https://eprints.ncl.ac.uk/file_store/production/213262/AAB0A20B-44A6-49C4-A952-745B0139910F.pdf

Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: Implications for prognosis and clinical management

Nonalcoholic fatty liver disease (NAFLD) is recognized as the leading cause of chronic liver disease in adults and children. NAFLD encompasses a spectrum of liver injuries ranging from steatosis to steatohepatitis with or without fibrosis. Fibrosis may progress to cirrhosis and complications including hepatocellular carcinoma. Histologic findings represent the complexity of pathophysiology. NAFLD is closely associated with obesity and is most closely linked with insulin resistance; the current Western diet, high in saturated fats and fructose, plays a significant role. There are several mechanisms by which excess triglycerides are acquired and accumulate in hepatocytes. Formation of steatotic droplets may be disordered in NAFLD. Visceral adipose tissue dysfunction in obesity and insulin resistance results in aberrant cytokine expression; many cytokines have a role in liver injury in NAFLD. Cellular stress and immune reactions, as well as the endocannabinoid system, have been implicated in animal models and in some human studies.

Nonalcoholic Fatty Liver Disease: Pathology and Pathogenesis

Non-alcoholic fatty liver disease (NAFLD) represents a histological spectrum of liver disease associated with obesity, diabetes and insulin resistance that extends from isolated steatosis to steatohepatitis and cirrhosis. As well as being a potential cause of progressive liver disease in its own right, steatosis has been shown to be an important cofactor in the pathogenesis of many other liver diseases. Animal models of NAFLD may be divided into two broad categories: those caused by genetic mutation and those with an acquired phenotype produced by dietary or pharmacological manipulation. The literature contains numerous different mouse models that exhibit histological evidence of hepatic steatosis or, more variably, steatohepatitis; however, few replicate the entire human phenotype. The genetic leptin-deficient (ob/ob) or leptin-resistant (db/db) mouse and the dietary methionine/choline-deficient model are used in the majority of published research. More recently, targeted gene disruption and the use of supra-nutritional diets to induce NAFLD have gained greater prominence as researchers have attempted to bridge the phenotype gap between the available models and the human disease. Using the physiological processes that underlie the pathogenesis and progression of NAFLD as a framework, we review the literature describing currently available mouse models of NAFLD, highlight the strengths and weaknesses of established models and describe the key findings that have furthered the understanding of disease pathogenesis.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.0959-9673.2006.00465.x

Mouse models in non-alcoholic fatty liver disease and steatohepatitis research

The authors investigated the dose-effect relation between alcohol drinking and hepatocellular carcinoma (HCC) in men and women separately, also considering hepatitis B and hepatitis C virus infections. They enrolled 464 subjects (380 men) with a first diagnosis of HCC as cases and 824 subjects (686 men) unaffected by hepatic diseases as controls; all were hospitalized in Brescia, northern Italy, in 1995-2000. Spline regression models showed a steady linear increase in the odds ratio of HCC for increasing alcohol intake, for values of >60 g of ethanol per day, with no substantial differences between men and women. Duration of drinking and age at start had no effect on the odds ratio when alcohol intake was considered. Former drinkers who had stopped 1-10 years previously had a higher risk of HCC than current drinkers did. The effect of alcohol drinking was evident even in the absence of hepatitis B or hepatitis C virus infection. In addition, a synergism between alcohol drinking and either infection was found, with approximately a twofold increase in the odds ratio for each hepatitis virus infection for drinkers of >60 g per day.

Alcohol and Hepatocellular Carcinoma: The Effect of Lifetime Intake and Hepatitis Virus Infections in Men and Women

https://www.journal-of-hepatology.eu/article/S0168-8278(12)00288-7/pdf

M.R Teli

Papers

Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver.