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?
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.
Among men, HFE p.C282Y homozygosity was significantly associated with increased risk for incident primary hepatic malignancy and excess mortality.
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.
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.
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.
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.
Atkins JL, Pilling LC, Masoli JAH, et al. Association of Hemochromatosis HFE p.C282Y Homozygosity With Hepatic Malignancy. JAMA. 2020;324(20):2048–2057. doi:10.1001/jama.2020.21566
Coronavirus Resource Center
Customize your JAMA Network experience by selecting one or more topics from the list below.
Create a personal account or sign in to: