Clinical Dilemmas in Non-Alcoholic Fatty Liver Disease E-Book

Roger Williams

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Serie: Clinical Dilemmas
• Sprache: Englisch

Seitenzahl: 686

Veröffentlichungsjahr: 2016

Beschreibung

Clinical Dilemmas in Non-Alcoholic Fatty Liver Disease offers hepatologists practical, up-to-date and expert guidance on the most topical dilemmas, difficulties and areas of controversy/difficulty surrounding this ever-increasing area of liver disease they face in daily practice. 

Roger Williams and Simon Taylor-Robinson, two of Europe’s leading hepatologists, have recruited leading figures from across the world to assist them, resulting in a truly international approach.  Each chapter covers a specific area of difficulty, containing clear learning points and providing evidence-based expert guidance on the latest hot topics in clinical management such as:

• Is NAFLD different in absence of Metabolic Syndrome?
• Are the pros outweighed by the cons of obtaining a liver biopsy?
• Is progression to cirrhosis more likely in children with NAFLD?
• What are the dangers as well as the true benefits of bariatric surgery?
• How is it best to use antifibrotic agents in clinical practice?

Clinical Dilemmas in Non-Alcoholic Fatty Liver Disease provides the answers to the questions and challenges that clinicians face every day in this area.  It is essential reading for hepatologists of all levels and researchers in hepatology, as well as all those involved in the care of patients with NAFLD, including gastroenterologists, pathologists and specialist hepatology nurses.

Leseprobe

Table of Contents

Cover

Title Page

List of contributors

Preface

PART I: Nature of the Condition

1 Non-alcoholic fatty liver disease

References

2 NAFLD

Introduction

Prevalence of NAFLD worldwide

Disease severity

Obesity and metabolic syndrome

Genetic predisposition

NAFLD as a cofactor

Conclusions

References

3 Is insulin resistance the principal cause of NAFLD?

Introduction

What is meant by insulin resistance?

How is insulin resistance measured

in vivo

in man?

Insulin resistance and NAFLD

Conclusions

References

4 Paediatric NAFLD

Introduction

Developmental origins of paediatric NAFLD

Paediatric NAFLD: Histological evidence of early progression

Paediatric NAFLD: A distinct disease?

Ductular reaction, hedgehog signalling and advanced fibrosis

What do we know from other types of paediatric chronic liver disease?

What are the known risk factors for progression of fibrosis in NAFLD?

Conclusion

References

5 Non-alcoholic fatty liver disease (NAFLD) as cause of cryptogenic cirrhosis

Introduction

Cryptogenic cirrhosis: Definition and characteristics

Pathological recognition of NAFLD/NASH in cryptogenic cirrhosis

Evidence for NAFLD as the cause of cryptogenic cirrhosis

Loss of steatosis in late NAFLD/NASH with cirrhosis

Other possible causes of cryptogenic cirrhosis and future directions

Summary

References

6 Is NAFLD different in absence of metabolic syndrome?

Introduction

Metabolically normal NAFLD, Hb, and iron

Genetic factors and metabolically normal NAFLD

Prognostic implications of metabolically normal NAFLD

Does metabolically normal NAFLD require a specific treatment approach?

Conclusions

References

7 Occurrence of noncirrhotic HCC in NAFLD

The metabolic syndrome, NAFLD, and HCC

Pathogenesis linking HCC and NAFLD

Conclusions

References

PART II: Factors in Disease Progression

8 Fibrosis progression

Introduction

The concept of liver repair

Mechanisms of liver fibrogenesis

Key molecular pathways

Conclusions and future

Acknowledgements

References

9 When is it NAFLD and when is it ALD?

Introduction

Steatosis

Inflammation

Hepatocellular injury

Fibrosis

Other lesions

Grading and staging: ALD and NAFLD

References

10 Of men and microbes

Introduction

Intestinal microbiome

Conclusion

References

11 Can genetic influence in non-alcoholic fatty liver disease be ignored?

Introduction

What evidence suggests a heritable component to NAFLD?

What genetic factors have been identified?

Conclusions and clinical relevance

References

12 Is there a mechanistic link between hepatic steatosis and cardiac rather than liver events?

Introduction

Evidence supporting the association between NAFLD and CVD

Mechanistic link between NAFLD and CVD

Genetic association between fatty liver and cardiometabolic risk

Conclusion

References

PART III: Diagnosis and Scoring

13 How to best diagnose NAFLD/NASH?

Primary or secondary NAFLD?

Histological diagnosis

Noninvasive diagnostic procedures

Recommendations for diagnosis in clinical practice

References

14 The clinical utility of noninvasive blood tests and elastography

Introduction

Use of noninvasive fibrosis tests in chronic liver diseases

Noninvasive diagnosis of NASH

Noninvasive fibrosis assessment

Conclusions: Future directions

References

15 Are the guidelines—AASLD, IASL, EASL, and BSG—of help in the management of patients with NAFLD?

A definition problem

To screen or not to screen?

The thin line between NAFL and NASH

Therapy: An open and evolving question

Special population: Pediatric patients

Conclusions

References

16 Imaging methods for screening of hepatic steatosis

Ultrasound

Computed tomography

Advantages and limitations of CT for screening

Magnetic resonance imaging

Qualitative estimation of hepatic fat on MRI

Quantitative estimation of hepatic fat on MRI

MRS

References

17 Are the advantages of obtaining a liver biopsy outweighed by the disadvantages?

Introduction

Diagnosis and assessment of disease severity

Technical and logistical matters

Conclusions

References

18 Screening for NAFLD in high-risk populations

Introduction

Nature of NAFLD: Relevance to screening

Current opinion and guidelines

The high-risk population

Potential screening tests

A practical approach to NAFLD screening

Summary

References

PART IV: Value of Treatment Measures

19 Defining the role of metabolic physician

Diagnosis and assessment of the obese patient

Medical management of obesity

Management of bariatric surgical patients

Conclusions

References

20 Should physicians be prescribing or patients self-medicating with orlistat, vitamin E, vitamin D, insulin sensitizers, pentoxifylline, or coffee?

Introduction

Coffee consumption

Orlistat

Pentoxifylline

Vitamin E

Insulin sensitizers

Vitamin D

Conclusion

References

21 Effects of treatment of NAFLD on the metabolic syndrome

Introduction

Effect of insulin-sensitizing antidiabetic treatments on NAFLD and the MetS (Table 8.1)

Conclusions

References

22 What are the dangers as well as the true benefits of bariatric surgery?

Introduction

Development of bariatric surgical procedures

What are the risks of bariatric surgery?

