Note from the U.S. Preventive Services Task Force (USPSTF): The USPSTF is redesigning its recommendation statement in response to feedback from primary care clinicians. The USPSTF plans to release, later in 2006, a new, updated recommendation statement that is easier to read and incorporates advances in USPSTF methodology. The recommendation statement below 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 U.S. Preventive Services Task Force (USPSTF) grades its recommendations (A, B, C, D, or I) and the quality of the overall evidence for a service (good, fair, poor). The definitions of these grades can be found at the end of the "Major Recommendations" field.
Summary of the Recommendation
The USPSTF recommends against routine genetic screening for hereditary hemochromatosis in the asymptomatic general population.
This is a grade D recommendation.
Clinical Considerations
This recommendation applies to asymptomatic persons. This recommendation does not include individuals with signs or symptoms that would include hereditary hemochromatosis in the differential diagnosis. Furthermore, it does not include individuals with a family history of clinically detected or screening-detected probands for hereditary hemochromatosis.
Clinically important disease due to hereditary hemochromatosis appears to be rare. Even among individuals with mutations on the hemochromatosis (HFE) gene, it appears that only a small subset will develop symptoms of hemochromatosis. An even smaller proportion of these individuals 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, great racial and ethnic variations exist. The frequency of homozygosity is 4.4 per 1000 among white persons, with much lower frequencies among Hispanic persons (0.27 per 1000), black persons (0.14 per 1000), and Asian-American persons (<0.001 per 1000). Screening of family members of probands identifies the highest prevalence of undetected C282Y homozygotes (23% of all family members tested), particularly among siblings (33% homozygosity).
The natural history of disease due to hereditary hemochromatosis is not well understood but appears to vary considerably among individuals. 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% of those undergoing further evaluation had cirrhosis (representing 1.4% 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.
Individuals with a family member, especially a sibling, who is known to have hereditary hemochromatosis may be more likely to develop symptoms. These individuals 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. While other mutations exist, C282Y homozygosity is most commonly associated with clinical manifestations. Identifying an individual with the genotypic predisposition does not accurately predict the future risk for disease manifestation.
Therapeutic phlebotomy is the primary treatment for hemochromatosis. Treated individuals 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 individuals with or without cirrhosis that are similar to rates in healthy controls. The degree to which clinically important manifestations can be averted remains uncertain, as does the optimal time for early treatment.
Definitions:
Strength of Recommendations
The USPSTF grades its recommendations according to one of five classifications (A, B, C, D, 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 [this 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.
Strength of Evidence
The USPSTF grades the quality of the overall evidence for a service on a 3-point scale (good, fair, 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.
