Relative contribution of iron genes, dysmetabolism and hepatitis C virus (HCV) in the pathogenesis of altered iron regulation in HCV chronic hepatitis.
OBJECTIVE
Hepatitis C virus (HCV) chronic hepatitis predisposes to iron overload, which negatively influences the prognosis of this infection. Since the underlying mechanisms of this iron overload are undefined, we analyzed the prevalence of altered iron parameters, and the relative contribution of viral, metabolic, and genetic factors in Italian patients.


METHODS
We studied the metabolic and biochemical characteristics of 143 previously untreated, biopsied patients with HCV who were not alcohol abusers. Hepatic iron was determined according to Deugnier, HFE genotype by restriction analysis, hepcidin, hemojuvelin, ferroportin-1, and transferrin receptor-2 mutations by denaturing high performance liquid chromatography and sequencing.


RESULTS
Increased transferrin saturation was observed in 20%, hyperferritinemia in 22%, and histological iron deposition in 32% of patients. Ferritin was independently correlated with iron stores and host metabolic parameters, whereas hepatic iron deposition was correlated with ferritin and histological severity of hepatitis. Sinusoidal iron deposition was associated with metabolic alterations, including body mass index, insulin resistance, and LDL cholesterol. Conversely, the prevalence of HFE mutations and serum ferritin values increased with the severity of steatosis. The prevalence of HFE and beta-globin mutations was not different from that of controls (31% and 2%, respectively). No tranferrin receptor-2, hemojuvelin, or ferroportin-1 mutations were detected, but two patients carried the -72C>T hepcidin promoter mutation. The C282Y HFE mutation, hepcidin and beta-globin mutations influenced iron stores. Both carriers of the -72C>T Hepcidin mutation had beta-thalassemia trait, moderate iron overload, and liver cirrhosis.


CONCLUSIONS
Iron genes influence iron overload and steatosis development, but the major burden is related to HCV itself and host metabolic factors.
Valenti
Luca
L
Department of Internal Medicine, Medicina Interna IB, Universita' di Milano, Ospedale Policlinico Mangiagalli Regina Elena IRCCS, Milano, Italy.
Pulixi
Edoardo A
EA
Arosio
Paolo
P
Cremonesi
Laura
L
Biasiotto
Giorgio
G
Dongiovanni
Paola
P
Maggioni
Marco
M
Fargion
Silvia
S
Fracanzani
Anna Ludovica
AL
D000328:Adult; D023181:Antimicrobial Cationic Peptides / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics; D008078:Cholesterol, LDL / Q000097:blood; D005234:Fatty Liver / Q000209:etiology; D005293:Ferritins / Q000097:blood; D058851:GPI-Linked Proteins; D005838:Genotype; D000071020:Hemochromatosis Protein; D016174:Hepacivirus / Q000472:pathogenicity*; D019698:Hepatitis C, Chronic / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D007501:Iron / Q000032:analysis / Q000378:metabolism*; D019190:Iron Overload / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008099:Liver / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011990:Receptors, Transferrin / Q000235:genetics; D014168:Transferrin / Q000032:analysis; D017086:beta-Thalassemia / Q000150:complications / Q000235:genetics; D000098742:Ferroportin
D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; D008078:Cholesterol, LDL; D058851:GPI-Linked Proteins; C578702:HAMP protein, human; C103673:HFE protein, human; C481006:HJV protein, human; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011990:Receptors, Transferrin; C503640:TFR2 protein, human; D014168:Transferrin; D000098742:Ferroportin; D005293:Ferritins; D007501:Iron