Benefits of bariatric surgery

Conclusion

References

23 Liver transplantation

Current results of liver transplantation for NASH

Frequency of NAFLD recurrence and of metabolic syndrome after transplantation and clinical significance

Impact of obesity on long-term outcome after liver transplantation for non-NASH indications

Conclusion

Acknowledgement

References

PART V: What Does the Future Hold?

24 Molecular antagonists, leptin or other hormones in supplementing environmental factors?

Introduction

Strategies to promote ‘healthier’ adipose tissue function

Beyond diabetes and insulin signalling

Lipid and dietary modification

Hepatic oxidative stress

Conclusion

Acknowledgement

References

25 What is the role of antifibrotic therapies in the current and future management of NAFLD?

Antifibrotic targets in NAFLD

Challenges of clinical trial design in NAFLD

What have we learnt from NAFLD antifibrotic trials to date?

What are the most promising emerging antifibrotic therapies in NAFLD?

Other emerging therapies

Conclusions

Acknowledgement

References

26 Developmental programmingof non-alcoholic fatty liver disease

Human studies

Animal models

Cellular and subcellular mechanisms

Nervous system

Epigenetic mechanism

Immune mechanism

Gut microbiota

Conclusions

References

Index

End User License Agreement

List of Tables

Chapter 02

TABLE 2.1 Estimated prevalence of NAFLD in different geographical regions

Chapter 03

TABLE 3.1 Some methods of assessing insulin resistance

TABLE 3.2 Portal venous insulin delivery before and during an intravenous glucose tolerance test in insulin-resistant men with NAFLD compared with controls

TABLE 3.3 Classical insulin-resistant states and NAFLD

Chapter 05

TABLE 5.1 Causes of cirrhosis

TABLE 5.2 Possible causes of fat loss in late NAFLD-related cirrhosis

Chapter 09

TABLE 9.1 Similarities and differences between ALD and NAFLD

Chapter 11

TABLE 11.1 GWAS relevant to NAFLD

TABLE 11.2 Additional genetic modifiers of NAFLD identified in candidate gene studies

Chapter 13

TABLE 13.1 Metabolic risk factors

TABLE 13.2 Causes of secondary NAFLD

Chapter 14

TABLE 14.1 Noninvasive tests for diagnosing NASH in patients with non-alcoholic fatty liver disease

TABLE 14.2 Noninvasive fibrosis tests in patients with non-alcoholic fatty liver disease

Chapter 17

TABLE 17.1 Table with examples of when the pros of liver biopsy outweigh the cons, and

vice versa

Chapter 18

TABLE 18.1 Screening principles [2] as applied to NAFLD

TABLE 18.2 Risk factors for NAFLD

TABLE 18.3 Potential screening tests for NAFLD

Chapter 19

TABLE 19.1 Genetic syndromes linked to obesity

TABLE 19.2 Edmonton obesity staging system

Chapter 21

TABLE 21.1 Examples of dissociation of effects of pharmacotherapy of NAFLD on liver fat content, insulin sensitivity, glycemia, and body weight

Chapter 22

TABLE 22.1 Summary of common bariatric surgical procedures

Chapter 25

TABLE 25.1 Summary of antifibrotic trials in NAFLD

List of Illustrations

Chapter 03

FIG 3.1 The two-step, low- and high-insulin infusion rate, euglycaemic hyperinsulinaemic clamp. Eight volunteers with familial combined hyperlipidaemia (FCHL: closed triangles) were compared with eight healthy controls (open triangles). Plasma glucose concentrations (panel A) were kept constant by a variable rate glucose infusion (panel B) in the presence of small and large increases in plasma insulin concentrations (panel C). The sensitivity to insulin of glucose elimination from plasma (conventional insulin sensitivity) was quantified by the rate of glucose infusion needed to maintain euglycaemia in the presence of constantly elevated insulin concentrations. As shown in panel B, differences between the two groups in insulin sensitivity were most clearly discriminated at high insulin concentrations between 150 and 300 min. The sensitivity of suppression of lipolysis to insulin was quantified by the magnitude of the fall in plasma NEFA concentrations (panel D), which was most clearly discriminated between the two groups in the presence of the small increase in insulin concentrations between 0 and 150 min. The FCHL group showed appreciably less of a reduction in NEFA concentrations in response to a low insulin infusion rate compared with the controls, indicating resistance to the antilipolytic effects of insulin

FIG 3.2 Suppression of lipolysis during an intravenous glucose tolerance test. A group of eight volunteers with non-alcoholic fatty liver disease (NAFLD: closed triangles) was compared with eight healthy controls (open triangles). A rapid, bolus, intravenous injection of glucose stimulates insulin secretion from the pancreas. Panel A shows that the rate at which glucose concentrations returned to normal differed little between the two groups. However, as shown in panel B, this was achieved with a marked difference in insulin concentrations. To restore normoglycaemia, significantly higher insulin concentrations were necessary in the NAFLD group, indicating appreciable insulin resistance. The sensitivity to insulin of glucose elimination from plasma (insulin sensitivity) was quantified by relating the rate of fall in glucose concentrations to the accompanying insulin concentrations in a mathematical modelling analysis. Accompanying changes in NEFA concentrations are shown in panel C. The sensitivity of suppression of lipolysis to insulin was quantified as the ratio of the rate of fall in plasma NEFA concentrations between 16 and 40 min divided by the incremental area under the insulin concentration profile between 16 and 40 min. The NAFLD group showed an appreciably slower rate of reduction in NEFA concentrations despite higher accompanying insulin concentrations compared with the controls, indicating resistance to the anti-lipolytic effects of insulin

Chapter 05

FIG 5.1 Classical non-alcoholic steatohepatitis (NASH). (A) Steatosis, hepatocyte ballooning, and inflammation (the trio of changes representing the minimal histological criteria of steatohepatitis) are evident in the centrilobular region (C). (B) Hepatocyte ballooning and intracellular Mallory–Denk bodies (arrow) are shown at high magnification. (C) The characteristic pericellular/perisinusoidal “chicken-wire” pattern of fibrosis surrounding centrilobular hepatocytes is seen on this trichrome stain (A and B, hematoxylin and eosin stain; C: Masson trichrome stain).

FIG 5.2 “Cryptogenic cirrhosis” due to NAFLD. (A) Cirrhosis without fat is seen at low magnification. Portal tracts and fibrous septa contain mild to moderate chronic inflammatory cell infiltrates, rendering a superficial resemblance to chronic hepatitis. However, careful examination of the hepatocytes located at the periphery of the nodules (arrow) allows recognition of remaining NASH features (seen at high power in panel B). (B) High magnification of the parenchyma near the arrow in panel A. Hepatocytes are variably ballooned and there is robust Mallory–Denk body formation (arrows). (C): Occasional periportal/periseptal hepatocytes show glycogenated nuclei (arrows) (A, B, and C: hematoxylin and eosin stain).

