer longitudinal and inner circular layers of muscles. The pharynx and upper third of the esophagus contain striated muscle (voluntary) that is directly innervated by skeletal motor neurons that control swallowing. The lower two-thirds contain smooth muscle (involuntary) that is innervated by preganglionic cholinergic fibres from the vagus nerve. The fibres are activated in a downward sequence and coordinated by the swallowing centre in the medulla. Peristalsis is stimulated when afferent fibres distributed along the length of the esophagus sense changes in wall tension caused by stretching as food passes. The greater the tension, the greater the intensity of esophageal contraction. Occasionally, intense contractions cause pain similar to “heartburn” or angina. Each end of the esophagus is opened and closed by a sphincter. The upper esophageal sphincter keeps air from entering the esophagus during respiration. The lower esophageal sphincter (cardiac sphincter) prevents regurgitation from the stomach and caustic injury to the esophagus. Swallowing is coordinated primarily by the swallowing centre in the medulla. During the oropharyngeal (voluntary) phase of swallowing, the following steps occur: 1. Food is segmented into a bolus by the tongue and forced posteriorly toward the pharynx. 2. The superior constrictor muscle of the pharynx contracts so the food cannot move into the nasopharynx. 3. Respiration is inhibited, and the epiglottis slides down to prevent the food from entering the larynx and trachea. This entire sequence takes place in less than 1 second. The esophageal phase of swallowing proceeds as follows: 1. The bolus of food enters the esophagus. 2. Waves of relaxation travel the esophagus, preparing for the movement of the bolus. 3. Peristalsis, the sequential waves of muscular contractions that travel down the esophagus, transports the food to the lower esophageal sphincter, which is relaxed at that point. 4. The bolus enters the stomach, and the sphincter muscles return to their resting tone. This phase takes 5 to 10 seconds, with the bolus moving 2 to 6 cm/sec.

Peristalsis that immediately follows the oropharyngeal phase of swallowing is called primary peristalsis. If a bolus of food becomes stuck in the esophageal lumen, secondary peristalsis—a wave of contraction and relaxation independent of voluntary swallowing—occurs. This secondary peristalsis occurs in response to stretch receptors (stimulated by increased wall tension) that activate impulses from the swallowing centre of the brain. The lower esophageal sphincter is normally constricted and serves as a barrier between the stomach and esophagus. The muscle tone of the lower sphincter changes with neural and hormonal stimulation and relaxes with swallowing. Cholinergic vagal input and the digestive hormone gastrin increase sphincter tone. Nonadrenergic, noncholinergic vagal impulses relax the lower esophageal sphincter, as do the hormones progesterone, secretin, and glucagon.1

Quick Check 35-1 1. What are the functions of saliva? 2. What are the phases of swallowing and how are they controlled?

Stomach The stomach is a hollow, muscular organ just below the diaphragm that stores food during eating, secretes digestive juices, mixes food with these juices, and propels partially digested food, called chyme, into the duodenum of the small intestine. The anatomy of the stomach is presented in Figure 35-5. The stomach's major anatomical boundaries are the lower esophageal sphincter, where food passes through the cardiac orifice at the gastroduodenal junction into the stomach, and the pyloric sphincter, which relaxes as food is propelled through the pylorus (gastroduodenal junction) into the duodenum. Functional areas are the fundus (upper portion), body of the stomach (middle portion), and antrum (lower portion).

FIGURE 35-5 Stomach. A portion of the anterior wall has been excised to reveal the muscle layers of the stomach wall. Note that the mucosa lining the stomach forms folds called rugae. The dashed lines distinguish the fundus, body, and antrum of the stomach. (Modified from Patton, K.T., & Thibodeau, G.A. [2014]. The human body in health & disease [6th ed.]. St. Louis: Mosby.)

The stomach has three layers of smooth muscle: an outer, longitudinal layer; a middle, circular layer; and an inner, oblique layer (the most prominent) (see Figure 35-5). These layers become progressively thicker in the body and antrum where food is mixed and pushed into the duodenum. The glandular epithelium is discussed under “Gastric Secretion” (see p. 904).

The stomach's blood supply comes from a branch of the celiac artery (Figure 35-6) and is so abundant that nearly all arterial vessels must be occluded before ischemic changes occur in the stomach wall. A series of small veins drain blood from the stomach toward the hepatic portal vein.

FIGURE 35-6 Major Blood Vessels and Organs Supplied With Blood in the Splanchnic Circulation. Numbers in parentheses reflect approximate blood flow values (mL/min) for each major vessel in an 80-kg normal, resting, adult human subject. Arrows indicate the direction of blood flow. (Modified from Johnson, L.R. [2001]. Gastrointestinal pathophysiology. St. Louis: Mosby.)

Sympathetic and parasympathetic divisions of the autonomic nervous system innervate the stomach. Some of the autonomic fibres are extrinsic—that is, they originate outside of the stomach and are controlled by nerve centres in the brain. The vagus nerve provides parasympathetic innervation, and branches of the celiac plexus innervate the stomach sympathetically. The myenteric plexus (Auerbach plexus) and the submucosal plexus (Meissner plexus) are intrinsic and part of the enteric (intramural) nervous system. They originate within the stomach and respond to local stimuli.

Gastric Motility In its resting state, the stomach is small and contains about 50 mL of fluid. There is no wall tension, and the muscle layers in the fundus contract very little. Swallowing causes the fundus to relax (receptive relaxation) to receive a bolus of food from the esophagus (see “Swallowing,” p. 901). Relaxation is coordinated by efferent, nonadrenergic, noncholinergic vagal fibres and is facilitated by gastrin and cholecystokinin—two polypeptide hormones secreted by the GI mucosa. (The actions of digestive hormones are summarized in Table 35-1.) Food is stored in vertical or oblique layers as it arrives in the fundus, whereas fluids flow relatively quickly down to the antrum. TABLE 35-1 Selected Hormonesa and Neurotransmitters of the Digestive System Source

Hormone/Neurotransmitter Stimulus for Secretion

Action

Mucosa of stomach

Gastrin

Presence of partially digested proteins in stomach

Histamine Somatostatin

Gastrin Acid in stomach

Acetylcholine Gastrin-releasing peptide (bombesin) Ghrelin

Vagus and local nerves in stomach Vagus and local nerves in stomach

Stimulates gastric glands to secrete hydrochloric acid, pepsinogen, and histamine; growth of gastric mucosa Stimulates acid secretion Inhibits acid, pepsinogen, and histamine secretion and release of gastrin Stimulates release of pepsinogen and acid secretion Stimulates gastrin and release of pepsinogen and acid secretion

Mucosa of small intestine

Motilin Secretin

High during fasting

Stimulates growth hormone secretion and hypothalamus to increase appetite Presence of acid and fat in duodenum Increases gastro-intestinal (GI) motility Presence of chyme (acid, partially digested proteins, fats) in duodenum Stimulates pancreas to secrete alkaline pancreatic juice and liver to secrete bile; decreases GI motility; inhibits gastrin and gastric acid secretion

Serotonin (5-hydroxytryptamine)

Cholecystokinin

Enteroglucagon Gastric inhibitory peptide (GIP) Peptide YY Pancreatic polypeptide Vasoactive intestinal peptide

Intestinal distension; vagal stimulation; presence of acids, amino Stimulates intestinal secretion, motility and sensation (i.e., pain acids, or hypertonic fluids; released from enterochromaffin cells and nausea), vasodilation; activates gut immune responses throughout intestine Presence of chyme (acid, partially digested proteins, fats) in duodenum Stimulates gallbladder to eject bile and pancreas to secrete alkaline fluid; decreases gastric motility; constricts pyloric sphincter; inhibits gastrin Intraluminal fats and carbohydrates Weakly inhibits gastric and pancreatic secretion and enhances insulin release, lipolysis, ketogenesis, and glycogenolysis Fat and glucose in small intestine Inhibits gastric secretion and emptying; stimulates insulin release Intraluminal fat and bile acids Inhibits postprandial gastric acid and pancreatic secretion and delays gastric and small bowel emptying Protein, fat, and glucose in small intestine Decreases pancreatic and enzyme secretion Intestinal mucosa and muscle Relaxes intestinal smooth muscle

a

The digestive hormones are not secreted into the gastro-intestinal (GI) lumen but instead into the bloodstream, where they travel to target tissues. There are more than 30 peptide hormone genes expressed in the GI tract and more than 100 hormonally active peptides. Modified from Johnson, L.R. (2014). Gastrointestinal physiology (8th ed.). St. Louis: Mosby. Data from Feldman, M., Friedman, L.S., & Brandt, L.J. (2015). Sleisenger and Fordtran's gastrointestinal and liver disease (10th ed.). Philadelphia: Saunders.

Gastric (stomach) motility increases with the initiation of peristaltic waves, which sweep over the body of the stomach toward the antrum. The rate of peristaltic contractions is approximately three per minute and is influenced by neural and hormonal activity. Gastrin, motilin (an intestinal hormone), and the vagus nerve increase the rate of contraction by lowering the threshold potential of muscle fibres. (The neural and biochemical mechanisms of muscle contraction are described in Chapter 38.) Sympathetic activity and secretin (another intestinal hormone) are inhibitory and raise the threshold potential. The rate of peristalsis is mediated by pacemaker cells that initiate a wave of depolarization (basic electrical rhythm), which moves from the upper part of the stomach to the pylorus. Gastric mixing and emptying of gastric contents (chyme) from the stomach take several hours. Mixing occurs as food is propelled toward the antrum. As food approaches the pylorus, the velocity of the peristaltic wave increases, forcing the contents back toward the body of the stomach. This retropulsion effectively mixes food with digestive juices, and the oscillating motion breaks down large food particles. With each peristaltic wave, a small portion of the gastric contents (chyme) passes through the pylorus and into the duodenum. The pyloric sphincter is about 1.5 cm long and is always open about 2.0 mm. It opens wider during antral contraction. Normally there is no regurgitation from the duodenum into the antrum. The rate of gastric emptying (movement of gastric contents into the duodenum) depends on the volume, osmotic pressure, and chemical composition of the gastric contents. Larger volumes of food increase gastric pressure, peristalsis, and rate of emptying. Solids, fats, and nonisotonic solutions (i.e., hypertonic or hypotonic gastric tube feedings) delay gastric emptying. (Osmotic pressure and tonicity are described in Chapters 1 and 5.) Products of fat digestion, which are formed in the duodenum by the action of bile from the liver and enzymes from the pancreas, stimulate the secretion of cholecystokinin. This hormone inhibits food intake, reduces gastric motility, and decreases gastric emptying so that fats are not emptied into the duodenum at a rate that exceeds the rate of bile and enzyme secretion. Osmoreceptors in the wall of the duodenum are sensitive to the osmotic pressure of duodenal contents. The arrival of hypertonic or hypotonic gastric contents activates the osmoreceptors, which delay gastric emptying to facilitate formation of an isosmotic duodenal environment. The rate at which acid enters the duodenum also influences gastric emptying. Secretions from the pancreas, liver, and duodenal mucosa neutralize gastric hydrochloric acid in the duodenum. The rate of emptying is adjusted to the duodenum's ability to neutralize the incoming acidity.2

Gastric Secretion The secretion of gastric juice is influenced by numerous stimuli that together facilitate the process of digestion. The phases of gastric secretion are the cephalic phase (stimulated by the thought, smell, and taste of food), the gastric phase (stimulated by distension of the stomach), and the intestinal phase (stimulated by histamine and digested protein). All phases promote the secretion of acid by the stomach. Gastric secretion is stimulated by the process of eating (gastric distension), by the actions of the hormone gastrin and paracrine pathways (e.g., histamine, ghrelin, somatostatin), and by the effects of the neurotransmitter acetylcholine (ACh) and other chemicals (e.g., ethanol, coffee, protein). The stomach secretes large volumes of gastric juices or gastric secretions, including mucus, acid, enzymes, hormones, intrinsic factor, and gastroferrin. Intrinsic factor is necessary for the intestinal absorption of vitamin B12, and gastroferrin facilitates small intestinal absorption of iron. The hormones are secreted into the blood

and travel to target tissues. The other gastric secretions are released directly into the stomach lumen.3 In the fundus and body of the stomach, the gastric glands of the mucosa are the primary secretory units (Figure 35-7). The composition of gastric juice depends on volume and flow rate (Figure 35-8). Potassium level remains relatively constant, but its concentration is greater in gastric juice than in plasma. The rate of secretion varies with the time of day. Generally, the rate and volume of secretion are lowest in the morning and highest in the afternoon and evening. Loss of gastric juices through vomiting, drainage, or suction may decrease body stores of sodium and potassium and result in fluid, electrolyte (e.g., hyponatremia, hypokalemia, dehydration), and acid–base imbalances (e.g., metabolic alkalosis) (see Chapters 5 and 36).4

FIGURE 35-7 Gastric Pits and Gastric Glands. Gastric pits are depressions in the epithelial lining of the stomach. At the bottom of each pit are one or more tubular gastric glands. Chief cells produce pepsinogen, which is converted to pepsin (a proteolytic enzyme); parietal cells secrete hydrochloric acid and intrinsic factor; G cells produce gastrin; endocrine cells (enterochromaffinlike cells and D cells) secrete histamine and somatostatin. (From Patton, K.T., Thibodeau, G.A., & Douglas, M.M. [2012]. Essentials of anatomy & physiology. St. Louis: Mosby.)

FIGURE 35-8 Gastric Electrolyte Concentrations and Flow Rate. Sodium (Na+) concentration is lower in the gastric juice than in the plasma, whereas hydrogen (H+), potassium (K+), and chloride (Cl−) concentrations are higher. Red line, chloride; orange line, hydrogen; green line, sodium; blue line, potassium.

Gastric secretion is inhibited by somatostatin, by unpleasant odours and tastes, and by rage, fear, or pain. A discharge of sympathetic impulses inhibits parasympathetic impulses. Increased secretions are

associated with aggression or hostility and may contribute to some forms of gastric pathology.

