Blood, 1 December 2000, Vol. 96, No. 12, pp. 3707-3711
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Asymptomatic hemochromatosis subjects: genotypic and
phenotypic profiles
Ronald L. Sham,
Richard F. Raubertas,
Caroline Braggins,
Joseph Cappuccio,
Margaret Gallagher, and
Pradyumna D. Phatak
From the Department of Medicine, Rochester General
Hospital, the Mary M. Gooley Hemophilia Center Inc, and The University
of Rochester School of Medicine and Dentistry, Rochester, NY; and The
Centers for Disease Control and Prevention, Atlanta GA.
 |
Abstract |
Screening for hereditary hemochromatosis (HHC) by means of
transferrin saturation (TS) levels has been advocated and will identify
many patients who are asymptomatic. The purposes of this study were (1)
to determine HFE genotypes among asymptomatic HHC patients and
correlate this profile with the degree of iron overload and (2) to
evaluate the relationship between mobilized iron (mob Fe), age, serum
ferritin (SF), and quantitative hepatic iron (QHI) in this population.
One hundred twenty-three asymptomatic HHC patients were evaluated;
all had quantitative phlebotomy to determine mob Fe and
genotyping for C282Y and H63D mutations. Liver biopsies with QHI
determinations were performed on 72 of the 123 patients. Of the entire
group, 60% were homozygous for C282Y, and 13% were compound
heterozygotes (C282Y/H63D). Among asymptomatic patients, the prevalence
of homozygous C282Y is lower compared with previous studies that
include clinically affected patients. Of those patients with more than
4 g mob Fe, 77% were homozygous C282Y. Asymptomatic patients with
lower iron burdens frequently had genotypes other than homozygous
C282Y. There was no correlation between age and mob Fe in these
patients; however, there was a correlation between mob Fe and both SF
(r = 0.68) and QHI (r = 0.75). In conclusion, asymptomatic
patients with moderate iron overload had a different genotypic profile
than was seen in advanced iron overload. The significance of
identifying patients with modest degrees of iron loading, who may not
be homozygous for C282Y, must be addressed if routine TS screening is
to be implemented.
(Blood. 2000;96:3707-3711)
© 2000 by The American Society of Hematology.
| |
Introduction |
Hereditary hemochromatosis (HHC) is a common
disorder with a prevalence of 3 to 8 per 1000.1,2 Patients
with HHC have enhanced gastrointestinal absorption of iron and may
accumulate excessive iron stores, causing organ
dysfunction.3,4 A clinical diagnosis of HHC can often be
established on the basis of serum iron studies5-8; however,
a liver biopsy and determination of quantitative hepatic iron
(QHI)9-11 are often required to confirm the presence of
tissue iron overload. Noninvasive alternatives to liver biopsy include
quantitative phlebotomy with determination of mobilized iron (mob
Fe)12 and, more recently, testing for HFE
mutations.13,14
Two point mutations in the HFE gene, C282Y and H63D (single-letter
amino acid codes), have been described in HHC patients; 64% to 100%
of HHC cases are homozygous C282Y, with other identified patients being
compound heterozygotes, H63D homozygotes, heterozygotes for either
mutation, or normal.15 These 2 HFE mutations have different prevalence rates and degrees of penetrance in causing iron overload. The C282Y mutation has a gene frequency of 0.029 to 0.07 and thus a heterozygote prevalence of 5.8% to 14%.16-19 The penetrance of this mutation has been speculated to be high, but
these conclusions are based on only a few tested individuals. The H63D
mutation is fairly prevalent in control (presumed normal) subjects,
with a heterozygote prevalence of 25% and a homozygote prevalence of
3.62%. The penetrance is presumed to be low and estimated by one group
at 0.017. Recently, another mutation in the HFE gene has been
identified and designated S65C.20 The prevalence of this
mutation and its role in clinically significant iron overload
remain to be determined.
Many features of HHC make it a rational candidate for population
screening,21-24 and both phenotypic and genotypic
screening strategies have been advocated. Phenotypic screening using
serum transferrin saturation (TS) levels has the advantages of being inexpensive and clinically relevant. Some practitioners are
implementing this approach. The role of HFE genotyping as a
confirmatory test in patients with suspected HHC has not been fully
studied. Some experts have suggested that HFE genotyping in the setting
of clinically suspected HHC can help confirm the diagnosis, precluding
the need for liver biopsy in some cases.14,25
The variability in the reported prevalence of homozygous C282Y in
HHC patients may reflect ethnic differences as well as the manner in
which patients are identified, hence reflecting total body iron burden.
