April 10, 2002 Access past issues

Reviewed by: Katheryn Thomas Rollins School of Public Health Emory University

The Health Outcome

Hereditary hemochromatosis is an iron-storage disease that displays autosomal recessive inheritance.  In the severe form of the disease, called “bronze diabetes,” the clinical features include hepatic cirrhosis, pancreatic insufficiency, darkening of the skin, and heart failure. Most people develop their first symptoms in their fifth to seventh decades, but people with severe cases may experience symptoms at a younger age.(1)

Incidence of hemochromatosis is greatest in northern European, especially Celtic, populations, where approximately 1 in 10 people are heterozygous carriers. The clinical presentation of the disease is modified by factors such as dietary iron intake and blood loss associated with menstruation or blood donation. Because of these modifying factors, clinical expression of the disease is greater than five times more common in men than in women.(1)

The HFE gene has been associated with hemochromatosis. The HFE protein is an HLA-like protein that is expressed on the surface of duodenal crypt enterocytes and participates in an unknown way in iron uptake and transport. Mutations in this gene appear to cause a loss of ability of these cells to sense the level of body iron stores. There are multiple known mutations of this gene that can lead to hemochromatosis, but the C282Y mutation is found in 85% of the patients with hemochromatosis (4). An important unresolved issue is the penetrance or lifetime risk of clinical disease among people with C282Y and other HFE mutations.

The Finding

In a population-based screening study of 41,038 Americans (2), members of the Kaiser-Permanente medical care program who attended the Health Appraisal Clinic in San Diego , California , were genotyped for the HFE gene. Questionnaire data collected from these individuals were analyzed to determine if an association existed between genotype and reported symptoms of hemochromatosis.

Of the genotyped sample, 152 homozygotes for the C282Y mutation, 1690 C282Y/wildtype heterozygotes, and 616 compound heterozygotes for the C282Y and H63D mutations were identified. The C282Y homozygotes and compound heterozygotes were predominantly white or Hispanic, with a mean age of 57.0 years. Similar participants with the wildtype genotype were used as the comparison group.

Standard binomial tests were performed to compare symptoms and laboratory findings in cases and controls. Mann-Whitney U statistics were calculated to evaluate quantitative data. None of the symptoms assessed were significantly more common in hemochromatosis genotypes than in wildtype genotypes. The number of symptoms reported by C282Y individuals and wildtypes did not differ significantly. After controlling for age and sex, C282Y homozygotes were 2.1 times (95% Confidence Interval: 1.1-4.0) more likely to report liver problems than were wildtypes and 2.1 times (95% C.I.: 0.9-5.1) more likely to have increased aspartate aminotransferase concentrations than were wildtypes.

It was determined that there was no significant aggregation of symptoms associated with hereditary hemochromatosis in C282Y homozygotes. Only a history of hepatitis or other liver disorders was significantly more frequent in homozygotes than in wildtypes. This indicates that penetrance of the C282Y mutation in the HFE gene was not as high as was expected from previous research. Thus, genotyping for C282Y mutation as a method of screening for hemochromatosis was not determined to be cost-effective.

Public Health Implications

Several factors must be taken into account to assess appropriateness of population screening for hemochromatosis, including prevalence, effectiveness of intervention, and penetrance of the gene being examined. Prevalence of the C282Y allele in the northern European population has been established to be high.(1) Phlebotomy is a simple and effective intervention for hemochromatosis. However, data from this study suggest that there is no strong relationship between genotypes and biochemical markers of iron overload and liver damage.(2)  In spite of the possible limitations of this study, including the population screened, the cross sectional sample, and the relatively small sample size, further research is needed to establish the clinical penetrance of HFE mutations.

References

1. Fauci AS, et al. Harrison 's Principles of Internal Medicine. 15th edition, New York : McGraw-Hill Professional, February 2001; 2149-2152
2. Beutler E, et al. Penetrance of 845G-->A (C282Y) HFE hereditary haemochromatosis mutation in the USA . Lancet 2002 January; 359:211-18
3. Beutler E et al. e-Journal abstraction template
4. OMIM entry #235200- HEMOCHROMATOSIS; HFE
5. Public Health Perspective on Hereditary Hemochromatosis
6. E-journal club abstraction template