Dietary Interventions in Liver Disease: Foods, Nutrients, and Dietary Supplements 012814467X, 9780128144671

Table of contents :
Content: Overview of liver health --
Fruits improve liver health --
Herb and plants for treating liver disease --
Dietary macronutrients and micronutrients for healthy liver function --
Toxic dietary materials including alcohol-induced liver dysfunction: treatment

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Dietary Interventions in Liver Disease

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Dietary Interventions in Liver Disease

Foods, Nutrients, and Dietary Supplements

Edited by

Ronald Ross Watson Victor R. Preedy

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2019 Elsevier Inc. All rights reserved. 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. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). 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. 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 of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-814466-4 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Stacy Masucci Acquisition Editor: Stacy Masucci Editorial Project Manager: Megan Ashdown Production Project Manager: Punithavathy Govindaradjane Cover Designer: Mark Rogers Typeset by TNQ Technologies

Contents List of Contributors xv Acknowledgmentsxix



2.3 Alcoholic Fibrosis 16 2.4 Alcoholic Cirrhosis 17 3. Current Therapies for Alcoholic Liver Disease 17 3.1 Abstinence and Lifestyle Modification17 3.2 Nutritional Support and Supplements17 3.3 Pharmacological Drugs and New Agents That Are Under Development17 3.4 Liver Transplantation 20 3.5 Natural and Herbal Medicines for the Prevention and Treatment of ALD 20 3.6 Herbal Formulas for Treatment of Alcoholic Liver Disease 20 3.7 The Combination Therapies of Drugs and Natural Agents 25 Endnotes 25 References 25

Section I Overview of Liver Health



1. Genome-Based Nutrition in Chronic Liver Disease Sonia Roman, Ingrid Rivera-Iñiguez, Claudia Ojeda-Granados, Maricruz Sepulveda-Villegas and Arturo Panduro

1. Introduction 1.1 Chronic Liver Disease 1.2 Hepatopathogenic Diet and Its Variations by Liver Disease Etiology 2. Genome-Based Nutrition: A Regionalized and Personalized Diet 3. Genes, Microbiota, and Regionalized Diet 4. Nutritional Intervention in Chronic Liver Disease 4.1 Nonalcoholic Fatty Liver Disease— Nonalcoholic Steatohepatitis 4.2 Alcoholic Liver Disease 4.3 Hepatitis C Virus Infection 5. Concluding Remarks List of Abbreviations Glossary References

3 3 3 4 5

3. Features of Hepatic Encephalopathy Mohamed M. Amin

5

6 8 9 11 11 12 12



2. Current Therapeutic Strategies for Alcoholic Liver Disease



Alaa El-Din El-Sayed El-Sisi, Samia Salim Sokar and Dina Zakaria Mohamed





1. Introduction 2. Pathogenesis of Alcoholic Liver Disease 2.1 Alcoholic Fatty Liver (Steatosis) 2.2 Alcoholic Hepatitis

15 16 16 16



1. Introduction 31 2. Pathogenesis 31 2.1 Ammonia Assumption 31 2.2 Gamma-Aminobutyric Corrosive Assumption 32 2.3 Changeability of Hepatic Encephalopathy32 3. Clinical Features of Hepatic Encephalopathy32 4. Laboratory Irregularities in Hepatic Encephalopathy 33 5. Regular Precipitants of Hepatic Encephalopathy33 6. Distinguishable Diagnosis for Hepatic Encephalopathy 34 7. Controlling of Hepatic Encephalopathy 34 7.1 Methodology Respects 34 7.2 Medications to Decrease Intestinal Ammonia Production 34 v

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7.3 Measurements to Upregulate Ammonia Clearance 36 7.4 Medicines to Improve Sleep Disturbances37 7.5 Post–Transjugular Intrahepatic Portosystemic Shunt Hepatic Encephalopathy37 8. Insignificant Hepatic Encephalopathy 37 References 37

2.1 The Ubiquitin–Proteasome System59 2.2 Autophagy 60 2.3 Crosstalk Between the UPS and Autophagy 60 3. ROS and Intracellular Proteolysis 61 3.1 Inhibition of UPS by ROS 61 3.2 Inhibition of Autophagy by ROS 61 4. The Interconnection of ROS, Intracellular Proteolysis, and NAFLD 63 4.1 Nonalcoholic Fatty Liver Disease63 4.2 Oxidative Stress and NAFLD 63 4.3 Impaired Intracellular Proteolysis in NAFLD 63 4.4 Multiple Mechanisms of Autophagic Dysfunction in NAFLD 64 4.5 Upregulation of Rubicon in NAFLD 65 5. Conclusion Remarks 66 References 66

4. The Liver Before and After Bariatric Surgery



Flavio A. Cadegiani

1. Introduction: The Liver of the Obese Patient 39 1.1 Biochemical Markers and Alterations of the Liver in Obesity 39 1.2 Gene Expressions and Polymorphisms in the Sick Liver of the Obese 42 1.3 The Challenging Management of NAFLD, NASH, Liver Fibrosis, and Cirrhosis in Obesity 42 1.4 Preparation for Bariatric Surgery in the Patient With Liver Dysfunction 42 2. The Liver After the Bariatric Surgery 45 2.1 Methods of Analysis of the Liver (Before and) After Bariatric Surgery 47 2.2 Biochemical Markers of the Liver After Bariatric Surgery 47 2.3 Genes Expression After Bariatric Surgery49 2.4 Liver Transplantation and Bariatric Surgery50 2.5 Liver Complications After Bariatric Surgery52 2.6 Weight-Loss-Independent Effects of Bariatric Surgery 52 3. Final Discussion 52 4. Conclusion 53 References 53

5. Oxidative Stress and Dysfunction of the Intracellular Proteolytic Machinery: A Pathological Hallmark of Nonalcoholic Fatty Liver Disease





Takujiro Homma and Junichi Fujii 1. Introduction 2. Intracellular Proteolysis

59 59

Section II Fruits Improve Liver Health 6. Polyphenols in the Management of Chronic Liver Diseases Including Hepatocellular Carcinoma Surendra Kumar Shukla and Vijay Kumar

1. Introduction 73 2. Dietary Polyphenols in the Prevention of Chronic Liver Diseases 73 3. Effect on Non–alcoholic Fatty Liver Diseases74 4. Effect on Nonalcoholic Steatohepatitis 75 5. Effect of Polyphenols on Alcoholic Liver Diseases75 6. Control of Hepatitis B Virus Infection 75 7. Control of Hepatitis C Virus Infection 76 8. Management of Hepatocellular Carcinoma76 9. Conclusions 76 List of Abbreviations 76 Glossary 77 References 77

Contents  vii

7. Phytochemicals in the Prevention of Ethanol-Induced Hepatotoxicity: A Revisit

9. Phytotherapy for the Liver Erika Ramos-Tovar and Pablo Muriel

Manjeshwar Shrinath Baliga, Arnadi Ramachandrayya Shivashankara, Sunitha Venkatesh, Harshith P. Bhat, Princy Louis Palatty, Ganesh Bhandari and Suresh Rao

1. Introduction 2. Phytochemicals in the Protection of Alcohol-Induced Hepatotoxicity 2.1 Beta-Carotene 2.2 Lutein 2.3 Meso-Zeaxanthin 2.4 Betaine 2.5 Ferulic Acid 2.6 Ellagic Acid 2.7 Epigallocatechin-3-Gallate 2.8 Quercetin 2.9 Morin 2.10 Hydroxystilbenes and Resveratrol 2.11 Ursolic Acid 2.12 Andrographolide and Arabinogalactan Proteins of Andrographis paniculata Nees 2.13 Picroliv 2.14 Silymarin 3. Mechanisms 4. Conclusions List of Abbreviations References

79



79 79 80 81 81 82 83 83 84 84 84 85

85 85 85 86 86 86 87

8. Protective Actions of Polyphenols in the Development of Nonalcoholic Fatty Liver Disease Yoojin Lee and Ji-Young Lee

1. Introduction 91 2. Pathogenesis and Progression of NAFLD 91 2.1 Liver Steatosis 91 2.2 Hepatic Oxidative Stress, Inflammation, and Apoptosis 92 2.3 Liver Fibrosis 93 3. Polyphenols in Foods and Natural Products93 4. Protective Action of Polyphenols Against NAFLD Progression 94 4.1 Quercetin 94 4.2 Epigallocatechin-3-O-Gallate 94 4.3 Anthocyanins 95 4.4 Resveratrol 95 5. Conclusion 96 References 96

1. Introduction 101 2. Liver Disease Treatment 101 3. Plant-Derived Compounds With Liver Beneficial Properties 101 4. Curcuma longa 102 4.1 Antiinflammatory Properties 102 4.2 Antifibrotic Properties 102 4.3 Anticancer Properties of Curcumin103 4.4 Antiheavy Metal Properties of Curcumin in the Liver 103 4.5 Antisteatotic Properties of Curcumin103 5. Silybum marianum 103 5.1 Antiinflammatory and Immunomodulation Activities 104 5.2 Silymarin Prevents Fibrosis 104 5.3 Beneficial Effects of Silymarin on NAFLD 104 5.4 Anticancer Properties of Silymarin104 6. Quercetin 105 6.1 Quercetin Inhibits Liver Inflammation105 6.2 Quercetin and Hepatic Fibrosis 105 6.3 Quercetin and Nonalcoholic Steatohepatitis106 6.4 Quercetin and Hepatocellular Carcinoma106 7. Naringenin 106 7.1 Antiinflammatory Properties of Naringenin106 7.2 Naringenin Antifibrogenic Effects 107 7.3 Naringenin and Hepatocellular Carcinoma107 8. Coffee 107 9. Stevia 108 10. Resveratrol 108 11.  l-Theanine108 12. Hesperidin 109 13. Colchicine 109 14. Rosemary 109 15. Glycyrrhizin (Glycyrrhizic Acid) 109 16. Other Plant-Derived Compounds 110 17. Conclusions and Perspectives 110 Acknowledgments 114 References 114

viii Contents

Section III Herbs and Plants for Treating Liver Disease

6. Conclusion List of Abbreviations References

12. The Flavone Baicalein and Its Use in Gastrointestinal Disease

10. Curcuma longa, the Polyphenolic Curcumin Compound and Pharmacological Effects on Liver

Yangchun Xie, Rui Kang and Daolin Tang

1. Introduction 145 2. Extraction and Purification 145 3. Metabolism and Conversion 145 4. Use of Baicalein in Gastrointestinal Disease146 4.1 Ulcerative Colitis 146 4.2 Gastric Ulceration 146 4.3 Ischemia-Reperfusion Injury 146 4.4 Liver Fibrosis 147 4.5 Cancer Prevention and Therapy 147 4.6 Colorectal Cancer 147 4.7 Pancreatic Cancer 147 4.8 Gastric Cancer 147 4.9 Hepatocellular Carcinoma 148 4.10 Diabetes Mellitus 148 5. Mechanism of Action of Baicalein 148 5.1 Regulation of Cell Death 148 5.2 Regulation of Signaling Transduction149 6. Conclusion 151 Acknowledgments 151 References 151