Our center has offered phlebotomy treatment to all patients with a
clinical diagnosis of HHC. This report describes the distribution of
HFE genotypes and body iron burdens in asymptomatic patients with
presumed HHC identified by TS screening in one of the following
settings: our screening study, family screening, or routine screening
by their primary care physicians. In addition, we evaluated the
relationship between mob Fe and age, serum ferritin (SF), and QHI
in patients who were C282Y homozygotes. As routine screening
for HHC using TS testing becomes more commonplace, it is necessary
to have a comprehensive understanding of the laboratory phenotypes and
genotypes that can be seen in identified patients.
| |
Patients and methods |
The 123 patients in this report were identified by TS testing
and referred to our treatment center. The mechanisms used include our
primary care screening study,2 family screening of
first-degree relatives of known patients, and routine screening by
primary care physicians. Of the 33 patients identified by family
screening, 11 have at least 1 first-degree relative who is also part of
our cohort. Thus, this group of 123 patients represents 113 distinct families. The 62 patients identified by "routine
screening" either were found to have an elevated serum iron level on
a routine chemistry profile or were screened with serum iron studies at
the discretion of their primary care physician. The rationale for
screening is unknown to us and was probably not the same for each
patient; however, when these patients were evaluated in our treatment
center, they were all asymptomatic with no history or findings that
would have warranted testing for HHC. This group includes patients with biopsy-proven HHC and patients presumed to have HHC on the basis of
clinical and laboratory parameters. The clinically diagnosed cases
include patients with elevated TS and SF values who have no known
underlying disorder associated with iron loading such as hepatitis,
alcoholic liver disease, thalassemia, or sideroblastic anemia.
(Although patients with increased TS and with such disorders were
referred to us, they are not included in this analysis.) Liver biopsies
were performed in 72 of the 123 patients. All patients underwent
therapeutic phlebotomy to achieve a state of iron depletion (SF lower
than 25), enabling us to determine their mob Fe stores. Mob Fe was
determined on the basis of the total blood volume removed prior to
achieving a state of iron depletion with the use of the following
formula: grams of iron = Hct/3 × weight of blood × 0.0035.
HFE genotyping was performed by means of a method known as TaqMan. This
technology uses the 5' to 3' exonuclease activity of DNA Taq polymerase
and 2 fluorescence-tagged DNA oligonucleotide probes to differentiate
the wild-type sequence and the mutant sequence during the DNA
amplification process. The genotyping and amplification processes were
carried out simultaneously in the Applied Biosystem's Prism 7700 Sequence Detection System. The fluorescent output of probes was
calculated by the manufacturer's software to define the 3 genotypes
(homozygous normal, heterozygous, and homozygous mutation) of each
locus. The validity of this genotyping process has been extensively
tested, and results are comparable to those with other methodologies.
Comparison of the distribution of genotypes between groups was made by
means of Fisher's exact test. Comparisons of iron load were made with
the Mann-Whitney test. Spearman rank correlation was used to assess the
association between measures of iron load.
| |
Results |
Table 1 shows the distribution of
HFE genotypes in 123 asymptomatic patients cared for in our HHC center
who were identified by screening. There was a trend toward a higher
prevalence of homozygous C282Y in patients identified by family
screening compared with other screening modalities, but differences in
genotype distributions were not statistically significant
(P = .10). Overall, there was a lower prevalence of
homozygous C282Y among our cohort of asymptomatic patients compared
with clinically affected patients reported in other
series.16,18,19,26,27 Since asymptomatic patients are
likely to have lower body iron stores, we examined the degree of iron
loading relative to genotype (Table 2).
Eight patients had less than 1.5 g mob Fe; 5 of these 8 patients
were homozygous C282Y yet had no evidence of significant iron overload.
Of the patients with iron burdens lower than 4 g identified by
screening, 50% had genotypes other than C282Y/C282Y. In the 48 patients with greater than 4 g mob Fe, 77% were C282Y homozygotes. There were 30 patients with greater than 5 g mob Fe;
27 of 30 (90%) of this group were homozygous C282Y. Thus, as the
degree of iron overload increased, so did the likelihood of having the
homozygous C282Y genotype.
It is known that iron stores increase throughout an individual's
lifetime.28 It is also known that because of the
physiologic blood loss associated with menses, pregnancy, and
childbirth, women with HHC accumulate iron more gradually than men.
Therefore, we evaluated our mob Fe data in the context of patient age
and sex among patients who are C282Y homozygotes (Figure
1). C282Y homozygous men had greater iron
loading than women (male median mob Fe = 4.6 g; female median mob
Fe = 3.4 g; P = .012). In neither sex was there a
significant correlation between age and degree of iron loading
(r = 0.22, P = .12 for men; r = 
0.01,
P = .98 for women).