Gastric acid. The major functions of gastric hydrochloric acid are to dissolve food fibres, act as a bactericide against swallowed micro-organisms, and convert pepsinogen to pepsin. The production of acid by the parietal cells requires the transport of hydrogen and chloride from the parietal cells to the stomach lumen. Acid is formed in the parietal cells, primarily through the hydrolysis of water (Figure 35-9). At a high rate of gastric secretion, bicarbonate moves into the plasma, producing an “alkaline tide” in the venous blood, which also may result in a more alkaline urine.4

FIGURE 35-9

Hydrochloric Acid Secretion by Parietal Cell. Cl−, Chloride; CO2, carbon dioxide; H+, hydrogen; H2CO3, carbonic acid; H2O, water; HCl, hydrochloric acid;

, bicarbonate; K+, potassium; OH−, hydroxyl ion.

Acid secretion is stimulated by the vagus nerve, which releases ACh and stimulates the secretion of gastrin; then gastrin stimulates the release of histamine from enterochromaffin cells (mast cells; see Chapter 6) in the gastric mucosa. Histamine stimulates acid secretion by activating histamine receptors (H2 receptors) on acid-secreting parietal cells. Caffeine stimulates acid secretion, as does calcium. Acid secretion is inhibited by somatostatin, secretin, and other intestinal hormones.3

Pepsin. ACh, gastrin, and secretin stimulate the chief cells to release pepsinogen during eating. Pepsinogen is quickly converted to pepsin in the acidic gastric environment (optimum pH for pepsin activation = 2.0). Pepsin is a proteolytic enzyme—that is, it breaks down protein and forms polypeptides in the stomach. Once chyme has entered the duodenum, the alkaline environment of the duodenum inactivates pepsin.

Mucus. The gastric mucosa is protected from the digestive actions of acid and pepsin by intercellular tight junctions, a coating of mucus called the mucosal barrier, and gastric mucosal blood flow. Prostaglandins protect the mucosal barrier by stimulating the secretion of mucus and bicarbonate and by inhibiting the secretion of acid. A break in the protective barrier may occur from ischemia or by exposure to H. pylori, Aspirin, nonsteroidal anti-inflammatory drugs (which inhibit prostaglandin synthesis), ethanol, or regurgitated bile. Breaks cause inflammation and ulceration. Few substances are absorbed in the stomach. The stomach mucosa is impermeable to water, but the stomach can absorb alcohol and Aspirin.

Quick Check 35-2 1. Why are there three layers of stomach muscle and how do they function? 2. What hormones stimulate gastric motility? 3. What are the phases of gastric secretion?

Small Intestine The small intestine is coiled within the peritoneal cavity and is about 5 to 6 m long. Functionally, it is divided into three segments: the duodenum, jejunum, and ileum (Figure 35-10). The duodenum begins at the pylorus and ends where it joins the jejunum at a suspensory ligament called the Treitz ligament. The end of the jejunum and beginning of the ileum are not distinguished by an anatomical marker. These structures are not grossly different, but the jejunum has a slightly larger lumen than the ileum. The ileocecal valve, or sphincter, controls the flow of digested material from the ileum into the large intestine and prevents reflux into the small intestine.

FIGURE 35-10

The Small Intestine.

The duodenum lies behind the peritoneum, or retroperitoneally, and is attached to the posterior abdominal wall. The ileum and jejunum are suspended in loose folds from the posterior abdominal wall by a peritoneal membrane called the mesentery. The mesentery facilitates intestinal motility and supports blood vessels, nerves, and lymphatics. The peritoneum is the serous membrane surrounding the organs of the abdomen and pelvic cavity. It is analogous to the pericardium around the heart and the pleura around the lungs. The visceral peritoneum lies on the surface of the organs, and the parietal peritoneum lines the wall of the body cavity. The space between these two layers is called the peritoneal cavity and normally contains just enough fluid to lubricate the two layers and prevent friction during organ movement. The arterial supply to the duodenum arises primarily from the gastroduodenal artery, a branch of the celiac artery. The jejunum and ileum are supplied by branches of the superior mesenteric artery. The superior mesenteric vein drains blood from the entire small intestine and empties into the hepatic portal circulation. The regional lymph nodes and lymphatics drain into the thoracic duct. Enteric nerves from both divisions of the autonomic nervous system innervate the small intestine. Secretion, motility, pain sensation, and intestinal reflexes (e.g., relaxation of the lower esophageal sphincter) are mediated parasympathetically by the vagus nerve. Sympathetic activity inhibits motility

and produces vasoconstriction. Intrinsic reflexive activity is mediated by the myenteric plexus (Auerbach plexus) and the submucosal plexus (Meissner plexus) of the enteric nervous system. The smooth muscles of the small intestine are arranged in two layers: a longitudinal outer layer and a thicker inner circular layer (see Figures 35-2 and 35-10). Circular folds of the small intestine slow the passage of food, thereby providing more time for digestion and absorption. The folds are most numerous and prominent in the jejunum and proximal ileum (see Figure 35-10). Absorption occurs through villi (sing., villus), which cover the circular folds and are the functional units of the intestine. A villus is composed of absorptive columnar cells (enterocytes) and mucussecreting goblet cells of the mucosal epithelium. Each villus (see Figure 35-10) secretes some of the enzymes necessary for digestion and absorbs nutrients. Near the surface, columnar cells closely adhere to each other at sites called tight junctions. Water and electrolytes are absorbed through these intercellular spaces. The surface of each columnar epithelial cell on the villus contains tiny projections called microvilli (sing., microvillus) (see Figure 35-10). Together the microvilli create a mucosal surface known as the brush border. The villi and microvilli greatly increase the surface area available for absorption. Coating the brush border is an “unstirred” layer of water that is important for the absorption of watersoluble substances, including emulsified micelles of fat. The lamina propria (a connective tissue layer of the mucous membrane) lies beneath the epithelial cells of the villi and contains lymphocytes and plasma cells, which produce immunoglobulins (see “The Gastro-Intestinal Tract and Immunity,” p. 910). Central arterioles ascend within each villus and branch into a capillary array that extends around the base of the columnar cells and cascades down to the venules that lead to the hepatic portal circulation (see Figure 35-10). A central lacteal, or lymphatic capillary, also is contained within each villus and is important for the absorption and transport of fat molecules. Contents of the lacteals flow to regional nodes and channels that eventually drain into the thoracic duct.5 Between the bases of the villi are the crypts of Lieberkühn, which extend to the submucosal layer. Undifferentiated cells arise from stem cells at the base of the crypt and move toward the tip of the villus, maturing to become columnar epithelial secretory cells (water, electrolytes, and enzymes) and goblet cells (mucus). After completing their migration to the tip of the villus, they function for a few days and then are shed into the intestinal lumen and digested. Discarded epithelial cells are an important source of endogenous protein. The entire epithelial population is replaced about every 4 to 7 days. Many factors can influence this process of cellular proliferation. Starvation, vitamin B12 deficiency, and cytotoxic medications or irradiation suppress cell division and shorten the villi. Decreased absorption across the epithelial membrane can cause diarrhea and malnutrition. Nutrient intake and intestinal resection stimulate cell production.

Intestinal Digestion and Absorption The process of digestion is initiated in the stomach by the actions of gastric hydrochloric acid and pepsin. The chyme that passes into the duodenum is a liquid with small particles of undigested food. Digestion continues in the proximal portion of the small intestine by the action of pancreatic enzymes, intestinal enzymes, and bile salts. In the proximal small intestine, carbohydrates are broken down to monosaccharides and disaccharides; proteins are degraded further to amino acids and peptides; and fats are emulsified and reduced to fatty acids (Box 35-1) and monoglycerides (Figure 35-11). These nutrients, along with water, vitamins, and electrolytes, are absorbed across the intestinal mucosa by active transport, diffusion, or facilitated diffusion. Products of carbohydrate and protein breakdown move into villus capillaries and then to the liver through the hepatic portal vein. Digested fats move into the lacteals and eventually reach the liver through the systemic circulation. Intestinal motility exposes nutrients to a large mucosal surface area by mixing chyme and moving it through the lumen. Different segments of the GI tract absorb different nutrients. Digestion and absorption of all major nutrients and many medications occur in the small intestine. Sites of absorption are shown in Figure 35-12. Box 35-2 outlines the major nutrients involved in this process.

Box 35-1

Dietary Fat Saturated Fatty Acids (e.g., Palmitic Acid [C16H32O2]) Each carbon atom in the chain is linked by single bonds to adjacent carbon and hydrogen atoms. 1. They are solid at room temperature; they include animal fat and tropical oils (coconut and palm oils). 2. They increase low-density lipoprotein (LDL) cholesterol (“bad” cholesterol) blood levels. 3. They increase the risk of coronary artery disease.

Unsaturated Fatty Acids 1. They are soft or liquid at room temperature. 2. Omega-6 fatty acids are found in plants and vegetables (olive, canola, and peanut oils). 3. Omega-3 fatty acids are found in fish and shellfish.

Monounsaturated Fatty Acids (e.g., Oleic Acid [C18H34O2]) They contain one double bond in the carbon chain. 1. They are found in both plants and animals. 2. They may be beneficial in reducing blood cholesterol level, glucose level, and systolic blood pressure. 3. They do not lower high-density lipoprotein (HDL) cholesterol (“good” cholesterol) blood levels. 4. Low HDL levels have been associated with coronary heart disease.

Polyunsaturated Fatty Acids (e.g., Linoleic Acid [C18H32O2]) They contain two or more double bonds in the carbon chain. 1. They are found in plants and fish oils. 2. Omega-6 fatty acids lower total and LDL cholesterol blood levels. 3. High levels of polyunsaturated fatty acids may lower LDL levels. 4. Omega-3 fatty acids lower blood triglyceride levels and reduce platelet aggregation and, therefore, blood coagulation. 5. They are necessary for growth and development and may prevent coronary artery disease, hypertension, and inflammatory and immune disorders.

FIGURE 35-11

Digestion and Absorption of Foodstuffs.

FIGURE 35-12

Sites of Absorption of Major Nutrients.

Box 35-2

Major Nutrients Absorbed in the Small Intestine Water and Electrolytes • Approximately 85 to 90% of the water that enters the gastro-intestinal tract is absorbed in the small intestine. • Sodium passes through tight junctions and is actively transported across cell membranes; it is exchanged for bicarbonate to maintain electroneutrality in the ileum; sodium absorption is enhanced by co-transport with glucose. • Potassium moves passively across tight junctions with changes in the electrochemical gradient.

Carbohydrates • Only monosaccharides are absorbed by intestinal mucosa; therefore complex carbohydrates must be hydrolyzed to simplest form. • Salivary and pancreatic amylases break down starches to oligosaccharides (sucrose, maltose, lactose) in stomach and duodenum; brush-border enzymes hydrolyze them in intestine so they can pass through the unstirred water layer by diffusion. • Fructose diffuses into the bloodstream; glucose and galactose diffuse or are actively transported. • Cellulose remains undigested and stimulates large intestine motility.

Proteins • From 90 to 95% of protein is absorbed; major hydrolysis is accomplished in the small intestine by the pancreatic enzymes trypsin, chymotrypsin, and carboxypeptidase. • Brush-border enzymes break down proteins into smaller peptides that can cross cell membranes. In the cytosol, they are metabolized into amino acids, specifically neutral amino acids, basic amino acids, and proline and hydroxyproline.

Fats Digestion and absorption occur in four phases: 1. Emulsification and lipolysis: agents cover small fat particles and prevent them from re-forming into fat droplets; then lipolysis divides them into diglycerides, monoglycerides, free fatty acids, and glycerol. 2. Micelle formation: products are made water soluble. 3. Fat absorption: fat products move from micelle to absorbing surface of intestinal epithelium and diffuse through resynthesis. 4. Triglycerides and phospholipids: they then become chylomicrons that eventually enter the systemic circulation.

Minerals • Calcium: it is absorbed by passive diffusion and transported actively across cell membranes bound to a carrier protein; absorption primarily in ileum. • Magnesium: 50% is absorbed by active transport or passive diffusion in jejunum and ileum. • Phosphate: it is absorbed by passive diffusion and active transport in small intestine. • Iron: it is absorbed by epithelial cells of duodenum and jejunum; vitamin C facilitates iron absorption.

Vitamins • They are absorbed mainly by sodium-dependent active transport, with vitamin B12 bound to intrinsic factor and absorbed in terminal ileum.

Intestinal Motility The movements of the small intestine facilitate digestion and absorption. Chyme leaving the stomach and entering the duodenum stimulates intestinal movements that help blend secretions from the liver, gallbladder, pancreas, and intestinal glands. A churning motion brings the luminal contents into contact with the absorbing cells of the villi. Propulsive movements then advance the chyme toward the large intestine. Intestinal motility is affected by the following two movements: 1. Haustral segmentation. Localized rhythmic contractions of circular smooth muscles divide and mix the chyme, enabling the chyme to have contact with digestive enzymes and the absorbent mucosal surface, and then propel it toward the large intestine. 2. Peristalsis. Waves of contraction along short segments of longitudinal smooth muscle allow time for digestion and absorption. The intestinal villi move with contractions of the muscularis mucosae, a thin layer of muscle separating the mucosa and submucosa, with absorption promoted by the swaying of the villi in the luminal contents.

Neural reflexes along the length of the small intestine facilitate motility, digestion, and absorption. The ileogastric reflex inhibits gastric motility when the ileum becomes distended. This reflex prevents the continued movement of chyme into an already distended intestine. The intestinointestinal reflex inhibits intestinal motility when one part of the intestine is overdistended. Both of these reflexes require extrinsic innervation. The gastroileal reflex, which is activated by an increase in gastric motility and secretion, stimulates an increase in ileal motility and relaxation of the ileocecal valve (sphincter). It empties the ileum and prepares it to receive more chyme. The gastroileal reflex is probably regulated by the hormones gastrin and cholecystokinin. During prolonged fasting or between meals, particularly overnight, slow waves sweep along the entire length of the intestinal tract from the stomach to the terminal ileum. This interdigestive myoelectric complex appears to propel residual gastric and intestinal contents into the colon. The ileocecal valve (sphincter) marks the junction between the terminal ileum and the large intestine. This valve is intrinsically regulated and is normally closed. The arrival of peristaltic waves from the last few centimetres of the ileum causes the ileocecal valve to open, allowing a small amount of chyme to pass. Distension of the upper large intestine causes the sphincter to constrict, preventing further distension or retrograde flow of intestinal contents.

Quick Check 35-3 1. What cells arise from the crypts of Lieberkühn? 2. How are fats absorbed from the small intestine? 3. Which reflexes inhibit intestinal motility? Which promote it?

