Clinical Review of Nonalcoholic Steatohepatitis in Liver Surgery and Transplantation

Nonalcoholic fatty liver disease (NAFLD) refers to an increasingly diagnosed condition involving triglyceride accumulation in hepatocytes, resulting in a broad spectrum of liver injury. This injury ranges from simple hepatic steatosis, steatohepatitis, and chronic fibrosis to cirrhosis, and pathologically resembles alcoholic hepatitis in individuals without extensive alcohol use.1 This disease process has become progressively more prevalent and it is important that clinicians are fully aware of its pathophysiology and clinical implications. The term nonalcoholic fatty liver disease was introduced by Schaffner and Thaler2 in 1986 and is the current terminology used to describe a progressive spectrum of liver disease beginning with simple steatosis and leading to non-alcoholic steatohepatitis (NASH), fibrosis, and ultimately, cirrhosis (Fig. 1). Figure 1 Histologic progression of nonalcoholic fatty liver disease from simple steatosis to cirrhosis. The term nonalcoholic steatohepatitis was coined by Ludwig and colleagues3 in 1980 to describe a cohort of 20 patients with no history of alcohol abuse but with liver biopsies demonstrating fatty change, lobular inflammation, focal necrosis, and Mallory bodies consistent with alcoholic hepatitis. These patients were predominantly female and moderately obese. Nonalcoholic steatohepatitis is the term currently used to describe patients in whom simple steatosis has progressed to histologic evidence of inflammation, including hepatocyte ballooning, mixed acute and chronic lobular inflammation, and zone 3 perisinusoidal fibrosis.4,5 Progression of NAFLD, a relatively benign condition, to NASH is characterized by hepatic infiltration of inflammatory cells and subsequent hepatocellular injury. This inflammatory phase distinguishes NASH from simple NAFLD.6,7 Recent clinical observations have shown a clear link between development of NASH and presence of the metabolic syndrome. The metabolic syndrome is defined as insulin resistance, hypertension, dyslipidemia, and visceral obesity,8–11 and some have suggested that NAFLD be considered an additional feature of the metabolic syndrome.12 There is evidence that inflammatory changes seen in the metabolic syndrome might be an important feature of the progression of NAFLD to NASH. Obesity and insulin resistance have been found to be associated with a chronic state of systemic inflammation involving abnormal cytokine release, secondary mediators, and signaling pathways.13–15 The pathophysiology of the progression of NAFLD to NASH has yet to be fully elucidated. The first insult is the production and accumulation of triglycerides in the liver. This is primarily due to the presence of insulin resistance and hyperinsulinemia resulting in dysregulated lipogenesis and lipolysis peripherally and increased hepatic fatty acid synthesis.16 This results in simple steatosis. Progression to NASH is thought to evolve by way of a “2-hit” phenomenon17 (Fig. 2). The primary insult is lipid accumulation leading to development of steatosis, and the second is oxidative stress and lipid peroxidation resulting in cytokine-mediated recruitment and retention of inflammatory cells. Multiple cytokines, chemokines, and adipokines have been implicated in the development of NASH, including leptin,18–21 adiponectin,21,22 tumor necrosis factor–α,23,24 resistin,25,26 interluekin-6,27 and others. Figure 2 Progression of nonalcoholic fatty liver disease demonstrating the 2-hit hypothesis. The first hit consists of lipid accumulation resulting in simple benign steatosis. This primes the liver for a second hit, which can be multifactorial. This 2-hit process ...