Recommendation Statement
This statement summarizes the U.S. Preventive Services Task Force
(USPSTF) recommendation on screening for hemochromatosis and
the supporting scientific evidence. The complete information on
which this statement is based, including evidence tables and references,
is available in the accompanying
review.
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
methods. The recommendation statement in this paper 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.
This recommendation statement was first published in the Annals of Internal Medicine. Select for copyright and source information.
Contents
Summary of the Recommendation
Clinical Considerations
Other Considerations
Discussion
Recommendations of Others
References
Appendix
Disclaimer
Copyright and Source Information
Summary of the Recommendation
- The U.S. Preventive Services Task Force (USPSTF)
recommends against routine genetic screening for hereditary
hemochromatosis in the asymptomatic general population.
Rating: D recommendation.
|
Rationale
Importance: There is fair evidence that disease due to
hereditary hemochromatosis is rare in the general population.
(Select for a description of the USPSTF
classification of levels of evidence.)
Detection: The USPSTF found fair evidence that a low
proportion of individuals with a high-risk genotype
(C282Y homozygote at the HFE locus, 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 in screening-detected versus clinically
detected individuals.
Harms of detection and early treatment: Screening could
lead to identification of a large number of individuals 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.
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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 percent of all
family members tested), particularly among siblings (33 percent
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 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.
- 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.
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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 followup,
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 optimum 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: While clinical disease associated
with hereditary hemochromatosis is uncommon, there is
significant variation in the prevalence of C282Y homozygotes
according to race and ethnicity.
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Discussion
Burden of Illness
Iron overload leading to organ damage is the main
mechanism associated with morbidity and mortality. Specifically,
liver damage associated with cirrhosis and hepatocellular
cancer can contribute to decreased life expectancy.
Understanding the burden of disease requires both a standardized
case definition and longitudinal cohort studies.
For this review, the USPSTF defined disease as the presence
of clinical signs and symptoms; serum biochemical or
genetic abnormalities alone were insufficient. The clinical
case definition varies greatly in the literature, from late
stages of liver disease to iron overload or elevated serum
iron measures.
Two retrospective cohort studies followed
33 individuals with C282Y homozygosity for between 17
and 25 years.1,2
Approximately 25 percent (8 of 33) were lost
to followup. Another 25 percent were women age 50 years or
younger at final followup, the fifth decade being the time
most women begin to present clinically. Of those followed,
approximately 75 percent had elevated serum iron measures. For
10 individuals, iron overload was assessed, with 5 of 6
undergoing a biopsy indicating iron overload. When the 2
studies were combined, approximately one-tenth (3 of 33)
of individuals had liver disease.
Cross-sectional data obtained from health clinics,
blood donor settings, mass screening, and family screening
support the incomplete penetrance of C282Y homozygosity,
while the actual estimates must be interpreted with
caution because of inherent bias in these types of data.
Pooled data provided information on 67,771 individuals
identified from general screening and 200 family members
of probands. A total of 228 (0.3 percent) individuals were identified
as C282Y homozygotes as a result of non-family based
genetic screening. Of those further evaluated, 38 percent
demonstrated iron overload, 25 percent liver fibrosis, and 6 percent
cirrhosis. A larger proportion of family members of probands
had iron overload (49 percent to 86 percent) and cirrhosis (8 percent).
Of the 150 individuals identified through family-based
screening assessed genetically, 25 were C282Y homozygotes.
Scope
After the discovery of the HFE gene and its clinically
relevant mutations in 1996, hereditary hemochromatosis
was proposed as a potentially ideal model for universal
genetic screening of a disease.3
In taking up the issue of screening for hereditary hemochromatosis
for the first time, the USPSTF focused its review of evidence on 2
points: first, to determine the actual penetrance of the
phenotype among genetically identified individuals; and
second, to assess the evidence about the benefits of early
treatment to determine whether genetic screening of asymptomatic
individuals could lead to a substantial health benefit.
MEDLINE®, CINAHL, and Cochrane Library databases
from 1996 through February 2005 were reviewed.
Supplemental literature was added from examining bibliographies
of key reviews and from suggestions by experts in
the field.4
Accuracy of Screening Tests
Because of the targeted nature of this review, the
USPSTF did not focus on the accuracy of genetic screening
tests. Nor did the USPSTF assess the validity of various
combinations of phenotypic and genotypic approaches to
screening. Rather, the USPSTF focused on genetic screening
for hereditary hemochromatosis, specifically C282Y
homozygosity. The USPSTF did not assess the role of increased
serum iron measures such as transferrin saturation
and serum ferritin in screening. While elevated serum iron
measures may provide more “clinically” relevant information
about early disease, the predictive value for progression
of disease is limited.2
Intervention and Treatment
Genetic screening for HFE mutations can accurately
identify individuals at risk for hereditary hemochromatosis,
but the predictive value of determining clinically significant
disease, especially that associated with liver fibrosis, is
low. Beutler and colleagues5 found that among C282Y
homozygotes, 50 percent demonstrated no elevation in transferrin
saturation and 99 percent were free of clinical symptoms.
