Hereditary
Hemochromatosis
Giuseppina Imperatore, Rodolfo Valdez, Wylie Burke
| References |
Background
Disease
Hereditary hemochromatosis (HHC, OMIM #235200) is an inherited disorder
of iron metabolism characterized by an increased absorption of iron
from the diet. Over time the excess iron accumulates in body tissues,
a condition known as iron overload, and can lead to organ damage. Iron
accumulation occurs primarily in the liver, pancreas, heart, joints,
and pituitary gland. This may result in organ failure including liver
cirrhosis, primary liver cancer, impotence, arthritis, diabetes, or
cardiomyopathy. The disease onset is insidious and often characterized
by common non-specific symptoms such as fatigue, arthralgia, and abdominal
pain. For this reason, it can be undetected for a long time and it is
usually diagnosed when advanced organ damage has already occurred. Two
methods of screening for the detection of early stage of HHC are available:
serum iron measures and molecular testing to detect mutations in the
HHC gene, called HFE. Iron overload due
to HHC can be detected before the appearance of organ damage. The most
commonly used test to identify persons at risk of developing iron overload
disease is the percent transferrin saturation (TS) (1).
An elevated TS usually occurs well before HHC clinical symptoms. The
first step for ascertaining HHC is measuring a non-fasting TS. If this
results elevated (usually > 45%), the test should be repeated after
an overnight fast (2). If fasting TS is also elevated
then more tests need to be performed to check for the presence of increased
iron stores. First, serum ferritin levels should be measured. Serum
ferritin levels above 300 μg/L in men and post-menopausal women
and > 200 μg/L in pre-menopausal
women indicate primary iron overload. Liver biopsy or quantitative phlebotomy
confirms the diagnosis of HHC and quantifies the degree of iron overload
(2). Treatment of iron overload consists in removing
the excess iron through repeated phlebotomy, which improves survival
in symptomatic persons (3-6). If phlebotomy is initiated
before the development of cirrhosis, survival rate of individuals with
HHC is similar to that of the general population (3,7,8).
Epidemiology
The lack of a standardized disease definition makes the estimate of
the prevalence of HHC complicated. HHC can be defined by the presence
of genetic mutations in the HFE gene, or
biochemical markers of iron metabolism, or the presence of clinical
symptoms. The genetic analysis identifies persons carrying one or two
copies of the two known mutations in the HFE
gene, C282Y and H63D. In the U.S., a recent population-based study estimated
that among whites the frequency of HFE
genotypes containing two mutations (C2982Y/C282Y, C282Y/H63D, and H63D/H63D)
is about 5% (9). Among these genotypes, however, the
highest risk for iron overload disease occurs with the C282Y homozygous
genotype (10). The preponderance of clinically diagnosed
HHC cases with C282Y/C282Y genotype, despite the fact that it is much
rarer than other HFE genotypes, is evidence
of the higher risk associated with this genotype. In the U.S., for example,
among whites the prevalence of homozygosity for C282Y mutation is 0.30%
(95% CI 0.12-0.82), about 1 in 333 individuals (9).
Similar estimates were reported among members of a health maintenance
organization where the prevalence of C282/C282Y genotype in whites was
0.4% (11). If we assume that about 81% of affected
individuals in the U.S. are homozygous for C282Y (12),
based on mutation analysis the estimate of HHC in the white population
of the U.S. ranges between 37 in 10,000 (30/0.81) to 62 in 10,000 (50/0.81).
In population-based intervention trials, the estimated prevalence of
homozygosity based on phenotype, defined as biochemical evidence of
iron overload, is 50 per 10,000 (95% confidence interval 17-84) for
men and 62 per 10,000 (95% confidence interval 27-97) for women (13).
In primary care settings among whites, the estimated prevalence of clinically
proven or liver biopsy proven HHC is 54 per 10,000 (14).