Bui Thanh Tung, Dong Thi Nham, Nguyen Thanh Hai and Dang Kim Thu 1. Introduction of Curcuma longa125 1.1 Chemical Composition in the Rhizome of Curcuma longa L. 125 2. The Polyphenolic Curcumin Compound 127 2.1 The Therapeutic Potential of Curcuma longa Components 127 2.2 Antibacterial Activity 127 2.3 Antioxidant Activity 127 2.4 Anti-inflammatory Activity 128 2.5 For Treatment of Arthritis 128 2.6 For Treatment of Metabolic Syndrome129 2.7 For Treatment of Cancer 130 3. Curcumin and Liver Disease 131 3.1 Curcumin Against Heavy Metals– Induced Liver Damage 131 3.2 The Effects of Curcumin in Preclinical In Vitro and In Vivo HCC 131 3.3 Hepatitis B Virus 132 4. Conclusions 132 List of Abbreviations 132 References 133







13. Pyrroloquinoline Quinone: Its Profile, Effects on the Liver and Implications for Health and Disease Prevention

11. Nymphaea alba and Liver Protection

Karen R. Jonscher and Robert B. Rucker

Riham O. Bakr







1. Introduction 135 2. Traditional Uses 135 3. Phytoconstituents 136 3.1 Flower Phytoconstituents 136 3.2 Leaf Phytoconstituents 136 3.3 Rhizome Phytoconstituents 137 4. Validated Studies 137 4.1 Hepatoprotective Effect of Flowers and a Powerful Anti-Inflammatory Activity 138 4.2 Leaf Extract and Potent Biological Activities139 4.3 Rhizomes’ Biological Activities 139 5. Phenolics of N. alba and Liver Protection140

141 141 142



1. Introduction: Pyrroloquinoline Quinone157 2. Factors Contributing to the Development of NAFLD/NASH 161 3. Systemic Effects of PQQ on NAFLD/NASH162 3.1 Mechanistic Modes of Action 162 3.2 Pyrroloquinoline Quinone as an Antioxidant162 3.3 Pyrroloquinoline Quinone and Lipid Metabolism 162 3.4 Pyrroloquinoline Quinone and Inflammation165 3.5 Pyrroloquinoline Quinone and the Microbiome165 3.6 Pyrroloquinoline Quinone and Fibrosis166

Contents  ix



4. Human Studies and Implications for Health167 4.1 Pyrroloquinoline Quinone and Cognition167 4.2 Pyrroloquinoline Quinone and Skin Elasticity 167 4.3 Pyrroloquinoline Quinone and Metabolism168 5. Conclusions 168 References 168



3. Validated Uses 183 4. Tea Protects Against the Alcohol-Induced Hepatotoxicity 184 5. Tea Protects Against Carbon Tetrachloride–Induced Hepatotoxicity 185 6. Effect of Tea on N-AcetaminophenInduced Hepatotoxicity 186 7. Tea Is Effective in Viral Hepatitis 186 8. Effect of Tea on Ischemia-Reperfusion Injury186 9. Effect of Tea on Fatty Liver Disease 186 10. Effect of Tea on Hepatotoxicity of Lead 187 11. Effect of Tea on Hepatotoxicity of Arsenic 187 12. Effect of Tea on PhenobarbitolInduced Liver Damage 187 13. Effect of Tea on Hepatotoxicity of Microcystin 187 14. Effect of Tea on Hepatotoxicity of Aflatoxins 187 15. Effect of Tea on Hepatotoxicity of Azathioprine188 16. Effect of Tea on Galactosamineand Lipopolysaccharide-Induced Liver Damage 188 17. Effect of Tea on Hepatotoxicity of Insecticides 188 18. Effect of Tea on Hepatocarcinogenesis 188 19. Conclusions 189 List of Abbreviations 190 References 190

14. Herbal Weight Loss Supplements: From Dubious Efficacy to Direct Toxicity



Armando E. González-Stuart and José O. Rivera

1. Introduction 2. The Surge of Herbal Product Use Within Complementary and Alternative Medicine 3. The Internet as a Source of Information About Herbal Weight Loss Supplements 4. Herbal Supplement Identity, Efficacy, and Safety: Bedlam in the Cyber Marketplace 5. Mexican Hawthorn Root 5.1 Yellow Oleander or “Codo de Fraile” 6. Toxicity of Thevetia spp. 7. Candlenut Tree Seed 8. Botanical Characteristics 9. Use of the Candlenut Tree in Asian Traditional Medicine 10. Weight Loss and Other Health Claims Made on the Internet for Candlenut Tree Seeds 11. International Health Agencies Ban Candlenut Seed Due to Its Toxicity 12. Conclusions References

175



175

176

176 176 177 177 178 178 178

179 179 180





Arnadi Ramachandrayya Shivashankara, Suresh Rao, Thomas George, Soniya Abraham, Marshal David Colin, Princy Louis Palatty and Manjeshwar Shrinath Baliga 1. Introduction 2. Phytochemistry of Tea

Manjeshwar Shrinath Baliga, Arnadi Ramachandrayya Shivashankara, K.R. Thilakchand, M.P. Baliga-Rao, Princy Louis Palatty, Thomas George and Suresh Rao

179

15. Tea (Camellia sinensis L. Kuntze) as Hepatoprotective Agent: A Revisit



16. Hepatoprotective Effects of the Indian Gooseberry (Emblica officinalis Gaertn): A Revisit

183 183



1. Introduction 2. Phytochemicals 3. Traditional Uses 4. Scientifically Validated Studies 5. Effect of Amla on Hepatotoxicity of Ethanol 6. Effect of Amla on Hepatotoxicity of Heavy Metals Arsenic and Cadmium 7. Effect of Amla on Hepatotoxicity of Iron Overload 8. Effect of Amla on Hepatotoxicity of Ochratoxin 9. Effect of Amla on Hepatotoxicity of Antitubercular Drugs

193 193 193 194 195 195 196 196 196

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10. Effect of Amla on Hepatotoxicity of Hexachlorocyclohexane 11. Effect of Amla on Hepatotoxicity of Carbon Tetrachloride 12. Effect of Amla on Hepatotoxicity of Paracetamol 13. Effect of Amla Phytochemicals on Galactosamine- and Lipopolysaccharide-Induced Liver Damage 14. Effect of Amla Phytochemicals on Hepatotoxicity of Microcystin 15. Effect of Amla on Hepatocarcinogenesis 16. Effect of Amla on Hepatic Lipid Metabolism and Metabolic Syndrome 17. Effect of Amla on Nonalcoholic Fatty Liver Disease 18. Mechanism of Action(s) Responsible for the Hepatoprotective Effects 19. Conclusions List of Abbreviations References Further Reading



16. Bile Acids and Fiber 17. Prebiotics and Probiotics 18. The Mediterranean and Other Diets 19. Zinc 20. Niacin (Nicotinic Acid) 21. Astaxanthin 22. Curcumin 23. Conclusion References

196 196 197

197

18. The Effects of Dietary Advanced Glycation End Products (AGEs) on Liver Disorders

197 197 198

Fahimeh Agh and Farzad Shidfar

1. Advanced Glycation End Products 213 2. Circulating AGEs and Liver Disorders 215 3. The AGEs–RAGE System in Liver Disorders216 4. The Effects of Dietary AGEs on Liver Disorders 218 4.1 Liver Histology 218 4.2 Liver Enzymes 221 4.3 Metabolic and Inflammatory Profiles221 4.4 Reactive Oxygen Species Production222 4.5 Receptor for Advanced Glycation End Products 223 4.6 De Novo Lipogenesis 223 4.7 Weight Gain 224 5. Dietary Interventions to Reduce the AGEs 224 6. Summary 224 List of Abbreviations 227 References 228

198 198 199 199 200 201

Section IV Dietary Macronutrients and Micronutrients for Healthy Liver Function 17. Major Dietary Interventions for the Management of Liver Disease Idris Adewale Ahmed















1. Introduction 2. Liver as an Organ 3. Liver Failure 4. Causes of Hepatic Injury 5. Nonalcoholic Fatty Liver Disease 6. Alcoholic Liver Disease 7. Chronic Hepatitis B and Chronic Hepatitis C 8. Hepatocellular Carcinoma 9. Dietary Interventions in the Management of Liver Diseases 10. Diet Types 11. Fat 12. Protein 13. Carbohydrates 14. Glycemic Index 15. Antioxidants

205 206 206 206 206 207 207 207 208 208 208 208 208 209 209

209 209 210 210 210 210 210 210 211

19. Molecular Mechanisms of the Protective Role of Wheat Germ Oil Against Oxidative Stress–Induced Liver Disease El-Sayed Akool

1. Introduction 2. Reactive Oxygen Species and Liver Diseases 3. Wheat Germ Oil and Liver Diseases 3.1 Nutritional Composition 3.2 Antioxidant Activity References

233



233 235 235 235 236

Contents  xi

20. Critical Role of Hepatic Fatty-Acyl Phospholipid Remodeling in Obese and Nonobese Fatty Liver Mouse Models



2. Materials and Methods 2.1 Drugs 2.2 Study Design 2.3 Induction of Acute Hepatotoxicity 2.4 Statistical Analysis 3. Results 4. Discussion References

Walee Chamulitrat, Gerhard Liebisch, Anita Pathil and Wolfgang Stremmel

1. Introduction 239 1.1 Causes of Obesity: Genetics and Diets 239 1.2 Consequence of Obesity: NAFLD and NASH 239 1.3 Animal Models of Obese and Nonobese NAFLD/NASH 240 1.4 Comparison of Hepatic Lipids Among Obese and Nonobese NAFLD/NASH241 2. Phospholipids in NAFLD and NASH 241 2.1 Linking Hepatic Triglyceride to Phospholipid in NAFLD 241 2.2 Comparison of Hepatic Phospholipid Among Obese and Nonobese NAFLD/NASH 241 2.3 Comparison of Hepatic Phospholipid Ratios Among Obese and Nonobese NAFLD/NASH243 3. Phospholipid-Metabolizing Genes in Obesity and NAFLD 244 3.1 PLA2G6 or iPLA2β in Obesity and NAFLD 245 3.2 Effects of iPLA2β Deficiency on Phospholipids in Obese Ob/Ob and HFD-Fed Mice 245 3.3 Effects of iPLA2β Deficiency on Phospholipids in MCD-Fed Mice 247 4. Summarized Findings and Proposed Mechanisms247 5. Perspectives 251 5.1 Use of iPLA2β Antagonists for Steatosis Protection in Obese Versus Nonobese NAFLD 251 5.2 Considerations and Precautions 252 6. Conclusions 252 List of Abbreviations 252 Acknowledgments 253 References 253