Chapter 06

FIG 6.1 Interrelationship between the main variables that may influence the development of metabolically normal NAFLD.

Chapter 07

FIG 7.1 Shared pathways in the pathogenesis of NAFLD and HCC. AMPK, adenosine monophosphate-activated protein kinase; DEN, diethylnitrosamine; IGF-1, insulin growth factor-1; IRS-1, insulin receptor substrate-1; JNK, c-Jun amino-terminal kinases; MAPK, mitogen-activated protein kinase; NF-κβ, nuclear factor kappa beta; P13K, phosphatidylinositol-3-kinase/Akt=protein kinase B; PTEN, phosphatase and tensin homolog; TAK1, transforming growth factor-β-activated kinase 1; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor-alpha.

Chapter 08

FIG 8.1 Link between cell death and fibrogenic liver repair. Liver cell injury or death from lipotoxicity, oxidative stress and immune imbalance leads to the release of signalling factors (such as Hedgehog ligands), which promote the proliferation of ductular progenitors and liver pericytes (hepatic stellate cells) as part of the repair response. Stimulated hepatic stellate cells transition into collagen-producing myofibroblasts, and ductular progenitor cells secrete high levels of cytokines and growth factors that recruit immune cells into the liver. In turn, recruited immune cells secrete even more cytokines and growth factors that perpetuate the inflammatory and fibrogenic response. Ductular progenitors may also undergo direct differentiation into scar-producing myofibroblasts.

FIG 8.2 Local factors regulating liver fibrogenesis. Hepatic stellate cell activation occurs in the presence of pro-fibrogenic factors. Cytokines (e.g. IFN-γ, TNF-α, TGF-β, IL4, IL13, OPN), growth factors (PDGF, CTGF) and morphogens (Hedgehog, Wnt, Notch) are secreted by resident liver cells, as well as recruited immune cells (T cells, NK cells, NKT cells, T regulatory cells, γδT cells, monocytes and macrophages). Matrix composition is dynamically regulated by endopeptidases (matrix metalloproteinase (MMP)) responsible for matrix degradation. In turn, MMPs are inhibited by extracellular tissue inhibitors of metalloproteinases (TIMPs), which bind to active MMPs to inhibit enzymatic activity. The relative expressions of MMPs and TIMPs modulate rate and pattern of matrix degradation and influence fibrosis outcomes.

FIG 8.3 Non-hepatic regulators of liver fibrogenesis.

Gut

: changes to the gut microbiota (dysbiosis) lead to loss of intestinal barriers and increase translocation of lipopolysaccharides (LPS) into the portal circulation. Binding of LPS to Toll-like receptor 4 (TLR4) on liver immune cells enhances secretion of pro-fibrogenic TNF-α and TGF-β.

Adipose tissues

: secrete multiple cytokines (adipokines) including leptin, adiponectin and resistin. Leptin is a pro-fibrogenic cytokine that directly activates hepatic stellate cells and potentiates TGF-β effects. Adiponectin is hepatoprotective and is anti-fibrotic.

Brain and hormones

: (i) in the autonomic nervous system, norepinephrine and acetylcholine induce HSC fibrogenesis. (ii) Growth hormone (GH) resistance is common among individuals with liver fibrosis, and impaired GH signalling leads to increased levels of oxidative stress and hepatocyte cell death.

Lung

: obstructive sleep apnoea is common among individuals with NAFLD and is associated with an increased risk of NASH and advanced fibrosis. Nocturnal hypoxia induces VEGF expression in HSC via hypoxia-inducible factor (HIF)-1α; VEGF, in turn, activates HSC.

Chapter 09

FIG 9.1 Non-alcoholic fatty liver disease. Examples of the zone 3 and zone 1 injury patterns. (A) Typical steatohepatitis with perivenular inflammation and ballooning (arrows). (B) Masson trichrome stain from the same case showing delicate zone 3 perisinusoidal fibrosis. (C) Zone 1 borderline pattern with periportal steatosis and portal inflammation. No injury is seen around the terminal hepatic venule (arrowhead). (D) Masson trichrome stain from the same case showing periportal fibrosis but no perivenular fibrosis (arrowhead).

FIG 9.2 Alcoholic liver disease. (A) This is an example of alcoholic steatohepatitis. Steatosis is apparent along the right side; marked ballooning and Mallory–Denk bodies are noted in hepatocytes along the left. Satellitosis is also seen as well as ductular reaction. (B–D) These figures are from a patient who presented with signs and symptoms of venous outflow obstruction. (B) In this example of several alcoholic hepatitis, there is very little steatosis, and one can appreciate near obliteration of all vascular (terminal hepatic venule and portal tract) structures. The primary component of the cellular infiltrate is neutrophils. With close inspection, Mallory–Denk bodies can be seen, as well as bile-stained hepatocytes. This is an example of sclerosing hyaline necrosis and would not be seen in NAFLD/NASH. (C) A low-power trichrome stain shows obliterative fibrosis of a centrilobular region; this extent and type of fibrotic response are not described in NAFLD/NASH. (D) The high-power view of the Masson trichrome highlights the remnant of a terminal hepatic venule centrally and dense sinusoidal fibrosis in the lobules. Capillarization to this extent in alcoholic liver disease results in portal hypertension without the classic histologic features of cirrhosis.

Chapter 10

FIG 10.1 Weight gain leads to adipose tissue expansion and inflammation, which results in a proinflammatory state. These adipokines worsen adipose tissue and hepatic and systemic insulin resistance. The deterioration in insulin sensitivity leads to pancreatic β-cell loss, de novo lipogenesis, and hepatic steatosis.

FIG 10.2 NAFLD is associated with an increase in small intestinal bacterial overgrowth (SIBO). The intestinal microbiome breaks down polysaccharides into short-chain fatty acids (SCFAs), and increased bacterial productions (i.e., LPS) are then readily absorbed into the portal circulation. These by-products of digestion and intestinal microbiome subsequently influence insulin resistance and hepatic triglyceride synthesis and impair hepatic triglyceride synthesis leading to hepatic steatosis.

FIG 10.3 The gut microbiota catalyzes the conversion of dietary choline into methylamines, which enter the portal circulation and promote hepatocellular injury. The conversion of choline to methylamines also reduces the bioavailability of choline, leading to phosphatidylcholine deficiency, which impairs VLDL secretion and promotes steatosis.

Chapter 11

FIG 11.1 Outcomes of the metabolic syndrome:

TM6SF2

dissociates NAFLD from cardiovascular disease.