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| Figure 1.
Distribution of mob Fe in relation to age and
sex.
Mob Fe is plotted here as a function of age and sex for C282Y
homozygotes. Overall, women had lower degrees of iron loading than men
(median = 3.4 g for women; median = 4.6 g for men). In this
asymptomatic population of men and women identified by screening, there
was no correlation between age and degree of iron loading (r = 0.22
for men; r = 0.01 for women). The mean age for patients with
greater than 4 g mob Fe was 48.9 years, and the mean age for
patients with between 1.5 and 4 g mob Fe was 51.2 years.
|
|
SF is a rough indicator of total body iron, and SF levels are used to
monitor phlebotomy therapy. There is evidence that end organ damage
such as cirrhosis is rare in patients with SF values lower than 750 to
1000 µg per liter.29 We therefore looked at the
relationship between SF and mob Fe in patients who are homozygous C282Y
(Figure 2). We focused on this subgroup
of patients because it is a more defined, genotypically uniform
population. There was a significant correlation between mob Fe and SF
of 0.68 (P < .001). There was also a correlation between
mob Fe and SF in the entire group of patients (r = 0.59,
P < .001; data not shown). In patients with greater than
4 g mob Fe, the range of SF was 289 to 2995 µg per liter. It is
notable that some of these patients have significant iron overload
despite an SF that is only slightly above the upper limit of normal.
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| Figure 2.
Correlation between SF and mob Fe.
SF values from the homozygous C282Y patients are plotted here against
mob Fe. The Spearman rank correlation between mob Fe and ferritin
is r = 0.68 (P < .001). The correlation
between mob Fe and ferritin in all 123 patients is r = 0.59
(P < .001; data not shown).
|
|
Finally, we evaluated the correlation between QHI and mob Fe in C282Y
homozygous patients who underwent liver biopsy (Figure 3). The correlation between QHI and mob
Fe in C282Y homozygotes was 0.75 (P < .001). When the
entire patient population (all genotypes) was evaluated, the
correlation was 0.70 (P < .001; data not shown). Of the 72 patients who underwent liver biopsy, 47 were C282Y
homozygotes; 13 of these patients had a hepatic iron index
(HII) less than 1.9. Of the C282Y/C282Y patients, 2 had
cirrhosis; one of these had typical histologic features of HHC and an
HII of 6.4, and the other had steatohepatitis and a modest degree of
iron overload (QHI 52.1 µmol/gram). Cirrhosis was not seen in
any patients with the other genotypes.
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| Figure 3.
Correlation between quantitative hepatic iron and mob
Fe.
Liver biopsy and QHI determinations were done for 47 C282Y/C282Y
patients. QHI is plotted here against mob Fe. The Spearman rank
correlation between QHI and mob Fe is r = 0.75
(P < .001).
|
|
| |
Discussion |
Many questions remain regarding the optimal screening strategy for
HHC, the need for liver biopsy, the role of HFE genotyping, and the
relationship between HFE genotype and clinical measures of iron
stores.23 Population screening using TS levels has been advocated by some, and efforts to implement TS screening are under way.
However, there are many unanswered questions regarding the diagnosis,
natural history, and management of HHC in asymptomatic patients
identified by screening.23 The purpose of this study was
to analyze the distribution of HFE genotypes in asymptomatic patients
diagnosed with HHC following TS testing and to further delineate the
phenotypes of identified patients. A better understanding of the
penetrance and natural history of the disease in patients identified in
this manner is crucial before population screening by means of TS
levels is widely implemented.
The definition of HHC for the purpose of this study is a clinical one.
All patients with repeat TS values greater than 45%, SF greater than
200, and no clinically identifiable secondary cause of iron loading
were considered to have presumed HHC and underwent quantitative
phlebotomy. Liver biopsy was performed when indicated. We recognize
that not all these individuals may meet strict genotypic or phenotypic
disease definitions. Advocates of genotypic disease definition would
argue that only C282Y homozygotes have true HHC. Of our patients, 60%
were C282Y homozygotes, and an additional 13% were compound
heterozygotes for the C282Y and H63D mutations. However, significant
iron loading is seen in the absence of these genotypes,30
and 9 out of 33 (27%) of our patients with other genotypes had more
than 4 g of mob Fe.
A strict phenotypic definition requires documented tissue iron loading
established by liver biopsy with quantitative iron determination (HII
of 1.9 or more or QHI of 71 µmol/gram). However, liver biopsy
is invasive and probably not necessary in all cases. A more practical
approach to TS screening would be to perform therapeutic phlebotomy and
estimate mob Fe in identified patients that have suspected HHC.