22. The Role of Carbohydrate Response Element–Binding Protein in the Development of Liver Diseases



21. Vitamin D3 and Liver Protection





Malath Azeez Al-Saadi 1. Introduction 1.1 Mechanism of Action

257 257

258 258 258 258 258 259 259 260

Katsumi Iizuka

1. Introduction 2. ChREBP, a Glucose-Activated Transcription Factor That Regulates Glucose and Lipid Metabolism 3. Dietary Composition and ChREBP 4. ChREBP and Liver Diseases 4.1 Nonalcoholic Fatty Liver Disease 4.2 Alcoholic Liver Disease 4.3 Liver Tumors 4.4 Virus Infection 4.5 Glycogen Storage Diseases 5. Supplement and ChREBP 5.1 Polyunsaturated Fatty Acids 5.2 Ketone Bodies 5.3 Vinegar (Acetic Acid) 5.4 Polyphenols 6. Conclusion Acknowledgments References

263



263 263 264 264 265 267 267 268 268 268 269 269 269 270 270 271

23. Trans Fatty Acid in the Liver and Central Nervous System

1. Introduction 2. Hydrogenation Process 3. Biochemical Metabolism 4. Trans Fatty Acids and Liver Damage 4.1 Cell Culture 4.2 Animal Models 4.3 Human Trials 5. Trans Fatty Acids and the Central Nervous System 5.1 Animal Studies 5.2 Human Trials 6. Final Considerations References



Rafael Longhi 275 275 276 276 276 277 279 280 281 283 284 284

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24. Fish Oil Supplements During Perinatal Life: Impact on the Liver of Offspring

3.2 Functional Categories of Identified Hepatic Proteins of Diabetic Rats and Diabetic Rats With Purple Rice Bran Supplement301 3.3 Bioinformatic Analysis of Unique Proteins Found in the Hepatic Tissues of Diabetic Rats and Diabetic Rats With Purple Rice Bran Supplement 303 3.4 mRNA Expression Level of Candidate Genes of Diabetic Rats’ Liver 304 3.5 mRNA Expression Level of Rangap1 Gene 304 3.6 mRNA Expression Level of Candidate Genes of Purple Rice Bran–Supplemented Diabetic Rats’ Liver 304 3.7 mRNA Expression Level of Affected Genes From Hepatic Proteomic Analysis 304 3.8 Protein Expression Level of Affected Proteins From Hepatic Proteomic Analysis 305 4. Discussion and Conclusion 305 Acknowledgments 312 References 312 Further Reading 312

Emilio Herrera and Encarnación Amusquivar





1. Introduction 287 2. Role of Fatty Acids in Fetal Development287 3. Fatty Acids and Epigenetics 288 4. Fish Oil Supplements During Pregnancy288 5. Prevalence and Pathogenic Aspects of Nonalcoholic Fatty Liver Disease 290 6. Fetal Programming Origins of NAFLD 290 7. Potential Protective Role of Fish Oil in the NAFLD Development 291 Acknowledgments 292 References 292

25. Purple Rice Bran Improves Hepatic Insulin Signaling via Activation of Akt and Stabilization of IGF in Diabetic Rats Ei Ei Hlaing, Supicha Rungcharoenarrichit, Narissara Lailerd, Sittiruk Roytrakul and Pichapat Piamrojanaphat



1. Introduction 297 2. Methods 298 2.1 Tissue Preparation and Homogenization298 2.2 Determination of Tissue Protein Concentration298 2.3 One-Dimensional SDS-PAGE Analysis298 2.4 In-Gel Tryptic Digestion Before LC-MS/MS Analysis 298 2.5 Peptide Identification and Quantitation by LC-MS/MS Analysis299 2.6 Bioinformatics Analysis 299 2.7 Confirmation of Candidate Genes and Their Affected Proteins 299 2.8 mRNA Level of Affected Genes by Quantitative Real-Time PCR 300 2.9 Affected Protein Expression Level by Western Blot Analysis 300 2.10 Statistical Analysis 300 3. Results 300 3.1 LC-MS/MS Analysis and Hepatic Proteins Identification 300

Section V Toxic Dietary Materials Including Alcohol-Induced Liver Dysfunction: Treatment 26. Heavy Metals and Low-Oxygen Microenvironment—Its Impact on Liver Metabolism and Dietary Supplementation Kusal K. Das, Rajesh Honnutagi, Lata Mullur, R. Chandramouli Reddy, Swastika Das, Dewan Syed Abdul Majid and M.S. Biradar

1. Introduction 2. Heavy Metals and Its Interactions 2.1 Heavy Metal Toxicities: Nickel and Lead 3. Hypoxia Pathophysiology 3.1 Hypoxia Microenvironment 3.2 Hypoxia and Heavy Metals (Nickel and Lead)

315 317 317 318 318 318

Contents  xiii

4. Heavy Metals in Liver Diseases 319 4.1 Heavy Metals and Liver Pathophysiology (Nickel and Lead) 319 4.2 Possible Mechanism of Altered Hepatocellular Architecture by Heavy Metals 321 5. Hypoxia and Liver Diseases 321 5.1 Hypoxia—Liver Histopathology 322 5.2 Hypoxia and Heavy Metals (Nickel and Lead)—Liver Histopathology323 6. Heavy Metals (Nickel and Lead), Hypoxia, and Liver Functions— Role of Dietary Supplementations 323 6.1 Heavy Metals, Liver Functions, and Dietary Supplementation 324 6.2 Hypoxia, Liver Function, and Dietary Supplementation 324 6.3 Heavy Metals, Hypoxia, and Liver Functions—Dietary Supplementation325 7. Conclusion 328 Acknowledgments 329 References 329

28. Beneficial Effects of Natural Compounds on Heavy Metal–Induced Hepatotoxicity



Parisa Hasanein and Abbasali Emamjomeh

1. Introduction 345 2. Arsenic Hepatotoxicity 346 2.1 Mechanisms of Arsenic-Induced Hepatotoxicity346 3. Cadmium Hepatotoxicity 346 3.1 Mechanisms of CadmiumInduced Hepatotoxicity 347 4. Chromium Hepatotoxicity 347 4.1 Mechanisms of ChromiumInduced Hepatotoxicity 347 5. Copper Hepatotoxicity 348 5.1 Mechanisms of Copper-Induced Hepatotoxicity348 6. Lead Hepatotoxicity 348 6.1 Mechanisms of Lead-Induced Hepatotoxicity348 7. Mercury Hepatotoxicity 349 7.1 Mechanisms of Mercury-Induced Hepatotoxicity349 8. Effects of Natural Products on Heavy Metal–Induced Hepatotoxicity 350 8.1 Vitamins C and E 350 8.2 Curcumin 350 8.3  N-Acetylcysteine350 8.4  α-Lipoic Acid 351 8.5 Melatonin 351 8.6 Flavonoid-Rich Extracts 351 8.7 Anthocyanidins 352 8.8 Quercetin 352 8.9 Naringenin 352 8.10 Black Tea 352 8.11 Olive Oil 352 8.12 Sesame Oil 352 8.13 Combination Therapy 352 References 353

27. Cadmium and Fullerenes in Liver Diseases



Sinisa Djurasevic, Zoran Todorovic, Sladjan Pavlovic and Snezana Pejic

1. Introduction 333 1.1 Cytochromes P450 333 1.2 Xenobiotic Metabolism and Hepatotoxicity334 2. Liver and Oxidative Stress 335 2.1 Oxidative Stress and Liver Disorders 335 3. Cadmium as the Model of Hepatotoxicity336 3.1 Molecular Mechanisms of Cadmium Toxicity 337 3.2 Cadmium and Oxidative Stress 337 3.3 Cadmium and Liver Injury in Animals338 3.4 Cadmium and Mitochondria 338 4. Fullerenes and Liver Protection 338 4.1 Chemical Properties of Fullerenes 338 4.2 Pharmacological Properties of Fullerenes339 4.3 Fullerenes as the Protectors in the Carbon Tetrachloride Model of Liver Toxicity 339 Acknowledgments 340 References 340

29. Nutritional and Dietary Interventions for Nonalcoholic Fatty Liver Disease













Cindy X. Cai, Stella Carlos, Pejman Solaimani, Bansari J. Trivedi, Chuong Tran and Shobha Castelino-Prabhu 1. Introduction 2. Epidemiology 3. Risk Factors 4. Pathogenesis 5. Clinical Manifestations 6. Histopathology

357 357 357 358 360 360

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7. Diagnosis 8. Natural Course and Outcomes 9. Treatment 9.1 Lifestyle Modification for NAFLD 9.2 Pharmacological Treatment 9.3 Bariatric Surgery and Endoscopic Bariatric Intervention 10. Conclusions References

360 361 361 361 365 366 366 367

30. Dietary Management of Nonalcoholic Fatty Liver Disease (NAFLD) by n-3 Polyunsaturated Fatty Acid (PUFA) Supplementation: A Perspective on the Role of n-3 PUFA-Derived Lipid Mediators SM Jeyakumar and A Vajreswari

1. Background 2. NAFLD—Worldwide Burden 3. Dietary Carbohydrates: A Glance at Fructose

373 373 374



4. Hepatic Fructose Metabolism 5. Fructose, the Common Etiological Factor of NAFLD 6. Management of NAFLD 7. Pharmacotherapy 8. Lifestyle Intervention 9. Dietary Fat 10. Metabolic Fate of n-3 Long-Chain PUFA: Bioactive Lipid Mediators 11. Eicosapentaenoic Acid (EPA; C20:5n-3)–Derived Lipid Mediators 12. Docosahexaenoic Acid (DHA; C22:6n-3)–Derived Lipid Mediators 13. n-3 PUFA and NAFLD 14. Lipid Mediators of n-3 PUFA and NAFLD 15. Conclusion Acknowledgments References

