Gene Mutations as Risk Factors in Chronic Hepatitis C
Gene Mutations as Risk Factors in Chronic Hepatitis C
Background: Chronic hepatitis C is frequently associated with increased hepatic iron stores. It remains controversial whether heterozygous mutations of hemochromatosis genes affect fibrosis progression. Therefore our aim was to assess associations between HFE mutations and hepatic inflammation and stage of fibrosis in German hepatitis C patients.
Methods: Liver biopsies from 166 patients were scored for inflammatory activity (A0-4) and hepatic fibrosis (F0-4). Gene mutations were determined by LightCycler, restriction fragment length polymorphism analysis, or direct sequencing.
Results: The frequencies of common HFE mutations C282Y and H63D are 4.2% and 21.3%, whereas the recently described S65C substitution and the Y250X mutation in the transferrin receptor 2 gene are very rare. In regression analysis, heterozygous carriers of C282Y or H63D mutations display significantly (P<0.05) higher inflammatory activities and more advanced fibrosis than patients without mutations. For C282Y heterozygous patients, the odds ratios for marked inflammatory activity (A2-4) and advanced liver fibrosis or cirrhosis (F2-4) are 4.9 and 4.6, respectively, compared with patients carrying homozygous wild-type alleles. C282Y mutations are associated with significantly (P<0.05) increased serum iron and aminotransferase levels, whereas H63D heterozygotes display higher transferrin saturation, serum iron, and ferritin concentrations compared to wild-type (P<0.01).
Conclusions: Common heterozygous hemochromatosis mutations are associated with higher grades of inflammation and more severe hepatic fibrosis. Our findings support a role of HFE mutations as primary risk factors for fibrogenesis and disease progression in chronic hepatitis C.
Progressive hepatic fibrosis and cirrhosis develops in 20-30% of patients with chronic hepatitis C virus (HCV) infection. In epidemiological studies, several host factors such as higher age at the time point of infection, excessive daily alcohol consumption, and male gender are independent risk factors associated with an accelerated progression of fibrosis. However, host genetic factors influencing fibrogenesis may also account for some of the variability in disease progression among individual patients. Consistent with this hypothesis, associations have been observed between polymorphisms of the gene encoding transforming growth factor ß1 and the progression of hepatic fibrosis in patients with chronic hepatitis C. Other case-control studies correlated progressive liver disease to variants of the genes encoding tumor necrosis factor , the transporter associated with antigen processing 2, angiotensinogen, myeloperoxidase, microsomal epoxide hydrolase, the LDL receptor, and apolipoprotein E4.
Mild-to-moderate iron overload is common among patients with chronic hepatitis C. Furthermore, HCV-infected patients with stainable iron in liver biopsies showed enhanced liver fibrosis compared with controls without detectable iron. Hence, mutations in hemochromatosis genes are among the most likely genetic risk factors to affect the severity of hepatic fibrosis.
Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism characterized by progressive iron accumulation and multi-organ dysfunction. Three common missense mutations in the HFE gene have been identified in patients with HH. Overall, 85-90% of patients with clinical features of HH carry the homozygous C282Y missense mutation (G to A at nucleotide 845) that disrupts a critical disulfide bond in the 3 domain of the HFE protein and abrogates binding to ß2-microglobulin. A second mutation H63D (C to G at nucleotide 187) located in the 1 domain was not associated with the same degree of iron loading as C282Y. The third mutation S65C is considered to be a rather neutral polymorphism. In addition, rare mutations in other genes controlling iron metabolism like the signaling molecule hepcidin (HAMP), the transferrin receptor 2 (TFR2), and the intestinal iron transporter ferroportin 1 (SLC40A1) have been identified in adult patients with HH (a.k.a. types 2B, 3, and 4, respectively).
Iron is commonly believed to promote liver fibrosis as a result of oxidative stress upon lipid peroxidation with subsequent production of free oxygen radicals. The mechanism by which iron accumulates in livers infected with chronic HCV has not yet been established. Whether iron accumulation is the primary cause or a secondary result of liver injury is still unclear. However, the coexistence of hemochromatosis gene mutations represents another possible explanation. Our aim now was to assess the association of common and rare HFE mutations with hepatic inflammation and stage of fibrosis in a cohort of German patients with chronic HCV infection.
Background: Chronic hepatitis C is frequently associated with increased hepatic iron stores. It remains controversial whether heterozygous mutations of hemochromatosis genes affect fibrosis progression. Therefore our aim was to assess associations between HFE mutations and hepatic inflammation and stage of fibrosis in German hepatitis C patients.
Methods: Liver biopsies from 166 patients were scored for inflammatory activity (A0-4) and hepatic fibrosis (F0-4). Gene mutations were determined by LightCycler, restriction fragment length polymorphism analysis, or direct sequencing.
Results: The frequencies of common HFE mutations C282Y and H63D are 4.2% and 21.3%, whereas the recently described S65C substitution and the Y250X mutation in the transferrin receptor 2 gene are very rare. In regression analysis, heterozygous carriers of C282Y or H63D mutations display significantly (P<0.05) higher inflammatory activities and more advanced fibrosis than patients without mutations. For C282Y heterozygous patients, the odds ratios for marked inflammatory activity (A2-4) and advanced liver fibrosis or cirrhosis (F2-4) are 4.9 and 4.6, respectively, compared with patients carrying homozygous wild-type alleles. C282Y mutations are associated with significantly (P<0.05) increased serum iron and aminotransferase levels, whereas H63D heterozygotes display higher transferrin saturation, serum iron, and ferritin concentrations compared to wild-type (P<0.01).
Conclusions: Common heterozygous hemochromatosis mutations are associated with higher grades of inflammation and more severe hepatic fibrosis. Our findings support a role of HFE mutations as primary risk factors for fibrogenesis and disease progression in chronic hepatitis C.
Progressive hepatic fibrosis and cirrhosis develops in 20-30% of patients with chronic hepatitis C virus (HCV) infection. In epidemiological studies, several host factors such as higher age at the time point of infection, excessive daily alcohol consumption, and male gender are independent risk factors associated with an accelerated progression of fibrosis. However, host genetic factors influencing fibrogenesis may also account for some of the variability in disease progression among individual patients. Consistent with this hypothesis, associations have been observed between polymorphisms of the gene encoding transforming growth factor ß1 and the progression of hepatic fibrosis in patients with chronic hepatitis C. Other case-control studies correlated progressive liver disease to variants of the genes encoding tumor necrosis factor , the transporter associated with antigen processing 2, angiotensinogen, myeloperoxidase, microsomal epoxide hydrolase, the LDL receptor, and apolipoprotein E4.
Mild-to-moderate iron overload is common among patients with chronic hepatitis C. Furthermore, HCV-infected patients with stainable iron in liver biopsies showed enhanced liver fibrosis compared with controls without detectable iron. Hence, mutations in hemochromatosis genes are among the most likely genetic risk factors to affect the severity of hepatic fibrosis.
Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism characterized by progressive iron accumulation and multi-organ dysfunction. Three common missense mutations in the HFE gene have been identified in patients with HH. Overall, 85-90% of patients with clinical features of HH carry the homozygous C282Y missense mutation (G to A at nucleotide 845) that disrupts a critical disulfide bond in the 3 domain of the HFE protein and abrogates binding to ß2-microglobulin. A second mutation H63D (C to G at nucleotide 187) located in the 1 domain was not associated with the same degree of iron loading as C282Y. The third mutation S65C is considered to be a rather neutral polymorphism. In addition, rare mutations in other genes controlling iron metabolism like the signaling molecule hepcidin (HAMP), the transferrin receptor 2 (TFR2), and the intestinal iron transporter ferroportin 1 (SLC40A1) have been identified in adult patients with HH (a.k.a. types 2B, 3, and 4, respectively).
Iron is commonly believed to promote liver fibrosis as a result of oxidative stress upon lipid peroxidation with subsequent production of free oxygen radicals. The mechanism by which iron accumulates in livers infected with chronic HCV has not yet been established. Whether iron accumulation is the primary cause or a secondary result of liver injury is still unclear. However, the coexistence of hemochromatosis gene mutations represents another possible explanation. Our aim now was to assess the association of common and rare HFE mutations with hepatic inflammation and stage of fibrosis in a cohort of German patients with chronic HCV infection.
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