A higher prevalence (80/10,000) was obtained in one study when elevated
TS alone was used for defining HHC (15). This may
simply reflect the fact that a significant proportion of unaffected
or heterozygous individuals have TS levels above the cutoff, especially
when TS thresholds of 50% are used (13). Lower estimates
(3 to 19 per 10,000) are derived from autopsy studies and review of
death records. In 1992, the HHC-associated mortality rate in the American
population was reported at 1.8 deaths per million (16),
far lower than the estimated prevalence of HHC. Similarly, a study using
data from the National Hospital Discharge Survey from 1979 through 1997
estimated that the rate of hemochromatosis-associated hospitalizations
was 2.3 per 100,000 persons in the United States (17).
There are, therefore, fewer people requiring treatment or dying from
HHC than is predicted by the frequency of the HHC mutations. This may
reflect the fact that the disease is under-diagnosed, or that the penetrance
(the likelihood that a person carrying a given genotype will develop
clinical disease) of the genotype is low, or both.
Genetics
More than twenty years ago, Simon et al. (18) described
HHC as an autosomal recessive disorder linked to the HLA-A3 complex
on the short arm of chromosome 6. In 1996, Feder et al. mapped the HFE
gene on the short arm of chromosome 6 (6p21.3) and described two missense
mutations of this gene (C282Y and H63D) that accounted for the majority
of HHC patients in their study (19).
HHC due to mutations of the HFE gene occurs
commonly among whites, especially those of northern European descent
(20). HFE mutations so
far identified, however, do not account for all cases of hemochromatosis
(12). For example, in Southern Europe, non-HFE
related iron overload disorders have been described due to mutations
of the transferrin receptor 2 (TFR2) and the ferroportion gene (SLC11A3)
(21-22). Therefore, the genetics of HHC is complex.
Allelic Variants
The HFE gene codes for a 343 residue type
I transmembrane protein that associates with class I light chain beta2-microglobulin
(19). This protein binds to the transferrin receptor
and reduces its affinity for iron-loaded transferrin by 5- to 10-fold
(23). The localization of the HFE
protein in the crypt cells of the duodenum (the site of dietary iron
absorption) and its association with the transferrin receptor in those
cells are consistent with a role in regulating iron absorption (24-25).
The observation that HFE-deficient mice
(HFE gene knockout model) develop iron
overload similar to that seen in human HHC provides further evidence
that the HFE protein is involved in r iron
homeostasis (26). The C282Y mutation results from
a G-to-A transition at nucleotide 845 of the HFE
gene (845G->A) that produces a substitution of cysteine for a tyrosine
at the amino acid position 282 in the protein product. This substitution
alters the HFE protein structure and beta2-microglobulin
association, disrupting its transport to and presentation on the cell
surface (27). In the H63D mutation, a G replaces C
at nucleotide 187 of the gene (187C->G), causing aspartate to substitute
for histidine at the amino acid position 63 in the HFE
protein. The H63D mutation does not seem to prevent beta2-microglobulin
association or cell surface expression (24), indicating
that the C282Y mutation results in a greater loss of protein function
than does H63D (28).
In addition to C282Y and H63D, nine other missense mutations causing
amino acid substitutions have been documented. In one, a substitution
of a cysteine for serine at the amino acid position 65 (S65C) has been
implicated in a mild form of HHC (29). A number of intronic polymorphisms
have also been found (30). One polymorphism occurs
within the intron 4 (5569G-A) of the HFE
gene in the binding region of the primer originally described by Feder
et al. (19). One laboratory reported that when a polymerase
chain reaction (PCR)-based restriction endonuclease digestion assay
is used, the presence of this polymorphism might cause C282Y heterozygosity
to be misdiagnosed as C282Y homozygosity (31-32).
However, three groups could not replicate this finding (33-34).
Beutler et al. reported that a mutation in intron 3 (IVS3-48c) can also
lead to misdiagnose heterozygotes for the C282Y mutation as homozygotes
(35).
Genotype Prevalence
A number of studies have reported on both the general population and
the probands frequencies of the HFE genotype.
Recently, a review has summarized the results of these studies according
to the geographic origin of the populations studied (12).
