Sandbox: NASH

Non-alcohoic fatty liver disease is a form of chronic hepatitis that shares the histologic features of alcohol-induced hepatitis but is found in patients who have no history of alcohol abuse It encompasses a range of disorders including mild steatosis, steatohepatitis, advanced fibrosis, cirrhosis, and—less commonly—fulminant hepatic failure. Rarely, hepatocellular carcinoma has been known to develop in NASH patients Risk factors include obesity, diabetes mellitus type 2, hyperlipidemia, and sudden dramatic weight loss; the occurrence of diabetes and obesity together appears to exert an additive effect The diagnosis should be considered in any patient presenting with elevated transaminases for which no other cause is apparent Although there is emerging data regarding the efficacy of medication therapy for NAFLD, the mainstay of treatment is still lifestyle modification and treatment of underlying risk factors (eg, diabetes mellitus type 2 and hyperlipidemia) It remains unclear why some patients develop milder disease and others develop fibrotic disease and cirrhosis, although oxidative stress related to disruption of the lipogenesis/lipolysis equilibrium may be partially responsible NAFLD should be distinguished from steatosis and steatohepatitis due to secondary causes. These include various forms of malnutrition, drugs (eg, warfarin, methotrexate, amiodarone, glucocorticoids, synthetic estrogens, tamoxifen, and various antibiotic and antiviral agents), metabolic and genetic disorders (eg, lipodystrophy, dysbetalipoproteinemia, and acute fatty liver of pregnancy), use of total parenteral nutrition, and gastric bypass and other weight loss surgeries Alcohol intake, even in moderate amounts, is a confounding factor in determining the prevalence of NAFLD. In women as small an amount as 20 g per week of alcohol can cause steatosis and 20 to 40 g per day may be hepatotoxic; the value is believed to be at least 30 g per week for men NAFLD is mostly seen in obese individuals but may be encountered in thin or normal weight patients Insulin resistance is a core feature of NAFLD, diabetes, obesity, and dyslipidemia. NAFLD can therefore be considered part of the insulin resistance (or metabolic) syndrome. Insulin resistance leads to accumulation of fat within hepatocytesvialipogenesis (and inhibition of lipolysis) and hyperinsulinemia The seriousness of this condition is demonstrated by the fact that approximately 50% of patients develop fibrosis, 15% develop cirrhosis, and 3% may advance to liver failure requiring transplantation The pathogenesis of NAFLD and its progression to NASH appears to result from a two-step process, whereby an initial insult in the form of insulin resistance due to genetic and acquired factors leads to hyperinsulinemia and accumulation of fat within hepatocytes (steatosis). The steatotic liver is then vulnerable to further insult; hepatocellular injury and fibrosis may develop in the presence of oxidative stress and the proinflammatory activity of cytokines and similar agents. This leads to exacerbation of insulin resistance; further oxidative stress; and acceleration of inflammatory, degenerative, and fibrotic processes The natural history of NAFLD is dependent on the stage of the disease. The prognosis of simple steatosis seems to be relatively benign, with a 1% to 2% risk of developing cirrhosis over 15 to 20 years. Patients with NASH and fibrosis can progress to cirrhosis, which can lead to end-stage liver disease; hepatic decompensation; or hepatocellular carcinoma, a rare, end-stage outcome The diagnosis of NAFLD is usually made when elevated liver enzymes are discovered. Imaging techniques can be helpful by showing steatosis, but liver biopsy is the only way to assess the severity of inflammation and fibrosis. Efforts are made to develop less invasive ways to assess disease severity The mainstay of treatment for NAFLD is still lifestyle modification and treatment of underlying risk factors such as obesity, diabetes mellitus type 2, and hyperlipidemia