Therapeutic phlebotomy is the mainstay of treatment
for hereditary hemochromatosis. The goal of therapeutic
phlebotomy is to decrease total body iron overload. Phlebotomy
is generally thought to have few side effects. However,
because the progression from iron overload to clinically
significant disease among persons with C282Y/
C282Y mutations is uncertain, it is difficult to quantify the
potential impact of phlebotomy on all individuals with
these mutations. Multiple studies demonstrate that therapeutic
phlebotomy does decrease serum iron indices, but
data are lacking appropriate control groups.
Other studies reporting improved outcomes from
phlebotomy also are confounded by unmeasured factors,
such as duration of disease, age, and historical factors
(for example, hepatitis, alcohol ingestion, and diet).
Among individuals with biopsy-proven liver fibrosis,
phlebotomy was associated with an
improvement of 13 percent to 50 percent, with the greatest improvement
among individuals with the least degree of liver fibrosis.
Individuals served as their own controls, and improvement
was based on qualitative histologic measures.
When liver fibrosis is present and in its early stages,
therapeutic phlebotomy appears to control or slow progression
of liver disease.6,7
No controlled therapeutic studies were identified
among patients with hemochromatosis due to any cause.
No studies were found that compared the effectiveness of
early as opposed to delayed treatment. Three fair-quality
case series of referred patients provided data on 447 individuals
(85 with genotypically confirmed hemochromatosis)
who underwent phlebotomy.6,8,9 These studies demonstrate that the 10-year survival of individuals recently
diagnosed with hereditary hemochromatosis or
treated prior to the development of cirrhosis does not differ
from that in age- and sex-matched population controls;
however, no data are available on untreated controls.
Harms of Screening and Treatment
Harms associated with screening are not well studied:
Potential harms include the psychological burden of being
labeled as having a chronic disease, the potential consequence
of this labeling on a person's ability to obtain
health or life insurance, and concern associated with genetic
testing in the absence of qualified genetic counseling.
Phlebotomy, a somewhat invasive procedure, is associated
with some harms.
Research Needs
The penetrance of clinical disease among individuals
with hereditary hemochromatosis is unknown. It is clear,
however, that most of those identified at any point in time
with the most common genetic mutation associated with
clinical disease (the C282Y mutation) do not manifest clinically
significant disease. While further studies on the natural
history of untreated individuals who are homozygous
for C282Y would provide more precise estimates of penetrance,
other questions may be even more relevant to clinical
preventive services. As genotyping of individuals becomes
more common, understanding the factors that
influence phenotypic expression will be critical in assessing
an individual's risk for disease. The optimum timing and
effectiveness of early therapy need to be established.
Other mutations associated with hereditary hemochromatosis
have been identified, but these mutations have low
frequencies. There are likely to be some mutations at other
gene loci that affect the likelihood of hereditary hemochromatosis
that have not been identified.
One study identified treatment harms associated with
phlebotomy, but more could be known about:
- The impact of unnecessary procedures
(that is, those that have no benefit).
- The cost and burden of disease surveillance
and monitoring.
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Recommendations of Others
Other groups have reviewed the utility of screening for
hereditary hemochromatosis. The Centers for Disease
Control and Prevention does not recommend universal
testing for hereditary hemochromatosis but rather suggests
evaluating iron overload in individuals with a family history,
and in symptomatic individuals.10
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.11
The American Association for the Study of Liver Disease,
the American College of Gastroenterology,
and the American Gastroenterological Association
recommend genotyping individuals who have abnormal
iron screening tests and first-degree relatives of those identified
with C282Y homozygosity.12
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References
1. Olynyk JK, Hagan SE, Cullen DJ, Beilby J, Whittall DE. Evolution of untreated hereditary hemochromatosis in the Busselton population: a 17-year
study. Mayo Clin Proc 2004;79:309-13. [PMID: 15008603]
2. Andersen RV, Tybjaerg-Hansen A, Appleyard M, Birgens H, Nordestgaard BG. Hemochromatosis mutations in the general population: iron overload progression rate. Blood 2004;103:2914-9. [PMID: 15070663]
3. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996;13:399-408. [PMID: 8696333]
4. Whitlock E, Garlitz BA, Harris EL, Beil TL, Smith PR. Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task
Force. Ann Intern Med 2006;145:209-23.
