Iron Accumulation Gene Mutations and Liver Fibrosis in Patients with Hepatitis C

[Guest guest]

Iron Accumulation Gene Mutations and Liver Fibrosis in Patients with Hepatitis C

By Liz Highleyman

Two recent studies examined the influence of iron accumulation in the liver on the development of fibrosis and response to therapy in patients with chronic hepatitis C.

Study 1

The first study, published in the November 29, 2006 electronic edition of Gut, evaluated the role of HFE, ferroportin, and beta-globin gene mutations in promoting hepatic iron accumulation and fibrosis in patients with chronic HCV infection.

The investigators performed genetic analyses together with the assessment of hepatic iron content and liver histology in 100 patients with biopsy-proven chronic hepatitis C, without HIV or HBV coinfection.

Results

Among the patients analyzed, 12 were heterozygous (carried 2 different gene variants) for various beta-globin gene mutations (e.g., 39C-T, IVS1.1G-A, IVS1.6T-C). 29 subjects carried HFE gene mutations (C282Y, H63D and S65C). 1 additional patient was heterozygous for both HFE (H63D) and beta-globin (39C-T) variants. 58 subjects had wild-type (non-mutated) alleles of both genes. Hepatic iron concentration and hepatic stainable iron were significantly higher in patients carrying beta-globin mutations than in those with HFE mutations or wild-type alleles (P < 0.05). Multivariate analysis confirmed that the presence of beta-globin gene mutations was independently associated with both hepatic iron concentration (P = 0.008) and hepatic stainable iron (OR 6.11; P = 0.009). Moderate to severe fibrosis or cirrhosis (Ishak score > 2) was observed in 48 of the 100 patients. Logistic regression demonstrated that patient age (OR 1.05; P < 0.005) and beta-globin mutations (OR 4.99; P = 0.025) were independent predictors of fibrosis severity.

"Heterozygosis for beta-globin mutations is a novel risk factor for both hepatic iron accumulation and the progression to fibrosis in chronic hepatitis C patients," the authors concluded.

Study 2

In the second study, described in the November 2006 issue of Gastroenterology, investigators assessed the influence of HFE mutations and serum and hepatic measures of iron accumulation on baseline features and response to re-treatment with interferon-based therapy in patients with advanced chronic hepatitis C (Ishak score > 2) in the HALT-C trial.

A total of 1051 subjects (out of 1145) agreed to be tested for HFE mutations (C282Y, H63D, and S65C). Hepatic iron concentrations were measured in 144 liver biopsy specimens.

Results

35% of patients analyzed carried at least 1 HFE gene mutation. There were no significant differences in the prevalence of HFE gene mutations among subjects with fibrosis (35.5%) versus cirrhosis (32.9%). 33% of subjects achieved an end-of-treatment response and 16% achieved sustained virological response (SVR). Patients with HFE mutations - in particular H63D - had a higher end-of-treatment response rate compared to individuals lacking these mutations (40% vs 29%; P = 0.0078). The same held true for SVR rates (20% vs 14%; P = 0.009).

In conclusion, the authors wrote, "Although HFE mutations (especially the most frequent H63D mutation) are associated with increased iron loading, they are also associated with increased sustained virologic responses in U.S. patients with advanced chronic hepatitis C."

Further research is needed to explain how HFE mutations might promote improved response to therapy.

12/12/06

References

M Sartori, S Andorno, M Pagliarulo, and others. Heterozygous beta-globin gene mutations as a risk factor for iron accumulation and liver fibrosis in chronic hepatitis C. Gut. November 29, 2006 [Epub ahead of print].

H L Bonkovsky, D Naishadham, R W Lambrecht, and others. Roles of iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C. Gastroenterology 131(5): 1440-1451. November 2006.

http://www.hivandhepatitis.com/hep_c/news/2007/121206_b.html