In the general population, a total of 6,203 samples from European countries
revealed on average a C282Y homozygous and heterozygous prevalence of
0.4 percent and 9.2 percent, respectively. However, C282Y homozygosity
has not been reported in the general population of Southern or Eastern
Europe. The frequency of the C282Y heterozygosity varies from 1 to 3
percent in Southern and Eastern Europe to as high as 24.8 percent in
Ireland. In North America, among 3,752 samples the HFE
genotype distribution had a similar pattern: C282Y/C282Y genotype was
the rarest with a frequency of 0.5 percent and C282Y heterozygosity
was present in 9.0 percent of the samples. In the Asian, Indian subcontinent,
African/Middle Eastern, and Australasian populations, C282Y homozygotes
were not found and the frequency of C282Y heterozygosity was very low
(range: 0 to 0.5 percent). C282Y/H63D compound and H63D homozygosity
each accounted for 2 percent of the European general population and
2.5 percent and 2.1 percent in the American populations, respectively.
The heterozygous frequency of the H63D mutation was 22 percent in Europe
and 23 percent in North America.
Hanson et al. (12) recently reviewed 17 studies reporting
the frequency of the HFE genotypes among
patients with clinically diagnosed HHC. Most of the studies used case
definitions that included diagnostic evidence of iron overload from
either liver biopsy or quantitative phlebotomy. The exceptions were
a French (29) and a U.S. study (36),
which used a case definition of persistently elevated TS or elevated
serum ferritin. In all case series, the majority of patients had the
homozygous C282Y genotype. However, there was some variability across
studies. For example, among 2,229 European HHC patients, the estimated
prevalence of homozygosity for the C282Y genotype ranged from 52 percent
(37) to 96 percent (38). In North
America, among 588 patients the C282Y homozygosity ranged between 67
to 95 percent. Heterozygosity for the H63D mutation and compound heterozygosity
(C282Y/H63D) each accounted for 6 percent of European cases and 4 percent
of cases in North America. Overall, 3.6 percent (95 percent CI: 2.9,
4.3) of the patients had the C282Y/wild genotype, and 1.5 percent (95
percent CI: 1.1, 2.1) had the H63D/H63D genotype. Worldwide, among 2,929
patients 6.9 percent (95 percent CI: 6.0, 7.9) were homozygous for the
wild allele. These findings suggest that non?genetic influences, additional
HFE mutations; or variation at additional
genes affecting iron metabolism, as recently reported, may also cause
or modulate iron overload (21,22,39).
Gene-gene and Gene-environment Interactions
The clinical expression of HHC is influenced by a variety of factors,
both genetic and environmental. In HFE
knockout mice, mutations of other genes involved in iron metabolism,
such as beta2-microglobulin, transferrin receptor, and transmembrane
iron import molecule (DTM1), strongly modify the amount of liver iron
(40). It is, therefore, conceivable, that similar
gene-gene interactions may influence the course of HHC in humans. The
finding of the C282Y heterozygote genotype among some persons classified
as being affected with HHC is also suggestive of the influence of other
yet-to-be-identified HFE mutations; or
of the combination of the C282Y heterozygous state with environmental
modifying factors (e.g., high iron intake, viral hepatitis or alcohol
abuse); or of a second genetic disorder (e.g., beta-thalassemia trait,
iron loading anemia) that could account for clinical disease (41-44).
There is also evidence that sex plays a primary role in the clinical
manifestation of HHC. Family studies based on HLA-typing indicate that
the frequency of affected brothers and sisters is similar, as expected
for an autosomal recessive disorder, but the proportion of females among
probands diagnosed on the basis of clinical symptoms is 11 to 35 percent,
rather than the expected 50 percent (3,4,45).
In a large study, the prevalence of iron overload, as determined by
liver biopsy or phlebotomy, was twice as frequent in males as females
(46). This sex difference has been attributed to the
lower degree of iron overload in women because of menstruation, pregnancy
and lactation.