374 374 376 376 376 376 378 378 378 379 382 384 384 384

Index391

List of Contributors Soniya Abraham Undergraduate student, Father Muller Medical College, Mangalore, India Fahimeh Agh Department of Nutrition, School of Health, Iran University of Medical sciences, Tehran, Iran Idris Adewale Ahmed Department of Biotechnology, Faculty of Science, Lincoln University College Malaysia, Petaling Jaya, Malaysia El-Sayed Akool Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt Malath Azeez Al-Saadi Basic Science\PharmacologyDentistry College, University of Babylon, Al-hilla, Babil, Iraq Mohamed M. Amin Department of Pharmacology, Medical Division, National Research Centre, Giza, Egypt Encarnación Amusquivar Department of Biochemistry and Chemistry, University San Pablo CEU, Madrid, Spain Riham O. Bakr Pharmacognosy Department, Faculty of Pharmacy, October University for Modern Sciences and Arts, Giza, Egypt Manjeshwar Shrinath Baliga Department of Research, Mangalore Institute of Oncology, Mangalore, India M.P. Baliga-Rao Department of Research, Mangalore Institute of Oncology, Mangalore, India Ganesh Bhandari Undergraduate student, Father Muller Medical College, Mangalore, India Harshith P. Bhat Mangalore Institute of Oncology, Mangalore, India M.S. Biradar Department of Medicine, Shri B.M. Patil Medical College, Hospital and Research Centre, BLDE Deemed to be University, Vijayapur, India Flavio A. Cadegiani Division of Endocrinology and Metabolism, Department of Medicine, Federal University of São Paulo, São Paulo, Brazil; Corpometria Institute, Centro Clínico Advance, Brasília, Brazil Cindy X. Cai Division of Gastroenterology and Hepatology, Department of Internal Medicine, VA Loma Linda Healthcare System, Loma Linda University, Loma Linda, CA, United States

Stella Carlos Department of Nutrition Services, VA Loma Linda Healthcare System, Loma Linda, CA, United States Shobha Castelino-Prabhu Department of Pathology, VA Loma Linda Healthcare System, Loma Linda, CA, United States Walee Chamulitrat Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany Marshal David Colin Undergraduate student, Father Muller Medical College, Mangalore, India Kusal K. Das Laboratory of Vascular Physiology and Medicine, Department of Physiology, Shri B.M. Patil Medical College, Hospital and Research Centre, BLDE Deemed to be University, Vijayapur, India Swastika Das Department of Chemistry, BLDE Association’s, Dr. P.G. Halakatti College of Engineering and Technology, Vijayapur, India Sinisa Djurasevic University of Belgrade Faculty of Biology, Belgrade, Serbia Alaa El-Din El-Sayed El-Sisi Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt Abbasali Emamjomeh Computational Biotechnology Lab (CBB), Department of Plant Breeding and Biotechnology (PBB), University of Zabol, Zabol, Iran Junichi Fujii Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata, Japan Thomas George Undergraduate student, Father Muller Medical College, Mangalore, India Armando E. González-Stuart School of PharmacyUniversity of Texas at El Paso, El Paso, TX, United States Nguyen Thanh Hai School of Medicine and Pharmacy, Vietnam National University, Hanoi, Vietnam Parisa Hasanein Department of Biology, School of Basic Sciences, University of Zabol, Zabol, Iran Emilio Herrera Department of Biochemistry and Chemistry, University San Pablo CEU, Madrid, Spain xv

xvi  List of Contributors

Ei Ei Hlaing Department of Biochemistry, Chiang Mai University, Chiang Mai, Thailand; Department of Biochemistry, University of Medicine, Mandalay, Myanmar Takujiro Homma Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata, Japan Rajesh Honnutagi Department of Medicine, Shri B.M. Patil Medical College, Hospital and Research Centre, BLDE Deemed to be University, Vijayapur, India Katsumi Iizuka Department of Diabetes and Endocrinology, Graduate School of Medicine, Gifu University, Gifu, Japan; Gifu University Hospital Center for Nutritional Support and Infection Control, Gifu, Japan SM Jeyakumar Division of Lipid Biochemistry, National Institute of Nutrition, Indian Council of Medical Research, Hyderabad, India Karen R. Jonscher Department of Anesthesiology, University of Colorado Denver, Aurora, CO, United States Rui Kang Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States Vijay Kumar Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India Narissara Lailerd Department of Physiology, Chiang Mai University, Chiang Mai, Thailand

Dong Thi Nham School of Medicine and Pharmacy, Vietnam National University, Hanoi, Vietnam Claudia Ojeda-Granados Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, “Fray Antonio Alcalde”, Guadalajara, Mexico; Health Sciences Center, University of Guadalajara, Guadalajara, Mexico Princy Louis Palatty Department of Pharmacology, Amrita Institute of Medical Sciences, Kochi, India Arturo Panduro Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, “Fray Antonio Alcalde”, Guadalajara, Mexico; Health Sciences Center, University of Guadalajara, Guadalajara, Mexico Anita Pathil Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany Sladjan Pavlovic University of Belgrade Institute for Biological Research “Sinisa Stankovic”, Belgrade, Serbia Snezana Pejic University of Belgrade “Vinca” Institute of Nuclear Sciences, Belgrade, Serbia Pichapat Piamrojanaphat Department of Biochemistry, Chiang Mai University, Chiang Mai, Thailand Arnadi Ramachandrayya Shivashankara Undergraduate student, Father Muller Medical College, Mangalore, India

Ji-Young Lee Department of Nutritional Sciences, University of Connecticut, Storrs, CT, United States

Erika Ramos-Tovar Laboratory of Experimental Hepatology, Department of Pharmacology, CinvestavIPN, Mexico City, Mexico

Yoojin Lee Department of Nutritional Sciences, University of Connecticut, Storrs, CT, United States

Suresh Rao Mangalore Institute of Oncology, Mangalore, India

Gerhard Liebisch Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany

R.

Rafael Longhi Department of Basic Health Sciences, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Brazil Dewan Syed Abdul Majid Department of Physiology, School of Medicine, Tulane University, New Orleans, LA, United States Dina Zakaria Mohamed Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt Lata Mullur Laboratory of Vascular Physiology and Medicine, Department of Physiology, Shri B.M. Patil Medical College, Hospital and Research Centre, BLDE Deemed to be University, Vijayapur, India Pablo Muriel Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav-IPN, Mexico City, Mexico

Chandramouli Reddy Laboratory of Vascular Physiology and Medicine, Department of Physiology, Shri B.M. Patil Medical College, Hospital and Research Centre, BLDE Deemed to be University, Vijayapur, India

Ingrid Rivera-Iñiguez Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, “Fray Antonio Alcalde”, Guadalajara, Mexico; Health Sciences Center, University of Guadalajara, Guadalajara, Mexico José O. Rivera School of Pharmacy-University of Texas at El Paso, El Paso, TX, United States Sonia Roman Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, “Fray Antonio Alcalde”, Guadalajara, Mexico; Health Sciences Center, University of Guadalajara, Guadalajara, Mexico Sittiruk Roytrakul National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand

List of Contributors  xvii

Robert B. Rucker Department of Nutrition, University of California, Davis, CA, United States Supicha Rungcharoenarrichit Department of Biochemistry, Chiang Mai University, Chiang Mai, Thailand Samia Salim Sokar Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt Maricruz Sepulveda-Villegas Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara, “Fray Antonio Alcalde”, Guadalajara, Mexico; Health Sciences Center, University of Guadalajara, Guadalajara, Mexico Farzad Shidfar Department of Nutrition, School of Health, Iran University of Medical sciences, Tehran, Iran Surendra Kumar Shukla Eppley Cancer Institute, University of Nebraska Medical Centre, Omaha, NE, United States Pejman Solaimani Division of Gastroenterology and Hepatology, Department of Internal Medicine, VA Loma Linda Healthcare System, Loma Linda University, Loma Linda, CA, United States Wolfgang Stremmel Department of Internal Medicine IV, University of Heidelberg Hospital, Heidelberg, Germany Daolin Tang The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, School of Basic Medical Sciences,

Guangzhou Medical University, Guangzhou, People’s Republic of China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States K.R. Thilakchand Department of Research, Mangalore Institute of Oncology, Mangalore, India Dang Kim Thu School of Medicine and Pharmacy, Vietnam National University, Hanoi, Vietnam Zoran Todorovic University of Belgrade Faculty of Medicine, University Medical Center “Bezanijska kosa”, Belgrade, Serbia Chuong Tran Division of Gastroenterology and Hepatology, Department of Internal Medicine, VA Loma Linda Healthcare System, Loma Linda University, Loma Linda, CA, United States Bansari J. Trivedi Department of Nutrition Services, VA Loma Linda Healthcare System, Loma Linda, CA, United States Bui Thanh Tung School of Medicine and Pharmacy, Vietnam National University, Hanoi, Vietnam A Vajreswari Division of Lipid Biochemistry, National Institute of Nutrition, Indian Council of Medical Research, Hyderabad, India Sunitha Venkatesh Mangalore Institute of Oncology, Mangalore, India Yangchun Xie Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, People’s Republic of China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States

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Acknowledgments The work of Dr. Watson’s editorial assistant, Bethany L. Steven, in communicating with authors, editors, and working on the manuscripts was critical to the successful completion of the book. It is very much appreciated. Support for Ms. Stevens’ and Dr. Watson’s editing was graciously provided by Southwest Scientific Editing & Consulting, LLC. Direction and guidance from Elsevier staff was critical. Finally, the work of the librarian at the Arizona Health Science Library, Mari Stoddard, was vital and very helpful in identifying key researchers who participated in the book.

