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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Hemochromatosis mutations in the general population: iron
overload progression rate
Rolf Værn Andersen, Anne Tybjærg-Hansen, Merete Appleyard, Henrik Birgens, and Børge Grønne Nordestgaard
The progression rate of iron overload in
hereditary hemochromatosis in individuals in the general population is unknown.
We therefore examined in the general
population iron overload progression rate
in C282Y homozygotes. Using a cohort
study of the Danish general population,
The Copenhagen City Heart Study, we
genotyped 9174 individuals. The 23 C282Y
homozygotes identified were matched to
2 subjects each of 5 other HFE genotypes
with respect to sex, age, and alcohol
consumption. As a function of biologic
age, transferrin saturation increased from
50% to 70% from 25 to 85 years of age and
from 70% to 80% from 35 to 80 years of
age in female and male C282Y homozygotes, respectively. Equivalently, ferritin
levels increased from 100 to 500 ␮g/L and
decreased from 800 to 400 ␮g/L in female
and male C282Y homozygotes. As a function of 25 years follow-up irrespective of
age, transferrin saturation and ferritin levels increased slightly in male and female
C282Y homozygotes. None of the C282Y
homozygotes developed clinically overt
hemochromatosis. In conclusion, individuals in the general population with
C282Y homozygosity at most demonstrate modest increases in transferrin
saturation and ferritin levels, and clinically overt hemochromatosis is rare.
Therefore, C282Y homozygotes identified
during population screening, and not because of clinically overt hemochromatosis, at most need to be screened for
manifestations of hemochromatosis every 10 to 20 years. (Blood. 2004;103:
2914-2919)
© 2004 by The American Society of Hematology
Introduction
Hereditary hemochromatosis is a disease caused by iron accumulation in the body due to excess iron absorption from the intestinal
tract.1 This leads to increased transferrin saturation and ferritin
levels, and may cause progressive organ damage such as liver
cirrhosis, type 1 diabetes mellitus, hypogonadotropic hypogonadism, cardiomyopathy, arthritis, and bronze coloring of the skin.
Most hereditary hemochromatosis patients are homozygous for
C282Y (Cys282Tyr) of the HFE gene.2
Hereditary hemochromatosis may be one of the most common genetic disorders among people of Northern European
descent.3,4 Therefore, hereditary hemochromatosis could be an
ideal condition for population screening5,6; however, penetrance of C282Y homozygosity remains controversial.7-19 Accordingly, before such screening procedures can be recommended we need to know the iron overload progression rate
among healthy C282Y homozygotes in individuals from the
general population.
We genotyped 9174 individuals from the Danish general
population, The Copenhagen City Heart Study.20 Measured as
increases in transferrin saturation and ferritin levels, we studied
iron overload progression rate in C282Y homozygotes during 25
years follow-up. In addition, we assessed all symptoms, signs,
hospitalizations, and deaths of C282Y homozygotes.
Patients, materials, and methods
From the Department of Clinical Biochemistry and Department of Hematology,
Herlev University Hospital, Copenhagen, Denmark; Department of Clinical
Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen,
Denmark; and The Copenhagen City Heart Study, Bispebjerg University
Hospital, University of Copenhagen, Copenhagen, Denmark..
Boserup’s and Lise Boserup’s Fund.
Subjects
The basis for this study was 9174 subjects from The Copenhagen City Heart
Study (third examination, 1991-1994).20,21 These individuals were selected
after age and sex stratification based on the Danish Central Population
Register code to represent the Danish general population.
More than 99% were of white Danish descent. The study protocol
conformed to the ethical guidelines of the Declaration of Helsinki: the study
was approved by the Steering Committee of The Copenhagen City Heart
Study, Herlev University Hospital, and the Danish ethics committee for
Copenhagen and Frederiksberg (No.100.2039/91). All participants gave
written informed consent in accordance with the Helsinki protocol.
Design
In a cross-sectional design, each subject homozygous for C282Y was
matched to 2 subjects each of wild type/wild type, H63D/wild type,
H63D/H63D, C282Y/wild type, and C282Y/H63D genotypes with respect
to sex, age (in 10-year groups), and alcohol consumption (in sex-specific
tertiles).
