Prepared by the National Office of Public Health Genomics, Paula Yoon, ScD, MPH
Efforts to Advance the Appropriate Use of
DNA-based Testing for Hemochromatosis
Presented to the Secretary's Advisory Committee on Genetic Testing, May 7, 2002
The purpose of this case study was to describe the steps involved in the development and clinical introduction of a genetic test for hemochromatosis and the roles played by government and private sector entities in order to identify any additional steps that could be taken by Federal agencies to facilitate the translation of gene discoveries into safe and effective genetic tests.
Hereditary hemochromatosis (HHC) is an autosomal recessive disorder of iron metabolism characterized by increased iron absorption and deposition in the liver, pancreas, heart, joints, and pituitary gland. Without treatment, death may occur from cirrhosis, primary liver cancer, diabetes, or cardiomyopathy. In 1996, HFE, the gene for HHC, was mapped on the short arm of chromosome 6 (6p21.3). Two of the 37 allelic variants of the HFE gene described to date ( C283Y and H63D ) are significantly correlated with HHC. Homozygosity for the C283Y mutation is present in 52-100% of clinically diagnosed probands. Five percent of HHC probands are compound heterozygotes ( C283Y/H63D ), and 1.5% are homozygous for the H63D mutation; 3.6% are C283Y heterozygotes, and 5.2% are H63D heterozygotes. In 7% of cases, C283Y and H63D mutations are not present. In the general population, the frequency of the C283Y/C283Y genotype is 0.4%. C283Y heterozygosity ranges from 9.2% in Europeans to nil in the Asian, Indian subcontinent, African/Middle Eastern, and Australasian populations. The H63D carrier frequency is 22% in European populations. Accurate data on the penetrance of the different HFE genotypes are not available. Extrapolating from limited clinical observations in screening studies, an estimated 40-70% of persons with the C283Y homozygous genotype will develop biochemical evidence of iron overload. A smaller proportion will die from complications of iron overload. To date, population screening for HHC is not recommended because of uncertainties about optimal screening strategies, optimal care for susceptible individuals, laboratory standardization and the potential for possible stigmatization or discrimination.
The following paragraph comes from: Kowdley KV, Tait JF, Bennett RL, Motulsky AG, Hereditary hemochromatosis. GeneReviews 2000. Available at http://www.genetests.org
The diagnosis of HHC in individuals with clinical symptoms consistent with HHC and/or biochemical evidence of iron overload is typically based on screening serum transferrin-iron saturation and serum ferritin concentration and on confirmatory tests such as histologic assessment of hepatic iron stores on liver biopsy and/or molecular genetic testing for the C283Y and H63D mutations in the HFE gene. The usual therapy is removal of excess iron by routine phlebotomy (i.e., removal of blood) to maintain serum ferritin concentration at 10-20 ng/mL. If patients are identified before hepatic cirrhosis develops and if total body iron depletion is successfully accomplished by therapeutic phlebotomy, life expectancy approaches normal.
Population screening for HHC is being considered because of the high prevalence, lack of clinical findings early in the course of the disease, the lack of specificity of clinical findings once they appear, the low cost of diagnosis and treatment, the efficacy of early treatment, and the high cost and low success rate of late diagnosis and treatment. However, because controversies exist regarding the penetrance of the disease and natural history of untreated patients, no uniform recommendations for population-based screening have been adopted. Furthermore, the social implications (e.g., possible loss of health or life insurance) of identifying individuals with early disease or predisposition to disease need to be considered.
II. Timeline of milestones in test development
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1889 |
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HHC was first described as a triad of symptoms (diabetes, bronzing, and cirrhotic liver). |
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1935 |
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Hereditary nature of the disease was described. |
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1975 |
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Disease was linked to specific HLA genotype on chromosome 6. |
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1996 |
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Feder et al. of Mercator Genetics identified HFE gene and described two missense mutations of this gene: C283Y and H63D ("A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis." Nat Genet 1996;13:399-408). To date 37 allelic variants of the HFE gene have been reported (Pointon JJ et al. Uncommon mutations and polymorphisms in the hemochromatosis gene. Genetic Testing 2000;4:151-61).
