Hemochromatosis gene mutations in chronic hepatitis C patients with and without liver siderosis

Abstract

Chronic hepatitis C is often associated with liver iron overload, which may affect the long-term prognosis and the response to antiviral treatment. The occurrence of hemochromatosis (HFE) mutations were studied to determine whether may contribute to the liver iron overload of chronic hepatitis C patients. The prevalence of two HFE mutations (C282Y and H63D) in 120 chronic hepatitis C patients was determined and the findings were correlated with clinical, histological and virological features. Hepatic iron was determined semiquantitatively by a histochemical hepatic iron index, defined as the ratio of a histochemical staining score to the patient's age, after correction for heterogeneous lobular iron distribution. Serum hepatitis C virus (HCV) RNA was measured by bDNA assay and typed by restriction fragment length polymorphism. Liver HCV RNA was measured by a semi-quantitative strand-specific reverse transcription-polymerase chain reaction (RT-PCR). Excess liver iron was stained in the liver of 36 patients (30%). Siderotic patients had the same geographic origin, serum and liver HCV RNA levels and H63D and C282Y mutations frequency as non-siderotic patients. However, siderotic patients were older (P = 0.015), more frequently males (P = 0.02), less frequently infected with HCV genotype 3 (P = 0.037) and had a higher liver fibrosis score (P = 0.008). The liver iron content did not correlate with the serum or liver HCV RNA titers. Ten of the 36 patients with liver siderosis had neither a history of excess alcohol intake, multiple transfusions, or HFE mutations. In conclusion, the pathogenesis of the liver iron overload in chronic hepatitis C patients cannot be fully explained by the occurrence of HFE mutations. The exact mechanism of iron accumulation in these patients therefore remains unexplained.

Review article: chronic hepatitis C – natural history and cofactors

“…The observation that patients with chronic hepatitis C often have increased deposits of iron in the liver and that this condition is associated with more advanced liver damage and poor response to anti-viral therapy promoted a number of studies aimed at assessing the role of mutations in the haemochromatosis gene in hepatitis C. The results so far obtained have been controversial and not conclusive. Although in one study 18 patients with hepatitis C and C282Y heterozygotic mutation of the HFE gene had more advanced liver fibrosis and higher frequency of cirrhosis, other reports have not been able to confirm a significant association between mutations of the haemochromatosis gene and severity of hepatitis C. 19,20 Nevertheless, from a practical point of view it seems reasonable to evaluate iron metabolism and overload in patients with chronic hepatitis C, particularly in the presence of more advanced fibrosis, and to remove the excess by phlebotomy, whatever the cause of iron overload might be, as this approach has been shown to reduce ALT levels and disease progression and to improve the response to anti-viral therapy.…”

Genetic Polymorphisms and the Progression of Liver Fibrosis: A Critical Appraisal

“…We identified 8 case control studies seeking an association between HFE C282Y gene mutation in patients with chronic hepatitis C and progression of fibrosis. 5,6,[110][111][112][113][114][115] Based on a threshold of P ϭ .05, only 2 of the studies showed an association between polymorphisms in the HFE gene and progression of fibrosis. Because of its prevalence and clinical interest, it is important to conduct additional well-designed studies to solve this question.…”

Host genetic determinants in hepatitis C virus infection

“…80,92,93,97,98,102,109,111,101 Two major polymorphisms are recognised in the literature: Cys282Tyr and His63Asp (often abbreviated as C282Y and H63D, respectively, in single-letter amino-acid notation). Of these two polymorphisms, the Cys282Tyr has been of greater interest.…”