Hemochromatosis and Iron Overload Screening Study (HEIRS)

BACKGROUND:

Hereditary iron overload, or hemochromatosis, is a common inherited disorder among Caucasians, with an estimated prevalence of 0.25-0.50 percent, though it is mistakenly believed by many to be quite rare. The disease is insidious in onset, and many or even most individuals diagnosed with this disorder are not identified until advanced organ damage is present. However, in the absence of anemia, which can be caused by tissue damage from iron in late stages of the disease, it is relatively easy to treat the disorder by removing the excess iron through repeated phlebotomy. Evidence suggests that early diagnosis and treatment can prevent disease manifestations and enable normal life expectancy The discovery of the HFE C282Y and H63D variants in the HLA gene region on chromosome 6 provides an opportunity for early and rapid genetic identification of individuals at risk for development of hereditary hemochromatosis. Much remains to be learned about the penetrance and expression of these alleles, including their relevance to the full spectrum of clinical disease. To date, the HFE alleles appear predominantly associated with disease mainly in populations of Caucasian descent. While 80-90 percent of Caucasian hemochromatosis patients have HFE abnormalities, there are hetero- and homozygotes that do not manifest any evidence of disease, or manifest disease at different ages and with different outcomes, implying the existence of other genetic or environmental factors. Similarly, not all hemochromatosis patients have HFE abnormalities. Other genes yet to be discovered are also likely to be involved in pathogenesis of iron overload and familial hemochromatosis in non-Caucasian populations as well. This project is intended to examine the genetic and environmental determinants and correlates of iron overload and hereditary hemochromatosis in diverse populations.

Increases in body iron may be due to increased absorption (hemochromatosis), increased oral intake of non-therapeutic iron, unneeded iron therapy, or multiple blood transfusions in the absence of bleeding. The excess iron is deposited in body tissues, and can reach toxic levels leading to organ damage. The toxicity can affect most tissues and organs, but particularly the liver, causing cirrhosis; the endocrine system, causing diabetes, hypogonadism, and sometimes hypoparathyroidism; and the heart, causing arrhythmias and cardiomyopathy.

Iron overload and hereditary hemochromatosis have not been as extensively studied in non-Caucasian racial/ethnic groups as they have in Caucasians. The toxicity of excess iron in non-Caucasians appears to be similar to that in Caucasians, but the prevalence of iron overload is unknown and while a genetic contribution to that overload is suspected it has not been proven in all groups. It has long been assumed that iron storage disease in populations of sub-Saharan Africa is due to increased iron absorption from beer brewed in iron pots, but more recent information suggests there is also a hereditary component to that accumulation of iron. However, iron overload among Africans does not appear to be due to HFE abnormalities, nor to other genes in the HLA region at all. Primary iron overload has been reported in African Americans but it remains to be determined whether or not this is linked to HFE or other genetic factors. Iron overload has been reported in Asian populations, but the frequency and genetic contributions (if any) are not known. In some studies where HFE variants have been found in non-Caucasians, additional genetic testing has suggested that Caucasian admixture may have been involved. Hispanic-Americans appear to have a frequency of iron overload similar to non-Hispanic Caucasians, although further study of the genetic and environmental correlates is warranted. There has been almost no study of iron overload and hereditary hemochromatosis in Native American populations.

Hemochromatosis may be suitable for detection and intervention through primary care or population-based screening strategies because: 1) it is relatively common; 2) it is asymptomatic in its early stages; 3) screening methods are reliable; 4) standard diagnostic methods are widely available in developed countries and relatively inexpensive; 5) it is easily treatable; and 6) if untreated, the subsequent burden of morbidity and mortality is substantial. The feasibility and benefits of such programs remain to be assessed, however, since the prevalence of the disorder and the factors related to its phenotypic expression (such as the optimal age for reliable detection and effective intervention) are unknown. Other questions needing to be addressed include public acceptability of screening and testing; sensitivity and specificity of the screening methods, particularly in non-Caucasians; optimal timing and setting of screening and testing; as well as the benefits and costs and/or other burdens associated with screening and testing.