Chapter 12

FIG 12.1 Role of oxidative stress in the pathogenesis of steatohepatitis. Under conditions of insulin resistance, an increased amount of free fatty acids (FFAs) is released from the adipose tissue and is taken up by the liver. This overflow of FFAs increases reactive oxygen species (ROS) production and decreases the activity of antioxidant systems, thereby inducing oxidative stress.

FIG 12.2 Pathogenetic link between non-alcoholic fatty liver disease and atherosclerosis and cardiovascular diseases. ER, endoplasmic reticulum.

Chapter 13

FIG 13.1 Diagnostic workup to assess and monitor disease severity in patients with metabolic risk factors and suspected NAFLD.

1

Steatosis biomarkers: fatty liver index, SteatoTest, NAFLD fat score.

2

Liver tests: ALT AST, GGT.

3

Any increase in ALT, AST, or GGT.

4

Serum fibrosis markers: NAFLD fibrosis score, FIB-4, commercial tests (FibroTest, FibroMeter, ELF).

5

Low risk: indicative of no/mild fibrosis; Medium/high risk: indicative of significant fibrosis or cirrhosis.

Chapter 15

FIG 15.1 Disproportionately low number of clinical trials in comparison with the large number of publications in the field of nonalcoholic fatty liver disease. Search in PubMed showing the number of publications over the time. Date of the search: September 26, 2014.

Chapter 16

FIG 16.1 Ultrasound image of a fatty liver. Note the hyperechoic featureless liver with poor visualization of the deep liver and diaphragm (arrow) and the intrahepatic vessel walls (arrowhead).

FIG 16.2 Unenhanced CT image of a fatty liver. The intrahepatic vessels (arrowheads) appear brighter than the low-attenuation fatty liver parenchyma that measures 19 Hounsfield units (HU).

FIG 16.3 Enhanced CT image of a fatty liver. The liver measures 29 HU and the spleen 94 HU. The liver spleen attenuation difference is −65 HU.

FIG 16.4

T

2

-weighted (

T

2

W) fast spin-echo (FSE) images of the liver without (A) and with (B) fat suppression. Note that the high signal intensity of the liver relative to the spleen on the nonfat-suppressed

T

2

W FSE image (A) decreases on the fat-suppressed

T

2

W FSE image (B).

FIG 16.5 Opposed-phase (OP) (A) and in-phase (IP) (B) gradient recalled echo (GRE) images of a fatty liver. There is signal loss in the liver on the OP image (A) relative to the IP image (B) due to hepatic steatosis.

FIG 16.6 Standard 6 echo opposed-phase/in-phase GRE sequence at 3 T used for measuring the hepatic fat fraction (HFF). The measured signal needs to be corrected for

T

1

and

bias and spectral fat complexity.

FIG 16.7 The hepatic fat fraction (HFF) map calculated using water and fat separation GRE images. The color scale on the side indicates the percent HFF.

FIG 16.8 Proton density hepatic fat fraction (PD-HFF) map of the entire liver. The color scale on the side indicates the percent HFF.

FIG 16.9 Liver proton spectrum at 3 T. Hepatic fat and water protons are displayed as a function of their resonance frequency. There is a single water peak at 4.7 parts per million (ppm) and several fat peaks. The dominant fat peak is the methylene peak at 1.3 ppm with three smaller adjacent peaks encompassed by the black circle and two additional small peaks (arrowheads) in close proximity to the water peak.

FIG 16.10 Single-voxel proton MR spectroscopy of a fatty liver at 1.5 T. Note the small red voxel placed in the right lobe of the liver and the water (arrowhead) and dominant fat (methylene) (arrow) peaks in the sampled parenchyma.

Chapter 17

FIG 17.1 (A) Liver biopsy section with H&E staining at ×200 magnification, showing simple severe steatosis. (B) Liver biopsy section with H&E staining at ×400 magnification, showing non-alcoholic steatohepatitis with ballooning, Mallory’s hyaline, glycogenated nuclei, portal and lobular inflammation.

Chapter 18

FIG 18.1 Prevalence of NAFLD and NASH in the general and severely obese populations.

FIG 18.2 Suggested Algorithm for NAFLD screening in risk groups.

Chapter 19

FIG 19.1 The spectrum of disease linked to overweight and obesity

Chapter 22

FIG 22.1 Gastric bypass.

FIG 22.2 Sleeve gastrectomy.

Chapter 25

FIG 25.1 Potential pharmacological targets in NASH. Ang-2, angiotensin 2; CB, cannabinoid receptor; CCR, CC chemokine receptors; ER, endoplasmic reticulum; FFA, free fatty acids; FXR, farnesoid X receptor; GLP, glucagon-like peptide; LOX, lysyl oxidase; LPS, lipopolysaccharide; PPAR, peroxisome proliferator-activated receptor; TLR, toll-like receptor; vit E, vitamin E.

Chapter 26

FIG 26.1 The main epigenetic reactions are the methylation of CpG sites and the modifications on amino acidic tails of histones such as by methylation, acetylation or phosphorylation. These reactions could be influenced by factors such as lifestyles, diseases and diet, and the final conformation of DNA could facilitate joining of the transcription factors

FIG 26.2 Factors that might impact on the development of NAFLD in offspring.

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Clinical Dilemmas in

Non-Alcoholic Fatty Liver Disease

EDITED BY

Roger Williams, CBE

The Institute of HepatologyFoundation for Liver ResearchLondon, UK

Simon D. Taylor-Robinson

Digestive Diseases DivisionImperial College LondonLondon, UK

This edition first published 2016 © 2016 by John Wiley & Sons, Ltd

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Library of Congress Cataloging-in-Publication Data

Names: Williams, Roger, 1931–, editor. | Taylor-Robinson, Simon D., author.Title: Clinical dilemmas in non-alcoholic fatty liver disease /  [edited by] Roger Williams, Simon Taylor-Robinson.Description: Chichester, West Sussex ; Hoboken, NJ : John Wiley & Sons Inc., 2016. |  Includes bibliographical references and index.Identifiers: LCCN 2015040510 | ISBN 9781118912034 (pbk.)Subjects: | MESH: Non-alcoholic Fatty Liver Disease.Classification: LCC RC848.F3 | NLM WI 700 | DDC 616.3/62–dc23LC record available at http://lccn.loc.gov/2015040510

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List of contributors

Dr Quentin M. AnsteeInstitute of Cellular MedicineNewcastle UniversityNewcastle upon Tyne, UK;Liver Unit, Freeman HospitalNewcastle upon Tyne, UK

Professor Curtis K. ArgoDivision of Gastroenterology and HepatologyUniversity of VirginiaCharlottesville, VA, USA