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Section I

Overview of Liver Health

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Chapter 1

Genome-Based Nutrition in Chronic Liver Disease Sonia Roman1,2, Ingrid Rivera-Iñiguez1,2, Claudia Ojeda-Granados1,2, Maricruz Sepulveda-Villegas1,2, Arturo Panduro1,2 1Department 2Health

of Molecular Biology in Medicine, Civil Hospital of Guadalajara, “Fray Antonio Alcalde”, Guadalajara, Mexico; Sciences Center, University of Guadalajara, Guadalajara, Mexico

1. INTRODUCTION 1.1 Chronic Liver Disease Liver cirrhosis is a chronic disease that initiates by an inflammatory process with or without accumulation of fat, followed by fibrosis. The degree of fibrosis (F) can be staged F1 (initial), F2 (intermediate), F3 (advanced), and F4 (cirrhosis). Once clinical cirrhosis becomes manifest, the patient may die due to systemic complications of liver cirrhosis or progress to hepatocellular carcinoma. The main etiological agents that lead to liver cirrhosis are alcoholism, viral hepatitis B and C, and most recently, obesity in subjects that are susceptible to develop nonalcoholic steatohepatitis (NASH). The progression of each disease may last from 25 to 30 years due to differential interactions between genes and key environmental lifestyle factors such as diet, physical activity, and emotional state. Therefore, this time span may be shorter or longer. Furthermore, with the use of noninvasive techniques such as transient elastography or serum markers, liver damage may be detected in early stages (F1–F3) before cirrhosis is present so that an appropriate medical-nutritional therapy can be implemented. The best strategy would be to eliminate the etiological agent to prevent or reverse liver damage. In regard to this point, there has been considerable enthusiasm worldwide for the efficacy of the new antiviral agents for hepatitis B and C,1 whereas alcoholism has diminished in some developing countries.2 However, the obesity epidemic is a new threat that compromises the health of liver-diseased patients regardless of the etiology in both wealthy and impoverished countries. Therefore, each nation needs to evaluate the impact of these illnesses to implement nutritional strategies for liver-diseased patients aimed to avoid or reverse the progression of chronic liver diseases and nutrition-related comorbidities. This obesity epidemic is driven by a global wave of nutritional transition where populations waive their traditional diet and lifestyle. This transition has created an imbalance between the ancestral genes respective to the current lifestyle which has been associated with an increased risk of developing some of the highly prevalent nutrition-related chronic diseases (NRCDs) of today. For example, in the last 50 years, the Mexican population underwent a nutrition transition from a traditional dietary pattern, passing through undernutrition, and currently overnutrition. Excess weight is prevalent in 72.1% of the adult population affecting all socioeconomic statuses but mostly those with low income that comprises more than 50% of the population. Furthermore, the leading causes of mortality are type 2 diabetes, cardiovascular disease, and liver cirrhosis.3 The leading causes of liver cirrhosis are the excessive consumption of alcohol, followed by hepatitis B and C virus (HCV), and an increasing rate of NASH.4,5 Furthermore, the main dyslipidemias in Mexico are hypercholesterolemia, hypertriglyceridemia, and hypoalphalipoproteinemia.6 All three types have been associated with genetic susceptibility combined with a particular dietary pattern described as a hepatopathogenic diet that places individuals at risk for NRCDs as aforementioned.6,7

1.2 Hepatopathogenic Diet and Its Variations by Liver Disease Etiology Among the Mexican population, the characteristics of a hepatopathogenic diet have been defined.7 This dietary pattern is characterized by an excessive energy intake, an imbalance of macronutrients, as well as a low content of fiber and micronutrients with antioxidant and anti-inflammatory properties such as vitamins A and E, folates, magnesium, selenium, and zinc. Notably, this diet contains a disproportionate amount of simple sugars (>10%), saturated fats (>10%), more than Dietary Interventions in Liver Disease. https://doi.org/10.1016/B978-0-12-814466-4.00001-X Copyright © 2019 Elsevier Inc. All rights reserved.

3

4  SECTION | I  Overview of Liver Health

200 mg of dietary cholesterol, and an increased ratio of n-6: n-3 polyunsaturated fatty acids (PUFAs) (12:1)8. Overall, this unhealthy diet has been associated with the increase in the consumption of industrial food containing high-fructose corn syrup such as sweetened beverages, together with overfried foods cooked in oil or lard, red meat, high-fat dairy products, and confectionery foods. Furthermore, an increase in the number of sedentary activities is common, leading to less calorie expenditure. This dietary pattern has been identified in both lean and excess weight patients, as well as those with chronic liver disease.7,8 However, the dietary composition of the hepatopathogenic diet may have differential features according to the etiology of liver disease and related lifestyle. For example, it has been documented that patients who are normal weight consume a hepatopathogenic diet containing high amounts of animal fat (saturated fat) obtained from red meat, cold cuts, and processed foods and less amount of fruits, vegetables, legumes, and selenium. However, those with excess weight eat the same diet but consume a lower amount of monounsaturated fats and fish meat. These dietary patterns have been associated with dyslipidemias such as hypercholesterolemia and hypertriglyceridemia, respectively. On the other hand, alcoholic patients present hypertriglyceridemia and consume excess calories through the consumption of carbohydrates (cereals, alcoholic beverages, soft drinks), high cholesterol levels (red meat), and high sodium due to salty snacks.7 In contrast, patients with HCV manifest metabolic alterations such as hypoalphalipoproteinemia, insulin resistance, and high levels of liver enzymes. These alterations may be related to the metabolic dynamics between circulating lipids and the viral particle. However, despite the fact that they tend to consume a healthier diet compared with the other groups of patients, most of them are overweight and obese, suggesting the influence of the hepatopathogenic diet.7 In conclusion, an adequate dietary intervention should be oriented to reverse the hepatopathogenic effect of this diet based on the identification of food group responsible for the excess calories, nutrient imbalance, and metabolic dysfunction in each etiology of liver disease.

2. GENOME-BASED NUTRITION: A REGIONALIZED AND PERSONALIZED DIET Genomic medicine provides a new approach to how health professionals prevent, manage, and treat many types of diseases. Regardless that they may be infectious or noncommunicable, the onset and progression will depend on the presence of genetic and environmental risk factors.9 In the field of nutritional genomics, genome-based nutrition refers to a strategy that considers the population’s or individual’s genetic background and lifestyle to set tailored nutritional recommendations or interventions. Most modern-day NRCDs may be considered as an imbalance between several ancestral polymorphic genes generated by gene-culture coevolutionary processes and the current-day lifestyle.10 Therefore, restoring this balance should be the main target of a nutritional genomic therapy in which the correct diet that should be recommended to healthy individuals would take into account ethnicity, genetics, and cultural, social, and environmental factors of the population they belong to.11 The morbidity and mortality due to NRCDs have been tackled in some countries by promoting the consumption of traditional diets or integrating regional foods, as in the case of the Mediterranean-type diet.12 However, each region provides its biodiversity with differences in genotype frequencies, food products, and food culture. As an example, genome-based nutrition strategies in Mexico would include the knowledge of the Mexican genome and the food cultural history of the population. First, the Mexican population is an admixture of the ancestral Amerindian population with Caucasian and African lineages.11 However, this admixture is heterogeneous throughout the country.13 Therefore, it is expected that the proportion of the ancestral Amerindian genes vary from 50% to 100% based on the geographic location and demographic history of the population. Second, the Mesoamerican diet is the basis of the Mexican food culture.14 However, this traditional diet is widely diverse in regional food ingredients as the result of the miscegenation between the Old and New World cultural food patterns. However, these regional diets have evolved toward the westernized and hepatopathogenic diet that currently has a negative impact on the population’s health. Given these antecedents, studies have been carried out to evaluate the prevalence profile of some diet-related adaptive gene polymorphisms to determine the dietary features to which the Mexican population is genetically adapted. These studies have shown that diet-related gene polymorphisms have a heterogeneous distribution in which the ethnic groups (Amerindians) revealed the highest frequencies of adaptive alleles such as MTHFR 677T, ABCA1 230C, and APOE ε4 followed by mestizos, while the mean of AMY1 diploid copy number was 6.82 ± 3.3 copies.15 Nonetheless, the frequency of the European-related LCT-13910T adaptive allele was highest in mestizos with high European ancestry but extremely low in Amerindians.16 The abovementioned diet-related genes are involved in folate (MTHFR) and lipid (ABCA1 and APOE) metabolism, as well as in dairy (LCT) and starch (AMY1) digestion. Being carriers of adaptive alleles may require nutritional specifications related to traditional dietary practices to avoid the risk of disease to which they have currently been associated. For example, the highly prevalent MTHFR 677T may demand an adequate folate intake or even higher than the Recommended Daily Allowances for the general population. The high frequency of ABCA1 230C and APOE ε4 suggests a genetic adaptation to low-saturated fat/ cholesterol diet, so the excess in the consumption of these nutrients should be discouraged. Furthermore, a mean AMY1 gene copy number of ≥6 copies is consistent with agricultural societies capable of digesting high-starch foods, and the low

Genome-Based Nutrition in Chronic Liver Disease Chapter | 1  5

prevalence of the European LCT-13910T allele indicates that this population is not genetically adapted to digest dairy in adulthood. Therefore, the consumption of milk and dairy products as essentials of the diet should not be recommended. Furthermore, the association of the risk alleles of some taste receptor genes such as TAS1R2, TAS2R38, and CD36 with dyslipidemia and liver damage should not be neglected.17–20 Thus, to modify the current hepatopathogenic dietary pattern, genome-based nutritional advice should be tailored in a regionalized or individualized manner according to the genetic background, regional foods, and traditional food culture of each population. Once the correct diet has been established, specific modifications can be made as required for each liver disease, for example, a correct diet plus antioxidant foods for NASH or a correct diet plus anti-HCV nutrients for patients with chronic HCV infection. This action may be worth replicating in other populations around the world to achieve sustainable and healthier lifestyles.

3. GENES, MICROBIOTA, AND REGIONALIZED DIET Beneficial bacteria from the intestine confer numerous health benefits to the host, including metabolism regulation, energy homeostasis, intestinal motility, immune system control, and host behavior regulation.21 However, gut microbiota alterations facilitate the progression of chronic diseases such as obesity, cardiovascular diseases, type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), as well as altered emotions and eating behaviors.22,23 Factors such as the type of birth, diet, alcohol consumption, viral infections, stress, age, body weight, exercise, use of antibiotics, genetics, and geography modify gut microbiota composition.24 The study of gene polymorphisms and environment interactions with gut bacteria is the main focus of research to understand the development of chronic diseases and negative emotions.25 The central nervous system maintains bidirectional communication with the intestine. Moreover, in the presence of energy balance/brain reward system alterations, negative emotions and stress promote the release of cortisol. Cortisol results in dysbiosis, allowing pathogens and toxins to permeate the gut barrier and activate inflammation.26 Cytokines such as TNFα and IL-1β facilitate abnormalities in lipid metabolism, signal insulin, promote apoptosis, impair lipid oxidation, and promote fibrogenesis.27 In an excess energy intake from a westernized type of diet, the input and type of short-chain fatty acids (SCFAs) are associated with a higher energy source, lipid accumulation, and liver damage.28,29 Concretely, acetate and propionate are involved in hepatic lipogenesis and gluconeogenesis.28 Probiotics, prebiotics, functional nutrients, and different dietary strategies are used to restore the balance in gut microbiota community. Emerging evidence shows that probiotics improve liver metabolism. One way of doing so is by preventing intestinal fat absorption, reducing fasting, and postprandial nonesterified fatty acids levels as showed when Lactobacillus gasseri SBT2055 in fermented milk was administered.30 Other probiotics contribute to SCFA production such as MIYAIRI 588 strain of C. butyricum which produces butyrate and in this way, prevents hepatic lipid accumulation, improves gut barrier permeability, and suppresses hepatic oxidative stress.31 Regarding prebiotics, dietary interventions provide prebiotics such as inulin and galacto-oligosaccharides, guar gum, hemicellulose, glutamine, pectin, and other oligosaccharides.32 These prebiotics produce SCFAs that contribute to increases in beneficial microorganisms such as Bifidobacteria and Lactobacilli, which are involved in protection against obesity as they inhibit the adhesion of pathogenic microorganisms to intestinal mucosa that could alter permeability.33 Also, intestinal fermentation of fructans increases incretin production such as GLP-1 and GLP2 secreted by intestinal lumen cells, which regulate insulin secretion by pancreatic B cells, promoting satiety.34 Dietary strategies based on a more regionalized concept such as the Mediterranean diet have proved to restore gut microbiota in obese patients.35 This diet improves gastrointestinal symptoms and increases adherence to dietary treatment.36 These promising results relate to the antioxidant, anti-inflammatory, and prebiotic capacity of Mediterranean foods such as tea, fermented milk products, vegetables, wheat bread, rice, chocolate, coffee, and many others.37 However, efficient response to foods is influenced by genetic adaptations to the environment.11,15 Recently, in Mexico, regional prebiotic foods (maize, beans, tomato, prickly pear, and chia and pumpkin seeds) based on the components of the Mesoamerican diet showed increments of beneficial bacteria that promote reductions in metabolic parameters, body composition, adipocyte size; decrease oxidative stress markers; and improve cognitive parameters in an experimental model.38 Both of these regional dietary strategies prevent chronic disease development and increase the level of treatment compliance by restoring the gut bacteria community, meaning that emotions and modulation of behavior by the gut microbiota need to be considered in the management of obesity and gastrointestinal and chronic liver diseases.25