Large Intestine The large intestine is approximately 1.5 m long and consists of the cecum, appendix, colon (ascending, transverse, descending, and sigmoid), rectum, and anal canal (Figure 35-13). The cecum is a pouch that receives chyme from the ileum. Attached to it is the vermiform appendix, an appendage having little or no physiological function. From the cecum, chyme enters the colon, which loops upward, traverses the abdominal cavity, and descends to the anal canal. The four parts of the colon are the ascending colon, transverse colon, descending colon, and sigmoid colon. Two sphincters control the flow of intestinal contents through the cecum and colon: the ileocecal valve, which admits chyme from the ileum to the cecum, and the rectosigmoid (O'Beirne) sphincter, which controls the movement of wastes from the sigmoid colon into the rectum. A thick (2.5 to 3 cm) portion of smooth muscle surrounds the anal canal, forming the internal anal sphincter. Overlapping it distally is the striated skeletal muscle of the external anal sphincter (anus).

FIGURE 35-13 Large Intestine. A, Structure of the large intestine. B, Microscopic cross-section illustrating cellular structures of the large intestine. The wall of the large intestine is lined with columnar epithelium in contrast to the villi characteristics of the small intestine. The longitudinal layer of muscularis is reduced to become the teniae coli. (A, modified from Patton, K.T., & Thibodeau, G.A. [2014]. The human body in health & disease [6th ed.]. St. Louis: Mosby; B, from Gartner, L.P., & Hiatt, J.L. [2007]. Color textbook of histology [3rd ed.]. Philadelphia: Saunders.)

In the cecum and colon, the longitudinal muscle layer consists of three longitudinal bands called teniae coli (see Figure 35-13). They are shorter than the colon and give it a gathered appearance. The circular muscles of the colon separate the gathers into outpouchings called haustra (sing., haustrum). The haustra become more or less prominent with the contractions and relaxations of the circular muscles. The mucosal surface of the colon has rugae (folds), particularly between the haustra, and Lieberkühn crypts but no villi. Columnar epithelial cells and mucus-secreting goblet cells form the mucosa throughout the large intestine. The columnar epithelium absorbs fluid and electrolytes, and the mucus-secreting cells lubricate the mucosa. The enteric nervous system regulates motor and secretory activity independently of the extrinsic nervous system. Extrinsic parasympathetic innervation occurs through the vagus nerve and extends from the cecum up to the first part of the transverse colon. Vagal stimulation increases rhythmic contraction of the proximal colon. Extrinsic parasympathetic fibres reach the distal colon through the sacral parasympathetic splanchnic nerves. The internal anal sphincter is usually contracted, and its reflex response is to relax when the rectum is distended. The myenteric plexus provides the major innervation of the internal anal sphincter, but responds to sympathetic stimulation to maintain contraction and parasympathetic stimulation that facilitates relaxation when the rectum is full. Sympathetic innervation of this sphincter arises from the celiac and superior mesenteric ganglia and the sphincter nerve. The external anal sphincter is innervated by the pudendal nerve arising from sacral levels of the spinal cord. Sympathetic activity in the entire large intestine modulates intestinal reflexes, conveys somatic sensations of fullness and pain, participates in the defecation reflex, and constricts blood vessels. The blood supply of the large intestine and rectum is derived primarily from branches of the superior and inferior mesenteric arteries6 (see Figure 35-6), and venous blood drains through the inferior mesenteric vein. The primary type of colonic movement is segmental. The circular muscles contract and relax at different sites, shuttling the intestinal contents back and forth between the haustra, most commonly during fasting. The movements massage the intestinal contents, called the fecal mass at that point, and facilitate the absorption of water. Propulsive movement occurs with the proximal-to-distal contraction of several haustral units. Peristaltic movements also occur and promote the emptying of the colon. The gastrocolic reflex initiates propulsion in the entire colon, usually during or immediately after eating, when chyme enters from the ileum. The gastrocolic reflex causes the fecal mass to pass rapidly into the sigmoid colon and rectum, stimulating defecation. Gastrin may participate in stimulating this reflex. Epinephrine inhibits contractile activity. Approximately 500 to 700 mL of chyme flows from the ileum to the cecum per day. Most of the water is

absorbed in the colon by diffusion and active transport. Aldosterone increases membrane permeability to sodium, thereby increasing both the diffusion of sodium into the cell and the active transport of sodium to the interstitial fluid. (See Chapters 5 and 18 for a discussion of aldosterone secretion.) The colon does not absorb monosaccharides and amino acids, but some short-chain free fatty acids, which are produced by fermentation, are absorbed. Absorption and epithelial transport occur in the cecum, ascending colon, transverse colon, and descending colon. By the time the fecal mass enters the sigmoid colon, the mass consists entirely of wastes and is called the feces, composed of food residue, unabsorbed GI secretions, shed epithelial cells, and bacteria. The movement of feces into the sigmoid colon and rectum stimulates the defecation reflex (rectosphincteric reflex). The rectal wall stretches, and the tonically constricted internal anal sphincter (smooth muscle with autonomic nervous system control) relaxes, creating the urge to defecate. The defecation reflex can be overridden voluntarily by contraction of the external anal sphincter and muscles of the pelvic floor. The rectal wall gradually relaxes, reducing tension, and the urge to defecate passes. Retrograde contraction of the rectum may displace the feces out of the rectal vault until a more convenient time for evacuation. Pain or fear of pain associated with defecation (e.g., rectal fissures or hemorrhoids) can inhibit the defecation reflex. Squatting and sitting facilitate defecation because these positions straighten the angle between the rectum and anal canal and increase the efficiency of straining (increasing intra-abdominal pressure). Intra-abdominal pressure is increased by initiating the Valsalva manoeuvre—that is, inhaling and forcing the diaphragm and chest muscles against the closed glottis to increase both intrathoracic and intraabdominal pressure, which is transmitted to the rectum.

Quick Check 35-4 1. What is the major arterial blood supply to the large intestine? 2. What is the function of haustra? 3. What is the Valsalva manoeuvre?

The Gastro-Intestinal Tract and Immunity The GI tract plays a major role in immune defences by killing many microorganisms.7 The mucosa of the intestine covers a large surface area, and muscosal secretions produce antibodies, particularly IgA, and enzymes that provide defences against microorganisms. Small intestinal Paneth cells, located near the base of the crypts of Leiberkühn, produce defensins and other antimicrobial peptides and lysozymes important to mucosal immunity. Small intestinal Peyer patches (lymph nodules containing collections of lymphocytes, plasma cells, and macrophages) are most numerous in the ileum and produce antimicrobial peptides and IgA as a component of the gut-associated lymph tissue in the small intestine (see Figures 352 and 7-3). Peyer patches are important for antigen processing and immune defence (see Chapter 7).

Intestinal Microbiome The type and number of bacterial flora vary greatly throughout the normal GI tract and among individuals. There are an increasing number of bacteria from the proximal to the distal GI tract, with the highest number in the colon. Genetics, diet, environmental pollution, personal hygiene, vaccination, and antibiotics and other medications affect the normal composition of bacterial flora. The intestinal bacteria do not have major digestive or absorptive functions but do play a role in metabolism of bile salts, estrogens, androgens, lipids, carbohydrates, various nitrogenous substances, and medications. They produce antimicrobial peptides, hormones, neurotransmitters, anti-inflammatory metabolites, and vitamins; destroy toxins; prevent pathogen colonization; and alert the immune system to protect against infection. They are important to overall health and when altered (dysbiosis) or translocated, they cause disease.8

The intestinal tract is sterile at birth but becomes colonized within a few hours. Within 3 to 4 weeks after birth, the normal flora are established. The number and diversity of bacteria decrease with aging, increasing the risk for infection. The normal flora do not have the virulence factors associated with pathogenic microorganisms, thus permitting immune tolerances.9 Bacteria in the stomach are relatively sparse because of the secretion of acid that kills ingested pathogens or inhibits bacterial growth (with the exception of H. pylori). Bile acid secretion, intestinal motility, and antibody production suppress bacterial growth in the duodenum. In the duodenum and jejunum, there is a low concentration of aerobes (10−1 to 10−4/mL), primarily streptococci, lactobacilli, staphylococci, and other enteric bacteria. Anaerobes are found distal to the ileocecal valve but not proximal to the ileum. They constitute about 95% of the fecal flora in the colon and contribute one-third of the solid bulk of feces. Bacteroides and Firmicutes are the most common intestinal bacteria.

Splanchnic Blood Flow The splanchnic blood flow provides blood to the esophagus, stomach, small and large intestines, liver, gallbladder, pancreas, and spleen (see Figure 35-6). Blood flow is regulated by cardiac output and blood volume, the autonomic nervous system, hormones, and local autoregulatory blood flow mechanisms. The splanchnic circulation serves as an important reservoir of blood volume to maintain circulation to the heart and lungs when needed. The superior and inferior mesenteric arteries provide the blood supply to the large intestine (see Figures 35-6 and 35-13).

Accessory Organs of Digestion The liver, gallbladder, and exocrine pancreas all secrete substances necessary for the digestion of chyme. These secretions are delivered to the duodenum through the sphincter of Oddi at the major duodenal papilla (of Vater) (Figure 35-14). The liver produces bile, which contains salts necessary for fat digestion and absorption. Between meals, bile is stored in the gallbladder. The exocrine pancreas produces (1) enzymes needed for the complete digestion of carbohydrates, proteins, and fats and (2) an alkaline fluid that neutralizes chyme, creating a duodenal pH that supports enzymatic action.

FIGURE 35-14

Location of the Liver, Gallbladder, and Exocrine Pancreas, Which Are the Accessory Organs of Digestion.

The liver also receives nutrients absorbed by the small intestine and metabolizes or synthesizes them into forms that can be absorbed by the body's cells. It then releases the nutrients into the bloodstream or stores them for later use.

Liver The liver weighs 1 200 to 1 600 g. It is located under the right diaphragm and is divided into right and left lobes. The larger right lobe is divided further into the caudate and quadrate lobes (Figure 35-15). The falciform ligament separates the right and left lobes and attaches the liver to the anterior abdominal wall. The round ligament (ligamentum teres) extends along the free edge of the falciform ligament, extending from the umbilicus to the inferior surface of the liver. The coronary ligament branches from the falciform ligament and extends over the superior surface of the right and left lobes, binding the liver to the inferior surface of the diaphragm. The liver is covered by the Glisson capsule, which contains blood vessels, lymphatics, and nerves. When the liver is diseased or swollen, distension of the capsule causes pain because it is innervated by sensory neurons.

FIGURE 35-15

Gross Structure of the Liver. A, Anterior surface. B, Visceral surface. (From Applegate, E. [2011]. The anatomy and physiology learning system [4th ed.]. St. Louis: Saunders.)

The metabolic functions of the liver require a large amount of blood. The liver receives blood from both arterial and venous sources. The hepatic artery branches from the celiac artery and provides oxygenated blood at the rate of 400 to 500 mL/min (about 25% of the cardiac output). The hepatic portal vein receives deoxygenated blood from the inferior and superior mesenteric veins, the splenic vein, and the gastric and esophageal veins, and delivers about 1 000 to 1 500 mL/min to the liver. The hepatic portal vein, which carries 70% of the blood supply to the liver, is rich in nutrients that have been absorbed from the intestinal tract (Figure 35-16).

FIGURE 35-16 Hepatic Portal Circulation. In this unusual circulatory route, a vein is located between two capillary beds. The hepatic portal vein collects blood from capillaries in visceral structures located in the abdomen and empties into the liver. Hepatic veins return blood to the inferior vena cava. (From Herlihy, B. [2015]. The human body in health and illness [5th ed.]. St. Louis: Saunders.)

Within the liver lobes are multiple, smaller anatomical units called liver lobules (Figure 35-17). They are formed of cords or plates of hepatocytes, which are the functional cells of the liver. These cells can regenerate; therefore damaged or resected liver tissue can regrow. Small capillaries, or sinusoids, are located between the plates of hepatocytes. They receive a mixture of venous and arterial blood from branches of the hepatic artery and portal vein. Blood from the sinusoids drains to a central vein in the

middle of each liver lobule. Venous blood from all the lobules then flows into the hepatic vein, which empties into the inferior vena cava. Small channels (bile canaliculi) conduct bile, which is produced by the hepatocytes, outward to bile ducts and eventually drain into the common bile duct (see Figure 35-17). This duct empties bile into the ampulla of Vater, and then into the duodenum through an opening called the major duodenal papilla (which is surrounded by the sphincter of Oddi).

FIGURE 35-17 Schematic View of the Liver Lobule. The central vein is shown in the centre of the lobule, separated by cords of hepatocytes forming sinusoids from six portal areas at the periphery. The portal areas contain a portal vein, hepatic artery, and bile duct. Blood flow is toward the centre of the lobule, while bile flows toward the portal triads at the margins. Note the hepatic artery providing oxygenated blood to the hepatic sinusoids as well as the peribiliary plexus. (From Polin, R.A., Fox, W.W., & Abman, S.H. [2011]. Fetal and neonatal physiology [4th ed.]. St. Louis: Saunders.)

The sinusoids of the liver lobules are lined with highly permeable endothelium. This permeability enhances the transport of nutrients from the sinusoids into the hepatocytes, where they are metabolized. Immune functions of the liver are carried out by various cells. The sinusoids are lined with phagocytic Kupffer cells (tissue macrophages) and are part of the mononuclear phagocyte system. Kupffer cells are important for healing of liver injury, are bactericidal, and are important for bilirubin production and lipid metabolism.10 Stellate cells contain retinoids (vitamin A), are contractile in liver injury, regulate sinusoidal blood flow, may proliferate into myofibroblasts, participate in liver fibrosis, produce erythropoietin, can act as antigen-presenting cells, remove foreign substances from the blood, and trap bacteria.11 Natural killer cells (pit cells) also are found in the sinusoidal lumen; they produce interferon gamma and are important in tumour defence.12 Between the endothelial lining of the sinusoid and the hepatocyte is the Disse space, which drains interstitial fluid into the hepatic lymph system.

Quick Check 35-5 1. Where does blood in the hepatic portal vein originate? 2. What is the function of hepatocytes? 3. What is the function of Kupffer cells?

