HFE C282Y mutations are associated with advanced hepatic fibrosis in Caucasians with nonalcoholic steatohepatitis

Abstract

Previous studies examining the relationship between HFE mutations and severity of nonalcoholic steatohepatitis (NASH) have been limited by small sample size or ascertainment bias. The aim of this study was to examine the relationship between HFE mutations and histological severity in a large North American multicenter cohort with NASH. Data from 126 NASH patients were collected from 6 North American centers. Liver biopsy and genotyping for the C282Y and H63D HFE mutations were performed in all subjects. Serum transferriniron saturation and ferritin levels as well as hepatic iron content were recorded whenever available. Univariate and multivariate logistic regression analyses were performed to identify factors associated with advanced hepatic fibrosis.

Risk of nonalcoholic steatohepatitis and fibrosis in patients with nonalcoholic fatty liver disease and low visceral adiposity

“…Interestingly, the C282Y mutation in the HFE gene, associated with mild iron overload in patients with NALFD, was more frequent in lean than in obese subjects [40] and [41], suggesting that a mild increase in liver iron may lead to augmented lipotoxicity of the fat accumulated in the liver or alter adipocytes function. However, the results of additional ongoing studies are required to clarify this issue, and it should be noted that the majority of genetic factors possibly involved is presently still unknown.…”

Composite prognostic models across the non-alcoholic fatty liver disease spectrum: Clinical application in developing countries

“…The C282Y mutation has been associated with NASH [169] as well as hepatocellular iron accumulation which could promote the progression of hepatic fibrogenesis, thereby conferring risk for increased histological severity secondary to ironmediated oxidative stress and lipotoxicity [170][171][172] . Findings from conflicting studies [173,174] as well as a systematic review and meta-analysis [175] however fail to support the notion that HFE genotype is a significant genetic determinant of risk for the onset or progression of NAFLD and/or DIOS.…”

Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury

“…1 Increased iron indices are frequently reported in ALD and NAFLD, where iron is regarded as an important determinant of progressive liver injury. [2][3][4] Patients with the genetic hemochromatosis who consume excessive amounts of alcohol have greatly increased risk of cirrhosis, and NAFLD patients with increased hepatic iron have greater levels of fibrosis than those without. 5 The pathogenesis by which iron promotes further liver injury in ALD and NAFLD has been relatively unclear.…”