HFE C282Y heterozygosity in hepatocellular carcinoma: evidence for an increased prevalence.
OBJECTIVE
Iron overload is observed frequently in chronic liver disease, and some studies have suggested that chronic iron overload may contribute to the pathogenesis of hepatocellular carcinoma (HCC). Heterozygosity for hereditary hemochromatosis (HH) is associated with increased body iron stores. The discovery of the HH gene HFE has enabled identification of the heterozygote status. The aim of this study was to evaluate if heterozygosity for HH is a risk factor for HCC.


METHODS
The C282Y and the H63D mutation of the HFE gene were analyzed in 137 patients with HCC and no history of HH, 107 patients with cirrhosis without HCC and 126 healthy controls. Hepatic iron content was measured by using a semiquantitative histologic score.


RESULTS
Seventeen of 137 HCC patients (12.4%) were C282Y heterozygote, compared with only 4 of 107 (3.7%) cirrhotic patients without HCC and 6 of 126 (4.8%) healthy controls (P < 0.05). The frequency of the H63D mutation showed no significant differences. C282Y heterozygote HCC patients had significantly higher levels of serum ferritin and transferrin saturation than C282Y wild-type patients (793 +/- 122 vs. 355 +/- 23 ng/mL, and 42.3% +/- 7.3% vs. 29.2% +/- 1.7%, respectively), and significantly higher iron deposition in HCC as well as in nontumorous liver tissue.


CONCLUSIONS
The C282Y heterozygous genotype is significantly more common in HCC patients and is associated with significantly increased intrahepatic iron deposition and systemic iron stores. These results suggest that C282Y heterozygosity plays a role in liver iron deposition and could contribute to hepatocarcinogenesis via the accumulation of potentially carcinogenic iron. These findings may have implications for HCC screening and prevention strategies.
Hellerbrand
Claus
C
Department of Internal Medicine I, University of Regensburg, D-93042 Regensburg, Germany. claus.hellerbrand@klinik.uni-regensburg.de
Pöppl
Andreas
A
Hartmann
Arndt
A
Schölmerich
Jürgen
J
Lock
Guntram
G
D014408:Biomarkers, Tumor / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005293:Ferritins / Q000097:blood; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D005838:Genotype; D005858:Germany; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D019656:Loss of Heterozygosity / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D015995:Prevalence; D012307:Risk Factors; D012720:Severity of Illness Index; D012806:Siderosis / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D013223:Statistics as Topic; D014168:Transferrin / Q000378:metabolism
D014408:Biomarkers, Tumor; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D014168:Transferrin; D005293:Ferritins; D007501:Iron