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Witte DL et al. published "Practice guideline development task force of the College of American Pathologists. Hereditary hemochromatosis." ( Clin Chim Acta . 1996;245:139-200). "In view of the high prevalence in the American population (prevalence varies with ethnic background), the low cost of diagnosis and treatment, the efficacy of treatment if begun early, and, on the other hand, high costs and low success rate of late diagnosis and treatment, systematic screening for hemochromatosis is warranted for all persons over the age of 20 years. The initial screening should be by measurement of serum iron concentration and transferrin saturation. The practice guideline provides a diagnostic algorithm for cases in which the serum transferrin saturation is 60% or greater. It also provides guidelines for clinical management." |
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1996-2000 |
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Mercator Genetics folded and the HFE gene test passed through several biotech and pharmaceutical companies with some confusion over patent enforcement for clinical labs conducting gene tests.
Patient-based studies showed that the percentage of patients with C283Y and/or H63D varies greatly. |
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March 1997 |
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CDC/NHGRI conference, Iron Overload, Public Health, and Genetics, was held. Panel was convened with expertise in epidemiology; genetics; hepatology; iron overload disorders; molecular biology; public health; and the ethical, legal, and social implications addressed (1) whether screening for HHC was warranted and (2) the relative merits of biochemical laboratory tests of iron status that might be useful for screening. The conference attendees favored movement toward routine screening for all adults (HHC meets many of the U.S. Preventive Task Force criteria for candidacy for population screening) but realized that there is much that still needs to be learned about penetrance and expressivity of HHC and about patient age and disease stage at which detection is most beneficial. |
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June 1997 |
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American Medical Association (AMA) directive on hereditary hemochromatosis, "Routine Screening for Iron Overload/Hemochromatosis," stated that the AMA encourages the development of guidelines for screening patients for iron overload and hemochromatosis in association with the appropriate medical specialty societies, and that the AMA will work with the appropriate specialty societies and voluntary health agencies to disseminate information about iron overload and hemochromatosis. |
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July 1998 |
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Publication by Burke et al. in JAMA (1998;280(2):172-8) summarized findings from the CDC/NHGRI March 1997 conference: genetic testing is not recommended at this time in population-based screening, due to uncertainties about prevalence and penetrance of HFE mutations. Use of a genetic screening test raises concerns regarding possible stigmatization and discrimination. The expert group accorded high priority to population-based research to define the prevalence of HFE mutations, age- and sex-related penetrance of different HFE genotypes, interactions between HFE genotypes and environmental modifiers, and psychosocial outcomes of genetic screening for hemochromatosis. |
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December 1998 |
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Publication of papers in the Annals of Internal Medicine(1998;129(11):921-996) described the highlights of the CDC/NHGRI March 1997 conference and provided in-depth analysis of key issues related to hemochromatosis testing. |
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December 1998 |
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Two papers from a study supported by the Agency for Health Care Policy and Research (HS07616) examined the prevalence of hereditary hemochromatosis among primary care patients and the practical issues involved when iron status screening for hemochromatosis is implemented (Phatak PD et al. Prevalence of hereditary hemochromatosis in 16,031 primary care patients. Annals of Internal Medicine 129(11): 954-961, and McDonnell SM et al. Screening for hemochromatosis in primary care settings. Annals of Internal Medicine 129(11): 962-970). |
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December 1998 |
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The National Heart, Lung, and Blood Institute (NHLBI) solicited proposals to initiate an epidemiological study of the prevalence; genetic and environmental determinants; and potential clinical, personal, and societal impact of iron overload and hereditary hemochromatosis in a multi-center, multiethnic, primary-care-based sample of 100,000 adults. |
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December 1998 - February 2000 |
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The EASL International Consensus Conference on Haemochromatosis ( J of Hepatol 2000;33:485-504) - meeting at the World Iron Conference BioIron '99 in May 1999, drafted a document and released the final statement in February 2000. The objectives of the conference were to (1) define content for educational materials for health professionals and the public and (2) propose recommendations concerning early detection of HHC by evaluating the costs and benefits of different strategies. The attendees concluded that insufficient evidence exists today to recommend universal, population-based screening for HHC.
