(C) Fig 5.1 Classical non alcoholic steatohepatitis (NASH). (A) Steatosis, hepatocyte ballooning, and inflammation (the trio of changes

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1 (A) (B) (C) 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). Clinical Dilemmas in Non-Alcoholic Fatty Liver Disease, First Edition. Edited by Roger Williams and Simon D. Taylor-Robinson John Wiley & Sons, Ltd. Published 2016 by John Wiley & Sons, Ltd.

2 (A) (B) (C) 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).

3 Injury and death Dying hepatocytes Hepatocytes Release Hedgehog ligands Quiescent hepatic stellate cell Cholangiocytes/ ductular progenitors Release Hedgehog ligands Immune cells Release Hedgehog ligands Activated hepatic stellate cell/myofibroblast 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 collagenproducing 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.

4 (A) (B) (C) (D) 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).

5 (A) (B) (C) (D) 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.

6 Adipose Weight gain Adipose tissue expansion Macrophage infiltration TNF-α IL-6 Insulin resistance Lipolysis FFA generation Leptin Adiponectin Adipose Liver Pancreas Insulin sensitivity Pancreatic beta cell loss Hepatic insulin sensitivity Inflammation SREBP-1-mediated lipogenesis β-oxidation of fatty acids 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.

7 FFA pool TG synthesis VLDL secretion Hepatic insulin sensitivity Simple steatosis Intestinal microbiome Kupffer cell activation hscrp LPS Steatohepatitis Polysaccharide SCFA SCFA SCFA SCFA LPS LPS LPS LPS Constituent low-grade endotoxemia LPS LPS (Metabolic endotoxemia) Adipose tissue Increased intestinal permeability Expansion inflammation decreased insulin sensitivity Small intestinal bacterial overgrowth Disruption of tight junctions Intestinal lumen Intestinal epithelium Portal vein 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.

8 Gut lumen Dietary intake Choline Choline Phosphatidylcholine Availability Choline VLDL secretion Intrahepatic TG accumulation Microbiome Metabolism Methylamine Hepatotoxicity 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. 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

9 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. 0 Freq diff = Hz: or ppm Fig 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.

10 (A) (B) 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 (Source: Courtesy of Dr Eve Fryer, Oxford University Hospitals NHS Trust).

11 Pulmonary Hypoventilation Obstructive sleep apnoea Asthma Dermatological Hirsutism Sweating Psoriasis Gastrointestinal Gall stones Non-Alcoholic fatty liver Colon cancer Gastro oesophageal reflux Oesophageal cancer Periodontal disease Gynaecological/obstetric Oligomenorrhea Infertility Cancer of uterus, breast, cervix Pregnancy morbidity CNS Intracranial hypertension Migraine/headache Stroke Psychological/Psychiatric Dementia Cardiovascular Hypertension Ischaemic heart disease Heart failure Thromboembolism Metabolic Diabetes Dyslipaemia Hyperinsulinaemia Musculo skeletal Osteoarthritis Gout Andrology Hypogonadism Prostate cancer Fig 19.1 The spectrum of disease linked to overweight and obesity ( Source: Science Photo Library C007/2245 (Obese woman, MRI scan). Reproduced with permission from Science Photo Library).

12 Fig 22.1 Gastric bypass. Fig 22.2 Sleeve gastrectomy. Me DNA methylation Lifestyles Diseases Nutrition Me Me Methylation pattern Me Histone modification Lifestyles Diseases Nutrition Methylation pattern Others Chromatin remodeling microrna 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 (Source: (left) Qiu [40], reproduced with permission of Nature Publishing Group and (right) Cordero et al. [41]).