Other possible modifiers include chronic blood loss (gastrointestinal
bleeding, regular hematuria, helminthic or other parasitic infections)
and regular blood donation, alcohol abuse, excessive iron intake, or
vitamin C intake. Tannates, phytates, oxalates, calcium and phosphates
also modify HHC because they are known to bind iron and inhibit iron
absorption (47). Chronic viral hepatitis B and C and
metals such as zinc and cobalt may also influence expression of HHC
(47-48). Iron modulates the course
of hepatitis B (57), and iron reduction has been shown
to decrease the severity of chronic hepatitis C while increasing the
likelihood of response to antiviral therapy. Hepatitis C virus infection
and HFE mutations have also been identified
as risk factors for porphyria cutanea tarda
(49).
Laboratory Tests
Serum tests for iron status
The value of serum iron measures or HFE
mutation analysis in screening for individuals at high risk for developing
serious clinical manifestations of HHC is difficult to assess because
of uncertainties about the natural history of the disease. Thus, the
phenotype of interest must be specified before assessing the validity
of each test for screening. For example, the phenotype might be defined
by biochemical evidence of iron overload (e.g., hepatic iron index >1.9
or removal of more than 4 grams of iron by quantitative phlebotomy),
or by clinical symptoms compatible with iron overload in combination
with biochemical evidence of iron overload, or by evidence of serious
end-stage organ disease in combination with biochemical evidence of
iron overload.
The marker for serum iron status most used is percent transferrin saturation
(TS). This test can be used as a phenotypic screening test to identify
persons with biochemical evidence of iron overload. The cutoff TS values
recommended for screening have varied from 45 to 70 percent (1,14,15,50).
Using data collected in family studies and screening trials, the performance
of TS as a screening test (e.g., detection rate, false positive rate,
and positive and negative predictive values) has been estimated for
different TS cutoff levels. For example, based on published parameters,
screening at a TS cutoff level of 50% would identify about 94% and 82%
of men and women with HHC, respectively, along with a number of false
positives (about 6% of males and 3% of females screened). Assuming an
HHC genotype prevalence of about 50 in 10,000, the odds of being affected
given a positive result (OAPR) would be about 1 to 12 for males and
1 to 8 for females, corresponding to positive predictive values of 8
percent and 11 percent, respectively. Diagnostic testing (e.g., liver
biopsy or quantitative phlebotomy) is recommended for persons with a
positive screening result (either a single test result or persistently
elevated TS) and no other identifiable explanation for increased body
iron stores (e.g., chronic anemias, liver disease related to alcohol
abuse or hepatitis). In persons diagnosed to have iron overload related
to HHC by such a screening and diagnostic process, the probability of
developing at least one clinical symptom can be estimated from family
studies and screening trials to be about 50-70% for males and 40-50%
for females. It is worth noting that most complications recorded in
such studies were common and nonspecific clinical manifestations of
the disease such as joint pain and diabetes. In the absence of control
groups, the proportion of complications attributable to HHC is difficult
to determine; as a result, the probability of developing clinical complications
may be considerably lower.
Penetrance appears to be consistently lower in women than in men at
all ages. However, as many as 40% of genetically susceptible younger
individuals of both sexes do develop biochemical evidence of iron overload;
many also have non-specific symptoms compatible with early iron overload.
A smaller proportion, not well defined, may develop serious complications
such as diabetes, cirrhosis or cardiomyopathy.
Ferritin is an intracellular iron storage protein and serum ferritin
(SF) concentration significantly correlates with body iron stores (1ng/mL
= 10 mg of stored iron). SF values, but not TS values, are associated
with HHC clinical signs, and SF concentrations are higher for those
with clinical manifestations (13). SF has been used
as a second screening test in many trials, and it can be very effective
in reducing the number of false positives (46), if
cutoffs appropriate for age and sex are used. Elevation of the SF concentration
in HHC must be differentiated, however, from other liver disorders such
as alcoholic liver disease, chronic viral hepatitis, and nonalcoholic
steatohepatitis. Serum ferritin is also an acute phase reactant and
can be elevated as a result of inflammatory conditions.