4. NUTRITIONAL INTERVENTION IN CHRONIC LIVER DISEASE Management of chronic liver disease requires that patients are provided with a comprehensive medical and nutritional intervention. In the case of NAFLD/NASH, reversing the metabolic abnormalities induced by obesity is a primary goal, whereas halting the consumption of alcohol in patients with alcoholic liver disease (ALD) or fighting HCV with antivirals

6  SECTION | I  Overview of Liver Health

would be the ideal strategy. Commonly, these diseases are detected at advanced stages, in which the number of associated comorbidities is high and therapy becomes complex. How genome-based nutritional strategies are set up to prevent or reverse the deleterious effect on liver health will depend on the population’s genetic susceptibility to develop liver disease, the stage of fibrosis, and the specific composition of the regional hepatopathogenic diet. In this next section, examples of genome-based nutritional strategies to provide a healthier diet for liver-diseased patients are provided.

4.1 Nonalcoholic Fatty Liver Disease—Nonalcoholic Steatohepatitis NAFLD refers to the accumulation of ≥5% of fat in liver cells and is considered a risk factor for an aggressive form known as NASH. NAFLD and NASH have become a global trend parallel to the uprising rate of obesity in both children and adults in populations that have acquired a Westernized lifestyle.39 Physiopathologically, NASH is a stage of oxidative stress and hepatocyte inflammation activated by excess liver triglycerides (either dietary, driven by insulin resistance, or by de novo lipogenesis) which can eventually cause fibrosis, cirrhosis, and in some cases, hepatocellular carcinoma.40 However, genetic and environmental risk factors are involved in the progression of NAFLD/NASH. Two gene variations have been related to the differences in the prevalence of NAFLD worldwide: TMSF2 Glu167Lys variant which reduces protein function, and PNPLA3 Ile148 Met which limits hepatic triglyceride hydrolysis, both of which have been associated with severe steatosis.39,41,42 On the other hand, poor dietary habits and sedentary lifestyle are recognized as risk factors for progression.39 Therefore, considering these factors, tailoring the international recommendations by a genome-based nutritional strategy is required to provide a specific NAFLD/NASH treatment for different populations. For example, in patients with risk of NASH in Mexico, nutritional interventions should consider a correct genome-based regionalized diet as explained earlier with modifications given the high rate of obesity rate, the consumption of a hepatopathogenic diet, and low physical activity that affects the population. In the following subsections, these considerations are detailed.

4.1.1 Weight Loss Goals and Energy Restriction Losing weight through diet and exercise is the primary strategy. It is essential to consider realistic goals to promote a sustained and healthy weight loss. Considering that most NAFLD/NASH patients are overweight or obese, a weight loss strategy ranging from 5% to 10% of the initial weight in 6 months is desirable.43 According to different therapeutic guidelines for NAFLD/NASH (Table 1.1), a weight reduction of 3%–10% is expected. Improvements in simple steatosis are observed TABLE 1.1  International Recommendations for NAFLD/NASH Nutritional Treatment Parameter

AASLD, 201740

Weight loss

3%–10%

Energy restriction Carbohydrates

WGO, 201446

CSE, 201345

AISF, 2010b

APWP, 2007c

7%–10% or 0.5–1 kg/week

5%–10%

3%–10%

0.5 kg/week

0.5–3 kg

500–1000 kcal/ day

500–1000 kcal/ day

25%

500–1000 kcal/ day or 25 kcal/ kg day

Hypocaloric

–

–

Moderate/Low

–

–

Low

–

Avoid fructose

Avoid fructose

Moderate/Low

Higher ω3:ω6 PUFAs ratio Avoid trans-fats and fast foods

Simple sugars Lipids

EASL, EASD, EASO, 2016a

–

Avoid fructose –

Low SFAs

–

AASLD, American Association for the Study of Liver Diseases; AISF, Italian Association for the Study of the Liver; APWP, Asia-Pacific Working Party; CSE, Chinese Society of Endocrinology; EASL, EASD, EASO, European Association for the Study of the Liver, European Association for the Study of Diabetes, and European Association for the Study of Obesity; PUFAs, polyunsaturated fatty acids; SFA, saturated fatty acid; WGO, World Gastroenterology Organization. aEASL-EASD-EASO. Clinical Practice Guidelines for the management of nonalcoholic fatty liver disease. J Hepatol 2016;64(6):1388–402. bLoria P, Adinolfi LE, Bellentani S, et al. Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee. Dig Liver Dis 2010;42(4):272–82. cChitturi S, Farrell GC, Hashimoto E, Saibara T, Lau GKK, Sollano JD. Nonalcoholic fatty liver disease in the Asia-Pacific region: definitions and overview of proposed guidelines. J Gastroenterol Hepatol 2007;22(6):778–87. Adapted from Roman S, Ojeda-Granados C, Ramos-Lopez O, Panduro A. Genome-based nutrition: an intervention strategy for the prevention and treatment of obesity and nonalcoholic steatohepatitis. World J Gastroenterol 2015;21(12):3449–61.

Genome-Based Nutrition in Chronic Liver Disease Chapter | 1  7

with a 3%–5% of body weight loss, whereas a 7%–10% is associated with improvements in the histopathological features of NASH.40 However, a weight loss ≥10% is needed for resolution of NASH and fibrosis regression.44 Energy restriction through diet is required to achieve weight loss. Therefore, it is recommended that energy be reduced from 500 kcal/day to 1000 kcal/day or 30% less of the total energy requirement. The energy intake recommended for women is 1200–1500 kcal/ day and 1500–1800 kcal/day for men (considering physical activity and personal requirements). This aim intends to promote a healthy weight loss which comprises around 0.5–1 kg per week.43 In contrast, a dramatic weight loss of >1.6 kg/ week should be avoided as this may worsen NASH and promote the development of gallstones.45

4.1.2 Macronutrient Distribution Carbohydrates: Very restrictive diets or diets with abnormal macronutrient distribution can decrease long-term adherence. Carbohydrate distribution is relevant in nutritional therapy due to its metabolic effect on de novo lipogenesis. For NAFLD patients, a moderate carbohydrate restriction is recommended (40%–50%) in order to improve the hepatic and metabolic profile. A similar effect has been documented with low-carbohydrate diets ( 35 kg/m2,5 NASH can be present in up to 90% of patients,5 fibrosis in stage 2 or more, evaluated by histopathology, can be present in almost 40% of patients with severe obesity,6,7 whereas liver cirrhosis may be present in 2.5% (1 in every 40) patients with severe obesity,6 whose remission in this stage seems to be unlikely. Indeed, a considerable percentage of morbidly obese patients disclose altered alanine aminotransferase (ALT).8 The almost normal liver, diagnosed histologically, and almost normal biopsy that lacks significant inflammation, fatty change, nodular regenerative hyperplasia, inherited metabolic or storage disorder, or fibrosis, in patients with altered liver biomarkers or radiology, are normally present in patients with obesity when NAFLD is absent.9 The almost normal liver is not commonly diagnosed because liver biopsy is not routinely recommended for patients with BMI > 30 kg/m2. Although type 2 diabetes mellitus (T2DM) and metabolic syndrome were usually correlated with severe liver fibrosis,7,10 T2DM, hypertension, and high ALT were found to be predictors of NASH,7,10 even when metabolically healthy. Among the candidates for bariatric surgery (BS), those without dysglicemias, dyslipidemia, or hypertension (i.e., “metabolically healthy”), NAFLD Activity Score (NAS) showed moderate-to-severe liver alteration in almost half of the candidates, whereas 23% had lobular inflammation, almost 10% had hepatocyte ballooning, almost 10% also had NASH, and almost 5% had liver fibrosis, which shows that being “metabolically healthy” may actually mask liver dysfunctions in obese patients.8 Increased calorie intake is also an independent predictor of NAFLD, regardless of BMI.4

1.1 Biochemical Markers and Alterations of the Liver in Obesity Several markers have been investigated and linked to the liver of obese patients, many of them as independent predictors of severity of NAFLD or fibrosis, as well as overall morbidity and mortality. The current markers, as well as gene expressions related to the liver in the obese patient, are summarized in Table 4.1. An imbalanced adipokine profile, particularly adiponectin and leptin, has evolved as a crucial signal for the development of NAFLD, as adiponectin is critically involved in the prevention of proinflammatory state associated with obesity, whereas leptin seems to be a proinflammatory mediator.11 Dietary Interventions in Liver Disease. https://doi.org/10.1016/B978-0-12-814466-4.00004-5 Copyright © 2019 Elsevier Inc. All rights reserved.

39

FIGURE 4.1  Liver consequences of obesity. ALT, alanine aminotransferase; BMI, body mass index; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; T2DM, type 2 diabetes mellitus.

