Am Fam Physician. 2007;75(11):1696-1698
This statement summarizes the U.S. Preventive Services Task Force (USPSTF) recommendations on screening for hemochromatosis and the supporting scientific evidence. Explanations of the ratings and of the strength of overall evidence are given in Table 1 and Table 2, respectively. The complete information on which this statement is based, including evidence tables and references, is included in the systematic review for the USPSTF1 on this topic, available on the USPSTF Web site at http://www.uspreventiveservicestaskforce.org. The recommendation is also posted on the Web site of the National Guideline Clearinghouse at http://www.guideline.gov.
The USPSTF is redesigning its recommendation statement in response to feedback from primary care physicians. The USPSTF plans to release, later in 2007, a new, updated recommendation statement that is easier to read and incorporates advances in USPSTF methods. This recommendation statement is an interim version that combines existing language and elements with a new format. Although the definitions of grades remain the same, other elements have been revised.
| The USPSTF grades its recommendations according to one of five classifications (A, B, C, D, or I) reflecting the strength of evidence and magnitude of net benefit (benefits minus harms). | |
| A. | The USPSTF strongly recommends that clinicians provide [the service] to eligible patients. The USPSTF found good evidence that [the service] improves important health outcomes and concludes that benefits substantially outweigh harms. |
| B. | The USPSTF recommends that clinicians provide [the service] to eligible patients. The USPSTF found at least fair evidence that [the service] improves important health outcomes and concludes that benefits outweigh harms. |
| C. | The USPSTF makes no recommendation for or against routine provision of [the service]. The USPSTF found at least fair evidence that [the service] can improve health outcomes but concludes that the balance of benefits and harms is too close to justify a general recommendation. |
| D. | The USPSTF recommends against routinely providing [the service] to asymptomatic patients. The USPSTF found at least fair evidence that [the service] is ineffective or that harms outweigh benefits. |
| I. | The USPSTF concludes that the evidence is insufficient to recommend for or against routinely providing [the service]. Evidence that [the service] is effective is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined. |
| The USPSTF grades the quality of the overall evidence for a service on a three-point scale (good fair or poor). | |
| Good: | Evidence includes consistent results from well-designed well-conducted studies in representative populations that directly assess effects on health outcomes. |
| Fair: | Evidence is sufficient to determine effects on health outcomes but the strength of the evidence is limited by the number quality or consistency of the individual studies; generalizability to routine practice; or indirect nature of the evidence on health outcomes. |
| Poor: | Evidence is insufficient to assess the effects on health outcomes because of limited number or power of studies important flaws in their design or conduct gaps in the chain of evidence or lack of information on important health outcomes. |
Summary of Recommendations
The USPSTF recommends against routine genetic screening for hereditary hemochromatosis in the asymptomatic general population. D recommendation.
RATIONALE
Importance
There is fair evidence that disease caused by hereditary hemochromatosis is rare in the general population.
Detection
The USPSTF found fair evidence that a low proportion of persons with a high-risk genotype (C282Y homozygote at the locus of the hemochromatosis gene [HFE], which is a mutation common among white populations presenting with clinical symptoms) manifest the disease.
Benefits of Detection and Early Treatment
There is poor evidence that early therapeutic phlebotomy improves morbidity and mortality rates in screening-detected versus clinically detected persons.
Harms of Detection and Early Treatment
Screening could lead to identification of a large number of persons who possess the high-risk genotype but may never manifest the clinical disease. This may result in unnecessary surveillance, labeling, unnecessary invasive work-up, anxiety, and potentially unnecessary treatments.
USPSTF Assessment
The USPSTF concludes that the potential harms of genetic screening for hereditary hemochromatosis outweigh the potential benefits.
Clinical Considerations
This recommendation applies to asymptomatic persons. This recommendation does not include those with signs or symptoms that would include hereditary hemochromatosis in the differential diagnosis. Furthermore, it does not include persons with a family history of clinically detected or screening-detected probands for hereditary hemochromatosis.