HFE Gene Mutation Analysis
HFE mutation analysis identifies persons
carrying one or two copies of either of the two known mutations, C282Y
and H63D. Since the majority of clinically diagnosed probands are homozygous
for C282Y, individuals with this genotype are considered to be at the
highest risk for iron overload disease. However, approximately 20% of
HHC cases occur in persons with other HFE
genotypes, and as many as 7% have no identifiable mutation (12).
The penetrance of the different HFE genotypes
– that is, the likelihood that persons carrying a given HFE
genotype will develop manifestations of iron overload – can only
be roughly estimated from published data. The data suggest that a large
proportion of individuals with the C282Y homozygous genotype will develop
biochemical evidence of iron overload during their lifetime; we can
only speculate how many will develop clinical symptoms related to iron
overload (perhaps about half), or who will die from complications of
iron overload (likely to be a small proportion).
A screening study at a health maintenance organization in southern
California represents the only controlled study to evaluate penetrance
of the C282Y/C282Y genotype (11). The study included
41,038 adults attending a health appraisal clinic (a clinic providing
assessment of health status and prevention options, attended voluntarily)
with a mean age of 57 years, of whom 152 subjects (0.4%) had the C282Y/C282Y
genotype. Of these, 45 had previously been diagnosed with HHC (30%);
for most, the diagnosis had been made on the basis of screening. The
study evaluated 124 subjects with the C282Y/C282Y genotype, including
all those not previously diagnosed with HHC and 17 for whom data were
available prior to diagnosis. TS was elevated in 75% of men and 40%
of women and serum ferritin was elevated in 76% of men and 54% of women
with the C282Y/C282Y genotype. Compared with control subjects (22 394
white and Hispanic participants on whom questionnaire data were available
and who did not have any HFE mutations),
persons homozygous for C282Y were more likely to have a history of a“liver
problem or hepatitis” (8% vs. 4%), elevated serum aspartate aminotransferase
(8% vs. 4%), and elevated plasma collagen IV, a measure of mild liver
fibrosis (26 % vs. 11%), but were no more likely to have a history of
fatigue, joint pain, impotence, skin pigmentation, or diabetes. Among
the full cohort of 152 subjects with the C282Y/C282Y genotype, only
one, an alcoholic, had a clinical history of end-stage HHC. Two others,
out of 119 with complete data, had markedly abnormal laboratory values
suggestive of severe liver fibrosis. On the basis of these data, the
authors concluded that the likelihood of significant clinical disease
in persons with the C282Y/C282Y genotype was 1%.
This study has a potential selection bias that could have resulted
in an under-estimate of penetrance: subjects were drawn from a preventive
care setting, potentially selecting against patients with clinical disease.
The limited clinical findings among the large group of subjects with
the C282Y/C282Y genotype argues for low penetrance of the genotype,
even if it ultimately proves to be above 1%. In keeping with this conclusion,
the study found the prevalence of the C282Y/C282Y genotype was the same
among older and younger subjects (11); high penetrance
would be expected to result in premature mortality for some people with
the genotype, resulting in a lower prevalence of the genotype at older
ages. The penetrance of all other HFE genotypes
is estimated to be much lower than that of C282Y/C282Y (10).
Implications of Genetic Testing
Screening for HHC using HFE mutation analysis
could involve testing for both HFE mutations,
or only for C282Y. If both mutations are tested, about 5-6 percent of
persons of northern European descent will have a test result indicating
the presence of two HFE mutations. However,
about 0.5 percent of the general screened population with the C282Y
homozygous genotype will be at high risk of iron overload. Another 2
percent of the general population will have the compound heterozygous
(C282Y/H63D) genotype, but only about 1 in a 100 of these persons would
be expected to develop significant iron loading. If testing is limited
to C282Y, about 10 percent of the northern European population would
be identified as heterozygote, but only 0.5 percent of the population
homozygous for C282Y would be at high risk for iron overload. Either
approach would identify the majority of persons at risk for hemochromatosis,
though the risk for some persons would be low and difficult to quantify.
