Cytokines and the pathogenesis of non-alcoholic steatohepatitis

Histopathological characteristics distinguish steatohepatitis from other causes of chronic liver injury. For years, the main cause of steatohepatitis was thought to be excessive consumption of alcohol. Increasingly, steatohepatitis is being diagnosed in individuals who deny alcohol abuse. Arbitrarily, “non-alcoholic” steatohepatitis (NASH) is subcategorised into “primary” and “secondary” NASH.1 Primary NASH refers to steatohepatitis that is associated with the dysmetabolic syndrome (that is, obesity, type 2 diabetes, dyslipidaemia).2 Primary NASH is thought to be the predominant form of NASH, afflicting at least as many individuals in the USA as chronic hepatitis C. Secondary NASH refers to steatohepatitis that accompanies other syndromes (for example, lipodystrophy) or that is caused by certain drugs (for example, amiodarone).3 Accumulating evidence suggests that common mechanisms may mediate the pathogenesis of alcohol induced steatohepatitis and primary NASH.4 Although unproven, it is likely that primary and secondary NASH also share common pathogenic mechanisms. ### Obesity Obesity, especially visceral adiposity, is a major risk factor for NASH in humans.5 Even if they do not have an elevated body mass index, patients with NASH are very likely to be insulin resistant.2 Basic research on fat cell (adipocyte) biology provides some clues about why obesity, insulin resistance, and NASH may be interrelated. Obesity increases adipose tissue mass. It has long been known that adipose tissue is a source of free fatty acids that are delivered to the liver and a depot for triglycerides that are synthesised by hepatocytes and released into the blood. Only recently however has the neuroendocrine role of adipose tissue been appreciated. Fat produces hormones, such as leptin, resistin, and adiponectin, that regulate metabolism in other tissues, as well as fat itself. Fat is also a source of neurotransmitters, such as noradrenaline and angiotensin II. In addition, because adipocytes produce immunomodulatory cytokines, such as …