Screening for Hereditary Hemochromatosis: A Clinical Practice Guideline from the American College of Physicians

4 October 2005 | Volume 143 Issue 7 | Pages 517-521

Hereditary hemochromatosis is a genetic disorder of iron metabolism. Diagnosis of hereditary hemochromatosis is usually based on a combination of various genetic or phenotypic criteria. Decisions regarding screening are difficult because of the variable penetrance of mutations of the HFE gene and the absence of any definitive trials addressing the benefits and risks of therapeutic phlebotomy in asymptomatic patients or those with only laboratory abnormalities. The purpose of this guideline is to increase physician awareness of hereditary hemochromatosis, particularly the variable penetrance of genetic mutations; aid in case finding; and explain the role of genetic testing. This guideline provides recommendations based on a review of evidence in the accompanying background paper by Schmitt and colleagues. The target audience for this guideline is internists and other primary care physicians. The target patient population is all persons who have a probability or susceptibility of developing hereditary hemochromatosis, including the relatives of individuals who already have the disease.

*This paper, written by Amir Qaseem, MD, PhD, MHA; Mark Aronson, MD; Nick Fitterman, MD; Vincenza Snow, MD; Kevin B. Weiss, MD, MPH; and Douglas K. Owens, MD, MS, was developed for the Clinical Efficacy Assessment Subcommittee of the American College of Physicians (ACP): Douglas K. Owens, MD, MS (Chair); Mark Aronson, MD; Patricia Barry, MD, MPH; Donald E. Casey Jr., MD, MPH, MBA; J. Thomas Cross Jr., MD, MPH; Nick Fitterman, MD; E. Rodney Hornbake, MD; Katherine D. Sherif, MD; and Kevin Weiss, MD, MPH (Immediate Past Chair). Approved by the ACP Board of Regents on 16 July 2005.

Recommendations

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Recommendation 1: There is insufficient evidence to recommend for or against screening for hereditary hemochromatosis in the general population.

There is currently insufficient evidence to determine whether the benefits of screening the general population outweigh the risks. The C282Y mutation is prevalent in certain populations, particularly white men, and treatment is not costly nor is it associated with any significant harm. Although patients homozygous for C282Y are more likely to have elevated serum ferritin level and transferrin saturation percentage, there currently is no way of predicting which patients will progress to overt disease. For clinicians who choose to screen, 1-time phenotypic screening of asymptomatic non-Hispanic white men with serum ferritin level and transferrin saturation would have the highest yield (1).

Recommendation 2: In case-finding for hereditary hemochromatosis, serum ferritin and transferrin saturation tests should be performed.

There is no information available on risk-stratifying in patients with an associated condition or conditions such as type 2 diabetes, cardiac arrhythmias and cardiomyopathies, liver failure, hepatomegaly, cirrhosis, elevated liver enzyme levels, hepatocellular carcinoma, arthritis, hypogonadism, or changes in skin pigmentation. The initial symptoms associated with iron overload might be nonspecific, and the decision to perform tests should be based on clinical judgment regarding what may cause such protean manifestations. If testing is performed for these patients, the cutoff values for serum ferritin level of more than 200 µg/L in women or more than 300 µg/L in men and transferrin saturation greater than 55% may be used as criteria for case-finding; however, there is no general agreement about diagnostic criteria. Case-finding may also be considered if there is a family history of hereditary hemochromatosis for an individual, as the risk for developing the disease may be higher than that of the general population.

Recommendation 3: Physicians should discuss the risks, benefits, and limitations of genetic testing in patients with a positive family history of hereditary hemochromatosis or those with elevated serum ferritin level or transferrin saturation.

Before genetic testing, individuals should be made aware of the benefits and risks of genetic testing. This should include discussing available treatment and its efficacy; costs involved (2); and social issues, such as impact of disease labeling, insurability and psychological well-being, and the possibility of as-yet-unknown genotypes associated with hereditary hemochromatosis.

Recommendation 4: Further research is needed to establish better diagnostic, therapeutic, and prognostic criteria for hereditary hemochromatosis.

The lack of information on the natural history of the disease makes it difficult to manage patients with hereditary hemochromatosis. There are no clearly defined criteria to risk-stratify patients into groups more or less likely to develop overt disease. Future developments in technology and genetic screening might help in the diagnosis and management of hereditary hemochromatosis. In addition, there is a need for more uniform diagnostic criteria.

Introduction

Hereditary hemochromatosis is a genetic disorder of iron metabolism and is characterized by tissue injury resulting from an abnormal accumulation of iron in various organs. This disease is usually a consequence of an increased absorption of iron from the gastrointestinal tract, which results in increased iron deposition in tissue, particularly in the liver, heart, and pancreas. If left untreated, it can lead to organ damage, such as cirrhosis, as well as hepatocellular cancer. However, early diagnosis of hereditary hemochromatosis is difficult because of variability in the case definition and diagnostic standard used.