Secretion of Bile The liver assists intestinal digestion by secreting 700 to 1 200 mL of bile per day. Bile is an alkaline, bitter-

tasting, yellowish green fluid that contains bile salts (conjugated bile acids), cholesterol, bilirubin (a pigment), electrolytes, and water. It is formed by hepatocytes and secreted into the canaliculi. Bile salts, which are conjugated bile acids, are required for the intestinal emulsification and absorption of fats. Having facilitated fat emulsification and absorption, most bile salts are actively absorbed in the terminal ileum and returned to the liver through the portal circulation for resecretion. The pathway for recycling of bile salts is termed the enterohepatic circulation (Figure 35-18).

FIGURE 35-18

Enterohepatic Circulation of Bile Salts.

Bile has two fractional components: the acid-dependent fraction and the acid-independent fraction. Hepatocytes secrete the bile acid–dependent fraction, which consists of bile acids, cholesterol, lecithin (a phospholipid), and bilirubin (a bile pigment). The bile acid–independent fraction, which is secreted by the hepatocytes and epithelial cells of the bile canaliculi, is a bicarbonate-rich aqueous fluid that gives bile its alkaline pH. Bile salts are conjugated in the liver from primary and secondary bile acids. The primary bile acids are cholic acid and chenodeoxycholic (chenic) acid. These acids are synthesized from cholesterol by the hepatocytes. The secondary bile acids are deoxycholic and lithocholic acid. These acids are formed in the small intestine by intestinal bacteria, after which they are absorbed and flow to the liver (see Figure 3518). Both forms of bile acids are conjugated with amino acids (glycine or taurine) in the liver to form bile salts. Conjugation makes the bile acids more water soluble, thus restricting their diffusion from the duodenum and ileum. The primary and secondary bile acids together form the bile acid pool. Some bile salts are deconjugated by intestinal bacteria to secondary bile acids. These acids diffuse passively into the portal blood from both the small and large intestines. An increase in the plasma concentration of bile acids accelerates the uptake and resecretion of bile acids and salts by the

hepatocytes. The cycle of hepatic secretion, intestinal absorption, and hepatic resecretion of bile acids completes the enterohepatic circulation. Bile secretion is called choleresis. A choleretic agent stimulates the liver to secrete bile. One strong stimulus is a high concentration of bile salts. Other choleretics include cholecystokinin, vagal stimulation, and secretin, which increases the rate of bile flow by promoting the secretion of bicarbonate from canaliculi and other intrahepatic bile ducts.

Metabolism of Bilirubin Bilirubin is a byproduct of the destruction of aged red blood cells. It gives bile a greenish black colour and produces the yellow tinge of jaundice. Aged red blood cells are absorbed and destroyed by macrophages (Kupffer cells) of the mononuclear phagocyte system (also called the reticuloendothelial system), primarily in the spleen and liver. Within these cells, hemoglobin is separated into its component parts: heme and globin (Figure 35-19). The globin component is further degraded into its constituent amino acids, which are recycled to form new protein. The heme moiety is converted to biliverdin by the enzymatic (heme oxygenase) cleavage of iron. The iron attaches to transferrin in the plasma and can be stored in the liver or used by the bone marrow to make new red blood cells. The biliverdin is enzymatically converted to bilirubin in the Kupffer cell and then is released into the plasma, where it binds to albumin and is known as unconjugated bilirubin, or free bilirubin, which is lipid soluble. Bilirubin also may have a role as an antioxidant and provide cytoprotection.13

FIGURE 35-19

Bilirubin Metabolism. See text for explanation.

In the liver, unconjugated bilirubin moves from plasma in the sinusoids into the hepatocyte. Within hepatocytes, unconjugated bilirubin joins with glucuronic acid to form conjugated bilirubin, which is water soluble and is secreted in the bile. When conjugated bilirubin reaches the distal ileum and colon, it is deconjugated by bacteria and converted to urobilinogen. Urobilinogen is then reabsorbed in the intestines and excreted in the urine as urobilin. A small amount is eliminated in feces, as stercobilin, which contributes to the stool's brown pigmentation.

Vascular and Hematological Functions Because of its extensive vascular network, the liver can store a large volume of blood. The amount stored at any one time depends on pressure relationships in the arteries and veins. The liver also can release blood to maintain systemic circulatory volume in the event of hemorrhage. The liver also has hemostatic functions. It synthesizes most clotting factors (see Chapter 20). Vitamin K, a fat-soluble vitamin, is essential for the synthesis of the clotting factors. Because bile salts are needed for reabsorption of fats, vitamin K absorption depends on adequate bile production in the liver.

Metabolism of Nutrients

Fats. Ingested fat absorbed by lacteals in the intestinal villi enters the liver through the lymphatics, primarily as triglycerides. In the liver the triglycerides can be hydrolyzed to glycerol and free fatty acids and used to produce metabolic energy (adenosine triphosphate), or they can be released into the bloodstream bound to proteins (lipoproteins). The lipoproteins are carried by the blood to adipose cells for storage. The liver also synthesizes phospholipids and cholesterol, which are needed for the hepatic production of bile salts, steroid hormones, components of plasma membranes, and other special molecules.

Proteins. Protein synthesis requires the presence of all the essential amino acids (obtained only from food), as well as nonessential amino acids. Proteins perform many important functions in the body; these functions are summarized in Table 35-2. TABLE 35-2 Importance of Proteins in the Body Function Example Contraction Energy Fluid balance Protection Regulation Structure Transport

Actin and myosin enable muscle contraction and cellular movement. Proteins can be metabolized for energy. Albumin is a major source of plasma oncotic pressure.

Antibodies and complement protect against infection and foreign substances. Enzymes control chemical reactions; hormones regulate many physiological processes. Collagen fibres provide structural support to many parts of body; keratin strengthens skin, hair, and nails. Hemoglobin transports oxygen and carbon dioxide in blood; plasma proteins, particularly albumin, serve as transport molecules (i.e., for hormones, cations, bilirubin, and medications); proteins in cell membranes control movement of materials into and out of cells. Coagulation Hemostasis is regulated by clotting factors and proteins that balance coagulation and anticoagulation.

Within hepatocytes, amino acids are converted to carbohydrates (keto acids) by the removal of ammonia (NH3), a process known as deamination. The ammonia is converted to urea by the liver and passes into the blood to be excreted by the kidneys. Depending on the nutritional status of the body, the keto acids either are converted to fatty acids for fat synthesis and storage or are oxidized by the Krebs cycle (also called the tricarboxylic acid cycle; see Chapter 1) to provide energy for the liver cells. The plasma proteins, including albumins and globulins (with the exception of gamma globulin, which is formed in lymph nodes and lymphoid tissue), are synthesized by the liver. They play an important role in preserving blood volume and pressure by maintaining plasma oncotic pressure. The liver also synthesizes several nonessential amino acids and serum enzymes, including aspartate aminotransferase (AST; previously serum glutamic oxaloacetic transaminase [SGOT]), alanine aminotransferase (ALT; previously serum glutamic pyruvic transaminase [SGPT]), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP).

Carbohydrates. The liver contributes to the stability of blood glucose levels by releasing glucose during hypoglycemia (low blood glucose level) and absorbing glucose during hyperglycemia (high blood glucose level) and storing it as glycogen (glycogenesis) or converting it to fat. When all glycogen stores have been used, the liver can convert amino acids and glycerol to glucose (gluconeogenesis). Insulin is a hormone synthesized in the pancreas by the beta cells of the islets of Langerhans and plays a vital role in glycogenesis. The primary stimulus for the secretion of insulin from the beta cells is glucose. The presence of insulin stimulates the diffusion of glucose into adipose and muscle tissue, and inhibits the production of glucagon. Declining glucose levels, on the other hand, stimulate the alpha cells of the pancreatic islets to secrete insulin antagonist, glucagon. Glucagon is a hyperglycemic hormone because it raises blood glucose levels. Glucagon works on the liver and fat tissue. Liver cells respond by accelerating glycogenolysis and gluconeogenesis, whereas fats cells mobilize their fatty stores (lipolysis) and release fatty acid and glycerol to the blood. Glucagon-stimulated glycogenolysis and gluconeogenesis are responsible for up to 75% of glucose production in the fasting state.

Metabolic Detoxification

The liver alters exogenous and endogenous chemicals (e.g., medications), foreign molecules, and hormones to make them less toxic or less biologically active. This process, called metabolic detoxification or biotransformation, diminishes intestinal or renal tubular reabsorption of potentially toxic substances and facilitates their intestinal and renal excretion. In this way alcohol, barbiturates, amphetamines, steroids, and hormones (including estrogens, aldosterone, antidiuretic hormone, and testosterone) are metabolized or detoxified, preventing excessive accumulation and side effects. Although metabolic detoxification is usually protective, the end products of metabolic detoxification sometimes become toxins (see Health Promotion: Acetaminophen and Acute Liver Failure) or active metabolites. Toxins of alcohol metabolism, for example, are acetaldehyde and hydrogen, which can damage the liver's ability to function (see Chapter 4 and Figure 4-19).

Health Promotion Acetaminophen and Acute Liver Failure Acetaminophen (Tylenol) is an over-the-counter analgesic and antipyretic that is considered by most users to be a safe medication. Acetaminophen has been misused by patients to the extent that it is now the most common cause of acute live failure in Canada. While the maximum daily dose is 4 grams, some patients exceed this dose (unintentionally, in one in five cases) due to the established safe profile and good reputation of this medication. Another cause of misuse is extending the duration of acetaminophen's intended use: acetaminophen is intended to be used for 5 days for pain and 3 days for fever, but some patients use it for months or even years to treat persistent pain. In addition, prescription analgesics that combine acetaminophen with a strong analgesic (e.g., codeine) are more likely to be misused because patients tend to use them for longer periods. In Canada, the number of patients admitted to hospital with acetaminophen overdose exceeds 4 000 per year, and the number of unintentional cases is increasing. Overdose on acetaminophen products has been shown to be prevalent among adolescents and young adults, primarily among females. In 2015, Health Canada made the following recommendations to the pharmaceutical industry to decrease the number of unintentional acetaminophen overdoses: • Improve product labelling and packaging (Health Canada imposed new labelling rules in 2016) • Reduce the amount of acetaminophen in over-the-counter products • Reduce the maximum recommended daily dose • Reconsider the practice of adding acetaminophen to narcotic products • Provide accurate and easy-to-use dosing devises for children's acetaminophen liquid products Acetaminophen toxicity from chronic use or overdose is the leading cause of acute liver failure in the developed world (see Figure 4-16). Concomitant alcohol use or abuse, medications, genetics, and nutritional status can influence the susceptibility and severity of hepatotoxicity. Hepatoxicity should be suspected when doses exceed 4 grams per day. Liver injury occurs in 17% of adults who have unintentionally overdosed on acetaminophen. The onset of toxicity is sudden and lasts for up to 24 hours. Symptoms include gastro-intestinal upset, nausea, vomiting, anorexia, diaphoresis, and pallor. Elevated levels of serum aminotransferase (AT) appear after 48 hours accompanied by hypoprothrombinemia, metabolic acidosis, and kidney failure. Early treatment (within 8 hours) with Nacetylcysteine (NAC) provides a 66% chance of recovery. The acetaminophen–aminotransferase multiplication product (APAP × AT) and the Psi parameter (acetaminophen level at 4 hours postingestion and the time-to-initiation of NAC) are predictors of acetaminophen toxicity in NACtreated individuals. Liver transplant is lifesaving, and there is about 70% survival at 1 year after liver transplantation. APAP, Acetaminophen.

Data from Blieden, M., Paramore, C., Shah, D., et al. (2014). Expert Rev Clin Pharmacol, 7(3), 341–348; Bunchorntavakul, C., & Reddy, K.R. (2013). Clin Liver Dis, 17(4), 587–607, viii; Chomchai, S., & Chomchai, C. (2014). Clin Toxicol (Phila), 52(5), 506–511; Craig, D.G., Bates, C.M., Davidson, J.S., et al. (2011). Br J Clin Pharmacol, 71(2), 273–282; Government of Canada. (2016). Revised guidance document: Acetaminophen labelling standard. Retrieved from https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applicationssubmissions/guidance-documents/revised-guidance-document-acetaminophen-labelling-standard.html; Health Canada. (2015). Summary safety review—acetaminophen—liver injury. Retrieved from http://www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/acetamino-eng.php; Hodgman, M.F., & Garrard, A.R. (2012). Crit Care Clin, 28(4), 499–516.

Storage of Minerals and Vitamins The liver stores certain vitamins and minerals, including iron and copper, in times of excessive intake and releases them in times of need. The liver can store vitamins B12 and D for several months and vitamin A for several years. The liver also stores vitamins E and K. Iron is stored in the liver as ferritin, an iron– protein complex, and is released as needed for red blood cell production. Common tests of liver function are listed in Table 35-3. TABLE 35-3 Common Tests of Liver Function Test Serum Enzymes Alkaline phosphatase (ALP) Gamma-glutamyltranspeptidase (GGT) Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Lactate dehydrogenase (LDH) 5′-Nucleotidase Bilirubin Metabolism Serum bilirubin Unconjugated (indirect) Conjugated (direct) TOTAL Urine bilirubin Urine urobilinogen Serum Proteins Albumin Globulin TOTAL Albumin/globulin (A/G) ratio Transferrin Alpha fetoprotein (AFP) Blood-Clotting Functions Prothrombin time (PT) Activated partial thromboplastin time (aPTT) Bromosulfophthalein (BSP) excretion

Normal Value

Interpretation

35–120 units/L Males: 8–38 units/L Females: 5–31 units/L 0–35 units/L 4–36 units/L 100–190 units/L

It increases with biliary obstruction and cholestatic hepatitis. It increases with biliary obstruction and cholestatic hepatitis.

2–16 units/L

It increases with an increase in ALP and in cholestatic disorders.

3.4–120 mcmol/L 1.7–5.1 mcmol/L 5.1–17 mcmol/L 0 0–34 mcmol/L

It increases with hemolysis (lysis of red blood cells). It increases with hepatocellular injury or obstruction. It increases with biliary obstruction. It increases with biliary obstruction. It increases with hemolysis or shunting of portal blood flow.

