Theme ArticlesScreening for hemochromatosis:: A public health perspective
Introduction
T he association of cirrhosis, diabetes, and skin bronzing with heavy hepatic deposits of iron-containing compounds was first recognized more than a century ago1 and termed “hemochromatosis” by von Recklinghausen in 1889.2 The clinical disease, which typically manifests at age 30 or later, results from an error in iron absorption that leads to progressive iron accumulation.3 Although Sheldon suggested in 1935 that the disease is genetic,4 it was not until 1975 that the autosomal recessive nature and the linkage of hemochromatosis to the major histocompatability complex (MHC) region on chromosome 6 (HLA) were recognized.5, 6 The HLA-H gene was discovered in 1996 and is now called HFEin deference to the WHO Nomenclature Committee for Factors of the HLA system.7, 8 The basic defect in iron absorption is under active investigation.9
In the United States, as many as one million persons may be affected by iron overload, the primary cause being hemochromatosis.10 If undetected and untreated, hemochromatosis can lead to hepatic cirrhosis, primary liver cancer, diabetes mellitus, cardiomyopathy, arthritis, hypopituitarism with hypogonadism and decreased life expectancy.3 It is one of the few genetic diseases for which simple effective therapy exists: iron removal by phlebotomy improves survival and morbidity in symptomatic persons,11, 12 and when phlebotomy is begun before the development of cirrhosis or diabetes, persons with hemochromatosis can have a normal life expectancy.11, 12, 13
The College of American Pathologists3 and others14, 15, 16, 17, 18 have advocated the use of elevated iron measures to detect and treat hemochromatosis before persons develop symptoms. In many instances experts recommend liver biopsy to confirm the diagnosis and evaluate prognosis.3 The discovery of the HFE gene has made DNA testing another possible tool for screening or diagnosis and has increased medical and public interest in hemochromatosis.
In this article, we consider the evidence required for recommending universal screening for hemochromatosis. As part of this consideration, we examine whether DNA (genetic) testing adds value to the current models for screening or diagnosis of hemochromatosis.
Section snippets
Public health impact of hemochromatosis
Determining the public health impact of hemochromatosis is complicated by the lack of a uniform case definition.3, 10 There is a progression of disease expression from genetic predisposition to increased iron absorption, increased iron transport, and tissue iron deposition and necrosis. In the past, diagnosis of the genetic predisposition for hemochromatosis has been pedigree analysis by HLA-typing of the person with hemochromatosis and family members.15 This may change with more information
Effectiveness of screening
The framework shown in Figure 1 identifies the chain of assumptions involved in the use of screening tests for early detection of hemochromatosis to prevent clinical disease.38 Each step is associated with a question to be addressed through an evaluation of the evidence. The central questions related to the effectiveness of screening are the accuracy of screening and diagnostic tests and the efficacy of treatment in reducing disease burden. The possibility of adverse consequences from
Ethical, legal, and social issues
If population-based screening for hemochromatosis is to be implemented successfully, the ethical, legal, and social issues related to screening, diagnosis, and treatment must be addressed.69, 70 In addition, decisions about screening should be based on a balanced consideration of risks and benefits.
Possible risks include a potential loss of health or life insurance or employment following diagnosis.71 Adverse effects may include anxiety, depression and loss of self-worth, and deleterious
Conclusions
To the extent that screening will identify people destined to develop symptoms of iron overload, the rationale for screening will be strong, despite the possible risks, because of the health benefits provided by phlebotomy. Screening under this circumstance offers benefits similar to those for other health conditions improved by early treatment, such as hypertension and cholesterol. As the analytic and clinical validity of the HFE test for hemochromatosis becomes established, researchers may
Acknowledgements
This work was supported in part under an agreement from the Centers for Disease Control and Prevention through the Association of Teachers of Preventive Medicine.
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Cited by (37)
Iron Metabolism and Related Disorders
2013, Emery and Rimoin's Principles and Practice of Medical GeneticsHemochromatosis Genotypes and Risk of Iron Overload-A Meta-Analysis
2011, Annals of EpidemiologyCitation Excerpt :Approximately 5%–11% of the subjects with clinical HH were C282Y/H63D compound heterozygous, 5.2% were single heterozygous, and 1.5% had H63D/H63D genotype (7, 8). Early enthusiasm for screening in hemochromatosis has not been sustained due to failure to establish the predictive value of the screening tests and the consequent benefit of detecting cases (9–12). The incomplete phenotypic penetrance of HFE genotypes (particularly other than C282Y/C282Y homozygotes) in relation to hemochromatosis poses a practical problem in the interpretation of HFE genotype results by clinicians.
Diabetes and a large liver
2007, LancetHereditary haemochromatosis: To screen or not to screen?
2005, Journal of HepatologyNewborn screening as a model for population screening
2002, Molecular Genetics and Metabolism