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Research Priorities in Hereditary Hemochromatosis
- Gary M. Brittenham, MD;
- Adele L. Franks, MD; and
- Frederick R. Rickles, MD
- From Columbia University College of Physicians and Surgeons, New York, New York; and the Centers for Disease Control and Prevention, Atlanta, Georgia. Requests for Reprints: Gary M. Brittenham, MD, Department of Pediatrics, Columbia University College of Physicians and Surgeons, Harkness Pavilion Room HP 550, 630 West 168th Street, New York, NY 10032. Current Author Addresses: Dr. Brittenham: Department of Pediatrics, Columbia University College of Physicians and Surgeons, Harkness Pavilion Room HP 550, 630 West 168th Street, New York, NY 10032. Dr. Franks: Division of Nutrition and Physical Activity, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Mailstop K-24, 4770 Buford Highway, Atlanta, GA 30341. Dr. Rickles: Division of AIDS, STD, and TB Laboratory Research, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Atlanta, GA 30333. Note: This article is one of a series of articles comprising an Annals of Internal Medicine supplement entitled “Iron Overload, Public Health, and Genetics.” To view a complete list of the articles included in this supplement, please view its Table of Contents.
Abstract
The Working Group on Research Priorities used a formal nominal group technique to identify and prioritize the specific aims of applied research needed to provide the scientific basis for population screening for iron overload disorders.The most important applied research goal was characterization of the natural history of the relation between genotype and phenotype in hereditary hemochromatosis and other iron overload disorders. Three other important research objectives were development of an optimal approach to screening for iron overload; analyses of the cost-effectiveness of screening; and assessment of the ethical, legal, and social implications of screening. To achieve these specific aims, two research studies were recommended as being of the highest priority: a multicenter, cross-sectional, population-based study of the natural history of iron overload and a multicenter, case–control study of patients with disease manifestations potentially attributable to hereditary hemochromatosis in primary care and subspecialty clinics.
The Working Group on Research Priorities, a panel of clinicians, basic scientists, and experts in laboratory medicine and public health, was asked to 1) identify unanswered questions about population screening for hereditary hemochromatosis and other iron overload disorders and 2) recommend specific research studies with which to answer these questions. The Working Group used a formal nominal group technique, described in detail elsewhere [1, 2], to identify and prioritize the specific aims of applied research that would need to be met to provide a scientific basis for population screening.
The members of the Working Group generally agreed that hereditary hemochromatosis seemed to be an almost ideal candidate for population screening: It is an inherited disorder that has a high prevalence in the U.S. population; may have serious clinical manifestations leading to premature death; can be identified by safe and reliable screening and diagnostic tests; and, after early diagnosis, can be treated effectively and inexpensively to prevent later complications. In the past two decades, almost all of more than 20 intervention trials [3] have provided evidence of the benefits of screening for iron overload. Practice guidelines for the detection, diagnosis, and management of hereditary hemochromatosis have been published [4]. Genetic testing for the disorder has been made possible by the recent identification of a gene (HFE) that is mutated in most patients with hereditary hemochromatosis [5]. An animal model of hereditary hemochromatosis has been developed in genetically engineered mice that do not express HFE [6].
Despite these favorable factors, the Working Group identified the incomplete characterization of the natural history of hereditary hemochromatosis (that is, the spontaneous evolution of the clinical and laboratory manifestations of iron overload in persons with a defined genotype) as the central remaining problem in determining the value of population screening to the public health. In particular, uncertainty remains about the penetrance of the disease (that is, the proportion of persons with the hemochromatosis genotype who, without treatment, will develop illness as a result of iron overload). Overall, the Working Group agreed that the highest priority for future research on hereditary hemochromatosis should be given to better characterization of the natural history of the condition and to clarification of the relation between genotype (hereditary predisposition) and phenotypic expression (penetrance and severity) of the disease. In addition to noting the need for applied research, the Working Group recognized that we need to develop and evaluate both a national program of laboratory standardization and a broad-based educational program for health care providers, patients, their families, and the general public before we implement a practical program for screening the U.S. population for iron overload.
