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Original Investigation
November 24, 2020

Association of Hemochromatosis HFE p.C282Y Homozygosity With Hepatic Malignancy

Author Affiliations
  • 1Epidemiology and Public Health Group, University of Exeter Medical School, Exeter, United Kingdom
  • 2Center on Aging, University of Connecticut Health Center, Farmington
  • 3Department of Healthcare for Older People, Royal Devon and Exeter Hospital, Barrack Road, Exeter, United Kingdom
  • 4Department of Gastroenterology, South Warwickshire NHS Foundation Trust, United Kingdom
  • 5Department of Medicine, University of Western Ontario, London, Ontario, Canada
JAMA. 2020;324(20):2048-2057. doi:10.1001/jama.2020.21566
Key Points

Question  What are the risks of primary hepatic malignancies or death by age 75 years in hemochromatosis HFE p.C282Y homozygotes identified in genotyping in a community sample?

Findings  In this cohort study that included 451 186 individuals, the risk of primary hepatic malignancy among 1294 male homozygous participants compared with men without pathogenic variants was 7.2% vs 0.6%, and the risk of all-cause death was 19.5% vs 15.1%; both differences were statistically significant. There were no statistically significant associations for women.

Meaning  Among men, HFE p.C282Y homozygosity was significantly associated with increased risk for incident primary hepatic malignancy and excess mortality.


Importance  Hereditary hemochromatosis is predominantly caused by the HFE p.C282Y homozygous pathogenic variant. Liver carcinoma and mortality risks are increased in individuals with clinically diagnosed hereditary hemochromatosis, but risks are unclear in mostly undiagnosed p.C282Y homozygotes identified in community genotyping.

Objective  To estimate the incidence of primary hepatic carcinoma and death by HFE variant status.

Design, Setting, and Participants  Cohort study of 451 186 UK Biobank participants of European ancestry (aged 40-70 years), followed up from baseline assessment (2006-2010) until January 2018.

Exposures  Men and women with HFE p.C282Y and p.H63D genotypes compared with those with neither HFE variants.

Main Outcomes and Measures  Two linked co–primary outcomes (incident primary liver carcinoma and death from any cause) were ascertained from follow-up via hospital inpatient records, national cancer registry, and death certificate records, and from primary care data among a subset of participants for whom data were available. Associations between genotype and outcomes were tested using Cox regression adjusted for age, assessment center, genotyping array, and population genetics substructure. Kaplan-Meier lifetable probabilities of incident diagnoses were estimated from age 40 to 75 years by HFE genotype and sex.

Results  A total of 451 186 participants (mean [SD] age, 56.8 [8.0] years; 54.3% women) were followed up for a median (interquartile range) of 8.9 (8.3-9.5) years. Among the 1294 male p.C282Y homozygotes, there were 21 incident hepatic malignancies, 10 of which were in participants without a diagnosis of hemochromatosis at baseline. p.C282Y homozygous men had a higher risk of hepatic malignancies (hazard ratio [HR], 10.5 [95% CI, 6.6-16.7]; P < .001) and all-cause mortality (n = 88; HR, 1.2 [95% CI, 1.0-1.5]; P = .046) compared with men with neither HFE variant. In lifetables projections for male p.C282Y homozygotes to age 75 years, the risk of primary hepatic malignancy was 7.2% (95% CI, 3.9%-13.1%), compared with 0.6% (95% CI, 0.4%-0.7%) for men with neither variant, and the risk of death was 19.5% (95% CI, 15.8%-24.0%), compared with 15.1% (95% CI, 14.7%-15.5%) among men with neither variant. Among female p.C282Y homozygotes (n = 1596), there were 3 incident hepatic malignancies and 60 deaths, but the associations between homozygosity and hepatic malignancy (HR, 2.1 [95% CI, 0.7-6.5]; P = .22) and death (HR, 1.2 [95% CI, 0.9-1.5]; P = .20) were not statistically significant.

Conclusions and Relevance  Among men with HFE p.C282Y homozygosity, there was a significantly increased risk of incident primary hepatic malignancy and death compared with men without p.C282Y or p.H63D variants; there was not a significant association for women. Further research is needed to understand the effects of early diagnosis and treatment.