Clinical Disease Common With Hereditary Hemochromatosis Genetic Variants

By Will Boggs MD

January 28, 2019

NEW YORK (Reuters Health) - As many as 20% of individuals with the HFE p.C282Y genetic variant responsible for most hereditary hemochromatosis type 1 will have disease manifestations, according to results from 22 centers participating in the UK Biobank.

"Early community studies concluded that less than 1% of HFE C282Y homozygotes develop clinical disease," Dr. David Melzer from University of Exeter Medical School, Exeter, UK told Reuters Health by email. "In homozygous men, we found rates 20 times higher, and 10 times higher in homozygous women - that was a surprise!"

The prevalence of the p.C282Y variant is 10-15% in populations of northern European descent, 9.5% among non-Hispanic white people in the USA, and lower among non-Hispanic black people (2.3%) and Mexican-Americans (2.8%).

Studies of close relatives of patients with p.C282Y-associated hemochromatosis have suggested high penetrance to clinical disease, but several studies in general populations have suggested much lower penetrance to clinical disease.

Dr. Melzer and colleagues used data from 451,243 UK Biobank participants to estimate associations between HFE p.C282Y status and common conditions potentially linked to hemochromatosis. In this population, 2890 individuals (0.6% or 1 in 156) were homozygous and 64,444 (14.3%) were heterozygous for p.C282Y.

Among p.C282Y homozygotes, hemochromatosis was diagnosed at baseline in 7.3% (versus 0.02% of those with no p.C282Y mutations) and by the end of follow-up in 15.1% (versus 0.04% of those with no p.C282Y mutations), with higher rates in men (12.1% at baseline and 21.7% during follow-up) than in women (3.4% at baseline and 9.8% during follow-up).

At baseline, male p.C282Y homozygotes had 411.1-fold higher odds of hemochromatosis and significantly higher odds of osteoarthritis, liver disease, rheumatoid arthritis, diabetes, osteoporosis, and pneumonia, compared with no p.C282Y mutations. Women p.C282Y homozygotes had 438.0-fold higher odds of hemochromatosis and significantly higher odds of osteoarthritis, compared with no p.C282Y mutations.

Results were similar during follow-up: male homozygotes were 286.2-fold more likely and female homozygotes were 427.3-fold more likely to be diagnosed with hemochromatosis during follow-up, according to the January 16th BMJ online report.

Even among participants who were heterozygous for p.C282Y, men were 5.77-fold more likely and women were 5.30-fold more likely to be diagnosed with hemochromatosis, compared with no p.C282Y mutations. The risk was even higher among p.C282Y/p.H63D compound heterozygotes: 33.63-fold higher for men and 34.74-fold higher for women.

"Now we know the penetrance is much higher, and with the cost of genetic testing much lower that it was, the case for routine clinical testing and screening is much stronger," Dr. Melzer said. "The economic studies suggest that both clinical routine testing and even population screening would be cost effective. It would be good if the screening committees could review the new evidence - it's great that the UK committee has already announced that they are going to."

"p.C282Y associated iron overload is preventable and treatable if intervention starts early," the researchers add.

Dr. James C. Barton from Southern Iron Disorders Center, Birmingham, Alabama, who has researched various aspects of HFE hemochromatosis, told Reuters Health in an email interview, "Based on available information, the traditional disease risks associated with p.C282Y homozygosity are attributable to iron overload, not the HFE genotype or linked genes/alleles on chromosome 6p. Even mild iron overload may enhance risks for liver disease, arthropathy, and diabetes, especially in persons who have other common non-iron risk factors for these conditions."

"HFE hemochromatosis (almost exclusively p.C282Y homozygotes) is common and easily diagnosed but typically overlooked," he said. "One the one hand, I estimate that the average primary care physician in the US or Britain 'misses' several hemochromatosis diagnoses every month at the known prevalence of the dominant genotype. On the other hand, heterozygosity for p.C282Y, homozygosity or heterozygosity for p.H63D, or an elevated serum ferritin level rarely represents 'hemochromatosis.'"

"Early diagnosis of p.C282Y homozygotes and subsequent timely phlebotomy to achieve and maintain iron depletion is associated with no increased risk for liver disease, arthropathy, or diabetes, and with normal longevity," Dr. Barton said.


BMJ 2019.