Aims of Applied Research in Hereditary Hemochromatosis
Characterization of the Relation between Genotype and Phenotype
The most important research aim identified by the Working Group was better characterization of the natural history of the relation between genotype and phenotypic expression in hereditary hemochromatosis and other iron overload disorders with respect to age, sex, ethnicity, and environmental factors. Despite the wealth of information about hereditary hemochromatosis that has already accumulated [3, 4], controlled, population-based studies of the evolution of clinical and laboratory manifestations of iron overload disorders in persons of defined genotype are still considered necessary to provide a scientific basis for the formulation of optimal screening strategies. The available population-based studies of screening for hereditary hemochromatosis all have methodologic limitations that might bias their results toward an overestimation of disease expression [3], and none has included a control group to allow comparison of the frequency of nonspecific symptoms or signs (this is necessary to determine the proportion of these symptoms and signs that may not be due to hereditary hemochromatosis). Studies of families of probands with hereditary hemochromatosis suggest that about 68% of female and 93% of male homozygotes for the HFE mutation meet current clinical diagnostic criteria for the disease [7], but family studies of persons with disease may overestimate disease expression among those with a genetic predisposition. Informed decisions about screening and therapy to prevent the complications of iron overload require accurate information not only about the prevalence and severity of disease manifestations among persons with the hereditary hemochromatosis genotype but also about the relation between iron overload and biochemical measures of iron status (such as transferrin saturation, unsaturated iron-binding capacity, serum ferritin level, and hepatic iron concentration) and the relation of these measures to the development and reversibility of organ damage. More data are needed about the effects on the expression of hereditary hemochromatosis of such factors as age; sex; ethnicity; and environmental factors, including diet, use of nutritional supplements, use of medications, use of alcohol, and viral hepatitis.
Identification of a candidate gene (HFE) for hereditary hemochromatosis [5] and development of a DNA-based test for this gene were major advances that now can be used in population-based studies to clarify patterns of clinical expression. It is likely that additional genes for hereditary hemochromatosis will be identified in the future and that different hereditary forms of iron overload are present in different populations. For example, a form of genetically linked primary iron overload that is distinct from hereditary hemochromatosis may be present in persons of African descent [8].
Determination of the Optimal Approach to Screening for Iron Overload
The second major research aim identified by the Working Group was to devise an optimal method for screening for hereditary hemochromatosis and other forms of iron overload. Studies should determine the best screening tests and evaluate algorithms for their application. These algorithms could include both phenotypic testing (done by using measures of iron status) and genotypic (DNA-based) testing, alone or in combination; should specify the age range in which the algorithms should be applied; and should include criteria for the identification of affected persons that would provide a suitable balance between adequate rates of detection and acceptable rates of false-positive results. Along with the development of screening algorithms, improvements in laboratory methods (with standardization and quality control for both phenotypic and genotypic tests) were recognized as necessary for the effective implementation of early detection and treatment programs.
Analysis of the Cost-Effectiveness of Screening for Iron Overload
The third major applied research aim was to conduct a formal analysis of the cost-effectiveness of screening for iron overload. Although numerous studies of cost-effectiveness have been done [3], the cost-effectiveness of screening algorithms could be assessed more realistically if we had a better understanding of the natural history of iron overload disorders (for example, the factors affecting disease expression and the length of time before irreversible organ damage develops). More data are needed before we can decide on the best use of phenotypic and genotypic testing, determine the optimal age for screening, and compare the sensitivities and specificities of various screening procedures. In this analysis, the cost-effectiveness of population screening would be compared with that of screening only affected persons who present for medical attention with signs and symptoms compatible with iron overload or only relatives of persons clinically affected by hereditary hemochromatosis. After the development of a model for population screening, sensitivity analyses could be done to assess the effects of varying levels of prevalence of hereditary hemochromatosis, the performance characteristics of screening and diagnostic tests, the probability of clinical manifestations in affected persons, and the costs of testing and treatment. Results of cost-effectiveness analyses will help clarify the economic implications of a variety of screening strategies.
Assessment of the Ethical, Legal, and Social Implications of Screening for Hereditary Hemochromatosis
The fourth and final identified research aim was to assess the ethical, legal, and social implications of screening for hereditary hemochromatosis. One of the anticipated impediments to implementation of a screening program was the risk that the genetic information resulting from screening might be used by insurers, employers, or others to deny health care coverage or services to persons identified as being at risk for iron overload. Concern was also raised that a diagnosis of hereditary hemochromatosis could lead to changes in self perception, family interactions, and risk-taking behaviors. Research deemed necessary included studies of 1) ways to ensure privacy and fairness in the use and interpretation of genetic information derived from hereditary hemochromatosis screening, 2) provision and evaluation of counseling for affected persons and their families, 3) methods for obtaining informed consent for screening, and 4) development of programs for effective public and professional education on issues in screening.
