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Cover
Title Page
List of contributors
Preface
PART I: Nature of the Condition
1. 1 Non-alcoholic fatty liver disease
  1. References
2. 2 NAFLD
  1. Introduction
  2. Prevalence of NAFLD worldwide
  3. Disease severity
  4. Obesity and metabolic syndrome
  5. Genetic predisposition
  6. NAFLD as a cofactor
  7. Conclusions
  8. References
3. 3 Is insulin resistance the principal cause of NAFLD?
  1. Introduction
  2. What is meant by insulin resistance?
  3. How is insulin resistance measured in vivo in man?
  4. Insulin resistance and NAFLD
  5. Conclusions
  6. References
4. 4 Paediatric NAFLD
  1. Introduction
  2. Developmental origins of paediatric NAFLD
  3. Paediatric NAFLD: Histological evidence of early progression
  4. Paediatric NAFLD: A distinct disease?
  5. Ductular reaction, hedgehog signalling and advanced fibrosis
  6. What do we know from other types of paediatric chronic liver disease?
  7. What are the known risk factors for progression of fibrosis in NAFLD?
  8. Conclusion
  9. References
5. 5 Non-alcoholic fatty liver disease (NAFLD) as cause of cryptogenic cirrhosis
  1. Introduction
  2. Cryptogenic cirrhosis: Definition and characteristics
  3. Pathological recognition of NAFLD/NASH in cryptogenic cirrhosis
  4. Evidence for NAFLD as the cause of cryptogenic cirrhosis
  5. Loss of steatosis in late NAFLD/NASH with cirrhosis
  6. Other possible causes of cryptogenic cirrhosis and future directions
  7. Summary
  8. References
6. 6 Is NAFLD different in absence of metabolic syndrome?
  1. Introduction
  2. Metabolically normal NAFLD, Hb, and iron
  3. Genetic factors and metabolically normal NAFLD
  4. Prognostic implications of metabolically normal NAFLD
  5. Does metabolically normal NAFLD require a specific treatment approach?
  6. Conclusions
  7. References
7. 7 Occurrence of noncirrhotic HCC in NAFLD
  1. The metabolic syndrome, NAFLD, and HCC
  2. Pathogenesis linking HCC and NAFLD
  3. Conclusions
  4. References
PART II: Factors in Disease Progression
1. 8 Fibrosis progression
  1. Introduction
  2. The concept of liver repair
  3. Mechanisms of liver fibrogenesis
  4. Key molecular pathways
  5. Conclusions and future
  6. Acknowledgements
  7. References
2. 9 When is it NAFLD and when is it ALD?
  1. Introduction
  2. Steatosis
  3. Inflammation
  4. Hepatocellular injury
  5. Fibrosis
  6. Other lesions
  7. Grading and staging: ALD and NAFLD
  8. References
3. 10 Of men and microbes
  1. Introduction
  2. Intestinal microbiome
  3. Conclusion
  4. References
4. 11 Can genetic influence in non-alcoholic fatty liver disease be ignored?
  1. Introduction
  2. What evidence suggests a heritable component to NAFLD?
  3. What genetic factors have been identified?
  4. Conclusions and clinical relevance
  5. References
5. 12 Is there a mechanistic link between hepatic steatosis and cardiac rather than liver events?
  1. Introduction
  2. Evidence supporting the association between NAFLD and CVD
  3. Mechanistic link between NAFLD and CVD
  4. Genetic association between fatty liver and cardiometabolic risk
  5. Conclusion
  6. References
PART III: Diagnosis and Scoring
1. 13 How to best diagnose NAFLD/NASH?
  1. Primary or secondary NAFLD?
  2. Histological diagnosis
  3. Noninvasive diagnostic procedures
  4. Recommendations for diagnosis in clinical practice
  5. References
2. 14 The clinical utility of noninvasive blood tests and elastography
  1. Introduction
  2. Use of noninvasive fibrosis tests in chronic liver diseases
  3. Noninvasive diagnosis of NASH
  4. Noninvasive fibrosis assessment
  5. Conclusions: Future directions
  6. References
3. 15 Are the guidelines—AASLD, IASL, EASL, and BSG—of help in the management of patients with NAFLD?
