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Cover of Screening for Hereditary Hemochromatosis

Screening for Hereditary Hemochromatosis

A Focused Evidence Review

Evidence Syntheses, No. 43

Investigators: , MD, MPH, , MD, , PhD, MPH, , MS, and , RN, BSN.

Author Information and Affiliations
Rockville (MD): Agency for Healthcare Research and Quality (US); .
Report No.: 09-05127-EF-1

Structured Abstract


To assess evidence sufficiency or insufficiency for hereditary hemochromatosis screening relating to two main United States Preventive Services Task Force (USPSTF) criteria: the burden of suffering and the potential effectiveness of a preventive intervention.

Data Sources:

MEDLINE®, CINAHL, and Cochrane Library databases from 1966 through February 2005. We supplemented literature searches with source materials from experts in the field and from examining the bibliographies of key reviews and included studies.

Review Methods:

In conjunction with USPSTF leads and AHRQ staff, we developed three key questions with supporting definitions to capture the sufficiency of critical evidence necessary to make a recommendation for hereditary hemochromatosis as a new USPSTF screening topic. The critical evidence we reviewed to answer these questions focused on the development of disease in screen-identified C282Y homozygotes (penetrance), the incremental benefit of earlier therapeutic phlebotomy treatment, and whether there are high-risk groups for possible targeted genetic screening.

Using inclusion/exclusion criteria specific to each key question (KQ), we reviewed 1886 abstracts for inclusion in all key questions and 133 full-text articles for inclusion in KQ1, 67 articles for KQ2, and 55 articles for KQ3. Using USPSTF methods, we critically appraised studies using quality criteria specific to their design. To augment criteria provided for non-randomized treatment effectiveness studies, we added methods from the Cochrane Collaboration. We listed studies excluded from analysis and rationales for their exclusion. Our review abstracted, critically appraised, and synthesized 18 articles meeting our criteria for KQ1, six studies for KQ2, and 10 studies for KQ3.

Using pre-established condition definitions and screening and diagnostic criteria, we abstracted all studies into evidence tables. We summarized study results for disease development in those identified through two strategies, initial genotypic and initial phenotypic (biochemical) screening followed by genotypic screening.


Disease expression or penetrance is less than 100% in C282Y homozygotes identified through some screening method, but data were insufficient to define a very precise estimate of penetrance. Although available data suggest that 38–50% of C282Y homozygotes develop iron overload and 10–25% develop some type of hemochromatosis-associated morbidity, current research represents very limited numbers of observations and research designs subject to bias. The incremental benefit of earlier therapeutic phlebotomy is logical but not well supported by the limited treatment evidence.


Research addressing genetic screening for hereditary hemochromatosis remains very limited. Not enough is yet known to confidently project the impact or benefit from widespread genetic screening for hereditary hemochromatosis.


An additional relevant study (Powell LW, Dixon JL, Famm GA, Purdie DM, Lincoln DJ, Anderson GJ, et.al. Screening for hemochromatosis in asymptomatic subjects with and without a family history. Arch Intern Med 2006;177:294–301) was published between the finalization of this evidence synthesis and the publication of the recommendation statement and peer-reviewed manuscript derived from this evidence synthesis in the Annals of Internal Medicine.

The findings from the Powell study are incorporated into key questions 1 and 2 in the published article, but not in this evidence synthesis. (Annals citation: Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR. Screening for Hereditary Hemochromatosis: Systematic Review. Ann Intern Med 2006;145:209–23. Also available at www.ahrq.gov/clinic/uspstf06/hemochromatosis/hemochrev.pdf.)

The USPSTF judged that the additional findings from this study confirm the earlier evidence and did not change its overall assessment of the evidence nor its recommendation statement.

This report is based on research conducted by the Oregon Evidence-based Practice Center (EPC)1 under contract to the Agency for Healthcare Research and Quality (AHRQ),2 Rockville, Maryland, under Contract Number 290-02-0024, Task Order Number 2.

The findings and conclusions in this document are those of the authors, who are responsible for its content, and do not necessarily represent the views of AHRQ. No statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services.

The information in this report is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This report is intended as a reference and not as a substitute for clinical judgment.


Center for Health Research, Kaiser Permanente, 3800 North Interstate Avenue, Portland OR, 97227


540 Gaither Road, Rockville, MD 20850. www‚Äč.ahrq.gov

Bookshelf ID: NBK33435PMID: 20722140


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