35–50 g/L 23–34 g/L 64–83 g/L 1.5 : 1 to 2.5 : 1 Males: 2–5 g/L Females: 1.9–4.4 g/L 0–40 mcg/L

It decreases with hepatocellular injury. It increases with hepatitis.

11–12.5 sec or 85–100% of control 30–40 sec 80 mmol/L Bicarbonate output: >10 mmol/L/30 sec 2–5 g/24 hr

Decreased volume occurs with pancreatic disease because a secretin stimulates pancreatic secretion. Decreased concentration or secretion can occur with pancreatic injury related to pancreatitis; lack of buffering of gastric acid can lead to intestinal ulcers and decrease activation of digestive enzymes and medications that require a higher pH. See above. This test measures fatty acids; decreased pancreatic lipase increases stool fat.

Quick Check 35-6 1. Trace the route of bile salts and acids from formation to recycling. 2. What are the sources of the two types of bilirubin? 3. What is the function of the gallbladder? 4. How do pancreatic beta cells differ from acinar cells?

Geriatric Considerations Aging and the Gastro-Intestinal System Age-related changes in gastro-intestinal (GI) function vary among individuals and within organ systems. Changes can include the following:

Oral Cavity and Esophagus 1. Tooth enamel and dentin deteriorate, so cavities are more likely. 2. Teeth are lost as a result of periodontal disease and brittle roots that break easily. 3. Taste buds decline in number. 4. Sense of smell diminishes. 5. Salivary secretion decreases. 6. Dysphagia is much more common. 7. Eating is less pleasurable, appetite is reduced, and food is not sufficiently chewed or lubricated; therefore swallowing is difficult.

Stomach 1. Gastric motility, blood flow, and volume and acid content of gastric juice may be reduced, particularly with gastric atrophy, and gastric emptying may be delayed. 2. Protective mucosal barrier decreases.

Intestines 1. There is a change in the composition of the intestinal microbiota and resultant increased susceptibility to disease. 2. Size of Peyer patches and degree of mucosal immunity decline, which increases the risk for infection and inflammation. 3. The brain–gut axis (bidirectional neuroendocrine communication) may be disrupted, and enteric neurons may degenerate with changes in GI motility, secretion, and absorption as well as the older adult's appetite and overall nutritional status. 4. Intestinal villi may become shorter and more convoluted, with diminished reparative capacity. 5. Intestinal absorption, motility, and blood flow may decrease, prolonging transit time and altering nutrient absorption. 6. Rectal muscle mass decreases and the anal sphincter weakens. 7. Constipation, fecal impaction, and fecal incontinence may develop and are related to immobility, low-fibre diet, and changes in enteric nervous system structure and functions.

Liver 1. There is decreased hepatic regeneration; size and weight of liver decrease. 2. The ability to detoxify medications decreases. 3. Blood flow decreases, influencing the efficiency of medication metabolism.

Pancreas and Gallbladder 1. Fibrosis, fatty acid deposits, and pancreatic atrophy occur.

2. Secretion of digestive enzymes, particularly proteolytic enzymes, decreases. 3. No changes in gallbladder and bile ducts occur, but there is an increased prevalence of gallstones and cholecystitis. Data from Britton, E., & McLaughlin, J.T. (2013). Proc Nutr Soc, 72(1), 173–177; Lakshminarayanan, B., Stanton, C., O'Toole, P.W., et al. (2014). J Nutr Health Aging, 18(9), 773–786; Rayner, C.K., & Horowitz, M. (2013). Curr Opin Clin Nutr Metab Care, 16(1), 33–38; Saffrey, M.J. (2013). Dev Biol, 382(1), 344–355; Saffrey, M.J. (2014). Age (Dordr), 36(3), 9603.

Did You Understand? The Gastro-Intestinal Tract 1. The gastro-intestinal (GI) tract is a hollow tube that extends from the mouth to the anus. 2. The major functions of the GI tract are the mechanical and chemical breakdown of food and the absorption of digested nutrients. 3. The wall of the GI tract is made up of four layers: mucosa, muscularis, submucosa, and serosa. 4. The peritoneum is a double layer of membranous tissue. The visceral layer covers the abdominal organs, and the parietal layer extends along the abdominal wall. The peritoneal cavity is the space between the two layers. 5. Except for swallowing and defecation, which are controlled voluntarily, the functions of the GI tract are controlled by extrinsic and intrinsic autonomic nerves and intestinal hormones. 6. Digestion begins in the mouth, with chewing and salivation. The digestive component of saliva is α-amylase, which initiates carbohydrate digestion. 7. The esophagus is a hollow, muscular tube that transports food from the mouth to the stomach. The tunica muscularis in the upper part of the esophagus is striated muscle, and that in the lower part is smooth muscle. 8. Swallowing is controlled by the swallowing centre in the reticular formation of the brain. The two phases of swallowing are the oropharyngeal phase (voluntary swallowing) and the esophageal phase (involuntary swallowing). 9. Food is propelled through the esophagus by peristalsis: waves of sequential relaxations and contractions of the tunica muscularis. 10. The lower esophageal sphincter opens to admit swallowed food into the stomach and then closes to prevent regurgitation of food back into the esophagus. 11. The stomach is a hollow, baglike structure that secretes digestive juices, mixes and stores food, and propels partially digested food (chyme) through the pylorus into the duodenum. 12. The hormones gastrin and motilin stimulate gastric emptying; the hormones secretin and cholecystokinin delay gastric emptying. 13. The vagus nerve stimulates gastric (stomach) secretion and motility. 14. The three phases of acid secretion by the stomach are the cephalic phase (anticipation and swallowing), the gastric phase (food in the stomach), and the intestinal phase (chyme in the intestine). 15. Gastric glands in the fundus and body of the stomach secrete intrinsic factor, which is needed for vitamin B12 absorption, and hydrochloric acid, which dissolves food fibres, kills microorganisms, and activates the enzyme pepsin. 16. Acid secretion is stimulated by the vagus nerve, gastrin, and histamine and is inhibited by sympathetic stimulation and cholecystokinin. 17. Chief cells in the stomach secrete pepsinogen, which is converted to pepsin in the acidic environment created by hydrochloric acid. 18. Mucus is secreted throughout the stomach and protects the stomach wall from acid and digestive enzymes. 19. The small intestine is 5 to 6 m long and has three segments: the duodenum, jejunum, and ileum. 20. The ileocecal valve connects the small and large intestines and prevents reflux into the small intestine. 21. Villi are small fingerlike projections that extend from the small intestinal mucosa and increase its absorptive surface area. 22. The duodenum receives chyme from the stomach through the pyloric valve. The presence of chyme stimulates the liver and gallbladder to deliver bile and the pancreas to deliver digestive enzymes. Bile and enzymes flow through an opening guarded by the sphincter of Oddi. 23. Enzymes secreted by the small intestine (maltase, sucrase, lactase), pancreatic enzymes, and bile

salts act in the small intestine to digest proteins, carbohydrates, and fats. 24. Digested substances are absorbed across the intestinal wall and then transported to the liver, where they are metabolized further. 25. Carbohydrates, amino acids, and fats are absorbed primarily by the duodenum and jejunum; bile salts and vitamin B12 are absorbed by the ileum. Vitamin B12 absorption requires the presence of intrinsic factor. 26. Minerals and water-soluble vitamins are absorbed by both active and passive transport throughout the small intestine. 27. Peristaltic movements created by longitudinal muscles propel the chyme along the intestinal tract, and contractions of the circular muscles (haustral segmentation) mix the chyme. 28. The ileogastric reflex inhibits gastric motility when the ileum is distended. 29. The intestinointestinal reflex inhibits intestinal motility when one intestinal segment is overdistended. 30. The gastroileal reflex increases intestinal motility when gastric motility increases. 31. The large intestine consists of the cecum, appendix, colon (ascending, transverse, descending, and sigmoid), rectum, and anal canal. 32. The teniae coli are three bands of longitudinal muscle that extend the length of the colon. 33. Haustra are pouches of colon formed with alternating contraction and relaxation of the circular muscles. 34. The mucosa of the large intestine contains mucus-secreting cells and mucosal folds, but no villi. 35. The large intestine massages the fecal mass and absorbs water and electrolytes. 36. Distension of the ileum with chyme causes the gastrocolic reflex, or the mass propulsion of feces to the rectum. 37. Defecation is stimulated when the rectum is distended with feces. The tonically contracted internal anal sphincter relaxes, and if the voluntarily regulated external sphincter relaxes, defecation occurs. 38. The immune system of the GI tract consists of Paneth cells, which produce defensins and other antimicrobial peptides and lysozymes; and the lymph nodes of Peyer patches, which contain lymphocytes, plasma cells, and macrophages. 39. There are an increasing number of bacteria from the proximal to the distal GI tract, with the highest number in the colon. Intestinal bacteria are important for metabolism of bile salts, metabolism of selected medications and hormones, and prevention of pathogen colonization. 40. The intestinal tract is sterile at birth and becomes totally colonized within 3 to 4 weeks. 41. The most numerous anaerobes in the colon are Bacteroides and Firmicutes. 42. The splanchnic blood flow provides blood to the esophagus, stomach, small and large intestines, gallbladder, pancreas, and spleen.

Accessory Organs of Digestion 1. The liver is the second largest organ in the body. It has digestive, metabolic, hematological, vascular, and immunological functions. 2. The liver is divided into the right and left lobes and smaller units called liver lobules. The liver is supported by the falciform, round, and coronary ligaments. 3. Liver lobules consist of plates of hepatocytes, which are the functional cells of the liver. 4. Bile is produced by the liver and is necessary for fat digestion and absorption. Bile's alkalinity helps to neutralize chyme, thereby creating a pH that enables the pancreatic enzymes to digest proteins, carbohydrates, and fats. 5. Bile salts emulsify and hydrolyze fats and incorporate them into water-soluble micelles, which are then transported through the unstirred water layer to the brush border of the intestinal mucosa. The fat content of the micelles readily diffuses through the epithelium into lacteals (lymphatic ducts) in the villi. From there, fats flow into lymphatics and into the systemic circulation, which delivers them to the liver.

6. The hepatocytes synthesize 700 to 1 200 mL of bile per day and secrete it into the bile canaliculi, which are small channels between the hepatocytes. The bile canaliculi drain bile into the common bile duct and then into the duodenum through an opening called the major duodenal papilla (which is surrounded by the sphincter of Oddi). 7. Sinusoids are capillaries located between the plates of hepatocytes. Blood from the portal vein and hepatic artery flows through the sinusoids to a central vein in each lobule and then to the hepatic vein and inferior vena cava. 8. Kupffer cells, which are part of the mononuclear phagocyte system, line the sinusoids and destroy microorganisms in sinusoidal blood; they are important in bilirubin production and lipid metabolism. 9. The primary bile acids are synthesized from cholesterol by the hepatocytes. The primary acids are then conjugated to form bile salts. The secondary bile acids are the product of bile salt deconjugation by bacteria in the intestinal lumen. 10. Most bile salts and acids are recycled. The absorption of bile salts and acids from the terminal ileum and their return to the liver are known as the enterohepatic circulation of bile. 11. Bilirubin is a pigment liberated by the lysis of aged red blood cells in the liver and spleen. Unconjugated bilirubin is fat soluble and can cross cell membranes. Unconjugated bilirubin is converted to water-soluble, conjugated bilirubin by hepatocytes and is secreted with bile. 12. The liver produces clotting factors and can store a large volume of blood. 13. The liver plays a major role in the metabolism of fats, proteins, and carbohydrates; and it stores minerals, vitamin B12, and fat-soluble vitamins. 14. The liver metabolically transforms or detoxifies hormones, toxic substances, and medications to less active substances. 15. The gallbladder is a saclike organ located on the inferior surface of the liver. The gallbladder stores bile between meals and ejects it when chyme enters the duodenum. 16. Stimulated by cholecystokinin, the gallbladder contracts and forces bile through the cystic duct and into the common bile duct. The sphincter of Oddi relaxes, enabling bile to flow through the major duodenal papilla into the duodenum. 17. The pancreas is a gland located behind the stomach. The endocrine pancreas produces hormones (glucagon, insulin) that facilitate the formation and cellular uptake of glucose. The exocrine pancreas secretes an alkaline solution and the enzymes (trypsin, chymotrypsin, carboxypeptidase, α-amylase, lipase) that digest proteins, carbohydrates, and fats. 18. Secretin stimulates pancreatic secretion of alkaline fluid, and cholecystokinin and acetylcholine stimulate secretion of enzymes. Pancreatic secretions originate in acini and ducts of the pancreas and empty into the duodenum through the common bile duct or an accessory duct that opens directly into the duodenum.

