Roles of iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C.
OBJECTIVE
Iron overload may cause or contribute to hepatic injury and fibrosis. Mutations in the HFE gene may influence development or progression of chronic liver disease by increasing iron stores or modulating immune responses. The aim of this work was to assess the influence of HFE mutations and serum and hepatic measures of iron status on baseline features and response to lead-in therapy in subjects with advanced chronic hepatitis C enrolled in the Hepatitis C Anti-viral Long-term Treatment to prevent Cirrhosis (HALT-C) Trial.


METHODS
Entry criteria included an Ishak fibrosis score >2 and lack of iron overload (Scheuer iron grade <3+) according to local study pathologists. All baseline biopsy specimens were rescored by consensus of study pathologists, and detailed assessment of stainable iron was performed. Hepatic iron concentrations were measured on portions of 144 liver biopsy specimens. A total of 1051 out of 1145 subjects agreed to HFE mutational testing (C282Y, H63D, S65C).


RESULTS
Thirty-five percent carried at least one 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%). Thirty-three percent of subjects had end-of-treatment and 16% sustained virologic responses. Presence of HFE mutations, in particular the H63D variation, was associated with increased end-of-treatment (40% vs 29%, P = .0078) and sustained virologic responses (20% with HFE mutation vs 14% sustained virologic response without HFE mutation; P = .009).


CONCLUSIONS
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 US patients with advanced chronic hepatitis C.
Bonkovsky
Herbert L
HL
Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA. bonkovsky@uchc.edu
Naishadham
Deepa
D
Lambrecht
Richard W
RW
Chung
Raymond T
RT
Hoefs
John C
JC
Nash
S Russell
SR
Rogers
Thomas E
TE
Banner
Barbara F
BF
Sterling
Richard K
RK
Donovan
John A
JA
Fontana
Robert J
RJ
Di Bisceglie
Adrian M
AM
Ghany
Marc G
MG
Morishima
Chihiro
C
D000328:Adult; D000368:Aged; D005260:Female; D005838:Genotype; D000071020:Hemochromatosis Protein; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000235:genetics* / Q000821:virology; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000502:physiology*; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000517:prevention & control; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation
C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D007501:Iron