Studies To Achieve Research Aims
The Working Group judged that the four major aims of applied research discussed above could be met with two types of carefully designed studies.
Multicenter, Cross-Sectional, Population-Based Study of the Natural History of Hereditary Hemochromatosis
The first priority for applied research was the characterization of the natural history of the relation between genotype and phenotype in hereditary hemochromatosis and other iron overload disorders with respect to age, sex, ethnicity, and environmental factors. The Working Group thought that this aim could best be met through a multicenter, cross-sectional, population-based study that includes comparison (“control”) populations in which the diagnosis of hemochromatosis is excluded by genetic or phenotypic methods (or both). This study was therefore given the highest priority by the Working Group. The primary goal of this study would be to provide age- and sex-specific data on the attributable risks for illness and death in persons who have iron overload identified by genotypic testing, candidate phenotypic screening tests (such as tests for transferrin saturation, unsaturated iron-binding capacity, and serum ferritin level), and diagnostic procedures (such as quantitative phlebotomy and liver biopsy with measurement of hepatic iron concentration). The combination of genotypic and phenotypic assessment was considered necessary because recent studies have found that some patients who are homozygous for the HFE mutation have not developed iron overload and that some patients with iron overload are not homozygous for the HFE mutation [7, 9]. Therapeutic phlebotomy would be provided for persons with iron overload; this would permit prospective assessment of prevention strategies in those with preclinical disease and of intervention strategies in those in whom organ damage has already developed.
The requisite study would be population-based and would include enough patients to yield reliable estimates of the prevalence of hereditary hemochromatosis, the sensitivity and specificity of the candidate phenotypic and genotypic screening tests, and the proportion of affected persons who develop preventable complications of iron overload. Vital data would be provided about the effects on the development of iron overload of age; sex; and environmental factors, such as diet, use of nutritional supplements, use of alcohol, and viral hepatitis. Comparison of identified case-patients and controls would yield essential information on the relevance of nonspecific symptoms as well as the prevalence of iron overload. Overall, these studies should provide a comprehensive view of the natural history of the relation between genotype and phenotype with respect to demographic and environmental factors. Study designs could incorporate comparisons of alternative strategies for hereditary hemochromatosis screening (including their cost-effectiveness) and could provide data that would be useful in evaluating the potential ethical, legal, and social implications of screening.
Multicenter, Case-Control, Population-Based Studies of Disease Manifestations and Their Relation to Iron Accumulation
The Working Group gave second priority to a multicenter, case–control study of screening for abnormal iron accumulation in patients in primary care and subspecialty clinics to evaluate the proportion of treated illnesses that may be due to hereditary hemochromatosis. Because iron overload can produce cardiac, hepatic, endocrine, and rheumatologic manifestations, an increased prevalence of hemochromatosis would be expected in both primary care settings and subspecialty clinics that treat patients for these clinical problems. If this prevalence were compared with the prevalence of hemochromatosis among patients free of these clinical problems, a relative risk for specific disease manifestations could be calculated. The relative risk estimates could be used to determine the proportion of the burden of chronic diseases (such as diabetes, arthritis, cardiomyopathy, or cirrhosis) that may be attributable to hereditary hemochromatosis. The major advantage of this approach over the cross-sectional method is its lower cost, and its major disadvantage is its inability to yield information on the penetrance of hereditary hemochromatosis. Nonetheless, the case–control study could address screening test performance in primary care and subspecialty clinics and could examine some of the ethical, legal, and social implications of screening and ongoing treatment. In addition, controlled intervention studies could be done in patients who are identified as iron overloaded, thereby providing new data about the extent to which iron removal can arrest or reverse organ damage in patients with hemochromatosis.
Summary
The Working Group on Research Priorities used a formal nominal group technique to 1) identify unanswered questions about population screening for hereditary hemochromatosis and other iron overload disorders and 2) recommend specific research studies with which to answer these questions. The most important aim of applied research identified by the Working Group was the characterization of the natural history of the relation between genotype and phenotype in hereditary hemochromatosis and other iron overload disorders with respect to demographic and environmental factors. Three other important objectives were also recognized: development of an optimal approach to screening for iron overload; analysis of the cost-effectiveness of screening; and assessment of the ethical, legal, and social implications of screening. To achieve these aims, two research studies were given the highest priority: a multicenter, cross-sectional, population-based study of the natural history of iron overload and a multicenter, case–control study of patients with disease manifestations potentially attributable to hereditary hemochromatosis in primary care and subspecialty clinics.
- Copyright ©2004 by the American College of Physicians