5. Beutler E, Felitti V, Ho NJ, Gelbart T. Relationship of body iron stores to levels of serum ferritin, serum iron, unsaturated iron binding capacity and transferrin saturation in patients with iron storage disease. Acta Haematol 2002;107:145-9. [PMID: 11978935]
6. Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 1996;110:1107-19. [PMID: 8613000]
7. Powell LW, Dixon JL, Ramm GA, Purdie DM, Lincoln DJ, Anderson GJ, et al. Screening for hemochromatosis in asymptomatic subjects with or without a
family history. Arch Intern Med 2006;166:294-301. [PMID: 16476869]
8. Adams PC, Speechley M, Kertesz AE. Long-term survival analysis in hereditary hemochromatosis. Gastroenterology 1991;101:368-72. [PMID: 2065912]
9. Bomford A, Williams R. Long term results of venesection therapy in idiopathic haemochromatosis. Q J Med 1976;45:611-23. [PMID: 188063]
10. Iron overload and hemochromatosis: home. Centers for Disease Control and Prevention. Accessed at www.cdc.gov/hemochromatosis on 31 May 2006.
11. Qaseem A, Aronson M, Fitterman N, Snow V, Weiss KB, Owens DK, et al. Screening for hereditary hemochromatosis: a clinical practice guideline from
the American College of Physicians. Ann Intern Med 2005;143:517-21. [PMID: 16204164]
12. Tavill AS. Diagnosis and management of hemochromatosis. Hepatology 2001;33:1321-8. [PMID: 11343262]
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Appendix
Members of the U.S. Preventive Services Task Force*:
Ned Calonge, M.D., M.P.H., Chair (Colorado Department of Public
Health and Environment, Denver, Colorado); Diana B.
Petitti, M.D., M.P.H., Vice-Chair (Kaiser Permanente Southern
California, Pasadena, California); Thomas G. DeWitt, M.D.
(Children's Hospital Medical Center, Cincinnati, Ohio); Leon
Gordis, M.D., M.P.H., Dr.P.H. (Johns Hopkins Bloomberg School
of Public Health, Baltimore, Maryland); Kimberly D. Gregory,
MD, MPH (Cedars-Sinai Medical Center, Los Angeles, California);
Russell Harris, M.D., M.P.H. (University of North Carolina
School of Medicine, Chapel Hill, North Carolina); Kenneth W.
Kizer, M.D., M.P.H. (National Quality Forum, Washington, DC);
Michael L. LeFevre, M.D., M.S.P.H. (University of Missouri School
of Medicine, Columbia, Missouri); Carol Loveland-Cherry,
Ph.D., R.N. (University of Michigan School of Nursing, Ann Arbor,
Michigan); Lucy N. Marion, Ph.D., R.N. (School of Nursing,
Medical College of Georgia, Augusta, Georgia); Virginia A.
Moyer, M.D., M.P.H. (University of Texas Health Science Center,
Houston, Texas); Judith K. Ockene, Ph.D. (University of Massachusetts
Medical School, Worcester, Massachusetts); George F.
Sawaya, M.D. (University of California, San Francisco, California);
Albert L. Siu, M.D., M.S.P.H. (Mount Sinai Medical Center,
New York, New York); Steven M. Teutsch, M.D., M.P.H. (Merck
& Co., Inc., West Point, Pennsylvania); and Barbara P. Yawn,
M.D., M.Sc. (Olmstead Research Center, Rochester, Minnesota).
* Members of the Task Force at the time this recommendation was finalized. For a list of current Task Force members, go to http://www.ahrq.gov/clinic/uspstfab.htm.
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Disclaimer
Recommendations made by the USPSTF are independent of
the U.S. Government. They should not be construed as an official position
of the Agency for Healthcare Research and Quality or the U.S.
Department of Health and Human Services.
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Copyright and Source Information
This document is in the public domain within the United States. For
information on reprinting, contact Randie Siegel, Director, Division of
Printing and Electronic Publishing, Agency for Healthcare Research and Quality,
540 Gaither Road, Rockville, MD 20850.
Requests for linking or to incorporate content in electronic resources should be sent to: info@ahrq.gov.
Source: Screening for Hemochromatosis: Recommendation Statement. August 2006. Ann Intern Med 2006;145:204-08.
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Current as of August 2006
Internet Citation:
U.S. Preventive Services Task Force. Screening for Hemochromatosis:
Recommendation Statement. August 2006. Originally published in Ann
Intern Med 2006;145:204-08. Agency
for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/uspstf06/hemochromatosis/hemochrs.htm
540 Gaither Road Rockville, MD 20850