To study iron overload progression rate, the matched individuals of wild
type/wild type, C282Y/H63D, and C282Y/C282Y genotypes were used to
follow the development of iron status from 25 to 85 years of age; we
followed each individual for up to 25 years comprising 4 investigations
between 1976 and 2001. Plasma samples from 1976 to 1978 and 1981 to
Reprints: Børge G. Nordestgaard, Dept Clinical Biochemistry, Herlev
University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark; e-mail:
[email protected].
Submitted October 22, 2003; accepted December 2, 2003. Prepublished online
as Blood First Edition Paper, December 4, 2003; DOI 10.1182/blood-2003-10-3564.
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.
Supported by the Danish Heart Foundation and Chief Physician Johan
© 2004 by The American Society of Hematology
2914
BLOOD, 15 APRIL 2004 䡠 VOLUME 103, NUMBER 8
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BLOOD, 15 APRIL 2004 䡠 VOLUME 103, NUMBER 8
1983 stored at ⫺20°C, serum samples from 1991 to 1994 stored at ⫺80°C,
as well as newly drawn serum samples from 2001 were used.
To study lifetime penetrance, we conducted a fourth examination in
2001 comprising the 20 C282Y homozygotes still alive. During this
examination, blood samples were obtained and in addition patients were
questioned about possible illnesses and examined physically by a hemochromatosis specialist (H.B.). Previous disease was also assessed by reviewing
the Danish National Hospital Discharge Register and the Danish National
Register of Causes of Deaths; these registers cover all citizens of Denmark
and all Danish hospitals from 1976 through 1999.
Measurements
HEMOCHROMATOSIS MUTATIONS IN GENERAL POPULATION
2915
Statistical analyses
Statistical analyses were performed using SPSS.22 A P value less than .05
on a 2-sided test was significant. Correction for multiple comparisons was
not performed. A priori we stratified by sex. We used Mann-Whitney U test
for 2-genotype comparisons. The smoothed relation between age and
transferrin saturation and ferritin levels (log transformed) in different
genotype groups was investigated using local linear regression (smoother
function, normal kernel, bandwidth multiplier value ⫽ 5 years); ferritin
levels were log transformed to approach normal distribution.
Results
described.20
Hemochromatosis genotyping was as
Transferrin was
measured on a Nephelometer Analyzer II (Behring, Düdingen, Switzerland), while follicle-stimulating hormone levels, luteinizing hormone
levels, and ferritin levels were determined on a Technicon Immuno 1
System (Bayer, Leverkusen, Germany). Ferritin level higher than 250
␮g/L in men and higher than 200 ␮g/L in women was chosen as
indication of iron overload. Aspartate aminotransferase was measured
on a Hitachi 705 autoanalyzer (Hitachi, Tokyo, Japan). Albumin levels,
alkaline phosphatase levels, bilirubin levels, and iron levels (except for
the 1976-1978 and 1981-1983 samples) were measured on a Vitros 950
autoanalyzer (Johnson & Johnson, Rochester, NY). Because plasma
samples from the 1976-1978 and 1981-1983 investigations contained
EDTA (ethylenediaminetetraacetic acid), iron contents of these samples
were measured by atomic absorption photometry on a Perkin-Elmer 403
photometer (Shelton, CT).
Of 9174 subjects from the Danish general population, 6135 were
wild type/wild type (66.9%; 95% CI, 65.9%-67.8%), 1881 were
H63D/wild type (20.5%; 95% CI, 19.7%-21.3%), 158 were
H63D/H63D (1.7%; 95% CI, 1.5%-2.0%), 846 were C282Y/wild
type (9.2%; 95% CI, 8.6%-9.9%), 131 were C282Y/H63D compound heterozygous (1.4%; 95% CI, 1.2%-1.7%), and 23 were
homozygous for C282Y (0.25%; 95% CI, 0.16%-0.38%).20
Iron status cross-sectionally
Transferrin saturation levels were increased in C282Y homozygotes (P ⬍ .001), C282Y/H63D compound heterozygotes
(P ⬍ .001), C282Y/wild type (P ⬍ .05), and H63D/H63D
(P ⬍ 0.01) when compared with wild type/wild type (Figure 1).