Professor Elizabeth M. BruntDepartment of Pathology and ImmunologyWashington University School of MedicineSt. Louis, MO, USA

Professor Stephen H. CaldwellDivision of Gastroenterology and HepatologyUniversity of VirginiaCharlottesville, VA, USA

Dr Jeremy F. L. CobboldOxford University Hospitals NHS TrustOxford, UK

Dr Paul CorderoInstitute for Liver and Digestive HealthUniversity College LondonLondon, UK

Professor Christopher P. DayInstitute of Cellular Medicine, Newcastle UniversityNewcastle upon Tyne, UK;Liver Unit, Freeman HospitalNewcastle upon Tyne, UK

Professor Anil DhawanPaediatric Liver Centre, King’s College London School of MedicineKing’s College HospitalLondon, UK

Professor Anna Mae DiehlDivision of GastroenterologyDepartment of MedicineDuke University, Durham, NC, USA

Dr Joanna K. DowmanDepartment of Gastroenterology and HepatologyQueen Alexandra Hospital, Portsmouth, UK

Professor Jean-François DufourUniversity Clinic for Visceral Surgery and MedicineInselspital University of BerneBern, Switzerland

Dr Jonathan FallowfieldMRC/University of Edinburgh Centre for Inflammation ResearchQueen’s Medical Research InstituteUniversity of EdinburghEdinburgh, UK

Professor Geoffrey C. FarrellThe Canberra HospitalAustralian Capital Territory, Australia;Department of Hepatic MedicineAustralian National UniversityCanberra, Australia

Professor Nicholas FinerCentre for Weight Loss, Metabolic and Endocrine SurgeryUniversity College London Hospitals, London, UKNational Centre for Cardiovascular Prevention and OutcomesUCL Institute of Cardiovascular ScienceLondon, UK

Dr Emer Fitzpatrick Paediatric Liver Centre, King’s College London School of MedicineKing’s College HospitalLondon, UK

Dr Shareen Forbes Endocrinology Unit, University/BHF Centre for Cardiovascular ScienceQueen’s Medical Research InstituteUniversity of EdinburghEdinburgh, UK

Dr Ian F. Godsland Division of Diabetes Endocrinology and MetabolismDepartment of MedicineFaculty of MedicineImperial College LondonLondon, UK

Dr Stephen A. HarrisonDivision of GastroenterologyDepartment of MedicineSan Antonio Military Medical CenterFort Sam HoustonSan Antonio, TX, USA

Dr Jonathan M. HazlehurstCentre for Diabetes, Endocrinology and MetabolismSchool of Clinical and Experimental MedicineUniversity of BirminghamBirmingham, UK

Professor Hero K. HussainDepartment of Radiology and MRIUniversity of Michigan Health SystemAnn Arbor, MI, USA

Mr Andrew JenkinsonClinical Lead Department of Metabolic and Bariatric Surgery, UniversityCollege London Hospital, London, UK

Professor Desmond G. JohnstonDepartment of Medicine, Faculty of MedicineImperial College London, London, UK

Dr David E. KleinerLaboratory of PathologyNational Cancer InstituteNational Institutes of HealthBethesda, MD, USA

Professor Jay H. LefkowitchDepartment of Pathology and Cell BiologyCollege of Physicians and SurgeonsColumbia University, New York, NY, USA

Dr Nader LessanImperial College London Diabetes CentreAbu Dhabi, United Arab Emirates,Imperial College London, United Kingdom

Ms Jiawei LiInstitute for Liver and Digestive HealthUniversity College London, London, UK

Dr Soo LimDepartment of Internal Medicine,Seoul National University College of MedicineSeoul National University Bundang HospitalSeoul, Korea

Dr Yang-Lin LiuInstitute of Cellular MedicineNewcastle UniversityNewcastle upon Tyne, UK

Dr Haripriya MaddurDivision of Gastroenterology and HepatologySaint Louis University, St. Louis, MO, USA

Dr Cristina MarginiHepatology, Department of Clinical ResearchUniversity of Bern, Bern, Switzerland

Dr Natasha McDonaldMRC/University of Edinburgh Centre for Inflammation ResearchQueen’s Medical Research InstituteUniversity of Edinburgh, Edinburgh, UK

Dr Sanjeev MehtaLondon North West Healthcare NHS Trustand Department of Diabetes and EndocrinologyImperial College London, Ealing HospitalLondon, UK

Dr Fabian MeienbergDepartment of DiabetologyEndocrinology and MetabolismUniversity Hospital BaselBasel, Switzerland

Dr Brent A. Neuschwander-TetriDivision of Gastroenterology and HepatologySaint Louis UniversitySt. Louis, MO, USA

Professor Philip NewsomeInstitute of Biomedical ResearchThe Medical SchoolUniversity of BirminghamBirmingham, UK

Dr Jude A. ObenInstitute for Liver and Digestive Health,University College LondonLondon, UK;Department of Gastroenterology and Hepatology, Guy’s and St Thomas’ HospitalNHS Foundation TrustLondon, UK

Professor Massimo PinzaniInstitute for Liver and Digestive HealthUniversity College LondonRoyal Free HospitalLondon, UK

Professor Vlad RatziuService d’hépatogastroentérologieHôpital Pitié salpêtrièreInstitute for Cardiometabolism and NutritionUniversité Pierre et Marie CurieParis, France

Dr Arun J. SanyalVirginia Commonwealth UniversityRichmond, VA, USA

Dr Mohammad Bilal SiddiquiDepartment of Internal MedicineUniversity of Texas Medical SchoolHouston, Texas, USA

Mohammad Shadab SiddiquiVirginia Commonwealth UniversityRichmond, VA, USA

Dr Wing-Kin SynFoundation for Liver ResearchInstitute of HepatologyLondon, UK

Professor Simon D. Taylor-Robinson Digestive Diseases DivisionImperial College LondonLondon, UK

Professor Jeremy W. TomlinsonOxford Centre for Diabetes, Endocrinology and MetabolismUniversity of OxfordChurchill HospitalHeadington, UK

Dr Dawn M. TorresDivision of GastroenterologyDepartment of MedicineWalter Reed National Military Medical CenterBethesda, MD, USA

Dr Emmanuel A. TsochatzisInstitute for Liver and Digestive HealthUniversity College LondonRoyal Free HospitalLondon, UK

Professor Roger Williams, CBEThe Institute of HepatologyFoundation for Liver ResearchLondon, UK

Dr Michael YeeMetabolic Medicine UnitSt Mary’s HospitalLondon, UK

Professor Yusuf YilmazDepartment of GastroenterologySchool of Medicine, Marmara UniversityIstanbul, Turkey

Professor Hannele Yki-JärvinenDepartment of MedicineUniversity of HelsinkiHelsinki, Finland

Preface

In this further volume in the Clinical Dilemmas series, we have attempted to provide for nonalcoholic fatty liver disease the latest and most critical information regarding the nature of the condition and the factors that lead to disease progression. How best to assess severity and value of currently available different treatment measures, including the role of bariatric surgery and its quite remarkable effects on diabetes, have separate sections. The final chapter is a look ahead—what does the future hold—and includes coverage of the new molecular targeted agents that are currently in preclinical and phase I clinical trial development.