TABLE 4.1  Summary of the Current Changes Observed in the Liver of Obese Patients Liver Alterations When BMI > 30 kg/m2 Imbalanced adipokine profile (reduced adiponectin and increased leptin) 53 phosphorylation sites in the carbohydrate metabolism pathways (other than in lipid- and glucose-induced hepatic insulin resistance) Tumor necrose factor α (TNF-α) Interleukin 8 (IL-8) Interleukin 33 (IL-33) Chemokine ligand 3 (CCL3, or macrophage inflammatory protein 1-alpha [MIP-1-alpha]) CCL2 (or monocyte chemoattractant protein-1 [MCP-1]) and its receptor chemokine receptor 2 (CCR2) Cluster of differentiation 44 (CD44) Gasdermin D (GSDMD) Galectin-3 (Gal-3) White adipose tissue (WAT) IL-6 and TNF-α mRNA expressions Genes involved in lipid-related processes (apoB, PPARα and PGC1α, CYP7a1, and HMGCR) Decreased desacyl ghrelin and increased acylated-to-desacyl ghrelin ratio FGF21 mRNA expression levels in hepatic ballooning and steatosis (inverse correlation) FGF21 mRNA expression (direct correlation with lobular inflammation and fibrosis) Omentin-1 mRNA expression (direct correlation with lobular inflammation and fibrosis) IGF-1 (protective role) Increased PKM2 (M2 isoenzyme of pyruvate kinase) Increased serum chemerin (RARRES2) Decreased hepatic chemerin mRNA expression (as a predictor of hepatic steatosis but not liver fibrosis or cirrhosis) Decreased aquaglyceroporin (AQP) 9 gene expression Increased AQP3 and AQP7 gene expressions in the subcutaneous WAT Patatin-like phospholipase domain-containing 3 (PNPLA3, also called as adiponutrin) 148 isoleucine to methionine protein variant (I148M—rs738409 C/G) polymorphism (variant) Lower serum vitamin A levels (but increased vitamin A metabolites in the liver)

The Liver Before and After Bariatric Surgery Chapter | 4  41

Moreover, abnormalities in carbohydrate metabolism other than hepatic insulin resistance were shown to be an independent and important trigger for the development of NASH, as observed by the alteration of 53 phosphorylation sites in the carbohydrate metabolism pathways and RNA posttranscriptional modifications.12 Although elevated lipopolysaccharides (LPS), lipopolysaccharide-binding protein (LBP), soluble CD14, intestinal-type fatty acid–binding protein (iFABP), and toll-like receptors 2 and 4 (TLR2 and TLR4) levels were directly correlated with BMI, they were not necessarily found as predictors of NAS and liver dysfunction severity, when adjusted for body weight and BMI.13 In contrast, tumor necrose factor α (TNF-α), interleukin 8 (IL-8), and chemokine ligand 3 (CCL3), macrophage inflammatory protein 1-α (MIP-1-α) were independently correlated with FAS, which shows that circulating inflammatory parameters, rather than endotoxins, are more strongly related to liver disease.13 The cluster of differentiation 44 (CD44) was demonstrated to regulate adipose tissue, inflammation in obesity, and recruitment of hepatic leukocyte, as the knockout of CD44, as well as neutralization of CD44, led to important decrease in liver inflammation, inflammatory foci number, macrophage, and neutrophil infiltration in the hepatic tissue, CCL2 (or monocyte chemoattractant protein-1 [MCP-1]) and its receptor chemokine receptor 2 (CCR2) levels, and fibrosis, whereas the soluble form of CD44 led to opposite effects.14 Also, CD44 in humans was strongly upregulated in NASH; high NAS, in the presence of hepatocyte ballooning, altered ALT, upregulated hepatic CCL2 expression, and macrophage marker CD68, whereas correction of NASH was associated with dramatic decrease of CD44.14 The gasdermin D (GSDMD) protein levels, involved in inflammation and control of interleukin (IL)-1β release, were independently and directly correlated with NAS, NASH, and fibrosis. GSDMD knockout rats disclosed importantly, decreased steatosis and inflammation, compared with wild rats with same body weight and receiving same diet.15 Finally, gasdermin D plays a key role in the pathogenesis of NASH by regulating lipogenesis, the inflammatory response, and the NF-ĸβ signaling pathway, as gasdermin D–driven pyroptosis is prominent in patients with NASH. Galectin-3 (Gal-3), a unique chimera-type β-galactoside-binding protein of the galectin family, has a regulatory role in immunometabolism and fibrogenesis, plays a protective role in the liver, as rats with knockout for Gal-3 yield exacerbated adiposity and hepatic steatosis, although shows impaired liver inflammation and fibrosis when fed an obesogenic high-fat diet.16,17 IL-33, a member of the IL-1 cytokine family, mediates immunometabolic and fibrotic disorders and was suggested to play protective role for the IL-33/IL-33R (ST2) signaling pathway in obesity, adipose tissue inflammation, and atherosclerosis but a profibrotic role in NASH development. The interaction between Gal-3 and IL-33 has a prominent role in the development of therapeutic interventions to antagonize the Gal-3/IL-33 system to prevent and/ or reverse obesity-associated hepatic inflammation and fibrosis, although the blockage of this interaction facilitates the fat accumulation in the liver.16,17 The white adipose tissue IL-6 and TNF-α mRNA expression can proportionally and directly reflect the level of NASH in the presence of NAFLD and be therefore indirect markers of dysfunctional liver in obesity.18 In regard to gene expressions, while expression of genes implicated in liver lipid uptake, including HL, LPL, VLDLr, and FAT/CD36, was increased in the presence of dyslipidemia or T2DM, the expression of genes involved in lipid-related processes outside of the liver, such as apoB, PPARα and PGC1α, CYP7a1, and HMGCR, was reduced in the absence of glycemic and lipid biochemical alterations in obese patients.19 The reduction of the expression of these genes favors the accumulation of liver fat content and consequent liver inflammation and fibrosis in these patients.19 NASH is also independently correlated with decreased circulating desacyl ghrelin without changes in acylated ghrelin, with consequent increase of the acylated-to-desacyl ghrelin ratio.20 Fibroblast growth factor (FGF) 21 serum level was significantly correlated with the extent of steatosis, particularly a strong correlation between FGF21 mRNA, omentin-1 mRNA expression levels, and lobular inflammation and fibrosis, whereas inverse correlation between FGF21 mRNA expression levels in hepatic ballooning and steatosis was found. However, both were poorly correlated with other parameters than steatosis.21 Conversely, insulin growth factor 1 (IGF-1) levels are inversely correlated with histologic severity of NAFLD, such as hepatocyte ballooning, NASH, and liver fibrosis, even after adjustment for age, BMI, and sex.22 However, whether the inverse correlation between IGF-1 levels and NAFLD severity is causal, or pleiotropic effects of inflammation and increased cytokines, remains unclear. In the presence of NAFLD and NASH, liver had increased M2 isoenzyme of pyruvate kinase (PKM2) expression levels, and the enzyme appears to be specifically localized in Kupffer cells, and PKM2, a new target for monitoring NAFLD and NASH.23 Additionally, chemerin or retinoic acid receptor responder protein 2 (RARRES2), an adipokyne mostly related to adipocyte differentiation and stimulation of lipolysis and also implicated in the glucose metabolism, yielded higher serum concentration in the presence of hepatocyte ballooning, greater extent of steatosis, and NASH, whereas had no correlation with BMI.24 Conversely, hepatic chemerin mRNA levels may predict hepatic steatosis, hepatocyte ballooning, and NAS but not liver fibrosis or cirrhosis.24 However, serum chemerin was not correlated with live mRNA expression, which shows that the putative main source of chemerin is the fat tissue.

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1.2 Gene Expressions and Polymorphisms in the Sick Liver of the Obese In regard to gene expressions, hepatic gene expression of aquaglyceroporin (AQP) 9 was decreased in response to weight gain induced by high-fat diet (contrasting the increase in AQP3 and 7 in the subcutaneous fat tissue).25 The most important polymorphism correlated with liver dysfunctions in response to excessive fat weight is the patatinlike phospholipase domain-containing protein 3 (PNPLA3, also called as adiponutrin) 148 isoleucine to methionine protein variant (I148M - rs738409 C/G).26–28 The PNPLA3 induces anabolic and catabolic activities in lipid metabolism and has strict correlation with liver fat content, and its I148M variant is directly and independently correlated to higher NAFLD scores, fat liver content, NASH, liver fibrosis,26–28 insulin resistance, even in normoglycemic populations,27 low adiponectin levels, and mRNA adiponectin expression, independent of the stage of NAFLD.29 The PNPLA3 i148M variant also impairs liver vitamin A metabolism. The Liver fibrosis and cirrhosis are associated with impaired vitamin A homeostasis and may lead to a “pseudo” vitamin A deficiency.30 Liver injury triggers hepatic stellate cells to differentiate myofibroblasts, which produce excessive amounts of extracellular matrix, leading to fibrosis; within this process, the retinyl ester stores are lost, ultimately leading to the apparent vitamin A deficiency. However, although PNPLA3 i148M is related to lower serum retinol levels, retinyl esters are increased in NAFLD of patients with this polymorphism. Therefore, low circulating retinol in NAFLD may not reflect a true “vitamin A deficiency” but disturbed vitamin A metabolism instead, and therefore providing more vitamin A may be more harmful than helpful.30 A summary of the metabolic markers, enzymes, and altered gene expressions in the liver before BS is shown in Fig. 4.2.

1.3 The Challenging Management of NAFLD, NASH, Liver Fibrosis, and Cirrhosis in Obesity NAFLD is a pathogenically complex, multifactorial, systemic, and clinically heterogeneous disease, and thus, diagnosis may be challenging, as despite the several proposed tools, none of the noninvasive markers disclose very high accuracy to detect NAFLD, NASH, liver fibrosis, or cirrrhosis.1 However, among the commercially available markers, LDLc and HbA1c were shown to be the best predictors of NAFLD in the presence of obesity.31 The recent raise in the incidence of hepatocellular carcinoma can be at least partly explained by the epidemic of NAFLD and consequent liver cirrhosis.8,32 Moreover, it was found that liver cirrhosis induced by NAFLD, NASH, and liver fibrosis has the same risk of development of hepatocellular carcinoma than the liver cirrhosis induced by hepatitis C virus.32 Both leptin and adiponectin have been related to liver tumorigenesis.11 Given the multiple concerns, the lack of accurate markers, and the underreported liver dysfunctions in the obese population, several specific lifestyle changes, including sorts of physical activity and diets,33–35 as well as several new classes of drugs, including already existing and new molecules,36–40 have been proposed or are currently being studied for the evaluation of safety and effectiveness in NAFLD, NASH, and other obesity-related liver dysfunctions. Nonetheless, BS has already been established as one of the major effective and fast-improving options for metabolic-related liver diseases, despite the lack of specific studies regarding liver improvement as the primary outcome of BS. Given the global pandemic of emerging and fast-growing liver disorders, the long time consumption of specific studies, and the multiple potential benefits of BS for the liver health and prevention of liver disease progression to NASH, fibroses, cirrhosis and need for transplantation, some authors have proposed BS as an urgent public health approach. They claim that if specific studies are waited for the formal implementation of BS for NAFLD and NASH, an epidemic need for liver transplantation (LT) will be likely observed in the near future.41 Therefore, regardless of being the primary outcome, BS should be urgently considered for patients with moderate and severe obesity, even when “metabolically healthy,” as we learned that liver dysfunctions are underestimated in this population.