Figure 1. Average levels with standard error of iron status parameters as a function of HFE genotype. Twenty-three C282Y homozygotes were each matched for sex,
age, and alcohol consumption with 2 persons each of the 5 other genotypes. Due to technical error, the sample from one of the 23 C282Y homozygotes was not measured, and
consequently the 2 matched persons in each of the other genotypes were also excluded. Dashed lines are upper borders of reference intervals; for ferritin these borders differ
between women and men. Levels in mutation carriers were tested against wild type/wild type (WT/WT) levels using Mann-Whitney U tests: *P ⫽ .05, **P ⫽ .01, ***P ⫽ .001.
Error bars indicate the standard error of the mean.
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2916
BLOOD, 15 APRIL 2004 䡠 VOLUME 103, NUMBER 8
ANDERSEN et al
These differences in C282Y homozygotes and C282Y/H63D
compound heterozygotes versus wild type/wild type were similar
when men and women were examined separately. Only C282Y
homozygotes had average transferrin saturation levels above 50%.
Ferritin levels were increased in C282Y homozygotes compared
with wild type/wild type, irrespective of whether men and women were
examined separately or together (Figure 1). However, there was no
difference in ferritin levels between C282Y/H63D compound heterozygotes and wild type/wild type, indicating that individuals with this
genotype did not show evidence of iron overload.
Iron overload progression rate
Transferrin saturation increased from 50% at 25 years of age to 70% at
85 years of age in female C282Y homozygotes and from 70% at 35
years of age to 80% at 80 years of age in male C282Y homozygotes on
local linear regression analysis, whereas transferrin saturation did not
increase with age in female or male wild type/wild type individuals and
in female or male C282Y/H63D compound heterozygotes (Figure 2).
Transferrin saturation values oscillated most in C282Y homozygotes,
somewhat less in C282Y/H63D compound heterozygotes, and least in
wild type/wild type individuals.
From 25 to 85 years of age, ferritin levels increased from 120 to
500 ␮g/L in female C282Y homozygotes, from 30 to 150 ␮g/L in
female C282Y/H63D compound heterozygotes, and from 25 to 80
␮g/L in female wild type/wild type individuals (Figure 2). From 35
to 80 years of age, ferritin levels declined from 800 to 400 ␮g/L in
male C282Y homozygotes, were stable around 150 ␮g/L in male
C282/H63D compound heterozygotes, but increased in male wild
type/wild type individuals from 40 to 150 ␮g/L. Ferritin values
oscillated more in C282Y homozygotes than in wild type/wild type
individuals or in C282/H63D compound heterozygotes.
As a function of 25-, 15-, and 15-year follow-up in female and
male C282Y homozygotes, C282Y/H63D compound heterozygotes, and wild type/wild type individuals, respectively, transferrin
saturation increased modestly at most (Figure 3). This was also the
case for ferritin levels.
Lifetime penetrance
Of the 23 C282Y homozygotes, 14 women and 6 men with median
ages of 66 years (range, 35-85 years) and 62 years (range, 45-81
years) were alive in 2001 (Table 1). Only 4 of these had been blood
donors, and only one gave more than 50 units. One patient died
from lung cancer, one patient died from atherosclerotic heart
disease, and one patient died from malignant melanoma.
Clinically overt hemochromatosis was not diagnosed in any of
the 23 C282Y homozygotes before the study (Table 1); one was
accidentally diagnosed with increased iron levels, which lead to
measurement of transferrin saturation of 80% and ferritin level of
452 ␮g/L and the subsequent finding of C282Y homozygosity
without clinically overt hemochromatosis (no.17). Among C282Y
homozygotes, 13 of 16 women and 5 of 7 men developed
transferrin saturation higher than 50%. Iron overload defined as
ferritin level higher than 200 ␮g/L was found in 10 of 16 women,
and iron overload defined as ferritin level higher than 250 ␮g/L was
found in 6 of 7 men.
