Hereditary haemochromatosis : lifetime risks of primary hepatic carcinoma and mortality in the UK Biobank

Abstract

Background:Hereditary haemochromatosis (HH) is predominantly caused by the HFE p.C282Y homozygous mutation. Hepatic carcinomas and mortality risks are raised in clinically diagnosed HH, especially with liver cirrhosis. However, outcomes are unclear in mutation carriers in the community setting without clinically diagnosed HH.

Methods:UK Biobank European descent participants (n = 451,186, 40-70 years) including 2,890 p.C282Y homozygotes, followed via hospitalization records, national cancer registry, primary care records and death certificates. Cox regression models adjusted for age, assessment center, genotyping array and genetic principal components. Kaplan Meier lifetable probabilities of incident diagnoses were estimated from age 40 to 75.

Results:Incidence of hepatic carcinomas was higher in male p.C282Y homozygotes compared to those without mutations (HR: 14.1, 95% CI: 7.6-26.1). However, no associations were observed in female p.C282Y homozygotes, p.C282Y heterozygotes or p.C282Y/p.H63D compound heterozygotes. Lifetables estimate project that by age 75, 7.2% (95% CI: 3.9-13.1) of male p.C282Y homozygotes develop hepatic carcinoma and 19.5% (95% CI 15.8-24.0) of homozygote men would die, compared to 15.1% (95% CI:14.7-15.5) in those without mutations. Female p.C282Y homozygotes also had an increased risk of death from hepatic carcinomas (HR: 3.36, 95% CI:1.06-10.67).

Conclusions:In a large sample of community volunteers, p.C282Y homozygosity was associated with substantial risks of hepatic cancer and excess mortality in males. As haemochromatosis iron overload is preventable and treatable by phlebotomy, early case ascertainment is needed for hereditary haemochromatosis, including at the community level. Our findings support the case that p.C282Y homozygous individuals identified incidentally during DNA sequencing should be notified.