Systematic Review
Evelyn P. Whitlock, M.D., M.P.H.a; Betsy A. Garlitz, M.D.b; Emily L. Harris, Ph.D., M.P.H.a; Tracy L. Beil, M.S.a; and Paula R. Smith, R.N., B.S.N.a
The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the U.S. Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
Address correspondence to: Dr. Whitlock, Center for Health Research, Kaiser Permanente, 3800 North Interstate Avenue, Portland, OR 97227-1110.
This systematic review was first published in the Annals of Internal Medicine. Select for copyright, source, and reprint information.
Contents
Abstract
Introduction
Background
Methods
Data Synthesis
Discussion
Conclusions
References
Notes
Copyright and Source Information
Abstract
Background: The U.S. Preventive Services Task Force (USPSTF) has
not previously considered screening for hereditary hemochromatosis
for a recommendation as a clinical preventive service for primary
care clinicians.
Purpose: To conduct a focused systematic review of hereditary
hemochromatosis screening relating to 2 USPSTF criteria, the
burden of suffering and the potential effectiveness of a preventive
intervention, to determine whether evidence is sufficient for a
USPSTF recommendation.
Data Sources: MEDLINE®, CINAHL, and Cochrane Library databases
from 1966 through February 2005. The authors supplemented
literature searches with source materials from experts in the field
and the bibliographies of key reviews and included studies.
Study Selection: Studies were retrieved to answer 3 key questions:
- What is the risk for developing clinical hemochromatosis among those with a homozygous C282Y genotype?
- Does earlier therapeutic phlebotomy of individuals with primary iron overload due to hereditary hemochromatosis reduce morbidity and mortality compared with treatment after diagnosis in routine clinical care?
- Are there groups at increased risk for developing hereditary hemochromatosis that can be readily identified before genetic screening?
The authors critically appraised studies using quality criteria specific
to their design.
Data Extraction: The authors abstracted all studies into evidence
tables using condition definitions and diagnostic criteria.
Data Synthesis: Data were insufficient to define a very precise
estimate of penetrance. Available data suggest that up to 38% to
50% of C282Y homozygotes may develop iron overload, with up
to 10% to 33% eventually developing hemochromatosis-associated
morbidity. Prevalence of C282Y homozygosity is higher in family
members of probands and other high-risk patient groups defined
by signs, symptoms, and phenotypic screening.
Limitations: This review considered genetic screening for HFE-related
hereditary hemochromatosis in C282Y homozygotes only.
Available research is limited, is based solely on observational designs,
and is plagued by poor or inconsistent reporting.
Conclusions: Research addressing genetic screening for hereditary
hemochromatosis remains insufficient to confidently project the impact
of, or estimate the benefit from, widespread or high-risk genetic
screening for hereditary hemochromatosis.
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Introduction
The U.S. Preventive Services Task Force (USPSTF) has
not previously considered screening for hereditary
hemochromatosis for a recommendation as a clinical preventive
service for primary care clinicians. We examined
key questions to assess hemochromatosis penetrance in
C282Y homozygotes (key question 1), address health outcomes
of therapeutic phlebotomy (key question 2), and
examine the possibility of targeted genetic screening (key
question 3). Key questions for this focused systematic review
were limited to addressing critical evidence gaps in
order for the USPSTF to recommend screening,1,2 and
were applied using strict and consistent definitions of disease,
which are described in more detail below.
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Background
Condition Definition
Hemochromatosis was originally thought to be a rare
idiopathic disorder characterized by end-stage disease (cirrhosis,
diabetes, and bronzed skin) but is now recognized
as having a hereditary component due to an autosomal
recessive inherited disorder of iron metabolism.3 In
hemochromatosis, body iron accumulates and can lead to
iron overload.4 In iron overload, excess iron is deposited
in the liver, pancreas, heart, joints, and endocrine glands,
resulting in tissue damage that can lead to disease conditions
(such as cirrhosis, diabetes, heart failure, arthropathy,
and impotence).4-6 Iron overload can be primary (as in hereditary hemochromatosis) or secondary (for example,
due to anemias with inefficient erythropoiesis or repeated
blood transfusions).7
In 1996, 2 base-pair alterations, termed C282Y and
H63D, of the HFE gene on the region of HLA-A on chromosome
6 were identified in hereditary hemochromatosis.8 C282Y homozygosity is now recognized as the most
common genotype in hereditary hemochromatosis.9 Estimates
are that 82% to 90% of cases of hereditary hemochromatosis
among white persons occur in C282Y/C282Y
homozygotes.10 The other 10% to 18% of cases appear
to be due to environmental factors or other genotypes.