With obesity constituting a worldwide epidemic with prevalent figures for NAFLD in some Western countries as high as 30–40% of the population, there are yet few signs of it being controlled by public health measures. Understanding the cross talk that underlies the involvement of a number of other organs and systems leading to cardiac and respiratory events and cancers of various organs is of critical importance. We hope that this volume will encourage the necessary investment in preventative, diagnostic, and treatment facilities needed if the effect of this lifestyle related and preventable condition on the health of many nations is to be reduced.

As editors we are grateful to the contributors worldwide who have made it possible with their expertise and commitment to produce what we believe is an outstanding volume. A personal thanks to Jasmine Chang, Project Editor; Jon Peacock, Senior Project Editor; Oliver Walter, Publisher at Wiley-Blackwell; and also to Enda O’Sullivan, Editorial Assistant in the Institute of Hepatology, London.

Professor Roger Williams, CBEProfessor Simon D. Taylor-Robinson

PART INature of the Condition

1Non-alcoholic fatty liver disease: Hype or harm?

Stephen H. Caldwell and Curtis K. Argo

Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA, USA

LEARNING POINTS

Non-alcoholic fatty liver (NAFL) often presents the clinician with a conundrum in deciding the significance of the problem.

It is now widely recognized that non-alcoholic steatohepatitis (NASH) can progress to advanced liver disease evident as cirrhosis with all of its attendant complications including portal hypertension and hepatocellular cancer, and sometimes this progression is associated with the perplexing loss of histological hallmarks of the antecedent process of steatohepatitis.

The challenge to clinicians is to discern NASH from the relatively more stable forms of fatty liver, which we prefer to call non-NASH fatty liver (NNFL).

Therapy of NASH is evolving and aside from common conservative measures like exercise and diet treatment is likely to involve drug therapy with potential side effects. Thus refining the prognosis and discerning harm from hype will be increasingly important.

Additional areas of special need for further study include what is sometimes referred to as “BASH,” which indicates the presence of metabolic risks such as obesity and insulin resistance and the use of ethanol above safe levels but below levels at which the risk of alcoholic steatohepatitis (ASH) rises steeply.

Few potentially fatal diseases have ever been referred to as “trash” in a serious and critical treatise on the topic [1] or have been specifically the subject of an unsuccessful legal action aimed at shutting down a particular form of animal-derived food production (Caldwell S, personal experience) or have at one time been, rather accurately, referred to as “big” and “little” varieties to indicate early recognized variability in severity from mild and essentially inconsequential to potentially fatal (McCullough AJ, personal communication). However, all of these attributes are true of non-alcoholic fatty liver disease (NAFLD) and its potentially more severe subset non-alcoholic steatohepatitis (NASH).

In many ways, NASH remains a very challenging disorder over 30 years after pathologist Jurgen Ludwig first coined the term “NASH” for a “hitherto unnamed” form of steatohepatitis [2], and in doing so, he and his colleagues ushered in the modern era of clinical and basic research into the various forms of nonalcohol-related fatty liver—a field that has grown from a few published papers per year to many publications per week or month. On a practical level, much of the persistent challenge hinges on questions about the natural history and prognosis of fatty liver when it is encountered in a given individual—currently an almost daily occurrence in many clinics whether on its own or in combination with other liver disorders. The patient usually presents with asymptomatic, mild to moderate range of abnormal liver enzymes, negative additional diagnostic testing, and fatty changes noted on diagnostic ultrasound. This raises a frequent clinical question: is fatty liver a benign physiological finding (possibly an ancient adaptation to feast or famine, where nowadays feast exceeds famine), is it a disease warranting liver biopsy (with inherent risk) and directed intervention, or is it an epiphenomenon of a metabolic disorder encompassing diabetes mellitus, vascular disease, and cancer risks with clinical consequences that supersede the significance of the fatty liver [3]? All of these posits have some truth in NAFLD/NASH and constitute the pressing clinical challenge to discern hype and harm.

“Big” NASH and “little” NASH are now somewhat forgotten terms used casually in the discussion of early natural history studies, which indicated a dichotomy in the clinical course: long-term stability of the liver in many patients and progression to cirrhosis and liver-related mortality in a smaller but substantial fraction [4]. Since those early days, the nomenclature has obviously evolved with recognition of potentially progressive “big” NASH, characterized by cellular injury and fibrosis, as a subset of the more global term, NAFLD, which indicates liver fat exceeding 5–10% triglyceride by weight. Subsequently, long-term natural history studies of NAFLD have consistently demonstrated this dichotomous natural history: non-NASH fatty liver tends to be stable over years with low liver-related mortality, while NASH carries a significant, tangible risk of progression to cirrhosis and associated liver-related mortality [5–8]. Most of these studies have focused on mortality rather than morbidity, and overall mortality is clearly dominated by cardiovascular disease and nonliver malignancy. These findings suggest that the emphasis on the liver disease itself may be somewhat misplaced. However, this overlooks the fact that a substantial number of patients, especially those with histological NASH will progress to cirrhosis and suffer many of the typical cirrhosis-related complications. Moreover, the development of cirrhosis and coexisting vascular disease or neoplasm significantly complicates the management of either condition. Thus, directing specific therapy at the liver is appropriate in some patients, but careful patient selection is essential, and unless a therapy is very safe and inexpensive (such as diet and exercise), many NAFLD patients warrant only conservative management. Riskier interventions should be directed at those with histological NASH especially with more advanced fibrosis stages.

Is steatosis ever physiologically adaptive? To some extent it can be viewed as such under certain circumstances [9]. This is most evident in certain species of migratory Palmipedes spp. (geese and ducks) where the development of steatosis is a normal premigratory process and presumably provides a source of energy during the long flight with little calorie intake. This process was recognized long ago, and for thousands of years, “foie gras” production has hinged on it. However, our own work in cooperation with several individuals in France demonstrated that the Palmipedes develop only non-NASH fatty liver. Hence, the effort by People for the Ethical Treatment of Animals (PETA) to block foie gras production in the United States—on the grounds that the meat represented a disease state—failed due to the absence of NASH. No doubt, the grounds for the attempted legal action were the result of some of the media publicity that has surrounded NAFLD.

