Hereditary Hemochromatosis Linked to Iron Overload Mainly in Men

By Judith Groch
MELBOURNE, Australia, Jan 17 -- In hereditary hemochromatosis with HFE mutations, iron overload developed in a substantial proportion of men but in only a small number of women, according to researchers here.
In a prospective study of 31,192 persons, iron-overload-related liver disease developed in 28% of men and 1% of women who were homozygous for C282Y, the HFE allele most commonly associated with hereditary hemochromatosis, found Katrina J. Allen, M.D., Ph.D., of the University of Melbourne, and colleagues.
Most persons who are homozygous for C282Y have elevated levels of serum ferritin and transferrin saturation reported, the researchers noted in the Jan. 17 issue of the New England Journal of Medicine. Diseases related to iron overload develop in some C282Y homozygotes, but the extent of the risk is debated.
To measure the risk and the disease expression, the researchers assessed HFE mutations in the 31,192 persons of northern European descent between the ages of 40 and 69 who participated in the Melbourne Collaborative Cohort Study. Individuals, enrolled from 1990 to 1994, were followed for an average of 12 years.
A random sample of 1,438 individuals stratified according to HFE genotype identified 203 C282Y homozygotes (108 women, 95 men). The researchers obtained clinical and biochemical data, including two sets of iron measurements done 12 years apart.
Disease related to iron overload was defined as documented iron overload and one or more of cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated aminotransferase levels, physician-diagnosed symptomatic hemochromatosis, and arthropathy of the second and third metacarpophalangeal joints.
The proportion of C282Y homozygotes with documented iron-overload-related disease was 28.4% (95% confidence interval: 18.8 to 40.2) for men and 1.2% (95% CI: 0.03 to 6.5) for women.
Only one non-C282Y homozygote (a compound heterozygote) had documented iron-overload-related disease.
In an accompanying editorial, Bruce R. Bacon, M.D., and Robert S. Britton, Ph.D., of Saint Louis University, pointed out that in clinical practice, genetic testing for HFE mutations is recommended for first-degree relatives of newly identified probands. Phlebotomy treatment is safe and effective to remove excess iron and can reverse preexisting hepatic fibrosis, they wrote.
The study by Dr. Allen and colleagues will spur the search for genetic and environmental factors that determine which C282Y homozygotes accumulate substantial amounts of iron and are at risk for clinically relevant tissue damage, Drs. Bacon and Britton concluded.
In confirmation of previous reports, the Australian researchers found that C282Y homozygotes with a serum ferritin level of 1,000 μg/L or more were at higher risk of symptoms and liver disease than were C282Y homozygotes with low levels or those with other HFE genotypes.
The prevalence of diabetes was not changed in C282Y individuals compared with controls, and the rate of death from any cause was not increased in these persons during the 12-year period (hazard ratio: 1.04, 95% CI: 0.667 to 1.62, P=0.87), a finding similar to that reported previously, the researchers said.
Male C282Y homozygotes with a serum ferritin level of 1,000 μg per liter or more were more likely to report fatigue, use of arthritis medicine, and a history of liver disease than were men who had the wild-type gene (substitution of aspartic acid for histidine at position 63).
For C282Y homozygotes, 21 of 74 men (28.4%) and one of 84 women (1.2%) satisfied the criteria for documented disease related to iron overload.
Of these 22 individuals, two had hepatocellular carcinoma, 12 had fibrosis or cirrhosis, six had raised levels of alanine aminotransferase or aspartate aminotransferase, five had abnormal metacarpophalangeal joints, and 11 had received a previous diagnosis of hereditary hemochromatosis as a result of symptoms that prompted an evaluation.
For 40 persons, liver biopsies were clinically indicated because of a serum ferritin level of 1,000 μg/L or more. Of these, 17 (including 16 men) underwent liver biopsy (42.5%). All had an iron grade of two or more, and 12 had liver cirrhosis or fibrosis.
No patients with biopsy results reported having had viral hepatitis, and only one reported having a high baseline level of alcohol consumption.
Only 37% of C282Y homozygotes were identified during follow-up, the researchers wrote, which may have modified the natural history of disease progression in these individuals leading to an underestimation of disease penetrance. They also noted that the association of the HFE mutation with less commonly reported features of the disorder, such as impotence and cardiomyopathy, were not addressed.
The increased prevalence of iron-overload-related disease in these men as compared with women is frequently ascribed to recurrent physiologic blood loss and the slower accumulation of iron in women, the investigators said.
However, they added, disparate frequencies of certain HLA haplotypes in men and women have been reported in individuals with the genetic disorder, which may be relevant to the sex-specific phenotypic expression of the disease.
Studies of iron regulatory pathways in African Americans have also suggested that serum ferritin levels may be genetically determined by sex differences as well as environmental factors, Dr. Allen and her colleagues wrote.
In their accompanying editorial, Drs. Bacon and Britton wrote that Dr. Allen and colleagues have provided valuable new information concerning the clinical penetrance of hereditary hemochromatosis.
Because the combination of C282Y homozygosity and a serum ferritin level of 1,000 ng/mL or more increases the risk of hepatic fibrosis and cirrhosis, this combination of factors may be an indication for liver biopsy, they said.
This study was supported by a grant from the National Institutes of Health and by grants from the National Health and Medical Research Council of Australia, and VicHealth and the Cancer Council Victoria.
No potential conflicts of interest were reported.
Primary source: New England Journal of MedicineSource reference:Allen KJ, et al "Iron-overload-related disease in HFE hereditary hemochromatosis" N Engl J Med 2008; 358: 221-230. Additional source: New England Journal of MedicineSource reference: Bacon B, Britton R, "Clinical penetrance of hereditary hemochromatosis" N Engl J Med 2008; 358: 291-293.