Clinically important disease caused by hereditary hemochromatosis appears to be rare. Even among persons with mutations on the HFE, it appears that only a small subset will develop symptoms of hemochromatosis. An even smaller proportion will develop advanced stages of clinical disease.
Clinically recognized hereditary hemochromatosis is primarily associated with the HFE mutation C282Y. Although this is a relatively common mutation in the U.S. population, racial and ethnic variations exist. The frequency of homozygosity is 4.4 per 1,000 among white persons, with much lower frequencies among Hispanic persons (0.27 per 1,000), black persons (0.14 per 1,000), and Asian American persons (less than 0.001 per 1,000). Screening of family members of probands identifies the highest prevalence of undetected C282Y homozygotes (23 percent of all family members tested), particularly among siblings (33 percent homozygosity).
The natural history of disease caused by hereditary hemochromatosis is not well understood but appears to vary considerably. Clinically recognized hereditary hemochromatosis is about twice as common in men as in women. Iron accumulation and disease expression are modified by environmental factors, including blood loss or donation, alcohol use, diet, and infections such as viral hepatitis.
Among C282Y homozygotes newly identified in the general population by genotypic screening, 6 percent of those undergoing further evaluation had cirrhosis (representing 1.4 percent of all newly screening-identified C282Y homozygotes). Cirrhosis is a serious, late-stage disease development, and its prevention would be a major goal of screening and treatment.
Persons with a family member, especially a sibling, who is known to have hereditary hemochromatosis may be more likely to develop symptoms. These persons should be counseled regarding genotyping, with further diagnostic testing as warranted as part of case-finding.
In addition to genotyping, more common laboratory testing can sometimes identify iron overload. Clinical screening with these laboratory tests, or phenotypic screening, was not included in the evidence synthesis on which this recommendation is based. Genotyping primarily focuses on the identification of the C282Y mutation on HFE. Although other mutations exist, C282Y homozygosity is most commonly associated with clinical manifestations. Identifying a person with the genotypic predisposition does not accurately predict the future risk of disease manifestation.
Therapeutic phlebotomy is the primary treatment for hemochromatosis. Treated persons report inconsistent improvement of their signs and symptoms. It is uncertain whether cirrhosis at diagnosis confers a worse prognosis based on the potential lack of reversibility of liver damage. Recent research reports survival rates in treated persons with or without cirrhosis that are similar to rates in healthy control subjects. The degree to which clinically important manifestations can be averted remains uncertain, as does the optimal time for early treatment.
Other Considerations
System issues
Genetic screening for hereditary hemochromatosis is not widespread in the United States.
Value
Systematic screening is potentially costly and may lead to additional diagnostic tests, regular follow-up, and treatment.
Research needs
Longitudinal studies that better define the natural history of the disease and penetrance of the disease among those with specific HFE mutations are needed. The effectiveness and optimal timing of therapy need to be determined.
Policy issues
There are important ethical concerns about screening for genetic conditions when the ability to predict the development of disease in those who screen positive is uncertain or very low. Identification of homozygosity could lead to diminished insurability.
Community issues
Although clinical disease associated with hereditary hemochromatosis is uncommon, there is significant variation in the prevalence of C282Y homozygotes according to race and ethnicity.
The Discussion section that usually is included in USPSTF recommendation statements is available in the full recommendation statement on the USPSTF Web site at http://www.ahrq.gov/clinic/uspstf06/hemochromatosis/hemochrs.htm.
Recommendations of Others
Other groups have reviewed the utility of screening for hereditary hemochromatosis. The Centers for Diseases Control and Prevention does not recommend universal testing for hereditary hemochromatosis but rather suggests evaluating iron overload in persons with a family history, and in symptomatic persons.2
The American College of Physicians found insufficient evidence to recommend for or against the use of transferrin saturation and serum ferritin levels to identify early stages of hereditary hemochromatosis.3
The American Association for the Study of Liver Disease, the American College of Gastroenterology, and the American Gastroenterological Association recommend genotyping persons who have abnormal iron screening tests and first-degree relatives of those identified with C282Y homozygosity.4