Diagnosis of hereditary hemochromatosis is usually based on a combination of various genetic or phenotypic criteria. Genetically, it can be based on direct DNA testing for the 2 HFE gene mutations (C282Y and H63D) associated with hereditary hemochromatosis. The mutation of C282Y in the HFE gene on chromosome 6 is present in almost 90% of those affected. Most patients are homozygous, and mutation transmission is autosomal recessive. The H63D mutation may be associated with hereditary hemochromatosis, but the actual clinical effects of this mutation are uncertain (3). Although in a small proportion, compound heterozygotes (C282Y/H63D) can develop iron overload. Phenotypic markers of hereditary hemochromatosis may be used to identify the disease. Percentage of transferrin saturation and serum ferritin level have been used to confirm the diagnosis of hereditary hemochromatosis. Transferrin saturation determines how much iron is bound to the protein that carries iron in the blood. Serum ferritin level is elevated in patients with hereditary hemochromatosis and correlates with liver iron and development of cirrhosis. Liver biopsy to measure hepatic iron concentration by staining is considered the gold standard to test for hereditary hemochromatosis. However, with the advent of genetic testing, liver biopsy is not widely used to confirm the diagnosis. There is a consensus on the various diagnostic tests that could be used to diagnose hereditary hemochromatosis. However, the threshold levels that should be used to define the disease remain controversial. On the basis of the review of the background paper by Schmitt and colleagues (4), also in this issue, and considering that lower cutoffs are more sensitive and less specific, serum ferritin level greater than 200 µg/mL and transferrin saturation greater than 55% suggest an increased risk for hereditary hemochromatosis and the need for further investigation (5).

Hereditary hemochromatosis is the most common recessive genetic trait in white persons. However, estimating the prevalence of this disease is difficult. Genetic testing of populations originating in northern Europe showed that approximately 0.5% are homozygous for the C282Y mutation (6). The Hemochromatosis and Iron Overload Screening (HEIRS) Study showed that the prevalence of C282Y homozygotes was highest among non-Hispanic white persons (0.44% [95% CI, 0.42% to 0.47%]) (1). Phenotypic screening of the population in the United States demonstrated that 1% to 6% have elevated transferrin saturation and 11% to 22% of this group have an increased serum ferritin level (7). Hereditary hemochromatosis has been estimated to be present in 3 to 5 people per 1000 in the general population (8). Decisions regarding screening are difficult because of the variable penetrance of mutations of the HFE gene and the absence of any definitive trials addressing the benefits and risks of therapeutic phlebotomy in asymptomatic patients or those with only laboratory abnormalities.

The purpose of this guideline is to increase physician awareness of hereditary hemochromatosis, particularly the variable penetrance of genetic mutations; aid in case finding; and explain the role of genetic testing. The target audience for this guideline is internists and other primary care physicians. The target patient population is all persons who have a probability or susceptibility of developing hereditary hemochromatosis, including the relatives of individuals who already have the disease. This guideline is based on the systematic review of the evidence in the background paper (4).

This guideline attempts to answer the following questions: 1) What is the prevalence of hereditary hemochromatosis in the primary care setting? 2) In asymptomatic patients with hereditary hemochromatosis, what is the risk for end-organ damage or death? 3) How diagnostically useful are transferrin saturation and serum ferritin in identifying patients with hereditary hemochromatosis in the primary care setting? 4) Is phlebotomy efficacious in reducing morbidity or fatal complications in asymptomatic patients with hereditary hemochromatosis? 5) Do the benefits of screening primary care patients for hereditary hemochromatosis outweigh the risks?

Prevalence

Estimates of the prevalence of hereditary hemochromatosis in the general population vary widely because no set criteria define what constitutes hereditary hemochromatosis (5, 9, 10). Some argue that genotyping should be used as the gold standard and that the sensitivity and specificity of phenotyping should be calculated and compared with those of genotyping. Others support the use of persistently elevated serum ferritin level and percentage of transferrin saturation as the case definition of hereditary hemochromatosis. Studies of differing populations, using strict criteria recommended in the HEIRS Study (11), have estimated that the prevalence of hereditary hemochromatosis ranges from 1 in 357 persons to 1 in 625 persons in the general population to rates almost as high as 1 in 135 persons among Norwegian men (4). The Table lists various studies showing the prevalence of hereditary hemochromatosis in primary care settings.

Author and Article Information

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From the American College of Physicians, Philadelphia, Pennsylvania; Beth Israel Deaconess Medical Center, Boston, Massachusetts; North Shore Medical Group, Huntington, New York; VA Palo Alto Health Care System and Stanford University, Stanford, California; and Hines VA Hospital and Northwestern University, Chicago, Illinois.

Note: Clinical practice guidelines are "guides" only and may not apply to all patients and all clinical situations. Thus, they are not intended to override clinicians' judgment. All ACP clinical practice guidelines are considered automatically withdrawn or invalid 5 years after publication, or once an update has been issued.

Annals of Internal Medicine encourages readers to copy and distribute this paper, providing such distribution is not for profit. Commercial distribution is not permitted without the express permission of the publisher.

Grant Support: Financial support for the development of this guideline comes exclusively from the ACP operating budget.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Amir Qaseem, MD, PhD, MHA, American College of Physicians, 190 N. Independence Mall West Philadelphia, PA 19106; e-mail, aqaseem{at}acponline.org.

Current Author Addresses: Drs. Qaseem and Snow: American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106.

Dr. Aronson: 330 Brookline Avenue, Boston, MA 02215.

Dr. Fitterman: 120 New York Avenue, Huntington, NY 11743.

Dr. Weiss: 151H, PO Box 5000, Hines, IL 60141.

Dr. Owens: 117 Encina Commons, Stanford, CA 94305.

References

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