UCI's Hemochromatosis and Iron Overload Screening (HEIRS) Study Link

We have been chosen to serve as one of five Field Centers in the U.S. and Canada to screen 20,000 primary-care patients for iron overload and hereditary hemochromatosis. Screening will be conducted at the ambulatory care clinics of the University of California, Irvine (UCI) and the University of California, Los Angeles (UCLA). Christine E. McLaren, Ph.D., Professor in the Epidemiology Division, is Principal Investigator of the study funded by the Heart Lung and Blood Institute and the National Human Research Genome Institute of the National Institutes of Health. The primary goal of our Field Center is to contribute to the epidemiologic study of iron overload and hereditary hemochromatosis, in a multi-center, multiethnic, primary care-based sample of 100,000 adults.

Approximately 1 million people in the United States are affected by iron overload, primarily attributable to the genetic disorder known as hereditary hemochromatosis. Once considered a rare disease, hemochromatosis is now recognized as one of the most common autosomal recessive disorders. This condition is characterized by increased intestinal iron absorption, leading to life-long accumulation of excessive amounts of iron in the body and damage to multiple organs. The serious and debilitating health effects that ensue include arthritis, cirrhosis of the liver, diabetes, impotence and cardiomyopathy. If untreated, the disease can eventually be fatal as a result of congestive heart failure, end-stage liver disease or hepatocellular carcinoma. However, this substantial morbidity and mortality from untreated hemochromatosis can be prevented completely by iron-removal therapy; thus, early detection is essential.

Serum transferrin saturation is regarded as a sensitive and specific screening test for hemochromatosis, although no consensus has been reached as to the most appropriate transferrin saturation level for the detection of individuals at risk for the disorder. A strong candidate gene has been identified near the region of the major histocompatibility complex on chromosome 6. This discovery may facilitate diagnosis of individuals identified as being at risk for the development of iron overload on the basis of elevated transferrin saturation. Studies suggest that systematic screening for iron overload can reduce health care costs and improve quality of life for persons who would otherwise suffer adverse effects.

At UCI, we have demonstrated success in meeting study recruitment goals for large-scale, multi-center, clinical research and observational studies. For this project, we will screen from four racial/ethnic subgroups enrolling approximately 30% Hispanic, 30% Asian, 5% African-American, and 35% White. A specific contribution of our Field Center will be to screen Asians, a population in which the frequency and genetic contributions to iron overload and hemochromatosis have not been systematically studied. We have previously made fundamental methodologic contributions to the analysis of screening with transferrin saturation (1-7). Our Field Center will now conduct a study designed to provide a statistical foundation for the analysis of the distribution of transferrin saturation in the population and thereby to assist in development of optimal screening regimens for hemochromatosis.

The specific aims of the UCI Field Center Project are to:

1. participate in protocol development, training, pilot testing, and protocol modification;
2. conduct phenotypic and genotypic screening for iron overload and hemochromatosis in primary care-based settings and assess quantitative and qualitatitive ethical, legal, and social implications (ELSI) related to implementation of primary care-based screening for iron overload and hemochromatosis;
3. perform comprehensive clinical examinations of phenotype and/or genotype-positive individuals and a random sample of control subjects;
4. conduct family studies of genotype-positive participants and/or participants with hemochromatosis including a morbidity and mortality follow-up in all main or family study participants;
5. determine optimal screening thresholds of transferrin saturation detection of iron overload and hemochromatosis.

The experiences provided by this national screening study will ultimately decide the place of hemochromatosis screening in health care policy. The type of information that will be collected is crucial to allow health practitioners and public health officials to formulate patient and population recommendations for iron overload disorders.

1. McLaren CE, Gordeuk VR, Looker AC, Hasselblad V, Edwards CQ, Griffen LM, Kushner JP, Brittenham, GM. Prevalence of heterozygotes for hemochromatosis in the white population of the United States. Blood, 86: 2021-2027, 1995.
2. McLaren CE Mixture models in hematology. Statistical Methods in Medical Research, 5(2), 129-153, 1996.
3. McLaren CE, McLachlan G.J., Halliday, J.W., Webb, S.I., Leggett, B.A., Jazwinska, E.C., Crawford, D.H.G., Gordeuk, V.R., McLaren, G.D., and Powell, L.W. The distribution of transferrin saturation in an Australian population: relevance to the early diagnosis of haemochromatosis. Gastroenterology, 114:543-549, 1998.
4. Gordeuk VR, McLaren CE, Looker A, Hasselblad V, Brittenham GM. Distribution of transferrin saturations in the African-American population. BLOOD, 91:2175-2179, 1998.
5. Adams PC, Kertesz AE, McLaren CE, Barr R, Bamford A, Chakrabarti S. Population screening for hemochromatosis: a comparison of unbound iron binding capacity, transferrin saturation and C282Y Genotyping in 5,211 voluntary blood donors, Hepatology 31:1160-1164, 2000.
6. McLaren CE. Ascertainment of Hemochromatosis Heterozygosity. In Hemochromatosis: Genetics, Pathophysiology, Diagnosis, and Treatmentt. Eds, Barton, J.C. & Edwards, C.Q. Cambridge University Press, Cambridge, pps. 419-426, 2000.
7. McLaren CE, Li K-T, Gordeuk VR, Hasselblad V, McLaren,GD, Looker AC. Relationship between transferrin saturation and iron stores. Blood 96:226a, 2000.