While other HFE-related and non-HFE-related genetic
mutations are associated with hereditary hemochromatosis
in a small number of cases,4 other genotypes do not
appear to be as strongly associated with hereditary hemochromatosis.3,9
HFE mutations are fairly common in the United
States, with 1 in 10 white persons heterozygous for the
HFE C282Y mutation (carriers) and 4.4 homozygotes per
1000.4,6 The frequency of C282Y homozygosity is
much lower among Hispanic persons (0.27 in 1000), Asian
Americans (<.0.001 per 1000), Pacific Islanders (0.12 per
1000), and black persons (0.14 per 1000).11
The availability
of genotyping has permitted identifying persons
who have the susceptible genotype but have little or no
evidence of disease. Thus, individuals homozygous for the
C282Y genotype can be characterized in 1 of 4 general
stages: genetic predisposition without any other abnormality;
iron overload without symptoms; iron overload with
early symptoms; and iron overload with organ damage,
especially cirrhosis.4 Clinically recognized hereditary
hemochromatosis is twice as common in males and occurs
predominantly in white populations.12
While the natural
history is not well understood, the condition appears to
have a long latent period, with wide individual variation in
biochemical expression.13 This is because iron accumulation
and disease expression are modified by environmental
factors, such as blood loss from menstruation or donation,
alcohol intake, diet, and comorbid disease (for
example, viral hepatitis).14,15 If symptomatic organ
involvement develops, it generally occurs in mid-life with
nonspecific signs and symptoms (such as unexplained fatigue,
joint pain, and abdominal pain).14 Age of onset is
delayed in females,16 perhaps because of blood loss
through menstruation.3 The liver is the first target organ
thought to be affected by iron accumulation.17 and is
central to both diagnosis and prognosis.13
While a clinical diagnosis is based on serum iron studies
and clinical evaluation, documented iron overload relies
on 1 of 2 methods: quantitative phlebotomy with calculation
of the amount of iron removed, or liver biopsy with
determination of quantitative hepatic iron.18 Although
liver biopsy was once essential to the diagnosis, it is currently
used more as a prognostic tool.19 While hepatic
iron concentration greater than 283 µmol/g (reference
range, 0 to 35 µmol/g) is associated with cirrhosis in
C282Y homozygotes,20 many patients with much
higher levels do not have cirrhosis.13 Even in the absence
of systemic iron overload, iron accumulates when the
liver is inflamed or cirrhosed because of other causes (such
as alcoholic steatohepatitis, transfusion and chronic hemolytic
disorders, or chronic viral hepatitis).21
Cirrhosis is a late-stage disease development and has
been reported to shorten life expectancy.22-25 Cirrhosis
is also a risk factor for hepatocellular carcinoma.13 and
typically occurs between the ages of 40 and 60 years.6
Cirrhosis prevention would be a major goal of screening
and treatment.26
Prevalence and Burden of Disease
Estimates of the general population prevalence of
hemochromatosis vary because of the long preclinical period
and lack of a consistent "case" definition. The prevalence
of cases of hemochromatosis defined biochemically
(elevated serum iron indices) will be higher than the prevalence
of cases based on documented iron overload, with or
without clinical signs and symptoms. The prevalence will
be lowest for cases based on diagnosed disease (cirrhosis,
diabetes).27 Experts have recommended defining iron
overload as distinct from hemochromatosis,4 and this
provides an objective, although not universally accepted,
standard for "early disease" based on documented increases
in body iron stores.27
On the basis of clinically diagnosed hemochromatosis
or hemochromatosis-compatible disease, 79,850 hemochromatosis-associated hospitalizations (2.3 per 100,000
residents) were projected in the United States over 18 years
(1979 to 1997), although annual rates could not be reliably
calculated.28 Of 29 million deaths from 1979 to 1992,
4858 (0.017%) were consistent with hemochromatosis as
an underlying cause.12 Age-adjusted mortality rates for
hemochromatosis-consistent deaths increased from 1.2 per
million in 1979 to 1.8 per million in 1992. These rates
were about twice as high in males as in females and in
white persons as in nonwhite persons. Both of these estimates
of the burden of disease suggest a disease prevalence
much lower than the prevalence of associated genetic mutations,
which has fueled the debate about disease penetrance.