Key Terms Ampulla of Vater, 915 Antrum, 902 Ascending colon, 909 Bile, 912 Bile acid pool, 912 Bile acid–dependent fraction, 912 Bile acid–independent fraction, 912 Bile canaliculi, 911 Bile salt, 912 Bilirubin, 913 Body of the stomach, 902 Brush border, 906 Cardiac orifice, 902 Cecum, 909 Chief cell, 905 Cholecystokinin, 903 Choleresis, 912 Choleretic agent, 912 Chyme, 902 Colon, 909 Common bile duct, 911 Conjugated bilirubin, 913 Crypts of Lieberkühn, 906 Cystic duct, 914 Deamination, 914 Defecation reflex (rectosphincteric reflex), 910 Descending colon, 909 Disse space, 912 Duodenum, 905 Enteric (intramural) plexus, 899 Enterocytes, 906 Enterohepatic circulation, 912 Enterokinase, 916 Esophageal phase of swallowing, 901 Esophagus, 901 Exocrine pancreas, 915 External anal sphincter, 909 Fecal mass, 910 Fundus, 902 Gallbladder, 914 Gastric emptying, 903 Gastric gland, 904 Gastrin, 903 Gastrocolic reflex, 910 Gastroileal reflex, 908 Gastro-Intestinal (GI) tract, 000 Glisson capsule, 911 Haustral segmentation, 908 Haustrum (pl., haustra), 909

Hepatic artery, 911 Hepatic portal vein, 911 Hepatic vein, 911 Hepatocyte, 911 Ileocecal valve (sphincter), 906 Ileogastric reflex, 908 Ileum, 905 Internal anal sphincter, 909 Intestinointestinal reflex, 908 Intrinsic factor, 904 Jejunum, 905 Kupffer cell (tissue macrophage), 911 Lacteal, 906 Lamina propria, 906 Large intestine, 909 Liver, 911 Liver lobule, 911 Lower esophageal sphincter (cardiac sphincter), 901 Major duodenal papilla, 910 Mesentery, 906 Metabolic detoxification (biotransformation), 914 Microvillus (pl., microvilli), 906 Motilin, 903 Mouth, 899 Mucosal barrier, 905 Myenteric plexus (Auerbach plexus), 902 Natural killer cells (pit cells), 912 Oropharyngeal (voluntary) phase of swallowing, 901 Pancreas, 915 Pancreatic duct (Wirsung duct), 915 Paneth cell, 910 Parietal cell, 904 Pepsin, 905 Peristalsis, 908 Peritoneal cavity, 906 Peritoneum, 906 Peyer patch, 910 Primary bile acid, 912 Primary peristalsis, 901 Pyloric sphincter, 902 Pylorus (gastroduodenal junction), 902 Rectosigmoid (O'Beirne) sphincter, 909 Rectum, 910 Reticuloendothelial system, 913 Retropulsion, 903 S cell, 916 Saliva, 899 Salivary α-amylase (ptyalin), 901 Salivary gland, 899 Secondary bile acid, 912 Secondary peristalsis, 901 Secretin, 903 Sigmoid colon, 909

Sinusoid, 911 Small intestine, 905 Sphincter of Oddi, 910 Splanchnic blood flow, 910 Stellate cells, 912 Stomach, 902 Submucosal plexus (Meissner plexus), 902 Swallowing, 901 Teniae coli, 909 Transverse colon, 909 Trypsin inhibitor, 916 Unconjugated bilirubin, 913 Upper esophageal sphincter, 901 Urobilinogen, 913 Valsalva manoeuvre, 910 Vermiform appendix, 909 Villus (pl., villi), 906

References 1. Woodland P, Sifrim D, Krarup AL, et al. The neurophysiology of the esophagus. Annals of the New York Academy of Sciences. 2013;1300:53–70; 10.1111/nyas.12238. 2. Hellström PM, Gryback P, Jacobsson H. The physiology of gastric emptying. Best Practice and Research: Clinical Anaesthesiology. 2006;20(3):397–407. 3. Chu S, Schuberft ML. Gastric secretion. Current Opinion in Gastroenterology. 2012;28(6):587–593; 10.1097/MOG.0b013e328358e5cc. 4. Niv Y, Fraser GM. The alkaline tide phenomenon. Journal of Clinical Gastroenterology. 2002;35(1):5– 8. 5. Miller MJ, McDole JR, Newberry RD. Microanatomy of the intestinal lymphatic system. Annals of the New York Academy of Sciences. 2010;1207(Suppl. 1):E21–E28; 10.1111/j.1749-6632.2010.05708.x. 6. Bobadilla JL. Mesenteric ischemia. The Surgical Clinics of North America. 2013;93(4):925–940; 10.1016/j.suc.2013.04.002 [ix]. 7. Mowat AM, Agace WW. Regional specialization within the intestinal immune system. Nature Reviews: Immunology. 2014;14(10):667–685; 10.1038/nri3738. 8. Schippa S, Conte MP. Dysbiotic events in gut microbiota: Impact on human health. Nutrients. 2014;6(12):5786–5805; 10.3390/nu6125786. 9. Khanna S, Tosh PK. A clinician's primer on the role of the microbiome in human health and disease. Mayo Clinic Proceedings. 2014;89(1):107–114; 10.1016/j.mayocp.2013.10.011. 10. Dixon LJ, Barnes M, Tang H, et al. Kupffer cells in the liver. Comprehensive Physiology. 2013;3(2):785–797; 10.1002/cphy.c120026. 11. Weiskirchen R, Tacke F. Cellular and molecular functions of hepatic stellate cells in inflammatory responses and liver immunology. Hepatobiliary Surgery & Nutrition. 2014;3(6):344–363; 10.3978/j.issn.2304-3881.2014.11.03. 12. Tian Z, Chen Y, Gao B. Natural killer cells in liver disease. Hepatology (Baltimore, Md.). 2013;57(4):1654–1662; 10.1002/hep.26115. 13. Jansen T, Daiber A. Direct antioxidant properties of bilirubin and biliverdin. Is there a role for biliverdin reductase? Frontiers in Pharmacology. 2012;3:30; 10.3389/fphar.2012.00030.

36

Alterations of Digestive Function Sue E. Huether, Mohamed El-Hussein

CHAPTER OUTLINE Disorders of the Gastro-Intestinal Tract, 921 Clinical Manifestations of Gastro-Intestinal Dysfunction, 921 Disorders of Motility, 925 Gastritis, 930 Peptic Ulcer Disease, 931 Malabsorption Syndromes, 935 Inflammatory Bowel Disease, 935 Diverticular Disease of the Colon, 938 Appendicitis, 939 Mesenteric Vascular Insufficiency, 939 Disorders of Nutrition, 940 Disorders of the Accessory Organs of Digestion, 943 Common Complications of Liver Disorders, 943 Disorders of the Liver, 947 Disorders of the Gallbladder, 951 Disorders of the Pancreas, 952 Cancer of the Digestive System, 953 Cancer of the Gastro-Intestinal Tract, 953 Cancer of the Accessory Organs of Digestion, 957

The gastro-intestinal (GI) tract is a continuous, hollow organ that extends from the mouth to the anus. It includes the esophagus, stomach, small intestine, large intestine, and rectum. The accessory organs of digestion include the salivary glands, liver, gallbladder, and pancreas. Disorders of the GI tract disrupt one or more of its functions. Structural and neural abnormalities can slow, obstruct, or accelerate the movement of intestinal contents at any level of the GI tract. Inflammatory

and ulcerative conditions of the GI wall disrupt secretion, motility, and absorption. Inflammation or obstruction of the liver, pancreas, or gallbladder can alter metabolism and result in local and systemic symptoms. Many clinical manifestations of GI tract disorders are nonspecific and can be caused by a variety of impairments.

Disorders of the Gastro-Intestinal Tract Clinical Manifestations of Gastro-Intestinal Dysfunction Anorexia Anorexia is lack of a desire to eat despite physiological stimuli that would normally produce hunger. This nonspecific symptom is often associated with nausea, abdominal pain, diarrhea, and psychological stress. Side effects of medications and disorders of other organ systems, including cancer, heart disease, and kidney disease, are often accompanied by anorexia.

Vomiting Vomiting (emesis) is the forceful emptying of stomach and intestinal contents (chyme) through the mouth.1 The vomiting centre lies in the medulla oblongata. Stimuli initiating the vomiting reflex include severe pain; distension of the stomach or duodenum; the presence of ipecac or copper salts in the duodenum; stimulation of the vestibular system through the eighth cranial nerve (motion sickness); side effects of many medications; torsion or trauma affecting the ovaries, testes, uterus, bladder, or kidney; motion; and activation of the chemoreceptor trigger zone (CTZ) (area postrema) in the medulla (e.g., morphine). Nausea and retching (dry heaves) are distinct events that usually precede vomiting. Nausea is a subjective experience associated with various conditions, including abnormal pain and labyrinthine stimulation (i.e., spinning movement). Specific neural pathways have not been identified, but hypersalivation and tachycardia are common associated symptoms. Retching is the muscular event of vomiting without the expulsion of vomitus. Vomiting begins with deep inspiration. The glottis closes, the intrathoracic pressure falls, and the esophagus becomes distended. Simultaneously, the abdominal muscles contract, creating a pressure gradient from abdomen to thorax. The lower esophageal sphincter (LES) and body of the stomach relax, but the duodenum and antrum of the stomach spasm. The reverse peristalsis and pressure gradient force chyme from the stomach and duodenum up into the esophagus. Because the upper esophageal sphincter is closed, chyme does not enter the mouth. As the abdominal muscles relax, the contents of the esophagus drop back into the stomach. This process may be repeated several times before vomiting occurs. A diffuse sympathetic discharge causes the tachycardia, tachypnea, and diaphoresis that accompany retching and vomiting. The parasympathetic system mediates copious salivation, increased gastric motility, and relaxation of the upper and lower esophageal sphincters. With vomiting, the duodenum and antrum of the stomach produce reverse peristalsis, while the body of the stomach and the esophagus relax. When the stomach is full of gastric contents, the diaphragm is forced high into the thoracic cavity by strong contractions of the abdominal muscles. The higher intrathoracic pressure forces the upper esophageal sphincter to open, and chyme is expelled from the mouth. Then the stomach relaxes and the upper part of the esophagus contracts, forcing the remaining chyme back into the stomach. The LES then closes. The cycle is repeated if there is a volume of chyme remaining in the stomach. Spontaneous vomiting not preceded by nausea or retching is called projectile vomiting. It is caused by direct stimulation of the vomiting centre by neurological lesions (e.g., increased intracranial pressure, tumours, or aneurysms) involving the brainstem or can be a symptom of GI obstruction (pyloric stenosis). The metabolic consequences of vomiting are fluid, electrolyte, and acid–base disturbances, including hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis (see Chapter 5).

Constipation Constipation is difficult or infrequent defecation. It is a common problem, particularly among older adults, and usually means a decrease in the number of bowel movements per week, hard stools, and difficult evacuation. The definition of constipation must be individually determined since normal bowel habits range from one to three evacuations per day to one per week. Constipation is not significant until it causes health risks or impairs quality of life.

Pathophysiology Constipation can occur as a primary or secondary condition.2 Primary constipation is generally classified into three categories. Normal transit (functional) constipation involves a normal rate of stool passage, but there is difficulty with stool evacuation. Functional constipation is associated with a sedentary lifestyle, low-residue diet (the habitual consumption of highly refined foods), or low fluid intake. Slow-transit constipation involves impaired colonic motor activity with infrequent bowel movements, straining to defecate, mild abdominal distension, and palpable stool in the sigmoid colon. Pelvic floor dysfunction or outlet dysfunction refers to an inability or difficulty expelling stool because of dysfunction of the pelvic floor muscles or anal sphincter. Examples include pelvic floor dyssynergia, rectal fissures, strictures, or hemorrhoids. Secondary constipation can be caused by diet, medications, or neurogenic disorders (e.g., stroke, Parkinson's disease, spinal cord lesions, multiple sclerosis, Hirschsprung's disease) in which neural pathways or neurotransmitters are altered and colon transit time delayed. Opiates (particularly codeine), antacids containing calcium carbonate or aluminum hydroxide, anticholinergics, iron, and bismuth tend to inhibit bowel motility. Endocrine or metabolic disorders associated with constipation include hypothyroidism, diabetes mellitus, hypokalemia, and hypercalcemia. Pelvic hiatal hernia (herniation of the bowel through the floor of the pelvis), diverticuli, irritable bowel syndrome (constipation predominant), and pregnancy are associated with constipation. Aging may result in decreased mobility, changes in neuromuscular function, use of medications, and comorbid medical conditions causing constipation.2 Constipation as a notable change in bowel habits can be an indication of colorectal cancer. Clinical manifestations Indicators of constipation include two of the following for at least 3 months: (1) straining with defecation at least 25% of the time; (2) lumpy or hard stools at least 25% of the time; (3) sensation of incomplete emptying at least 25% of the time; (4) manual manoeuvres to facilitate stool evacuation for at least 25% of defecations; and (5) fewer than three bowel movements per week.3 Changes in bowel evacuation patterns, such as less frequent defecation, smaller stool volume, hard stools, difficulty passing stools (straining), or a feeling of bowel fullness and discomfort, require investigation. Fecal impaction (hard, dry stool retained in the rectum) is associated with rectal bleeding, abdominal or cramping pain, nausea and vomiting, weight loss, and episodes of diarrhea. Straining to evacuate stool may cause engorgement of the hemorrhoidal veins and hemorrhoidal disease or thrombosis with rectal pain, bleeding, and itching. Passage of hard stools can cause painful anal fissures. Evaluation and treatment The history, current use of medications, physical examination, and stool diaries provide precise clues regarding the nature of constipation. The individual's description of frequency, stool consistency, associated pain, and presence of blood or whether evacuation was stimulated by enemas or cathartics (laxatives) is important. Palpation may disclose colonic distension, masses, and tenderness. Digital examination of the rectum and anorectal manometry are performed to assess sphincter tone and detect anal lesions. Colonic transit time and imaging techniques can assist in identifying the cause of constipation. Colonoscopy is used to visualize the lumen directly. The treatment for constipation is to manage the underlying cause or disease for each individual. Management of constipation usually consists of bowel retraining, in which the individual establishes a satisfactory bowel evacuation routine without becoming preoccupied with bowel movements. The individual also may need to engage in moderate exercise, drink more fluids, and increase fibre intake. Fibre supplements, stool softeners, and laxative agents are useful for some individuals. Enemas can be used to establish bowel routine, but they should not be used habitually. Biofeedback may be beneficial in some instances for forming new bowel evacuation habits. When there is failure to respond to dietary or medical therapies, surgery (colectomy) is considered as a last resort.4

Diarrhea Diarrhea is the presence of loose, watery stools. Acute diarrhea is more than three loose stools developing within 24 hours and lasting less than 14 days. Persistent diarrhea lasts longer than 14 to 30 days, and

chronic diarrhea lasts longer than 4 weeks.5,6 Diarrhea can have high rates of morbidity and mortality in children younger than 5 years of age, particularly in developing countries (see Chapter 37) and in older adults. Many factors determine stool volume, including water content of the colon, diet, the presence of nonabsorbed food, nonabsorbable material, and intestinal secretions. Stool volume in the normal adult averages less than 200 g per day. Stool volume in children depends on age and size. An infant may pass up to 100 g per day. The adult intestine processes approximately 9 L of luminal contents per day: 2 L are ingested and the remaining 7 L consist of intestinal secretions. Of this volume, 99% of the fluid is absorbed: 90% (7 to 8 L) in the small intestine and 9% (1 to 2 L) in the colon. Normally, approximately 150 mL of water is excreted daily in the stool. Pathophysiology Diarrhea in which the volume of feces is increased is called large-volume diarrhea. It generally is caused by excessive amounts of water or secretions or both in the intestines. Small-volume diarrhea, in which the volume of feces is not increased, usually results from excessive intestinal motility. The three major mechanisms of diarrhea are osmotic, secretory, and motile: 1. Osmotic diarrhea. A nonabsorbable substance in the intestine draws excess water into the intestine and increases stool weight and volume, producing large-volume diarrhea. Causes include lactase and pancreatic enzyme deficiency; excessive ingestion of synthetic, nonabsorbable sugars; full-strength tube-feeding formulas; or dumping syndrome associated with gastric resection. 2. Secretory diarrhea. Excessive mucosal secretion of fluid and electrolytes produces large-volume diarrhea. Infectious causes include viruses (e.g., rotavirus), bacterial enterotoxins (e.g., Escherichia coli and Vibrio cholerae), exotoxins from overgrowth of Clostridium difficile following antibiotic therapy (see Health Promotion: Clostridium difficile and Diarrhea), and small bowel bacterial overgrowth.7 Small-volume diarrhea is usually caused by an inflammatory disorder of the intestine, such as ulcerative colitis (UC), Crohn's disease (CD), or microscopic colitis, but also can result from colon cancer or fecal impaction. 3. Motility diarrhea is caused by resection of the small intestine (short bowel syndrome), surgical bypass of an area of the intestine or fistula formation between loops of intestine, irritable bowel syndrome–diarrhea predominant, diabetic neuropathy, hyperthyroidism, and laxative abuse. Excessive motility decreases transit time and opportunity for fluid absorption, resulting in diarrhea.

