Inflammation in Nonalcoholic Steatohepatitis

R Christopher Harmon; Dina G Tiniakos; Curtis K Argo

Disclosures

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]

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