Hemochromatosis and Hepatic Malignancy

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The predominant cause of hereditary hemochromatosis is 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 diagnosed HFE p.C282Y homozygousidentified community genotyping.

To estimate the incidence of primary hepatic carcinoma and death by HFE variant status, a cohort study of 451,186 UK Biobank participants of European ancestry aged 40 to 70 years old, followed up from baseline assessment (2006-2010), until January 2018 was carried out.

Men and women with HFE p.C282Y and p.H63D genotypes was compared with those with neither HFE variants. Two linked coprimary outcomes (incident primary liver carcinoma and death from any cause), were ascertained from followup by way of inpatient hospital records, national cancer registry, and death certificate records, and from primary care data among a subset of participants for whom data was available. Associations between genotype and outcomes were tested using Cox regression adjusted for age, assessment center, genotyping array, and population genetic 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 had a mean age of 56.8 years; 54.3% women, and were followed up for a median of 8.9 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 in baseline and pC2827 homozygous men had a higher risk of hepatic malignancies (HR 10.5), and all cause of mortality (N = 88; HR 1.2) compared with men with neither HFE variant.

In lifetable projections for male p.C282Y homozygotes to 75 years, the risk of primary hepatic malignancy was 7.2% compared with 0.6% for men with neither variant and the risk of death was 19.5%, compared with 15.1% 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 and death were not statistically significant (HR 2.1 and 1.2, respectively).

It is concluded that among men with HFE p.C282Y homozygosity, there was a significant increased risk of incident primary hepatic malignancy and death. Compared with men without p.C282Y or p.H63D variant, there was not a significant association for women. The effects of early diagnosis and treatment require further research.

Atkins, J., Pilling, L., Masoli, J., et al. “Association of Hemochromatosis HFE pC282Y Homozygosity With Hepatic Malignancy.” JAMA 2020; Vol. 324, pp. 20, 2048-2057.

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