Common heterozygous hemochromatosis gene mutations are risk factors for inflammation and fibrosis 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.
Department of Medicine III, University Hospital Aachen, Aachen University (RWTH), Germany.
Andreas
A
Geier
Michael
M
Reugels
Ralf
R
Weiskirchen
Hermann E
HE
Wasmuth
Christoph G
CG
Dietrich
Elmar
E
Siewert
Carsten
C
Gartung
Johann
J
Lorenzen
Anja K
AK
Bosserhoff
Marc
M
Brügmann
Axel M
AM
Gressner
Siegfried
S
Matern
Frank
F
Lammert
D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D006432:Hemochromatosis / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D000071020:Hemochromatosis Protein; D019698:Hepatitis C, Chronic / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D012307:Risk Factors
C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D007501:Iron