Health Promotion Clostridium difficile and Diarrhea Clostridium difficile is a gram-positive, spore-forming, anaerobic bacillus that causes infectious diarrhea by producing toxins. C. difficile is the most frequent cause of health care–associated infectious diarrhea in Canada and other developed countries. The reported incidence of health care–associated C. difficile infection in Canada has risen over the last decade. C. difficile infection manifestations range from uncomplicated diarrhea to life-threatening pseudomembranous colitis, bowel perforation, and sepsis. In Canadian hospitals, the mortality rate associated with C. difficile infection increased almost fourfold from 1997 to 2005 (1.5% of cases to 5.7% of cases, respectively, p < .001). The main mode of transmission for C. difficile in health care settings is person-to-person spread through the fecal–oral route. Momentary contamination of the hands of health care personnel with C. difficile spores and environmental contamination play an important role in the transmission of C. difficile in health care settings. C. difficile, unlike other bacterial pathogens, persists longer in the environment and resists routine disinfection processes. For this reason, environmental contamination is a significant factor in cross-transmission between patients and health care providers.

Often a C. difficile infection is associated with previous antibiotic use. Judicious administration of antibiotics is believed to have a role in preventing and terminating the incidence of C. difficile infection.

Measures to Prevent C. difficile Infections in Health Care Facilities • Facility design should include single rooms for the routine care of inpatients that includes private toilets inside the room, designated patient sinks, alcohol-based hand rub dispensers, and designated handwashing sinks for staff. • Special disposal systems should be used to manage the disposal of fecal matter when bedpans or commodes are required to avoid environmental contamination with C. difficile spores. • For patients with acute diarrhea due (suspected or confirmed) to C. difficile infection, contact precautions must be implemented immediately until the diarrhea is resolved or its cause is determined not to be infectious. • Patients with uncontrolled diarrhea or fecal incontinence should be given preference for single private rooms where possible. • Signage should be placed at the entrance to the infected patient's room, cubicle, and designated bed space to indicate the need to apply contact precautions. • Frequent hand hygiene should be performed using effective techniques: • Following patient care or contact with patient's environment • After removing gloves at point of care and just prior to leaving the patient's room • Following contact with fecal matter, bedpans, and commodes. • Handwashing with soap and water should be performed at the point of care and at an assigned staff handwashing sink. If an assigned staff handwashing sink is not available at the point of care, alcohol-based hand rub (with an alcohol concentration between 60 and 90%) must be used, and hand hygiene with soap and water must be performed as soon as a staff handwashing sink is available. • Hand wipes (impregnated with plain soap, antimicrobials, or alcohol) may be used as an alternative to soap and water when an assigned staff handwashing sink is not readily available, or when the handwashing sink is not appropriate (e.g., contaminated, no running water, no soap), when hands are not visibly soiled. When hands are visibly soiled, alcohol-based hand rub should be used after the use of hand wipes, and hands should be washed with soap and water once a suitable staff handwashing sink is available. • Unless medically indicated (e.g., for essential diagnostic and therapeutic tests or treatment) the transfer of patients suspected or confirmed to have C. difficile infection within and between facilities should be avoided. • The number of visitors for a patient on contact precautions must be restricted to essential visitors (e.g., immediate family member or parent, guardian, or primary caretaker) only. From Public Health Agency of Canada. (2013). Clostridium difficile infection: Infection prevention and control guidance for management in acute care settings. Retrieved from http://www.phac-aspc.gc.ca/nois-sinp/guide/c-dif-acs-esa/index-eng.php.

Clinical manifestations Diarrhea can be acute or chronic, depending on its cause. Systemic effects of prolonged diarrhea are dehydration, electrolyte imbalance (hyponatremia, hypokalemia), and weight loss. Manifestations of acute bacterial or viral infection include fever, with or without vomiting or cramping pain. Most infectious diarrhea usually lasts less than 2 weeks. The exceptions are C. difficile, Aeromonas, or Yersinia enterocolitica.8 Fever, cramping pain, and bloody stools accompany chronic diarrhea caused by inflammatory bowel disease (IBD) or dysentery. Steatorrhea (fat in the stools), bloating, and diarrhea are common signs of malabsorption syndromes. (Steatorrhea can also indicate alterations in liver and pancreatic functions.) Anal and perineal skin irritation can occur. Evaluation and treatment A thorough history is taken to document the onset, frequency, and duration of diarrhea, the volume of

stools, and the presence of blood in the stools. Malabsorption syndromes usually manifest as steatorrhea. Exposure to contaminated food or water is indicated if the individual has travelled in foreign countries or areas where drinking water might be contaminated. Iatrogenic diarrhea is suggested if the individual has undergone abdominal radiation therapy, intestinal resection, or treatment with selected medications (e.g., antibiotics, diuretics, antihypertensives, laxatives, anticoagulants or chemotherapy). Physical examination helps identify underlying systemic disease. Stool studies, abdominal imaging, endoscopy, and intestinal biopsies provide more specific data, particularly for persistent diarrhea. Treatment for diarrhea includes restoration of fluid and electrolyte balance, administration of antimotility (e.g., loperamide [Imodium]) medication, water absorbent medication (e.g., attapulgite [Kaopectate] and polycarbophil [Equalactin]), or both, and treatment of causal factors. Nutritional deficiencies need to be corrected in cases of chronic diarrhea or malabsorption.9

Abdominal Pain Abdominal pain is the presenting symptom of a number of GI diseases and can be acute or chronic.10 The causal mechanisms of abdominal pain are mechanical, inflammatory, or ischemic. Generally, the abdominal organs are not sensitive to mechanical stimuli, such as cutting, tearing, or crushing. These organs are, however, sensitive to stretching and distension, which activate nerve endings in both hollow and solid structures. Pain accompanies rapid distension rather than gradual distension. Traction on the peritoneum caused by adhesions, distension of the common bile duct, or forceful peristalsis resulting from intestinal obstruction causes pain because of increased tension. Capsules that surround solid organs, such as the liver and gallbladder, contain pain fibres that are stimulated by stretching if these organs swell. Abdominal pain may be generalized to the abdomen or localized to a particular abdominal quadrant. The nature of the pain is often described as sharp, dull, or colicky. Abdominal pain is usually associated with tissue injury and inflammation. Biochemical mediators of the inflammatory response, such as histamine, bradykinin, and serotonin, stimulate organic nerve endings and produce abdominal pain. The edema and vascular congestion that accompany chemical, bacterial, or viral inflammation also cause painful stretching. Hindrance of blood flow from the distension of bowel obstruction or mesenteric vessel thrombosis produces the pain of ischemia, and increased concentrations of tissue metabolites stimulate pain receptors. Abdominal pain can be parietal (somatic), visceral, or referred. Parietal pain, from the parietal peritoneum, is more localized and intense than visceral pain, which arises from the organs themselves. Parietal pain lateralizes because, at any particular point, the parietal peritoneum is innervated from only one side of the nervous system. Visceral pain arises from a stimulus (distension, inflammation, ischemia) acting on an abdominal organ. Inflammatory mediators associated with chronic low-grade inflammation can cause pain hypersensitivity.11 The pain is usually poorly localized, diffuse, or vague with a radiating pattern, because nerve endings in abdominal organs are sparse and multisegmented. Pain arising from the stomach, for example, is experienced as a sensation of fullness, cramping, or gnawing in the midepigastric area. Referred pain is visceral pain felt at some distance from a diseased or affected organ. It is usually well localized and is felt in the skin dermatomes or deeper tissues that share a central afferent pathway with the affected organ. For example, acute cholecystitis may have pain referred to the right shoulder or scapula.

Gastro-Intestinal Bleeding Upper gastro-intestinal bleeding is bleeding in the esophagus, stomach, or duodenum, and is characterized by frank, bright-red bleeding or dark, grainy digested blood (“coffee grounds”) that has been affected by stomach acids (Table 36-1). Upper GI bleeding is commonly caused by bleeding varices (varicose veins) in the esophagus, peptic ulcers, arteriovenous malformations, or a Mallory-Weiss tear at the esophageal-gastric junction caused by severe retching.12 Lower gastro-intestinal bleeding, or bleeding from the jejunum, ileum, colon, or rectum, can be caused by polyps, diverticulitis, inflammatory disease, cancer, or hemorrhoids. Occult bleeding is usually caused by slow, chronic blood loss that is not obvious and results in iron deficiency anemia as iron stores in the bone marrow are slowly depleted.13 Acute, severe GI bleeding is life-threatening depending on the volume and rate of blood loss, associated

disease and age of the affected individual, and effectiveness of treatment. TABLE 36-1 Presentations of Gastro-Intestinal Bleeding Presentations Definition Acute Bleeding Hematemesis Melena Hematochezia Occult Bleeding

Bloody vomitus; either fresh, bright-red blood or dark, grainy digested blood with “coffee grounds” appearance Black, sticky, tarry, foul-smelling stools caused by digestion of blood in gastro-intestinal tract; should be distinguished from black stools caused by dietary iron supplements, blackberries, or bismuth (e.g., Pepto-Bismol) Fresh, bright-red blood passed from rectum Trace amounts of blood in normal-appearing stools or gastric secretions; detectable only with positive fecal occult blood test (guaiac test)

Physiological response to GI bleeding depends on the amount and rate of the loss (Figure 36-1). Changes in blood pressure and heart rate are the best indicators of massive blood loss in the GI tract. During the early stages of blood volume depletion, the peripheral arteries and arterioles constrict to shunt blood to vital organs, including the brain. Signs of large-volume blood loss are postural hypotension (a drop in blood pressure that occurs with a change from the recumbent position to a sitting or upright position), lightheadedness, and loss of vision. Tachycardia develops as a compensatory response to maintain cardiac output and tissue perfusion. If blood loss continues, hypovolemic shock develops (see Chapter 24). Diminished blood flow to the kidneys causes decreased urine output and may lead to oliguria (low urine output), tubular necrosis, and kidney failure. Ultimately, insufficient cerebral and coronary blood flow causes irreversible anoxia and death.

FIGURE 36-1

Pathophysiology of Gastro-Intestinal Bleeding. GI, Gastro-Intestinal.

The presentations of GI bleeding are summarized in Table 36-1. The accumulation of blood in the GI tract is irritating and increases peristalsis, causing vomiting or diarrhea, or both. If bleeding is from the lower GI tract, the diarrhea is frankly bloody. Bleeding from the upper GI tract also can be rapid enough to produce hematochezia (bright-red stools), but generally some digestion of the blood components will have occurred, producing melena—black or tarry stools that are sticky and have a characteristic foul odour. The digestion of blood proteins originating from massive upper GI bleeding is reflected by an increase in blood urea nitrogen (BUN) levels (see Figure 36-1). The hematocrit and hemoglobin values are not the best indicators of acute GI bleeding because plasma volume and red cell volume are lost proportionately. As the plasma volume is replaced, the hematocrit and hemoglobin values begin to reflect the extent of blood loss. The interpretation of these values is modified to account for exogenous replacement of fluids and the hydration status of the tissues.

Quick Check 36-1 1. How does osmotic diarrhea differ from secretory diarrhea?

2. How is visceral pain “referred”? 3. What are the best clinical indicators of acute GI bleeding blood loss?

Disorders of Motility Dysphagia Pathophysiology Dysphagia is difficulty swallowing. It can result from mechanical obstruction of the esophagus or a functional disorder that impairs esophageal motility. Intrinsic obstructions originate in the wall of the esophageal lumen (esophageal dysphagia) and include tumours, strictures, and diverticular herniations (outpouchings). Extrinsic mechanical obstructions originate outside the esophageal lumen and narrow the esophagus by pressing inward on the esophageal wall. The most common cause of extrinsic mechanical obstruction is tumour. Functional dysphagia is caused by neural or muscular disorders that interfere with voluntary swallowing or peristalsis. Disorders that affect the striated muscles of the hypopharyngeal area and upper esophagus interfere with the oropharyngeal (voluntary) phase of swallowing (oropharyngeal dysphagia). Typical causes are dermatomyositis (a muscle disease) and neurological impairments caused by cerebrovascular accidents, Parkinson's disease, multiple sclerosis, muscular dystrophy, or achalasia.14 Achalasia is a rare form of dysphagia related to loss of inhibitory neurons in the myenteric plexus with smooth muscle atrophy in the middle and lower portions of the esophagus. The myenteric neurons are attacked by a cell-mediated and antibody-mediated immune response against an unknown antigen. This leads to altered esophageal peristalsis and failure of the LES to relax, causing functional obstruction of the lower esophagus with varying severity.15 Food accumulates above the obstruction, distends the esophagus, and causes dysphagia (Figure 36-2). Cough and aspiration can occur. As hydrostatic pressure increases, food is slowly forced past the obstruction into the stomach. Chronic esophageal distension requires dilation or surgical myotomy of the LES.

FIGURE 36-2

Achalasia. Increased lower esophageal sphincter muscle tone and loss of peristaltic function prevent food from entering the stomach, causing esophageal distension.