Liver disease or enlargement was not observed in any of the
C282Y homozygotes (Table 1). Diabetes mellitus type 1 was only
found in one C282Y homozygote, a 77-year-old woman diagnosed
at 72 years of age (Table 1 no.13). Lack of secondary hypogonadism was demonstrated by normal age-adjusted values of folliclestimulating hormone and luteinizing hormone in all C282Y homozygotes (Table 1). Levels of aspartate aminotransferase, folliclestimulating hormone, and luteinizing hormone did not differ
between C282Y homozygotes and wild type/wild type (Figure 4).
None of the C282Y homozygotes received treatment for heart
failure, indicating lack of hemochromatosis-associated cardiomyopathy (Table 1). Two homozygotes had acute myocardial infarction
at 55 years of age (no. 21) and 68 years of age (no. 13). Two C282Y
homozygotes had universal arthralgias (Table 1 nos.1 and 7), but
none had clinical signs of arthritis at physical examination. None of
the homozygotes had skin darkening.
Figure 2. Levels of transferrin saturation and ferritin in selected genotypes over a follow-up period of up to 25 years, shown as a function of age at measurement.
Twenty-three C282Y homozygotes were each matched for sex, age, and alcohol consumption with 2 persons each of wild type/wild type and C282Y/H63D genotypes. Data for
a given individual are connected with lines. Panels to the right show local linear regression curves for women and men separately.
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BLOOD, 15 APRIL 2004 䡠 VOLUME 103, NUMBER 8
HEMOCHROMATOSIS MUTATIONS IN GENERAL POPULATION
2917
Figure 3. Levels of transferrin saturation and ferritin in selected genotypes over a follow-up period of up to 25 years, shown as a function of follow-up time.
Twenty-three C282Y homozygotes were each matched for sex, age, and alcohol consumption with 2 persons each of wild type/wild type and C282Y/H63D genotypes. Data for
a given individual are connected with lines. Panels to the right show local linear regression curves for women and men separately.
Table 1. Characteristics of C282Y homozygotes at the 2001 investigation
Age at
Subject investigation,
no.
y
Previous
hemochromatosis
diagnosis
Blood donor,
units
Transferrin
saturation,
%
Ferritin, ␮g/L
Liver
disease*
Diabetes
mellitus†
Hypogonadism‡
Cardiomyopathy
Arthritis
Women
1
35
No
0
58
330
No
No
No
No
Arthralgia
2
42
No
0
6
24
No
No
No
No
No
3
48
No
0
45
351
No
No
No
No
No
4
51
No
0
66
116
No
No
No
No
No
5§
52
No
ND
100
117
No
No
No
No
No
6
56
No
12
77
73
No
No
No
No
No
7
57
No
2
63
280
No
No
No
No
Arthralgia
8§
66
No
ND
73
646
No
No
No
No
No
9
65
No
⬎ 50
55
623
No
No
No
No
No
10
67
No
0
44
43
No
No
No
No
No
11
73
No
10
77
570
No
No
No
No
No
12
76
No
0
86
156
No
No
No
No
No
13
77
No
0
56
595
No
Yes†
No
No
No
14
81
No
0
84
813
No
No
No
No
No
15
85
No
0
57
710
No
No
No
No
No
16
85
No
0
89
424
No
No
No
No
No
Men
17㛳
45
Yes㛳
0
80
452
No
No
No
No
No
18§
58
No
ND
63
1162
No
No
No
No
No
19
49
No
0
50
511
No
No
No
No
No
20
60
No
0
74
2062
No
No
No
No
No
21
63
No
0
75
557
No
No
No
No
No
22
77
No
0
45
188
No
No
No
No
No
23
81
No
0
97
668
No
No
No
No
No
ND indicates no data.
*Based on symptoms; aspartate aminotransferase level ⬎ 50 IU/L; alkaline phosphatase level ⬎ 275 IU/L; coagulation factors II ⫹ VII ⫹ X ⬍ 70%; bilirubin level ⬎ 17 ␮M.
†Based on symptoms; nonfasting glucose level ⬎ 8.3 mM; HbA1c (␤-N-valyl-1-deoxyfructose hemoglobin) ⬎ 0.063. Subject no. 13 was on insulin.