On the other hand, humans with histological NASH are at risk for progression of fibrosis through stages to cirrhosis. Serial biopsy studies suggest that this is a slow, steady march when it occurs [10]. However, it remains unclear whether or not the progression is uniform over time, and it is conceivable that NASH progression may occur in subclinical “fits and starts” with peaks and troughs of disease activity rather than by a slow, steady process. It has also been shown that some patients with non-NASH fatty liver may transition to histological NASH [11]. Presumably, changes in activity, diet, or weight with resultant worsening insulin resistance may trigger such a transition. Once cirrhosis develops in patients with NASH, complications of portal hypertension develop at a steady rate but somewhat slower than that seen with cirrhosis due to hepatitis C [12]. Patients are also at significantly increased risk of hepatocellular cancer usually, but perhaps not always, in the setting of coexisting cirrhosis [13].

Adding to the clinical diagnostic challenge, when cirrhosis develops in NASH, steatosis, a hallmark of NASH, tends to diminish significantly, sometimes leaving a picture of “cryptogenic cirrhosis,” especially in patients without a confirmed antecedent diagnosis of NASH [14–16]. Such patients often present with minor findings, such as asymptomatic and previously unexplained thrombocytopenia, often labeled in prior encounters as idiopathic thrombocytopenia purpura (“ITP”) or with cirrhosis, incidentally discovered at the time of elective surgery, especially for suspected or confirmed gallbladder disease. The mechanisms underlying diminished liver fat remain uncertain but may involve altered insulin exposure through changes in blood flow or repopulation of the liver from stem cells with altered physiology and fat metabolic capacity. Clearly, there are also other causes of cryptogenic cirrhosis, including silent autoimmune hepatitis, occult ethanol abuse, or as yet unrecognized viral infection, but NASH appears to be the leading etiology in many areas of the world [17].

Although it is well established that NAFLD has a largely dichotomous natural history, based on initial histology (NASH vs. non-NASH fatty liver), it is perplexing that certain aspects of NASH histology remain challenging. While there are a number of characteristic histological findings, the key features that usually are used to define NASH are steatosis, inflammation, cellular ballooning, and fibrosis; the first three of these parameters define the commonly utilized NAFLD activity score (NAS) [18, 19]. Perhaps not surprisingly, histological fibrosis appears to be a reliable finding with low interobserver variation rates and a reliable indicator of prognosis. However, agreement between scoring systems and individual parameters remains a potentially significant problem that can muddy clinical trials and natural history studies [20–22]. Defining criteria for cellular ballooning has been especially problematic although emergence of keratin staining as a means of characterizing pathological processes within these cells may lead to beneficial refinements of histological criteria [23–26].

ASH, NASH, BASH (indicating both alcohol exposure and risks for metabolic fatty liver), chemical-associated steatohepatitis (CASH), and drug-associated steatohepatitis (DASH): the nomenclature for the recognized varieties of steatohepatitis has continued to evolve over the years [27]. While by no means uniformly accepted, the term “BASH” (“B” for both alcohol and metabolic fatty liver) denotes possibly the most significant of these, as it indicates the presence of metabolic risks for NASH such as obesity, diabetes, and inactivity together with ethanol use above safe levels but below levels at which the risk of ASH rises steeply [28]. This represents a potentially important gray area, and it highlights the fact that the diagnosis of “NASH” is truly both a clinical- and pathology-based exercises that is not always clear cut [29, 30].

What about the individual patient who is seen in the clinic and presents with the “chief complaint” of abnormal liver enzymes, negative additional testing, and fatty changes on diagnostic ultrasound? Is it a benign finding, a marker for comorbid vascular disease and cancer risk, or a disease warranting liver biopsy and more aggressive therapeutic management recommendations than diet and exercise? Recent advances in genetic risks promise to further help sort hype from harm in NAFLD. PNPLA3 and TM6SF2 polymorphisms code for gene products that appear to be intimately involved with small fat droplet and lipoprotein metabolism and impart significant risk for steatosis and related organ injury [31–34]. Although far from being available as clinical tools, this work points out the continued clinical importance of the family history in NASH/NAFLD [35]. Indeed, we recommend earlier consideration of biopsy when, as often is the case, a family member is significantly affected even if the relative was reported to have had alcohol-related liver disease. Moreover, preliminary work from our group suggests that PNPLA3 polymorphism may predict response to such mild agents as omega-3 fatty acid supplements.

Clearly, NASH progresses to advanced stages of fibrosis, cirrhosis, and hepatocellular cancer reasonably often, and it may shed some its histological hallmarks in the process, which can complicate the diagnosis. Recognition of this phenomenon has allowed clinicians to avoid Dr. Ludwig’s “embarrassment” in diligently attempting to ferret out the occult alcoholic when actually confronted with frank NASH. Without doubt, the emergence of this field coexists with a degree of hype, which has likely been magnified due to the parallel obesity epidemic. It is all the more important to sort out, within the limitations of existing literature, the hype from the harm in order to best tailor emerging pharmacological treatment strategies and match risks and benefits.

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4. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999;116:1413–9.

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16. Caldwell SH, Lee VD, Kleiner DE, Al-Osaimi AM, Argo CK, Northup PG, Berg CL. NASH and cryptogenic cirrhosis: a histological analysis. Ann Hepatol 2009;8:346–52.

17. Ayata G, Gordon FD, Lewis WD, Pomfret E, Pomposelli JJ, Jenkins RL, Khettry U. Cryptogenic cirrhosis: clinicopathologic findings at and after liver transplantation. Hum Pathol 2002;33:1098–104.

18. Kleiner DE, Brunt EM, Van Natta ML, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ. Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histologic scoring system for NAFLD. Hepatology 2005;41:1313–21.

19. Brunt EM, Kleiner DE, Wilson LA, Belt P, Neuschwander-Tetri BA. NASH Clinical Research Network (CRN). Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology 2011;53:810–20.

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21. Juluri R, Vuppalanchi R, Olson J, Unalp A, Van Natta ML, Cummings OW, Tonascia J, Chalasani N. Generalizability of the NASH-CRN histologic scoring system for nonalcoholic fatty liver disease. J Clin Gastroenterol 2011;45:55–8.

22. Gawrieh S, Knoedler DM, Saeian K, Wallace JR, Komorowski RA. Effects of interventions on intra- and interobserver agreement on interpretation of nonalcoholic fatty liver disease histology. Ann. Diagn. Pathol. 2011;15:19–24.

23. Lackner C, Gogg-Kamerer M, Zatloukal K, Stumptner C, Brunt EM, Denk H. Ballooned hepatocytes in steatohepatitis: the value of keratin immunohistochemistry for diagnosis. J Hepatol 2008;48:821–8.

