Penetrance, cancer incidence and survival of hemochromatosis in a long-term follow-up and epidemiological modeling study

Background and Aims Hereditary hemochromatosis (HH) is associated with homozygosity for p.C282Y in HFE in 80 % of patients. Disease penetrance (= iron overload [IOL]) occurs in only 14 %. Due to cirrhosis and hepatocellular carcinoma (HCC) an even lower penetrance is assumed.The aim of the study was to determine age- and sex-dependent penetrance of IOL and assess the risk for cirrhosis and HCC during a long-term follow-up in a large cohort of HH patients.

Method Survival and cancer incidence data were extracted retrospectively from national databases for 498 p.C282Y homozygotes between 1996 and 2018. HH was defined as provisional IOL (males: Ferritin  > 300+Transferrin saturation  > 50 % | females: Ferritin  > 200+Transferrin saturation  > 45 %) at genotyping. From the allele frequency of p.C282Y in the general population and the age distribution in Tyrol, an expected number of homozygotes was derived. Disease penetrance was calculated based on patients diagnosed with HH and the expected number of homozygotes in 2008 and 2018. Crude incidence for HCC and survival status on 28 January 2019 were assessed to calculate age-standardized cancer incidence for HH patients.

Results 73 % of 498 p.C282Y homozygotes presented with provisional IOL and the mean age at diagnosis was 47.8 years. Among alive p.C282Y homozygotes with provisional IOL the crude penetrance was 14 %. In this group, 5 patients were diagnosed with HCC, representing an estimated risk for HCC of 1:60 by the age of 80, compared to 1:77 in men and 1:333 in women in the general population of Tyrol. This implies no increased HCC risk in patients with p.C282Y homozygosity. Regression analysis shows an independent association between age, sex and HH penetrance.

Conclusion Age and sex analyses allow a more precise prognosis of hemochromatosis penetrance in p.C282Y homozygotes. No increased mortality or risk of HCC development could be identified in this epidemiological modelling study.

Publication History

Article published online:
26 May 2020