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In response to recommendations of the Advisory Committee on Blood Safety and Availability, in August 1999 FDA announced that blood from therapeutic phlebotomies for persons with hemochromatosis could be used for transfusion if certain criteria were met: (1) The blood collection center may not charge for hemochromatosis therapeutic phlebotomy and (2) the blood center must apply to the FDA for exemption from existing regulations. As part of that exemption, the blood center must collect and submit specified data to the FDA. The FDA will consider exemption applications on a case-by-case basis. |
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April 2000 |
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Kowdley et al. published GeneReview on hereditary hemochromatosis on GeneTests website
(http://www.genetests.org). |
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May 2000 |
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CDC hosted a meeting of experts to develop educational materials to increase health care provider awareness of hemochromatosis. The resulting educational materials are available at CDC's hemochromatosis/iron overload website (http://www.cdc.gov/hemochromatosis/) |
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September 2000 |
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CDC awarded a cooperative agreement to the Foundation for Blood Research (FBR) to develop a model system for assembling, analyzing, disseminating and updating existing data on the safety and effectiveness of DNA-based genetic tests and testing algorithms. Testing for hemochromatosis will be evaluated from the standpoint of analytical validity, clinical utility, and related ethical/legal/social issues. The goal of this effort is to facilitate the appropriate transition of genetic tests from investigational settings to use in clinical and public health practice. |
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May 2001 |
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Steinberg et al. used NHANES data to estimate the prevalence of HFE mutations C283Y and H63D in the US population (Prevalence of C283Y and H63D mutations in the hemochromatosis ( HFE ) gene in the United States. JAMA 2001 May 2;285(17):2216-22). |
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August 2001 |
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HuGE review published on HFE Gene and Hereditary
Hemochromatosis ( Am J Epidemiol 2002;154(3):193-206). The paper summarized what is known about the prevalence of HFE in different populations and evidence for the gene-disease association.
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BioIron 2001 World Congress on Iron Metabolism recognized DMT1 (or nramp2) as the major mucosal iron transporter and ferroportin 1 (IREG!) as the basolateral iron transporter. Greater need was cited for more accurate methods for noninvasive estimation and measurement of iron content in parencymal tissues, as with magnetic resonance imaging technology. The issue of widespread population screening for hemochromatosis was revisited because of the recognition that many patients with the hemochromatosis genotype may not express the phenotype, resulting in ongoing active debate. Great interest was expressed in the possible ethical, legal and social impact of screening, including possible ramifications with regard to genetic discrimination in insurability and use. Also discussed was the need to develop novel, safe, and convenient chelation therapies for treatment of iron overload associated with blood transfusions and hyperabsorption of iron caused by red cell disorders. |
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2001 - Ongoing |
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Guide to Hemochromatosis was published by Iron Disorders Institute. (http://www.irondisorders.org/Publications/)
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US Surgeon General, David Satcher, MD, stated, "Early detection of iron overload disease (such as hemochromatosis) represents a major chronic disease prevention opportunity. Detection and treatment (phlebotomy) for iron overload early in the course of the illness can substantially reduce the severity of the symptoms, organ damage, and death from associated chronic diseases."
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The NIH Hemochromatosis and Iron Overload Screening Study, of 100,000 subjects from varying ethnic groups was begun. The study will identify factors that affect the genotype-phenotype association. The goal is to develop public health guidelines for detecting and treating HHC. |
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January 2002 |
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CDC is conducting a laboratory round robin in 23 laboratories to compare analytic methods for measuring iron overload among national and international laboratories. These results will be crucial for refining, standardizing, and monitoring laboratory tests for iron status. Analyses began in March 2002. |
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January 2002 |
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E.Beutler et al. evaluated 41,038 healthy individuals seeking comprehensive medical coverage for symptoms, genotype, transferrin saturation, and ferritin levels. The 152 homozygotes were only slightly more likely to have symptoms than the people with a normal genotype. The authors conclude that the penetrance of hereditary hemochromatosis is much lower than generally thought; less than 1% of homozygotes may develop frank clinical hemochromatosis (Penetrance of 845G--> A ( C283Y ) HFE hereditary hemochromatosis mutation in the USA. Lancet 2002 Jan 19;359(9302):211-8).
