The Health Outcome

Hereditary hemochromatosis (HHC) (also called classic or Type 1 hemochromatosis) is an autosomal recessive disease that results from significant iron overload. If left untreated, iron accumulates in tissues and can cause serious and sometimes fatal health problems. Early detection of iron overload and HHC treatment can delay or prevent irreversible complications and prolong life.

HFEC282Y and H63D mutations account for the majority of classic hereditary hemochromatosis cases (2,3). Approximately 0.5% of white persons of northern European descent are C282Y homozygotes (4). Iron overload can occur in nonwhites and may be related to undiscovered genetic mutations and/or environmental factors (5).

Because symptoms used to define hereditary hemochromatosis differ among studies, penetrance estimates vary, ranging from <1 to 50% (6-9). Some experts advocate population screening for HFE mutations; however, low penetrance would make screening inefficient.

The Finding

The Hemochromatosis and Iron Overload Screening (HEIRS) study (1) was designed to evaluate genetic and environmental determinants of iron overload and HHC in a multicenter, multiethnic sample of primary care adults >25 years of age. The 5-year study began in 2001 and identified adults through primary care clinics and blood-drawing laboratories. HFE alleles were determined from whole blood spots. In all, 99,711 participants were available for gene analysis and 98,529 for iron analysis.

Of the 99,711 participants, 299 were C282Y homozygotes. The estimated prevalence of C282Y homozygotes was highest in whites (0.44%), followed by Hispanics (0.027%) and lower in Asians (0.000039%), Pacific Islanders (0.012%) and blacks (0.014%). Of the 98,259 with results of iron analysis, 1.68% of whites had elevated iron levels, as defined as both an elevated transferrin saturation percentage (TS) (>50% for men, >45% for women) and elevated serum ferritin (SF) (>300 ug/L for men, >200 ug/L women). Elevated iron levels (both TS and SF) were found among 1.44% of blacks, 1.34% of Hispanics, 3.05% among Pacific Islanders, 4.84% among Asians, and 1.24% among Native Americans.

SF and TS were both significantly higher in C282Y homozygotes than in other genotypes. Among C282Y homozygotes, an elevated TS was found in 84% of men and 73% of women and an elevated SF in 88% of men and 57% of women. Elevated SF was common in all other genotypes. Pacific Islanders and Asians had the highest geometric mean levels of SF and TS despite the lowest prevalence of C282Y homozygotes.

Among self-reported conditions, only the prevalence of liver disease was significantly greater in male C282Y homozygotes than in participants without either HFE mutation. Among participants with other variants, there was an increase in arthritis in male H63D homozygotes, heart disease in female H63D homozygotes, and a decrease in diabetes among males with the C282Y/+ genotype (compared to participants without C282Y or H63D mutations). These findings were not explained by iron overload.

Overall, this screening study found that the C282Y mutation was most common in whites and that 9 of 10 men and 6 of 10 women who are homozygous for the C282Y mutation may have iron overload. The C282Y mutation does not account for high iron measures in nonwhites.

Public Health Implications

Screening patients to detect and treat chronic diseases early, before serious health consequences occur, has become a vital part of medicine and public health (10). For a population-based screening program to be effective, it must identify people who are at risk of developing the disease. For the program to be cost-effective as well, it should identify only those people who are very likely to develop the disease and thus most likely to benefit from intervention (11).

After the discovery of the HFE mutations, HHC quickly moved into the public health spotlight as experts and support groups called for population screening. However, when policymakers evaluated this issue in the late 1990s, important knowledge gaps were identified (12-14). For example, little was known about the clinical course of HHC or the prevalence of asymptomatic iron overload. In addition, reliable information about the prevalence and penetrance of the HFE variants was not available.

Genetic testing for HFE variants also raises issues related to ethical, legal, and social concerns. Even when these issues are addressed, decisions to institute population screening must also be supported with scientific evidence of public health effectiveness and enough available resources to treat those identified patients. To help fill in the knowledge gaps, the National Heart Lung and Blood Institute launched the HEIRS study of 100,000 racially diverse adults in primary care settings (15). The results of this study provide valuable data to re-examine the benefits and risks of using primary care-based screening for iron overload and hemochromatosis.

The prevalence of C282Y homozygosity among non-Hispanic whites was similar to that found in other studies, about 1 in 200. Although the majority of C282Y homozygotes in whom iron overload had not previously been diagnosed had elevated SF, 12% of men and 43% of women did not. Some of these individuals may have iron accumulation over time, but a progressive rise in iron stores is not to be expected for all (9, 16-18).

The HEIRS study elevated iron level results should not be considered indicative of the prevalence of true iron overload in the general population or this primary care population. Ferritin is an acute phase reactant protein and therefore can be elevated without the presence of iron overload. SF results presented in the study were from all participants. Analyses excluding individuals with inflammatory or infectious conditions could help estimate the true prevalence of iron overload in the primary care setting.

Verification of self-reported conditions using medical records would be helpful in interpreting the lack of findings associating C282Y homozygosity with medical conditions associated with HHC. Al though the association with diabetes in C282Y/wildtype males could be due to chance, further studies should be designed to investigate other genetic factors.

At this time, additional information is needed before population-based screening for hereditary hemochromatosis can be recommended as a prevention strategy. Currently, enhanced case detection among individuals with hemochromatosis symptoms and family-based detection are practical strategies for early diagnosis and treatment of hemochromatosis (http://www.cdc.gov/hemochromatosis).

References

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