1.4 Preparation for Bariatric Surgery in the Patient With Liver Dysfunction When evaluating risks for BS, besides initial BMI, weight loss prior to surgery, familial history of complications and diseases, and presence of comorbidities, it has been found that more severe liver dysfunctions, particularly liver cirrhosis, are linked to higher surgical morbidity and mortality,42,43 although liver fibrosis, even in advanced stages, does not increase early postoperative complications (except longer hospital stay after surgery,44 as well as NAFLD, regardless of the NAS).45 However, when analyzed in the long run (for 10 years after surgery), the presence of NASH is linked to a 190% increase in postbariatric death, with loss of mortality reduction observed in obese patients that undergo bariatric procedures.46 Whenever liver cirrhosis is present, sleeve gastrectomy (SG) should be preferred over Roux-en-Y gastric bypass (RYGB),43 and BPD is highly contraindicated in these cases.

The Liver Before and After Bariatric Surgery Chapter | 4  43

FIGURE 4.2  The liver before bariatric surgery. BMI, body mass index; CCL, chemokine ligand; CD, cluster of differentiation; CHO, carbohydrate; FGF, fibroblast growth factors; Gal, galactin; GLP, glucagon-like peptide; iFABP, intestinal-type fatty acid binding protein; IL, interleukin; LBP, lipopolysaccharide-binding protein; LPS, lipopolysaccharides; MIP, macrophage inflammatory protein; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; P1MP, procollagen type I propeptide; PK, pyruvate kinase; PNPLA, patatin-like phospholipase domain-containing; RARRES, retinoic acid receptor responder protein; SGLT, sodium-glucose linked transporter; TLR, toll-like receptors; TNF, tumor necrose factor; WAT, white adipose tissue.

While liver dysfunctions are highly underestimated in the obese population, younger patients tend to present higher capacity to store fat in the subcutaneous adipocytes. Therefore, younger obese patients tend to reach formal indication for BS in terms of BMI criteria before liver is affected,47 thus, BS in this population likely prevents permanent liver dysfunctions (i.e., cirrhosis and advanced fibrosis) in a more effective way compared with older patients. Nevertheless, although adipocyte volume is directly related to inflammation, more exposition to lipolysis, and consequent liver metabolism of

44  SECTION | I  Overview of Liver Health

TABLE 4.2  Predictors of Risks in Bariatric Surgery Initial body mass index (BMI) Weight loss prior to surgery Familial history of complications and diseases Presence of comorbidities Liver cirrhosis Nonalcoholic steatohepatitis (NASH) (only in the long term, i.e., >10 year) Older age Insulin resistance Higher procollagen type I propeptide (P1NP) Lower osteocalcin Lower albumin-corrected calcium Higher parathyroid hormone (PTH) Lower serum 25(OH) vitamin D Male sex Smoke Expression of 32 specific genes related to NASH PNPLA3 p.I148M (better improvement after bariatric surgery)

the free fatty acids, the time that body was exposed to enlarged adipocytes has a crucial role in the pathogenesis of liver dysfunctions; thus, older patients tend to have been exposed to hypertrophic inflammatory and macrophage-infiltrated adipocyte tissue for longer periods, which may explain the more significant affected liver in older obese patients.47 In regard to liver fibrosis, it was found that the insulin resistance, procollagen type I propeptide (P1NP), lower osteocalcin, albumin-corrected calcium, parathyroid hormone, lower vitamin D, male sex (OR 7.93 for moderate and 2.92 for severe fibrosis), BMI (OR 1.33 for moderate and 1.16 for severe fibrosis), smoking, and higher age were independent predictors.48–50 Thus, patients with concomitant obesity and any of these features should be screened for the presence of liver dysfunctions. Additionally to the risks related to the level of NAFLD, NASH, liver fibrosis, or cirrhosis, the expression of 32 specific genes related to NASH prior to surgery is linked to a 7.7-fold higher risk of mortality after BS.51 Conversely, the PNPLA3 p.I148M variant, besides linked to higher fat liver content and NAS in obese patients, is also correlated to more weight loss and greater improvement of NAFLD and NASH after BS, whereas other variants, including the transmembrane 6 superfamily member 2 (TM6SF2) p.E167K and the membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) rs641738 polymorphisms, previously thought to be correlated with BS outcomes, did not disclose any difference in regard to the response to BS.52 However, the adipose tissue PNPLA3 expression, but not the liver, which is silenced by TNF-α in obesity, is restored after BS.53 The predictors of risks of BS in patients with obesity, in regard to the liver alterations, are summarized in Table 4.2. For the preoperative improvement and possible reduction of risks during and after BS, a very low–calorie diet (VLCD) prior to the BS for 3 to 6 months can induce normalization of the liver histology and metabolic parameters, including insulin sensitivity, ALT, aspartate aminotransferase (AST), AST-to-ALT ratio, and lipid profile, in up to 25% of the candidates for BS,5 as well as 20% reduction in the liver volume.54 Even dietary interventions for very short periods (as short as 2 weeks), including VLCD and meal-replacement diets, may be enough to induce reduction of inflammatory markers, including C-reactive protein (CRP), fetuin-A, and interleukin-6 (IL-6), as well as improvement of liver histology.55 However, whether VLCD and short-term reduction of harmful liver markers reduce risks during and after BS is still unclear.54 Besides the pre-BS diets, prescription of some drugs, including the GLP-1 analogue liraglutide,56–59 metformin,59–61 sodium-glucose linked (or co-) transporter 2 (SGLT-2) inhibitors,62–64 pioglitazone (although induce weight gain),60,65 omega 360,66,67 vitamin E,60,68 silimarin69 or even statins,70,71 may help reduce severity of NASH and a likely reduction of the postoperative risk. However, none of the medications should be primarily and exclusively used for this outcome.

The Liver Before and After Bariatric Surgery Chapter | 4  45

TABLE 4.3  Modifiable Factors That Positively Affect the Liver Health and Bariatric Surgery Outcomes Modifiable Factors That May Improve Bariatric Surgery Outcomes Very low–calorie diet (VLCD) Physical activity Glucagon-like peptide 1 (GLP-1) analogue (liraglutide) Sodium-glucose linked transporter 2 (SGLT-2) inhibitors Pioglitazone (although induces weight gain) Omega 3 Vitamin E Orlistat Silimarin

The modifiable interventions that positively affect the liver health and BS outcomes are listed in Table 4.3.

2. THE LIVER AFTER THE BARIATRIC SURGERY BS is an effective and lasting therapy against obesity and provides weight-loss-dependent and weight-loss-independent improvement of many metabolic dysfunctions, including remission of T2DM72,73 and reduction in several metabolic and inflammatory markers.74 It results reductions of several risks, including cardiovascular events75 and long-term overall mortality,73,75 and currently discloses very low intraoperative mortality.76 However, BS can induce multiple nutritional deficiencies (that do not particularly affect the liver health, except in few cases) and77,78 increase some psychiatric conditions79 and alcohol abuse80 through the “addiction transfer” effect, as patients with severe obesity tend to present more compulsive behaviors and addictive trends. In regard to the BS effects on the liver, NASH tends to be completely remitted in most patients (94% of remission when mild and 70%, when moderate or severe)81 with normalization of ALT and gamma-GT,81–83 as well as leads to multiple improvements in the liver histology, as evidenced by reduction of histological diagnosis of steatosis from 60% to 90% before to 0%–10% after BS,81,82 hepatocellular ballooning in 84.2%–100%, and lobular inflammation in 67.1%–100%,81,82 whereas fibrosis was reduced by 33.8%–70%,81,82 as early as 3 to 6 months after surgery,83,84 and benefits last for at least 5 to 10 years after BS,82 except in the cases that liver failure occurs, as described later. However, results were highly heterogeneous. Despite the optimistic results shown in some studies,81–84 in a systematic review on liver biochemistry and histology in response to BS, an overall reduction in steatosis of 50.2% (95% CI 35.5%–65.0%), fibrosis of 11.9% (95% CI 7.4%–16.3%), hepatocyte ballooning of 67.7% (95% CI 56.9%–78.5%), and lobular inflammation of 50.7% (95% CI 26.6%–74.8%) is associated with significant reductions of ALT, AST, and gamma-GT.85 Moreover, this systematic review did not adjust improvements for weight loss to evaluate whether improvements had weight-loss-independent effects.85 Although there was not a strict correlation between amount of weight loss in absolute weight or in excess weight loss in percentage, and level of improvement of liver parameters,86 clinical predictors of poorer liver response to BS were basically poor weight loss and gastric banding (LAGB), compared to RYGB.81 Indeed, a weight loss of 10% or more, reduction of triglycerides, and in NAFLD, activity strongly predict normalization of ALT levels.87,88 In regard to the type of BS performed and liver outcomes, in a direct comparison between SG and RYGB evaluated by intraoperative and postoperative liver biopsies, similar reductions of the NAFLD activity were observed.89,90 However, RYGB presented less sensitive improvement in liver biochemical tests in one study,89 while liver markers improved similarly between RYGB and SG in another study.89 Moreover, RYGB tended to yield higher risk of transient liver dysfunction,85,89,90 as well as most severe live fibrosis at the time of the surgery.85 Even when matched for weight loss, liver improvements tend to be more prominent after SG when compared with restrictive caloric diets.91 Indeed, BS has the potential to prevent a likely future epidemic of the need of LT by dramatically reversing the dysfunctional liver92 and is highly cost-effective,51 effective, and safe for liver-injured patients.93 In regard to sex differences in response to BS, male rats tend to disclose a more substantial reduction in hepatic lipids, whereas females had a more important reduction of VLDLc production after SG.94 However, for a same increase in body weight, females tend to present a more prominent increase in the liver metabolic dysfunctions.94

46  SECTION | I  Overview of Liver Health

Children and adolescents with severe obesity are possible candidates for SG; 76% had NAFLD, 40% had NASH, and 37% had significant fibrosis (stage >2). Surprisingly, younger children (