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American Hemochromatosis Society president, Sandra Thomas, claimed that the reported prevalence from Beutler's study was a gross underestimate because the study excluded reporting of symptoms by some of the patients who had been previously diagnosed with HHC.
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Beutler et al. argued that the previously described cases were excluded to have a more credible basis for the self-described symptoms. The researchers included symptom reports if patients had made them before knowing their diagnosis. |
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The penetrance remains very low whether the deleted data are included or not. |
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February 2002 |
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Merz at al. conducted a study to assess why labs were not performing HHC genetic tests. Of the 119 labs that could perform the test, 36 did not, with 22 of those stating that it was due in part to GlaxoSmithKline's demand for fees from labs using test kits (Diagnostic testing fails the test. Nature 2002 Feb 7;415(6872):577-9).
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CDC published a booklet, Iron Overload/Hemochromatosis: Information for Patients and Their Families. The booklet is available online (www.cdc.gov/health/diseases.htm ) and in hard copy. It is intended for public use and will complement the physician and health care provider training website. |
III. Assessment of the process (translation of gene discoveries into safe and effective genetic tests) and existing gaps
Soon after the gene for hemochromatosis was discovered, federal research and public health agencies convened a meeting of experts to address testing and population-based screening for hemochromatosis. In addition to the federal participants, the experts came from academia, clinical medicine, and private companies. Although there was much to debate, the group recommended that, at that time, genetic testing for hemochromatosis on a population basis was not warranted. Papers from this meeting were published in the Annals of Internal Medicine that highlighted what was known and what was not known about the gene-disease association, diagnosis and management, and screening. The CDC/NHGRI meeting and several other meetings listed on the timeline led to some consensus about what studies were needed to fill in the knowledge gaps. This research agenda is ongoing and involves both extramural and intramural activities.
The following knowledge gaps exist. Some are currently being addressed by HHS agencies through intramural and extramural activities.
Natural History of the disease
More information is needed about the penetrance of HFE mutations and clinical expression among persons with elevated transferrin saturation. Most people who have clinical disease have mutations in the HFE gene, but most people who have those mutations never develop symptoms. The need exists to describe the clinical course of the illness and to characterize who develops symptoms and who does not. Researchers would like to know what risk factors are associated with the onset of the symptoms and what protects a person from developing symptoms.
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Investigation of other genetic contributors to iron overload is needed. Research in animal models has identified several genes related to iron metabolism, and variants in these genes might contribute to clinical manifestations of iron overload, either independently or by modifying the effect of an HFE genotype.
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Non-genetic factors are also likely to play a role in iron overload disease; excess alcohol intake, for example, is a risk factor for cirrhosis among persons with HHC. Understanding the biological processes of iron metabolism will lead to a better understanding of the various contributors to iron overload disease.
Public health impact
Data about the disease burden associated with HHC in the general population is inadequate.
Screening and genetic testing
The relative cost and efficacy of genetic testing versus phenotypic screening tests requires further study. Information on the penetrance of the gene is needed to enable accurate cost/benefit assessments for a genetic test.
The impact of screening on primary care practices has not been evaluated. The cost effectiveness of screening needs to be determined. The costs of screening are not routinely covered by medical insurance.
More research is also needed on the implications of identifying persons at risk. Genetic testing for HHC raises general concerns about stigmatization, discrimination, diminished selfworth, and as a result, increases concerns about possible breaches of privacy and confidentiality.
Little is known about the optimal approaches to family-based detection or about appropriate follow-up for relatives of patients with HHC whose iron status is currently normal. Similarly, tracking systems for persons with persistently elevated transferrin saturation but no evidence of iron overload may need to be developed and assessed to answer several unresolved questions:
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What follow-up strategies are most cost-effective?
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What is the yield of different testing strategies?
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What approaches can minimize the risk of discrimination and stigmatization that might be conferred by a known genetic risk?
Treatment
Questions on the efficacy of early treatment need to be answered. For example, evidence on the efficacy of early phlebotomy and its effect on life expectancy and quality of life has not been objectively studied.
If screening is recommended, efficient tracking of individuals testing positive must be developed to ensure that appropriate and continuing follow-up care is provided and that patient confidentiality is preserved.
Back to the Public Health Perspective on Hereditary Hemochromatosis
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