Thresholds of 4 and 5 g have been used to define clinically
significant iron overload. Many C282Y homozygotes do not have enough
iron overload to meet such strict phenotypic definitions. Of C282Y
homozygotes in our population, 37 of 74 (50%) had mob Fe less than
4 g, and 5 of 74 (7%) had Mob Fe less than 1.5 g. This is
consistent with recently reported population screening studies in which
50% of C282Y homozygotes had no clinical manifestations, 19% had
normal SF levels, and 19% had an HII of 1.9 or
less.31 However, 94% had an elevated TS and would have been detected by TS screening.
Mob Fe is a measure of total body iron stores and, in this study,
correlated reasonably well with QHI in patients who had a liver biopsy
(R = 0.75). Our data are consistent with other reports that show a
rough correlation between QHI and mob Fe.12 Our patient
population differs from populations in previous reports in that all
patients analyzed were asymptomatic C282Y homozygotes. Although the
correlation between mob Fe and SF was 0.68, we identified some patients
with clinically significant mob Fe who had SF values only at the upper
limit of normal. Thus, a relatively low ferritin level (300 to 500 µg
per liter) may not exclude clinically relevant iron overload.
Our study showed a poor correlation between mob Fe and age in both men
and women in this cohort of patients. The value of this analysis is
limited since our study, by definition, excludes those homozygotes with
normal SF levels who did not undergo therapeutic phlebotomy and also
excludes symptomatic patients with higher degrees of iron loading. Our
data are consistent with other series of modestly iron-loaded patients
in which iron load correlates poorly with age.12 It is
well known that iron stores in a given individual increase during that
person's lifetime.28 One would predict that inclusion of
all homozygotes in the population would show an increase of iron stores
with age. However, our data demonstrate that among this asymptomatic
cohort, there is low enough correlation between age and iron stores
that the value of the HII in this setting is questionable. In fact, 13 of 47 C282Y homozygotes who underwent liver biopsy had an HII of 1.9 or
lower. Women were more likely than men to have a low HII; 6 of 15 females and 7 of 32 males had an HII of 1.9 or lower.
Our study demonstrates that TS screening will identify many individuals
with only modest degrees of iron loading who may not meet traditional
phenotypic diagnostic criteria but who have genotypes associated with
iron loading. Those with lower degrees of iron overload are less likely
to be C282Y homozygotes. This concept is shown schematically in Figure
4.
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| Figure 4.
Iron overload: genotype versus phenotype.
The range of possible iron stores for each genotype is schematically
represented. Homozygosity for C282Y leads to the greatest amount of
iron loading, but many homozygotes may have normal iron stores.
Screening identifies individuals with lower body iron stores and thus a
higher proportion of individuals with genotypes other than
homozygous C282Y.
|
|
Patients with modest degrees of iron overload (mob Fe 1.5 to 4 g)
are less likely to have classic clinical features of HHC. The natural
history of these patients is not clear. Although some may, over time,
develop clinically significant iron overload, it is possible that
others may never be affected by their elevated iron stores. Modest iron
loading may potentially have other adverse effects, as suggested by
epidemiological studies showing an association with cardiovascular
disease.32 Until the natural history of patients with
modest iron loading is better defined, we would recommend empiric
phlebotomy treatments, particularly in those with genotypes considered
at risk, in an effort to maintain normal body iron stores.
TS screening will also identify many cases of HHC with significant iron
overload. Although SF is a useful measurement, it is only a
rough predictor of the degree of iron loading. When liver biopsy is
either unnecessary to the clinician or unacceptable to the patient,
quantitative phlebotomy with determination of mob Fe is a useful
diagnostic and therapeutic tool. Most individuals with significant iron
overload are homozygous for C282Y. The significance and natural history
of other genotypes with iron overload identified by TS screening need
to be determined by large-scale prospective studies. In the meantime,
implementation of TS screening seems reasonable provided practitioners
understand the clinical implications associated with detection in this manner.
| |
Acknowledgment |
The authors thank the Centers for Disease Control and Prevention
for processing the HFE genotyping.
| |
Footnotes |
Submitted March 22, 2000; accepted July 31, 2000.
Supported in part by Agency for Health Care Policy and Research grant
RO1 HS07616 and by the National Heart, Lung and Blood Institute grant
RO1 HL61428-01A1.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Ronald L. Sham, Rochester General Hospital, 1425 Portland Ave, Rochester, NY 14621; e-mail: ronald.sham{at}viahealth.org.
| |
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Abstract
Introduction
