From the Journals

Hemochromatosis variants may confer 10-fold higher risk of liver cancer



Men with genetic variants that cause hereditary hemochromatosis have an increased risk of liver cancer and death, according to a large cohort study.

Hereditary hemochromatosis is primarily caused by HFE gene variants. Past research suggested that 81% of patients with hereditary hemochromatosis carry the p.C282Y variant and 5% carry the p.C282Y/p.H63D compound heterozygote genotype.

In a new study, the presence of HFE p.C282Y and p.H63D genotypes was associated with a 10-fold greater risk of developing a hepatic malignancy among men of European ancestry aged 40-70 years. In addition, men with HFE variants were 1.2 times more likely to die of any cause, compared with men who had neither pathogenic variant.

Janice L. Atkins, PhD, of the University of Exeter (England), and colleagues reported these findings in JAMA.

For this study, Dr. Atkins and colleagues used follow-up data from a large genotyped community sample to estimate the incidence of primary hepatic carcinomas and deaths by HFE variant status in participants of European descent.

Data for the two linked coprimary endpoints, incident primary liver carcinoma and all-cause mortality, were derived from hospital and death certificate records. Where available, primary care data was also included.

Results: Increased risks for men, not women

The researchers analyzed data from 451,186 men and women, aged 40-70 years, from the UK Biobank. There were 2,890 (0.9%) patients who were p.C282Y homozygous, 1,294 of whom were men.

Among the 1,294 men with HFE p.C282Y homozygosity, 21 were diagnosed with a primary hepatic malignancy. Ten of these patients were not diagnosed with hemochromatosis at baseline.

At a median follow-up of 8.9 years, the risk of primary hepatic malignancy was significantly higher in men with HFE p.C282Y homozygosity, compared with men without HFE pathogenic variants (hazard ratio, 10.5; 95% confidence interval, 6.6-16.7; P < .001).

The risk of all-cause death was significantly higher in men with HFE p.C282Y homozygosity as well (HR, 1.2; 95% CI, 1.0-1.5; P  = .046).

In contrast, female HFE p.C282Y homozygotes had no significant increases in the risk of incident primary hepatic malignancy or all-cause mortality.

Life table projections estimated that 7.2% of men with HFE p.C282Y homozygosity will develop a primary hepatic malignancy by age 75, compared with 0.6% of men without p.C282Y or p.H63D variants.

The researchers acknowledged that a key limitation of this study was the ancestral homogeneity of the cohort. Thus, the findings may not be generalizable to all patient populations.

Implications: Earlier diagnosis and treatment

The results of this study underline the importance of early diagnosis and genetic testing, according to the researchers.

“Tragically, men with the hemochromatosis faulty genes have been dying of liver cancer for many years, but this was thought to be rare,” study author David Melzer, MBBCh, PhD, of University of Exeter, said in a press release.

“The large scale of the UK Biobank study allowed us to measure cancer risk accurately. We were shocked to find that more than 7% of men with two faulty genes are likely to develop liver cancer by age 75, particularly considering that the U.K. has the second-highest rate of these faulty genes in the world. Fortunately, most of these cancers could be prevented with early treatment,” Dr. Melzer added.

“Physicians and scientists have long acknowledged that iron overload is an important cofactor fueling the development of many serious diseases, including cancer,” said study author Jeremy Shearman, MBChB, DPhil, of Nuffield Health and South Warwickshire NHS Foundation Trust in the United Kingdom.

“This research is a vital step towards quantifying that risk and should raise awareness of the importance of iron in the minds of both clinicians and patients. Measurement of iron stores and recognition of the genetic risk of iron overload needs to become a routine part of health assessment and monitoring in the U.K.,” Dr. Shearman added.

“The UK Biobank project is a glimpse into the future of medicine where all known genes are tested and then treatable conditions are offered treatment before serious complications develop,” said study author Paul Adams, MD, of the University of Western Ontario in London.

This research was funded by the UK Medical Research Council. Dr. Melzer disclosed financial affiliations with the UK Medical Research Council during the conduct of the study.

SOURCE: Atkins JL et al. JAMA. 2020 Nov 24. doi: 10.1001/jama.2020.21566.

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