While these statistics are probably underestimates,
primarily because of underdiagnosis,29 the extent of this
underestimation is not clear. The prevalence of hemochromatosis-attributable morbid conditions (such as cirrhosis,
diabetes, arthralgias, and fatigue or other symptoms) has
been proposed as an estimate of the burden due to undiagnosed
disease, particularly since diagnosis may commonly
be delayed as a result of the nonspecific nature of
hemochromatosis-related signs and symptoms.30 Since
these signs and symptoms are also prevalent and nonspecific,
however, relevant evidence must establish their prevalence
due to iron overload, or their excess prevalence in
association with iron overload compared with controls.
In a previous study, 297 middle-aged patients with previously
undetected hereditary hemochromatosis (homozygous for
C282Y) had a higher prevalence of diagnosed osteoarthritis,
knee symptoms, hypothyroidism, and use of antihypertensive
or thyroid replacement medications than sex- and
age-specific controls.31 However, general health, mental
health, and 52 other questionnaire-based and clinical examination-based measures of cardiovascular, respiratory,
and liver diseases were not statistically different between
case-patients and controls.
In another cross-sectional comparison
of 124 C282Y screening-detected adult homozygotes
with 22,394 wild-type/wild-type genotypic controls,
common symptoms (chronic fatigue, joint symptoms, impotence,
and limited general health) and signs (diabetes)
were no more frequent in C282Y homozygotes than controls.32 While the relative risk for physician-diagnosed
liver problems or hepatitis was increased (relative risk, 2.1
[95% CI, 1.1 to 4.0]), the proportion of C282Y homozygotes
with liver problems was modest (10%).
Similarly, in
the Hemochromatosis and Iron Overload Screening
(HEIRS) study, C282Y homozygotes had an increased
odds of self-reported liver disease (odds ratio, 3.28 [CI,
1.49 to 7.22]) compared with wild-type controls. Almost
one fourth, however, were not identified by screening.11
Clearly, the prevalence of hemochromatosis-attributable
morbid conditions is not a simple, reliable way to estimate
the disease burden associated with hemochromatosis.
Rationale for Population Screening
Screening for hemochromatosis or iron overload is
theoretically attractive and has been widely discussed over
the past 10 to 15 years, with renewed interest and a focus
on hereditary hemochromatosis since the discovery of the
HFE mutations.4,33-36 Although hereditary hemochromatosis
appears to be ideal for population screening
7,16,37-39 and for a "new paradigm for genetics and
public health",34 inadequacies in the evidence supporting
genetic screening for hereditary hemochromatosis have
precluded widespread support for population-based screening.4,9,34,40
Aims of Focused Systematic Review
This review addresses 2 major uncertainties in the evidence:
"How much disease is actually caused by HFE mutations?"
and "Does therapeutic phlebotomy treatment,
initiated through earlier identification of those with hereditary
hemochromatosis, lead to better outcomes?" We also
considered evidence for high-risk (as opposed to general
population) screening.
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Methods
We focused on hereditary HFE-associated hemochromatosis
due to C282Y homozygosity in persons of northern
European descent, which is the most prevalent form of
hereditary hemochromatosis in the United States. Other
HFE and non-HFE genetic mutations are much rarer
causes of hemochromatosis,41 and data for their disease
association are more sparse than those for C282Y homozygosity.9
Key Questions
We developed 3 explicit questions with supporting
definitions (Appendix Table 2), in
conjunction with USPSTF leads and Agency for Healthcare
Research and Quality (AHRQ) staff.
- Key question 1: What is the risk for developing clinical hemochromatosis among those with a homozygous C282Y genotype?
- Key question 2: Does earlier therapeutic phlebotomy of individuals with primary iron overload due to hereditary hemochromatosis reduce morbidity and mortality compared with treatment after diagnosis in routine clinical care?
- Key question 3: Are there groups at increased risk for developing hereditary hemochromatosis that can be readily identified before genetic screening?
