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Screening for hemochromatosis:: A public health perspective

https://doi.org/10.1016/S0749-3797(98)00141-XGet rights and content

Abstract

Context: The discovery of the HFE gene in 1996 has introduced DNA testing as a possible tool for screening and diagnosis of hemochromatosis and increased interest in the disorder. Population screening using transferrin saturation has been advocated by experts to permit early detection and treatment with phlebotomy before the onset of clinical disease.

Methods: Based on a literature review, we consider the relative risks and merits of two screening tests as part of a broader look at the evidence required for the recommendation of universal screening for hemochromatosis.

Results: Several questions must be answered before universal screening can be recommended. Uncertainties remain about the penetrance and preventable disease burden, laboratory standardization, and optimal strategies to minimize potential risks of screening for hemochromatosis.

Conclusions: As a common genetic disorder with simple, effective therapy, hemochromatosis offers a model for other genetically influenced chronic diseases that some day may have interventions to improve prognosis. Resolution of questions related to prevention of chronic diseases from hemochromatosis, therefore, will have broad usefulness in the future.

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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