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Heterozygosity for hereditary hemochromatosis is associated with more fibrosis in chronic hepatitis C
B C Smith1, J Gorve, M A Guzail
1Centre for Liver Research, University of Newcastle upon Tyne, England, UK.
Insights
Hereditary hemochromatosis C282Y mutation carriers with chronic hepatitis C showed increased liver fibrosis and cirrhosis. Even minor iron increases in heterozygotes for hemochromatosis gene HFE may worsen liver disease.
Area of Science:
- Hepatology
- Genetics
- Internal Medicine
Background:
- Hepatic iron overload is linked to severe liver disease in chronic viral hepatitis.
- The C282Y mutation in the hemochromatosis gene (HFE) is a common cause of hereditary hemochromatosis.
Purpose of the Study:
- To investigate the association between the HFE C282Y mutation and advanced liver disease in patients with chronic hepatitis C.
- To determine if carrying the C282Y mutation influences fibrosis or necroinflammation severity in chronic hepatitis C.
Main Methods:
- Studied 137 patients with biopsy-proven chronic hepatitis C.
- Assessed liver biopsies for necroinflammation and fibrosis.
- Genotyped patients for the HFE C282Y mutation using PCR and restriction fragment analysis.
- Measured serum ferritin and liver iron staining.
Main Results:
- Ten patients (7.3%) carried the C282Y mutation; none were homozygous.
- Heterozygotes had higher serum ferritin and more frequent hepatocyte iron staining.
- Patients with the mutant allele showed significantly more advanced fibrosis (mean stage 3.6 vs. 1.5) and higher rates of cirrhosis (40% vs. 8.7%).
- No significant differences were observed in inflammation scores or HCV-RNA titers.
Conclusions:
- Individuals heterozygous for the HFE C282Y mutation experience more advanced liver fibrosis and cirrhosis in chronic hepatitis C.
- Minor increases in iron stores associated with hemochromatosis heterozygosity may contribute to more severe liver disease.
- Venesection (bloodletting) could be a beneficial therapeutic option for this patient subgroup.
Abstract:
Hepatic iron has been associated with more aggressive liver disease in chronic viral hepatitis. We evaluated whether the recently described C282Y mutation of the hemochromatosis gene, designated HFE (responsible for at least 83% of hereditary hemochromatosis), was associated with more advanced liver disease in chronic hepatitis C. One hundred thirty-seven patients with biopsy-proven chronic hepatitis C were studied and liver biopsies scored for necroinflammation (grade 0-18) and fibrosis (stage 0-6). Genomic DNA was amplified by polymerase chain reaction and the C282Y mutation identified by restriction with RsaI and electrophoretic separation of restriction fragments. Ten (7.3%) patients had the C282Y mutation. No C282Y homozygous patients were identified. Age, sex distribution, and estimated weekly alcohol consumption were not significantly different between those with and without the mutation. Serum ferritin was higher in the heterozygotes (mean, 339 microg/L) compared with homozygous wild types (153 microg/L; P = .0005). In the majority of patients, liver iron was graded 0 out of 4, but hepatocyte iron staining was more commonly present in heterozygotes compared with homozygous normals (30% compared with 4% [P = .02]). Liver disease was more advanced in those with the mutant allele (mean fibrosis stage: 3.6, compared with wild type: 1.5 [P = .01]). Cirrhosis was found more often in those with the mutation (40%) compared with those without (8.7%) (P = .01; odds ratio: 7.6 [1.9-31.2]). There was no significant difference in inflammation scores between heterozygotes and wild type (mean, 5.4 compared with 4.1). Hepatitis C virus (HCV)-RNA titers were measured by branched DNA assay (HCV RNA 2.0-Chiron), and there was no difference between heterozygous and homozygous normal patients. Thus, despite relatively minor increases in iron stores, individuals who are heterozygous for hemochromatosis appear to develop more fibrosis in chronic hepatitis C. Venesection may be useful therapy in this subgroup.