Data Sources
We developed literature search strategies and terms for
each key question (Appendix Table 1) and conducted 4 separate literature searches
(for key questions 1, 2, and 3 and for background) in the
MEDLINE®, CINAHL, and Cochrane Library databases
from 1966 through February 2005. Literature searches
were supplemented with source material from experts in
the field and by examining the bibliographies of included
studies. A single investigator reviewed abstracts, and a second
reviewer independently reviewed all excluded abstracts.
Interreviewer discrepancies were resolved by consensus.
Study Selection
Using inclusion criteria developed for each key question
(described in Appendix Table 2), we reviewed 1,886 abstracts for inclusion in all
key questions (Figure, 24 KB). Literature searches were focused for
each key question but were reviewed with all key questions
in mind. We reviewed 134 full-text articles for key question
1, 69 articles for key question 2, and 55 articles for
key question 3. Two investigators rated all included articles
for quality, as well as those excluded for quality-related
reasons, using the USPSTF criteria (Appendix Table 3). Excluded articles are listed in
Appendix Tables 4 to 6.
Data Extraction and Quality Assessment
To overcome the inconsistent uses of terminology in
the literature, we adopted the set of terms in the Appendix
for extracting data from studies into tables in a consistent
format. We also established a priori screening and diagnostic
criteria for elevated iron measures and iron overload due
to hereditary hemochromatosis to guide our review and to
establish comparability between studies (Table 1).
Data were abstracted into evidence tables by a single reviewer and checked by a second reviewer (Appendix Tables 7 to 10).
We critically appraised studies according to USPSTF
methods.67 using quality criteria specific to their design
(Appendix Table 3). To augment criteria provided for
nonrandomized studies of treatment effectiveness, we
added criteria from the Cochrane Non-Randomised Studies
Methods Group.68 We eliminated any case series or
nonrandomized comparative treatment study that used a
nonsystematic method of case accrual. We critically evaluated
reported results, including the comparability of constructed
comparison groups, concerning whether confounding
factors (age, sex, alcohol intake, population
prevalence of C282Y homozygosity, and comorbid liver
disease) and secular trends in disease diagnosis and medical
care were adequately considered. We eliminated studies
with possible serious biases.
Data Synthesis
Studies were extremely heterogeneous and could not
be easily synthesized quantitatively. To evaluate whether
our review identified adequate data to create one or more
outcomes tables for illustrating the expected yield from
screening, we used an approach adapted from a previous
report.35 We considered whether there were adequate
data for genetic screening of 2 different screening populations
(general population and family-based). Insufficient
data were available to create a reliable outcomes table for
either screening approach since very few studies reported
results for all required measures (genotype, iron measures, iron
overload, and disease) among screening study participants, resulting
in extremely small numbers for within-study morbidity
estimates. Therefore, we summarized screening data in
tables, as described later.
We selected data from studies that met minimum a
priori criteria for 3 variables:
- Screening positive for elevated iron measures
- Documented iron overload.
- Morbidity due to clinical hemochromatosis.
For iron overload
and morbidity, we calculated 2 proportions (selected
and all). Among patients selected for further evaluation, we
reported the proportion of positives among those who were actually tested for iron overload or morbidity (maximum
penetrance) and, for all, the proportion who screened positive
among all those evaluated at the first screening step
(minimum penetrance). We evaluated whether results were
similar enough to combine across studies and, when they
were, we quantitatively combined study results for each
variable to generate a single point estimate for that variable.
We reported a range of results for any variable for which
individual study results were too different to be meaningfully
combined. We did not include individual study results
with 10 or fewer patients in the denominator to define a range, but we did include these results if they could be combined with other results in a single variable estimate.
Study results were reported as raw numbers for denominators
of 10 or fewer.
Role of the Funding Source
This research was funded by AHRQ under a contract
to support the work of the USPSTF. The USPSTF members
participated in the initial design and reviewed interim
results and the final evidence review. Although AHRQ had
no role in the study design, data collection, or synthesis,
AHRQ staff reviewed interim and final evidence reports
and distributed the initial evidence report for external content
review by 7 outside experts, including representatives
of professional societies and federal agencies. The subsequently
revised systematic review on which this manuscript
is based is available at http://www.ahrq.gov/clinic/serfiles.htm.
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