Heterozygous beta-globin gene mutations as a risk factor for iron accumulation and liver fibrosis in chronic...

Iron accumulation is a well-known risk factor for the progression of chronic hepatitis C (CHC) to fibrosis. However, the profibrogenic role of the genes controlling iron homeostasis is still controversial.

To evaluate the relative role of haemachromatosis (HFE), ferroportin and beta-globin gene mutations in promoting iron accumulation and fibrosis in patients with CHC.

Genetic analysis was performed together with the assessment of hepatic iron content and histology in 100 consecutive HIV-antibody and hepatitis B surface antigen-negative patients with biopsy-proven CHC.

Among the patients investigated, 12 were heterozygous for various beta-globin gene mutations (39[C-->T], IVS1.1[G-->A], 22 7 bp deletion and IVS1.6[T-->C]) and 29 carried HFE (C282Y, H63D and S65C) gene mutations. One further patient was heterozygous for both HFE (H63D) and beta-globin (39[C-->T]) variants, whereas 58 had the wild-type alleles of both the genes. Hepatic iron concentration (HIC) and hepatic stainable iron were significantly higher (p<0.05) in patients with CHC carrying beta-globin mutations than in those with HFE mutations or the wild-type alleles. Multivariate analysis confirmed that the presence of beta-globin mutations was independently associated with both HIC (p = 0.008) and hepatic-stainable iron (odds ratio (OR) 6.11; 95% CI 1.56 to 23.92; p = 0.009). Moderate/severe fibrosis or cirrhosis (Ishak's score >2) was observed in 48 of 100 patients. Logistic regression demonstrated that age (OR 1.05; 95% CI 1.02 to 1.09; p<0.005) and beta-globin mutations (OR 4.99; 95% CI 1.22 to 20.3; p = 0.025) were independent predictors of the severity of fibrosis.

Heterozygosis for beta-globin mutations is a novel risk factor for both hepatic iron accumulation and the progression to fibrosis in patients with CHC.