  1. A definition problem
  2. To screen or not to screen?
  3. The thin line between NAFL and NASH
  4. Therapy: An open and evolving question
  5. Special population: Pediatric patients
  6. Conclusions
  7. References
4. 16 Imaging methods for screening of hepatic steatosis
  1. Ultrasound
  2. Computed tomography
  3. Advantages and limitations of CT for screening
  4. Magnetic resonance imaging
  5. Qualitative estimation of hepatic fat on MRI
  6. Quantitative estimation of hepatic fat on MRI
  7. MRS
  8. References
5. 17 Are the advantages of obtaining a liver biopsy outweighed by the disadvantages?
  1. Introduction
  2. Diagnosis and assessment of disease severity
  3. Technical and logistical matters
  4. Conclusions
  5. References
6. 18 Screening for NAFLD in high-risk populations
  1. Introduction
  2. Nature of NAFLD: Relevance to screening
  3. Current opinion and guidelines
  4. The high-risk population
  5. Potential screening tests
  6. A practical approach to NAFLD screening
  7. Summary
  8. References
PART IV: Value of Treatment Measures
1. 19 Defining the role of metabolic physician
  1. Diagnosis and assessment of the obese patient
  2. Medical management of obesity
  3. Management of bariatric surgical patients
  4. Conclusions
  5. References
2. 20 Should physicians be prescribing or patients self-medicating with orlistat, vitamin E, vitamin D, insulin sensitizers, pentoxifylline, or coffee?
  1. Introduction
  2. Coffee consumption
  3. Orlistat
  4. Pentoxifylline
  5. Vitamin E
  6. Insulin sensitizers
  7. Vitamin D
  8. Conclusion
  9. References
3. 21 Effects of treatment of NAFLD on the metabolic syndrome
  1. Introduction
  2. Effect of insulin-sensitizing antidiabetic treatments on NAFLD and the MetS (Table 8.1)
  3. Conclusions
  4. References
4. 22 What are the dangers as well as the true benefits of bariatric surgery?
  1. Introduction
  2. Development of bariatric surgical procedures
  3. What are the risks of bariatric surgery?
  4. Benefits of bariatric surgery
  5. Conclusion
  6. References
5. 23 Liver transplantation
  1. Current results of liver transplantation for NASH
  2. Frequency of NAFLD recurrence and of metabolic syndrome after transplantation and clinical significance
  3. Impact of obesity on long-term outcome after liver transplantation for non-NASH indications
  4. Conclusion
  5. Acknowledgement
  6. References
PART V: What Does the Future Hold?
1. 24 Molecular antagonists, leptin or other hormones in supplementing environmental factors?
  1. Introduction
  2. Strategies to promote ‘healthier’ adipose tissue function
  3. Beyond diabetes and insulin signalling
  4. Lipid and dietary modification
  5. Hepatic oxidative stress
  6. Conclusion
  7. Acknowledgement
  8. References
2. 25 What is the role of antifibrotic therapies in the current and future management of NAFLD?