In other populations – eg, southern European – this screening
approach may identify a smaller proportion of persons at risk. For either
approach, costs and sequelae of screening are influenced by decisions
concerning the provision of counseling and/or clinical follow-up. For
example, the follow-up offered to all persons with the C282Y homozygous
genotype should include counseling about the uncertainty of their prognosis,
and the possibility that risk of clinical complications is low. For
persons with other genotypes, risk of iron overload disease is known
to be low, and appropriate counseling and follow-up have not been established.
Decisions concerning the counseling needs of C282Y heterozygotes would
have an important effect on the cost and outcome of a screening program,
since these persons constitute a substantial proportion of the population
(about 9 percent in populations of northern European descent). Clinical
follow-up or counseling to address their potential risk for iron overload
related to alcohol abuse or other risk factors, as well as the potential
risk to family members, would be costly. In addition, there is currently
no data to assess the value of such intervention.
Family-based detection represents an important alternative approach
to identifying people with iron overload. When a diagnosis of HHC is
made, it also identifies family members who represent a group with a
markedly higher a priori risk of iron overload
disease than the general population. Therefore, it is reasonable to
consider assessment of iron status in relatives and to monitor them
for symptoms suggestive of iron overload.
HFE genotyping provides a one-time test
to determine which relatives of an identified proband have an increased
risk of iron overload. These relatives can be offered ongoing surveillance,
while others can be reassured. However, genotyping may also cause confusion
about clinical status and adverse labeling, so the value of genotyping
as a method for family-based detection of HHC is not entirely clear.
Siblings of an affected person with the homozygous C282Y genotype have
a 25% chance of sharing the same high risk genotype; for siblings who
do not share the genotype, this single test can greatly reduce the risk.
However, HHC has occurred in some people with other HFE
genotypes (e.g., C282Y/H63D, C282Y/+) (12), suggesting
the need for caution in the interpretation of a “negative”
test result. But even the implications of a “positive” result
are not straightforward; current penetrance data make risk of disease
hard to calculate even for relatives with a C282Y/C282Y genotype, and
argue against making a diagnosis of HHC on the basis of genotype alone.
In the uncommon instance of a proband with a different HFE
genotype, genotypic studies of relatives are even more difficult to
assess, given the very low penetrance of genotypes other than C282Y/C282Y.
Testing of offspring raises even more questions, because of the high
carrier rate for HFE mutations (e.g., 9%
for C282Y, 23% for H63D in populations of European descent) (12).
If the parent with HHC is a C282Y homozygote, offspring have a 4.5%
likelihood of inheriting the same genotype (calculated as: 100% chance
of inheriting the C282Y allele from the affected parent x 9% chance
that the other parent is a C282Y carrier x 50% chance of inheriting
C282Y from the unaffected parent) and an 11.5% chance of inheriting
a C282Y/H63D genotype. All other offspring will be C282Y carriers. Because
disease occurs in middle age, there is no rationale for testing during
childhood.
Genotype testing does not substitute for the serum iron studies needed
to identify iron overload and it could expose the family member to a
premature diagnosis, unnecessary treatment, and the potential for stigma
and discrimination. These considerations underscore the need for more
information about the clinical penetrance of HFE
genotypes in HHC, and also about effective ways to counsel patients
after genetic testing to ensure an accurate understanding of the results.
Potential Benefits and Harms Associated with Genetic
Testing for HFE Mutations.
There are important potential benefits from early detection of affected
HHC persons, including prevention of significant morbidity and mortality
and long-term reduction in health care costs for those who would otherwise
suffer from serious medical complications of hemochromatosis. TS screening
has been used successfully in pilot studies, suggesting that this is
a feasible screening approach. At the same time, universal screening
for HHC would expose a large number of persons to the possibility of
adverse psychological, social or economic consequences related to a
diagnosis of HHC. As reviewed in previous sections, a majority of those
identified through screening might remain healthy without treatment.