24. Guy CD1, Suzuki A, Burchette JL, Brunt EM, Abdelmalek MF, Cardona D, McCall SJ, Ünalp A, Belt P, Ferrell LD, Diehl AM. Nonalcoholic Steatohepatitis Clinical Research Network. Costaining for keratins 8/18 plus ubiquitin improves detection of hepatocyte injury in nonalcoholic fatty liver disease. Hum Pathol 2012;43:790–800.

25. Caldwell S, Ikura Y, Dias D, Isomoto K, Yabu A, Moskaluk C, Pramoonjago P, Simmons W, Scruggs H, Rosenbaum N, Wilkinson T, Toms P, Argo CK, Al-Osaimi AM, Redick JA. Hepatocellular ballooning in NASH. J Hepatol 2010;53:719–23.

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2NAFLD: A worldwide problem

Joanna K. Dowman1, Geoffrey C. Farrell2,3 and Philip Newsome4

1 Department of Gastroenterology and Hepatology, Queen Alexandra Hospital, Portsmouth, UK

2 The Canberra Hospital, Australian Capital Territory, Australia

3 Department of Hepatic Medicine, Australian National University, Canberra, Australia

4 Institute of Biomedical Research, The Medical School, University of Birmingham, Birmingham, UK

LEARNING POINTS

The prevalence of worldwide obesity has nearly doubled since 1980, now exceeding 50% in some regions. Obesity prevalence has also increased in children, with ~23% of children in developed countries and 13% of children in developing countries now either overweight or obese.

The close association between obesity and non-alcoholic fatty liver disease (NAFLD) has resulted in this now representing the most common cause of liver disease in Western countries, where it affects 20–30% of the adult population.

Prevalence of NAFLD in countries such as Asia, Latin America and the Caribbean has risen as a result of increasingly urban and westernised lifestyles.

The lowest estimates of NAFLD prevalence in Asia are from rural areas inhabited by more physically active, less affluent and lean populations.

Estimates from biopsy series indicate an overall prevalence of the more advanced form of NASH of 3–5% in the United States, rising to 12% in some populations.

In Europe and the United States, NAFLD is usually associated with obesity and insulin resistance. However in Asian countries the disease can manifest at a lower BMI; therefore application of ethnic-specific BMI thresholds is important to ensure accurate identification of higher-risk individuals.

The incidence of NASH-related HCC is rapidly increasing, with NASH now the second leading aetiology of HCC-related liver transplantation in the United States and an increasingly frequent cause of HCC in Asia.

Significant ethnic variations in propensity to NAFLD exist, which are largely accounted for by genetic factors. The extensively validated genetic modifier of NAFLD is the PNPLA3 polymorphism, which increases propensity to NAFLD, severity of disease and risk of HCC.

NAFLD frequently acts as a cofactor with viral hepatitis, alcohol and other liver diseases to increase severity of liver injury.

Introduction

NAFLD is a complication of over-nutrition, being closely associated with obesity, diabetes and insulin resistance (IR), dyslipidaemia and hypertension. It is therefore recognised to represent the hepatic manifestation of the metabolic syndrome. The increasing global levels of obesity, IR and metabolic syndrome, driven by the trend of post-industrialised countries towards urban and inactive lifestyles, with easy access to cheap processed foods, have led to an estimated 20-fold increase in the prevalence of NAFLD since 1983 [1]. NAFLD now represents the most common cause of abnormal liver tests and chronic liver disease in the Western world [2–4] and is projected to become the leading cause of cirrhosis and most common indication for liver transplantation in the United States by 2030 [5]. More recent data demonstrate that the trend towards more urban and Westernised lifestyles occurring in many countries, which until the last few decades have been less well-developed, has resulted in NAFLD now playing an equally important role in Asia, Latin America and the Caribbean, establishing it as a truly global disease.

Although NAFLD is highly prevalent worldwide, the epidemiology and demographic characteristics vary in different populations. In Europe and the United States, NAFLD is associated with obesity and IR in the great majority of cases; however in Asian countries the disease can manifest at a lower BMI, albeit most often after a period of weight gain and with central adiposity. NAFLD also frequently acts as a cofactor with other liver diseases, and its impact is therefore influenced by the prevalence of other injurious factors such as viral hepatitis and alcohol consumption in different populations.

Prevalence of NAFLD worldwide

A variety of methodologies have been used to study the prevalence of NAFLD in different populations (Table 2.1). Although histology provides the most definitive data, liver biopsy is invasive and not amenable to population studies. The most commonly used diagnostic modalities for such studies have been ultrasonography and/or elevations in liver transaminase levels, although data has also been obtained from autopsy studies and MRI imaging.

TABLE 2.1 Estimated prevalence of NAFLD in different geographical regions

Region

Estimated prevalence (%)

United States

20–46

Europe

20–30

South/South East Asia

5–32

East Asia

11–45

Australasia

20–30

Europe

Two large ultrasound-based studies in Italian and Spanish populations indicate a prevalence of NAFLD of between 20 and 30% in Europe. The Dionysos nutrition and liver study demonstrated the prevalence of NAFLD in a general Italian population to be 25 and 20% in subjects with and without suspected liver disease, respectively [6]. A Spanish multicentre population study demonstrated a prevalence of NAFLD of 33% in men and 20% in women [7].

United States

A large multi-ethnic, population-based study of 2287 individuals using proton magnetic resonance spectroscopy (MRS) to measure intrahepatic triglyceride content demonstrated NAFLD to be present in approximately one third of American adults [8]. A higher ultrasonographic NAFLD prevalence of 46% was demonstrated in a study of over 300 middle-aged patients performed at the Brooke Army Medical Center. In this study, 30% of those with NAFLD were confirmed by liver biopsy to have NASH [9]. Importantly, these figures mask significant ethnic variations in disease prevalence, with significantly higher rates in Hispanics > white populations > African Americans [8, 9]. The lower frequency of hepatic steatosis in blacks is not explained by ethnic differences in BMI or IR [8] and is fully accounted for by genetic factors (see later). Such studies, and the >30% obesity prevalence in the adult population, suggest an estimated NAFLD prevalence in the United States of at least 30%.

Although there are limited data from Latin America, the prevalence of NAFLD in this area has been reported to range between 17 and 35% [10]. A 2007 study reported an ultrasonographic NAFLD prevalence of 35% in community-dwelling middle-aged and older adults in Brazil, a high proportion of whom had metabolic syndrome [11]. The population prevalence of NAFLD in Mexico is estimated at 20–30%, based on an approximate 30% prevalence of obesity [12], with steatosis demonstrated in 83% of a cohort of 198 Mexican subjects with metabolic syndrome [13].

Asia