  1. Antifibrotic targets in NAFLD
  2. Challenges of clinical trial design in NAFLD
  3. What have we learnt from NAFLD antifibrotic trials to date?
  4. What are the most promising emerging antifibrotic therapies in NAFLD?
  5. Other emerging therapies
  6. Conclusions
  7. Acknowledgement
  8. References
3. 26 Developmental programmingof non-alcoholic fatty liver disease
  1. Human studies
  2. Animal models
  3. Cellular and subcellular mechanisms
  4. Nervous system
  5. Epigenetic mechanism
  6. Immune mechanism
  7. Gut microbiota
  8. Conclusions
  9. References
Index
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List of Tables

Chapter 02
1. TABLE 2.1 Estimated prevalence of NAFLD in different geographical regions
Chapter 03
1. TABLE 3.1 Some methods of assessing insulin resistance
2. TABLE 3.2 Portal venous insulin delivery before and during an intravenous glucose tolerance test in insulin-resistant men with NAFLD compared with controls
3. TABLE 3.3 Classical insulin-resistant states and NAFLD
Chapter 05
1. TABLE 5.1 Causes of cirrhosis
2. TABLE 5.2 Possible causes of fat loss in late NAFLD-related cirrhosis
Chapter 09
1. TABLE 9.1 Similarities and differences between ALD and NAFLD
Chapter 11
1. TABLE 11.1 GWAS relevant to NAFLD
2. TABLE 11.2 Additional genetic modifiers of NAFLD identified in candidate gene studies
Chapter 13
1. TABLE 13.1 Metabolic risk factors
2. TABLE 13.2 Causes of secondary NAFLD
Chapter 14
1. TABLE 14.1 Noninvasive tests for diagnosing NASH in patients with non-alcoholic fatty liver disease
2. TABLE 14.2 Noninvasive fibrosis tests in patients with non-alcoholic fatty liver disease
Chapter 17
1. TABLE 17.1 Table with examples of when the pros of liver biopsy outweigh the cons, and vice versa
Chapter 18
1. TABLE 18.1 Screening principles [2] as applied to NAFLD
2. TABLE 18.2 Risk factors for NAFLD
3. TABLE 18.3 Potential screening tests for NAFLD
Chapter 19
1. TABLE 19.1 Genetic syndromes linked to obesity
2. TABLE 19.2 Edmonton obesity staging system
Chapter 21
1. TABLE 21.1 Examples of dissociation of effects of pharmacotherapy of NAFLD on liver fat content, insulin sensitivity, glycemia, and body weight
Chapter 22
1. TABLE 22.1 Summary of common bariatric surgical procedures
Chapter 25
1. TABLE 25.1 Summary of antifibrotic trials in NAFLD

List of Illustrations

Chapter 03
1. 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
2. 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
1. 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).
2. 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
1. FIG 6.1 Interrelationship between the main variables that may influence the development of metabolically normal NAFLD.
Chapter 07
1. 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
1. 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.
2. 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.
3. 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
1. 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).
2. 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
1. 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.
2. 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.
3. 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
1. FIG 11.1 Outcomes of the metabolic syndrome: TM6SF2 dissociates NAFLD from cardiovascular disease.
Chapter 12
1. 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.
2. FIG 12.2 Pathogenetic link between non-alcoholic fatty liver disease and atherosclerosis and cardiovascular diseases. ER, endoplasmic reticulum.
Chapter 13
1. FIG 13.1 Diagnostic workup to assess and monitor disease severity in patients with metabolic risk factors and suspected NAFLD. ¹Steatosis biomarkers: fatty liver index, SteatoTest, NAFLD fat score. ²Liver tests: ALT AST, GGT. ³Any increase in ALT, AST, or GGT. ⁴Serum fibrosis markers: NAFLD fibrosis score, FIB-4, commercial tests (FibroTest, FibroMeter, ELF). ⁵Low risk: indicative of no/mild fibrosis; Medium/high risk: indicative of significant fibrosis or cirrhosis.
Chapter 15
1. 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
1. 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).
2. 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).
3. 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.
4. FIG 16.4 T ₂-weighted (T₂W) 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 T₂W FSE image (A) decreases on the fat-suppressed T₂W FSE image (B).
5. 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.
6. 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 T₁ and bias and spectral fat complexity.
7. 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.
8. 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.
9. 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.
10. 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
1. 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
1. FIG 18.1 Prevalence of NAFLD and NASH in the general and severely obese populations.
2. FIG 18.2 Suggested Algorithm for NAFLD screening in risk groups.
Chapter 19
1. FIG 19.1 The spectrum of disease linked to overweight and obesity
Chapter 22
1. FIG 22.1 Gastric bypass.
2. FIG 22.2 Sleeve gastrectomy.
Chapter 25
1. 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
1. 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
2. FIG 26.2 Factors that might impact on the development of NAFLD in offspring.