The potential for loss of insurance or employment after a genetic diagnosis
is a concern for consumers and policymakers (51-54).
Legislative efforts to minimize such loss are being implemented (53),
but the degree of protection they will provide is unknown. Although
adverse outcomes after a diagnosis of HHC have been reported (55),
no systematic study has been undertaken to further assess these outcomes.
A genetic diagnosis may be stigmatizing, and has the additional effect
of identifying a potential risk for family members. (56).
The psychological burdens of a diagnosis of HHC may be reduced by counseling
that the diagnosis does not imply a certainty of future disease, and
that effective treatment is available to reduce future risk. Whether
communication of this kind can change the stigmatizing potential of
a diagnosis of HHC, or reduce the likelihood of discrimination, remains
to be determined. These issues are not substantially different from
those identified for other types of genetic testing (e.g., cystic fibrosis,
cancer markers), and may influence decisions about the need for counseling
procedures as part of a screening program. As with other aspects of
HHC screening, judgments about the relevance of these issues to decisions
about HHC screening must be made in the absence of definitive data.
Conclusions
Iron overload can be treated or prevented by phlebotomy, but treatment
is often delayed, resulting in irreversible organ damage. Greater physician
awareness of HHC may help reduce the morbidity and mortality of primary
iron overload. HHC is usually diagnosed after a delay of several years,
during this period care has been sought for the early non-specific symptoms
of the disorder (57). Some persons with HHC are not
diagnosed until life-threatening complications are present, e.g., diagnoses
have occurred after a liver transplant for end stage cirrhosis (58).
The delay in diagnosis of hemochromatosis suggests that physicians lack
awareness of this disorder, or have a low index of suspicion when symptoms
compatible with the early stages of the disease are present and even
sometimes when late complications are present. With early diagnosis,
preventive therapy can be instituted in the form of regular phlebotomy.
If treatment is begun before cirrhosis or diabetes has occurred, the
prognosis is good. However, late and missed diagnoses lead to under
utilization of this readily accessible preventive treatment.
A number of questions remain about the benefits and risks of identifying
and treating asymptomatic persons at high risk for HHC. “Universal”
or “population-based” screening refers to screening performed
across an entire population of mainly asymptomatic individuals not referred
for testing due to symptoms of the disease. This could be accomplished
through public health screening programs, or as part of routine testing
within primary health care settings. This should be clearly distinguished
from the alternative approach of “case finding” or “enhanced
case detection”, which could include iron status testing and/or
HFE mutation analysis in targeted populations,
such as persons at increased risk due to an affected family member or
persons who present with clinical complaints consistent with a diagnosis
of HHC. Generally accepted criteria for an effective population-based
screening test include the following:
- The disorder screened for must be well-defined
and represent an important health problem. The natural history of
the disorder should be understood.
This is, in fact, a key question. Is the disorder for which we plan
to screen hereditary hemochromatosis (HHC) or iron overload? HHC,
as defined by the HFE genotype, better
fits the criterion of a “well-defined” disorder. HHC is
a serious, treatable disorder with life-threatening complications.
However, important questions about natural history, particularly age-related
penetrance, remain and recent data raise the possibility that very
few people with the genotype will develop clinically significant disease.
Iron overload, as defined by persistently elevated TS and diagnostic
evidence of increased body iron stores, however, encompasses a broad
range of disorders, and requires a complex diagnostic protocol to
differentiate HHC from other acquired (e.g., chronic anemias, alcoholic
liver disease) and inherited causes (e.g., juvenile hemochromatosis,
non-HFE hemochromatosis). Because the
natural history of hemochromatosis has not been systematically studied,
questions remain concerning the persons most likely to benefit from
early treatment.
- The prevalence must be known and the disorder
common enough that population-based screening will be cost-effective.