Clinical manifestations Distension and spasm of the esophageal muscles during eating or drinking may cause a mild or severe stabbing pain at the level of obstruction. Discomfort occurring 2 to 4 seconds after swallowing is associated with upper esophageal obstruction. Discomfort occurring 10 to 15 seconds after swallowing is more common in obstructions of the lower esophagus. If obstruction results from a growing tumour, dysphagia begins with difficulty swallowing solids and advances to difficulty swallowing semisolids and liquids. If motor function is impaired, both solids and liquids are difficult to swallow. Regurgitation of undigested food, unpleasant taste sensation, vomiting, aspiration, and weight loss are common manifestations of all types of dysphagia. Aspiration of esophageal contents can lead to cough and

pneumonia. Evaluation and treatment Knowledge of the person's history and clinical manifestations contributes significantly to a diagnosis of dysphagia. Further evaluation of swallowing should be performed by a speech language pathologist to determine what the person can eat/drink, and whether the swallowing reflex is intact, to prevent potential aspiration. Recommendations are then made based on the outcome of this assessment. (Note that this evaluation is not performed by the nurse). Imaging is used to visualize the contours of the esophagus and identify structural defects. Highresolution manometry and intraluminal impedance monitoring document the duration and amplitude of abnormal pressure changes associated with obstruction or loss of neural regulation. Esophageal endoscopy is performed to examine the esophageal mucosa and obtain biopsy specimens. The individual is taught to manage symptoms by eating small meals slowly, taking fluid with meals, and sleeping with the head elevated to prevent regurgitation and aspiration. Food and medications may need to be formulated so they can be swallowed. Anticholinergic medications (e.g., botulinum toxin type A [Botox]) may relieve symptoms of dysphagia. Mechanical dilation of the esophageal sphincter and surgical separation of the lower esophageal muscles with a longitudinal incision (myotomy) are the most effective treatments for achalasia.16

Gastroesophageal Reflux Disease (GERD) Gastroesophageal reflux disease (GERD) is the reflux of acid and pepsin or bile salts from the stomach into the esophagus that causes esophagitis. The prevalence of GERD is estimated at 18 to 27% in North America.17 Risk factors for GERD include older age, obesity, hiatal hernia, and medications or chemicals that relax the LES (anticholinergics, nitrates, calcium channel blockers, nicotine).18 GERD may be a trigger for asthma or chronic cough. Gastroesophageal reflux that does not cause symptoms is known as physiological reflux. In nonerosive reflux disease (NERD), individuals have symptoms of reflux disease but no visible esophageal mucosal injury (functional heartburn).19 Pathophysiology Abnormalities in LES function, esophageal motility, and gastric motility or emptying can cause GERD. The resting tone of the LES tends to be lower than normal from either transient relaxation or weakness of the sphincter. Vomiting, coughing, lifting, bending, obesity, or pregnancy increases abdominal pressure, contributing to the development of reflux esophagitis. Hiatal hernia can weaken the LES. Delayed gastric emptying can contribute to reflux esophagitis by (1) lengthening the period during which reflux is possible and (2) increasing gastric acid content. Disorders that delay emptying include gastroparesis, gastric or duodenal ulcers, which can cause pyloric edema and strictures that narrow the pylorus. The severity of the esophagitis depends on the composition of the gastric contents and the esophageal mucosa exposure time. An acid pocket is an area of postprandial unbuffered gastric acid immediately distal to the gastroesophageal junction. It is enlarged in hiatal hernia and can contribute to GERD. If the gastric content is highly acidic or contains bile salts and pancreatic or intestinal enzymes, reflux esophagitis can be severe. In individuals with weak esophageal peristalsis, refluxed chyme remains in the esophagus longer than usual. The prolonged presence of refluxed chime in the esophagus increases the amount of time the esophageal mucosa is exposed to acids, enzymes, and bile. The refluxate causes mucosal injury and inflammation with hyperemia, increased capillary permeability, edema, tissue fragility, and erosion. Fibrosis and thickening may develop. Precancerous lesions (Barrett esophagus) can be a long-term consequence. Precancerous lesions can progress to adenocarcinoma.20 Clinical manifestations The clinical manifestations of erosive reflux esophagitis are heartburn (pyrosis), acid regurgitation, dysphagia, chronic cough, asthma attacks (see Chapter 27), laryngitis, and upper abdominal pain within 1 hour of eating. The symptoms worsen if the individual lies down or if intra-abdominal pressure increases (e.g., as a result of coughing, vomiting, or straining at stool). Edema, strictures, esophageal spasm, or decreased esophageal motility may result in dysphagia with weight loss. Alcohol or acid-containing

foods, such as citrus fruits, can cause discomfort during swallowing. Evaluation and treatment Diagnosis of GERD is based on history and clinical manifestations. Esophageal endoscopy shows hyperemia, edema, erosion, and strictures. Dysplastic changes (Barrett esophagus) can be identified by tissue biopsy. Impedance or pH monitoring measures the movement of stomach contents upward into the esophagus and the acidity of the refluxate. Because heartburn also may be experienced as chest pain, cardiac ischemia must be ruled out. Proton pump inhibitors are the agents of choice for controlling symptoms and healing esophagitis. Other therapies include H2 receptor antagonists or prokinetics and antacids. Weight reduction, smoking cessation, elevation of the head of the bed 15 cm, and avoiding tight clothing also help to alleviate symptoms. Laparoscopic fundoplication is the most common surgical intervention when medical treatment fails.21 Eosinophilic esophagitis is an idiopathic inflammatory disease of the esophagus characterized by infiltration of eosinophils associated with atopic disease, including asthma and food allergies. It occurs in adults and children. Dysphagia, food impaction, vomiting, and weight loss are common symptoms. Endoscopy with biopsy identifies the eosinophilc infiltration and differentiation from GERD. Treatment is symptomatic, including elimination diets and steroids.

Hiatal Hernia Pathophysiology Hiatal hernia is a type of diaphragmatic hernia with protrusion (herniation) of the upper part of the stomach through the diaphragm and into the thorax (Figure 36-3).22 Sliding hiatal hernia (type 1) is the most common. With this type of hernia, the proximal portion of the stomach moves into the thoracic cavity through the esophageal hiatus, an opening in the diaphragm for the esophagus and vagus nerves. A congenitally short esophagus, fibrosis or excessive vagal nerve stimulation, or weakening of the diaphragmatic muscles at the gastroesophageal junction contributes to the hernia. GERD is associated with this type of herniation. Coughing, bending, tight clothing, ascites, obesity, and pregnancy accentuate the hernia.

FIGURE 36-3

Types of Hiatal Hernia. A, Sliding hiatal hernia (type 1). B, Paraesophageal hiatal hernia (type 2). Not shown is mixed hiatal hernia (type 3).

Paraesophageal hiatal hernia (type 2) is the herniation of the greater curvature of the stomach through a secondary opening in the diaphragm alongside the esophagus. The position of a portion of the stomach above the diaphragm causes congestion of mucosal blood flow, leading to gastritis and ulcer formation.

Strangulation of the hernia is a major complication. It can present with vomiting and epigastric and retrosternal epigastric pain and is a surgical emergency.23 Mixed hiatal hernia (type 3) is less common and is a combination of sliding and paraesophageal hiatal hernias. It tends to occur in conjunction with several other diseases, including reflux esophagitis, peptic ulcer, cholecystitis (gallbladder inflammation), cholelithiasis (gallstones), chronic pancreatitis, and diverticulosis. Clinical manifestations Hiatal hernias are often asymptomatic. Generally, a wide variety of symptoms develop later in life and are associated with other GI disorders, including GERD. Symptoms include heartburn, regurgitation, dysphagia, and epigastric pain. Ischemia from hernia strangulation causes acute, severe chest or epigastric pain, nausea, vomiting, and GI bleeding. Evaluation and treatment Diagnostic procedures include radiology with barium swallow, endoscopy, and high-resolution manometry. A chest X-ray film often will show the protrusion of the stomach into the thorax, indicating paraesophageal hiatal hernia. Treatment for sliding hiatal hernia is usually conservative. The individual can diminish reflux by eating small, frequent meals and avoiding the recumbent position after eating. Abdominal supports and tight clothing should be avoided, and weight control is recommended for obese individuals. Antacids alleviate reflux esophagitis. Individuals who are uncomfortable at night benefit from sleeping with the head of the bed elevated 15 cm. Surgery (fundoplication) is performed if medical management fails to control symptoms. Gastroparesis is delayed gastric emptying in the absence of mechanical gastric outlet obstruction. It is most commonly associated with diabetes mellitus, surgical vagotomy, or fundoplication. It can be idiopathic. The pathophysiology is not well understood but involves abnormalities of the autonomic nervous system, smooth muscle cells, enteric neurons, and GI hormones. Diabetic gastroparesis represents a form of neuropathy involving the vagus nerve. Symptoms include nausea, vomiting, abdominal pain, and postprandial fullness or bloating. Treatment options include dietary management; prokinetic medications; and, in some cases, gastric electrical stimulation or surgical venting gastrostomy.24

Pyloric Obstruction Pathophysiology Pyloric obstruction (gastric outlet obstruction) is the narrowing or blocking of the opening between the stomach and the duodenum. This condition can be congenital (e.g., infantile hypertrophic pyloric stenosis; see Chapter 37) or acquired. Acquired obstruction is caused by peptic ulcer disease or carcinoma near the pylorus. Duodenal ulcers are more likely than gastric ulcers to obstruct the pylorus. Ulceration causes obstruction resulting from inflammation, edema, spasm, fibrosis, or scarring. Tumours cause obstruction by growing into the pylorus. Clinical manifestations Early in the course of pyloric obstruction, the individual experiences vague epigastric fullness, which becomes more distressing after eating and at the end of the day. Nausea and epigastric pain may occur as the muscles of the stomach contract in attempts to force chyme past the obstruction. These symptoms disappear when the chyme finally moves into the duodenum. As obstruction progresses, anorexia develops, sometimes accompanied by weight loss. Severe obstruction causes gastric distension and atony (lack of muscle tone and gastric motility). Gastric distension stimulates gastric secretion, which increases the feeling of fullness. Rolling or jarring of the abdomen produces a sloshing sound called the succussion splash. At this stage, vomiting is a cardinal sign of obstruction. It is usually copious and occurs several hours after eating. The vomitus contains undigested food but no bile. Prolonged vomiting leads to dehydration, which is accompanied by a hypokalemic and hypochloremic metabolic alkalosis caused by

loss of gastric potassium and acid, respectively. Because food does not enter the intestine, stools are infrequent and small. Prolonged pyloric obstruction causes severe malnutrition, dehydration, and extreme debilitation. Evaluation and treatment Diagnosis is based on clinical manifestations, a history of ulcer disease, and examination of residual gastric contents. Endoscopy is performed if gastric carcinoma is the suggested cause of pyloric obstruction. Obstructions resulting from ulceration often resolve with conservative management. A large-bore nasogastric tube is used to aspirate stomach contents and relieve distension. Then nasogastric suction is maintained for 2 to 3 days to decompress the stomach and restore normal motility. Gastric secretions that contribute to inflammation and edema can be suppressed with proton pump inhibitors or H2 receptor antagonists. Fluids and electrolytes (saline and potassium) are given intravenously to promote rehydration and correct hypokalemia and alkalosis (see Chapter 5). Severely malnourished individuals may require parenteral hyperalimentation (intravenous nutrition). Surgery or the placement of pyloric stents may be required to treat gastric carcinoma or persistent obstruction caused by fibrosis and scarring.25

Intestinal Obstruction and Paralytic Ileus Intestinal obstruction can be caused by any condition that prevents the normal flow of chyme through the intestinal lumen (Table 36-2).26 Obstructions can occur in either the small or the large intestine (Table 36-3). The small intestine is more commonly obstructed because of its narrower lumen. Classifications of intestinal obstruction are summarized in Table 36-4. Intestinal obstruction is classified by cause as simple or functional. Simple obstruction is mechanical blockage of the lumen by a lesion and it is the most common type of intestinal obstruction. Paralytic ileus, or functional obstruction, is a failure of intestinal motility often occurring after intestinal or abdominal surgery, acute pancreatitis, or hypokalemia. Acute obstructions usually have mechanical causes, such as adhesions or hernias (Figure 36-4). Chronic or partial obstructions are more often associated with tumours or inflammatory disorders, particularly of the large intestine. TABLE 36-2 Common Causes of Intestinal Obstruction Cause

Pathophysiology

Hernia Protrusion of intestine through weakness in abdominal muscles or through inguinal ring Intussusception Telescoping of one part of intestine into another; this usually causes strangulation of blood supply; more common in infants 10–15 months of age than in adults (see Figure 36-4, D) Torsion Twisting of intestine on its mesenteric pedicle, with occlusion of blood supply; often associated with fibrous adhesions; occurs most often in middle-aged and older adult men (volvulus) Diverticulosis Inflamed saccular herniations (diverticuli) of mucosa and submucosa through tunica muscularis of colon; diverticuli are interspersed between thick, circular, fibrous bands; most common in obese individuals older than 60 years (see Figure 36-9) Tumour Tumour growth into intestinal lumen; adenocarcinoma of colon and rectum is most common tumoural obstruction; most common in individuals older than 60 years Paralytic Loss of peristaltic motor activity in intestine; associated with abdominal surgery, peritonitis, hypokalemia, ischemic bowel, spinal trauma, or pneumonia (adynamic) ileus Fibrous Peritoneal irritation from surgery, trauma, or Crohn's disease leads to formation of fibrin and adhesions that attach to intestine, omentum, or peritoneum and can cause adhesions obstruction; most common in small intestine Fecal mass Hardened stool impacted in the rectum or distal sigmoid colon, with subsequent obstruction; associated with lack of mobility due to aging or spinal cord injury; fecal (impaction) impaction is related to reduction of colonic mass movements and an inability to use abdominal muscles to assist in defecation

TABLE 36-3 Large and Small Bowel Obstruction Type of Obstruction Small bowel obstruction

Large bowel obstruction

Cause Adhesions: secondary to previous abdominal surgeries—75% Hernia: inguinal, ventral, or femoral—10% Tumours: may be associated with intussusception—10% Mesenteric ischemia—3–5% Crohn's disease—