Inflammation in Nonalcoholic Steatohepatitis

R Christopher Harmon; Dina G Tiniakos; Curtis K Argo


Expert Rev Gastroenterol Hepatol. 2011;5(2):189-200. 

In This Article

Epidemiology & Genetics of NAFLD

Nonalcoholic fatty liver disease is an increasingly common problem worldwide in association with the obesity epidemic. The prevalence of NAFLD in the general population ranges from 18% in Japan to 46% in the USA,[2,3] and ethnic variations in prevalence (Hispanic ≥ Asian > Caucasian > African–American) have been recognized.[4–6] High-risk populations include morbidly obese and diabetic subjects.[7,8] Recent series of living liver donors and symptomless outpatient adults without a history of liver disease indicate that the incidence of NASH is 1.1% in Japan,[2] and may be as high as 12% in the USA, respectively.[3] Obese subjects have a prevalence of 40% for NASH, 23% for advanced fibrosis, and 5.8% for cirrhosis.[5,9,10] NASH may progress to cirrhosis in 15–25% of patients and is now believed to be the major cause of cryptogenic cirrhosis in developed countries.[11–13]

Clinical evidence supports the heritability of NAFLD, with the majority of siblings and parents of overweight children with NAFLD demonstrated to have fatty liver.[14] The clinical observations are in keeping with recent data on specific polymorphisms in the patatin-like phospholipase 3 gene (PNPLA3) identified in pediatric[15] and adult[16–18] patients that confer susceptibility to NAFLD and are associated with the severity of steatosis, acinar inflammation, hepatocyte ballooning and fibrosis. PNPLA3 encodes for adiponutrin, a lipid droplet protein that catalyzes triglyceride hydrolysis and is expressed in adipose tissue, liver and the adrenals.[19] Polymorphisms in PNPLA3 may contribute to altered release of lipid and/or inflammatory mediators that are directly shunted to the liver.[20] In particular, the I148M missense mutation may promote intrahepatic triglyceride accumulation by limiting triglyceride hydrolysis within hepatocytes.[20] The contribution of PNPLA3 variants to the pathogenesis of NASH needs to be elucidated, since this is a minor triglyceride hydrolase not associated with adiposity or insulin resistance.

Polymorphisms in the apolipoprotein C3 (APOC3) gene have also been associated with NAFLD.[21] However, recent data from the Dallas Heart Study do not support a causal relationship between APOC3 variants and increased hepatic triglyceride content or insulin resistance.[22] Krüppel-like factor (KLF6) gene variants have been correlated with advanced NASH.[23] Genetic studies also implicate the involvement of polymorphisms in proinflammatory genes (TNF-α and IL-10) and genes influencing the immune response (CTLA-4 and IL-4) in the pathogenesis of NASH.[24]


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.