Based on evidence from family studies, screening trials and mutation
analysis, the prevalence of HHC, as defined by genotype, can be estimated
to be about 50 to 60 per 10,000; lower estimates (3 to 19 per 10,000)
are derived from autopsy studies and review of death records. Estimates
of phenotype prevalence in screening trials, as defined by diagnostic
testing (e.g., liver biopsy or quantitative phlebotomy) for iron overload,
range from about 26 to more than 50 per 10,000. The prevalence of
life-threatening complications due to HHC is not well established
and may be much lower.
- Suitable screening test(s) with known performance
(detection rate, false positive rate, OAPR) must be available.
As discussed before, two well-characterized screening tests are available,
TS and HFE mutation analysis. Both tests
are readily available (though there are licensing issues with regard
to HFE testing in the US). While consensus
may have to be reached on the distribution of TS measurements in homozygous,
heterozygous and unaffected individuals, enough information is available
to allow reasonably accurate prediction of detection rates and false
positive rates using different cutoff levels of TS (alone or in conjunction
with serum ferritin). A consistent set of data is available with regard
to expected distributions of HFE genotype
frequencies among patients and in the general population. However,
screening performance cannot be fully assessed due to uncertainties
about the age-related penetrance of HHC.
- For individuals identified as screen positive,
there must be an adequate and acceptable protocol for diagnosis and
an effective treatment.
Protocols for diagnosis and treatment of HHC are available. However,
limited data are available on the outcome of treatment in persons
with HHC who are asymptomatic at the time of diagnosis.
- Adequate facilities must be available to support
screening, diagnosis and treatment.
It is likely that laboratories capable of supporting screening and
diagnostic testing methodologies either exist now, or could be developed
within a reasonable time frame. However, a number of logistical issues
need to be considered further, including: the potential burden of
time and cost to health care providers to educate patients about HHC,
offer testing, and follow up on positive screens; the anticipated
level of patient compliance with screening, diagnosis, and treatment;
proposed mechanisms of long-term follow-up and maintenance of iron
status or genotype information in patients’ medical records.
- Costs have been examined and are reasonable.
TS-based screening is likely to be cost-effective even given unfavorable
assumptions (e.g., low prevalence or rate of progression to serious
disease, low compliance). Screening for the C282Y mutation may be
cost-effective due to a lower positive rate than TS screening, with
corresponding reduced costs and burden of intervention. However, published
studies to date have not considered all costs of screening, both medical
and societal; in particular, the physician and health system effort
required for long-term follow-up and the personal psychological and
economic consequences of screening have not been evaluated (47,50,59,60).
- The approach must be considered ethical and
must be acceptable to health care providers and consumers.
Potential benefits from early detection of affected persons are significant,
including prevention of significant morbidity and mortality and long-term
reduction in health care costs. TS screening has been used successfully
in pilot studies. Concern has been raised about potential harms of
screening, including psychological morbidity, stigmatization and discrimination
(e.g., insurance or employment) resulting from a diagnosis of HHC,
particularly if the risk of clinical complications is low among those
diagnosed by screening.
Health policies regarding use of genetic information
At this time genetic testing for HFE mutations
is not recommended for population-based screening for HHC (61,62)
due to the uncertainty about disease prevalence and penetrance, the
optimal care for asymptomatic persons found to carry HFE
mutations, and the psychosocial impact of genetic testing. Mutational
analysis of the HFE gene may be useful
in confirming the diagnosis of HHC in persons with elevated iron measures
or for identifying relatives at risk to develop HHC of patients with
HHC due to the known mutations
Agenda for future HuGE research
The discovery of the HFE gene represents
an important step in understanding the nature of HHC. However, much
remains to be learned about this disorder. It is crucial to know the
age- and sex-specific penetrance of the HFE
mutations. Future efforts should also be directed towards the identification
of environmental modifiers and assessment of their interactions with
HFE genotypes. Moreover, as more and more
genes involved in iron metabolism are being discovered, attempts should
be made to understand the complex interplay of the HFE
genotype and these genes. Future studies should be performed to assess
the effectiveness of interventions to reduce disease burden in asymptotic
individuals carrying susceptibility genotypes. In addition, more information
is needed regarding the social, ethical, and psychological outcomes
of genetic screening for HHC.
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