‡Based on symptoms; follicle-stimulating hormone levels ⬍ 24 IU/L for postmenopausal women, ⬍ 1.3 IU/L for others; luteinizing hormone levels ⬍ 13.5 IU/L for
postmenopausal women, ⬍ 1.3 IU/L for others.
§Subject nos. 5, 8, and 18 died before 2001; their data are from the 1991-1994 examination.
㛳Subject no. 17 was diagnosed with subclinical hemochromatosis in late 1999; all his data refer to this time point.
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2918
BLOOD, 15 APRIL 2004 䡠 VOLUME 103, NUMBER 8
ANDERSEN et al
Lifetime penetrance
Figure 4. Average levels with standard error of aspartate aminotransferase
(ASAT), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) as a
function of HFE genotype. Twenty-three C282Y homozygotes were each matched
for sex, age, and alcohol consumption with 2 persons each of the 5 other genotypes.
Levels in mutation carriers were tested against wild type/wild type (WT/WT) levels
using Mann-Whitney U tests, none were significant. Error bars indicate standard error
of the mean.
Discussion
Iron overload progression rate
Transferrin saturation increased from 50% to 70% from 25 to 85
years of age and from 70% to 80% from 35 to 80 years of age in
female and male C282Y homozygotes, respectively, a phenomenon
not observed for other genotypes. Within the same age ranges,
ferritin levels increased from 100 to 500 ␮g/L and decreased from
800 to 400 ␮g/L in female and male C282Y homozygotes. Our
observation of at most only modest increases in transferrin
saturation and ferritin levels with increasing age in C282Y
homozygotes are in accordance with results of previous crosssectional studies.8-15
Pathophysiologically, our data are compatible with the idea that
most C282Y homozygotes in the population at large will develop
biochemical iron overload early in adult life. Thereafter, the rate of
increase in ferritin levels and probably in accumulation of iron is
not larger in C282Y homozygotes than in individuals without
C282Y homozygosity. Thus, most C282Y homozygotes will only
reach a level of modest iron overload.
Each C282Y homozygote had an oscillating course in ferritin
levels. Some even had stable or decreasing levels, indicating
lack of progressive iron loading. This is in accordance with the
study of Olynyk et al,16 where 5 of 12 C282Y homozygotes
had static or decreasing ferritin levels during a 4-year observation period. We have no explanation for why one patient
dropped from greater than 1000 ␮g/L to less than half the
initial value. He was not treated with phlebotomy or loosing
blood in another manner.
Our data indicate that, although the majority of C282Y homozygotes biochemically had iron overload, none developed clinically
overt hemochromatosis. The only patient known to be a C282Y
homozygote before this study was accidentally diagnosed and did
not suffer from hemochromatosis. Only one patient had unequivocal biochemical signs of hemochromatosis, since he had serum
ferritin level higher than 2000 ␮g/L and aspartate aminotransferase
at the upper limit of the normal range, suggesting that he might
have hepatic fibrosis.23 In addition, one woman had been a blood
donor more than 50 times, and therefore these phlebotomies could
have protected her from developing clinically overt hemochromatosis. The C282Y homozygote with type 1 diabetes mellitus had a
very late disease onset and only slightly increased ferritin levels,
and therefore her diabetes mellitus might not be related to
hemochromatosis. Finally, the 2 C282Y homozygotes who suffered
from nonspecific arthralgias had ferritin levels of only 280 and 330
␮g/L, indicating that hemochromatosis most likely was not responsible for these complaints. In accordance with this, Beutler et al7
did not observe differences between C282Y homozygotes and
controls with respect to joint complaints.
Therefore, among the patients still alive in 2001, at most one
C282Y homozygote had biochemical signs compatible with subclinical hemochromatosis, indicating a penetrance of 0% to 5% at 64
years of age, which is supported by 3 previous studies.7-9 Consequently, other previous studies suggesting that at least half of
C282Y homozygotes ultimately will develop clinical signs of
hemochromatosis16-19 clearly is not supported by our data. In the
present study, all living C282Y homozygotes were informed about
their genotype status, the possibility of a slightly increased risk of
developing hemochromatosis, and that phlebotomy could be considered now or later on. Of the 20 C282Y homozygotes still alive in
2001, all were referred to a hospital for further control and possible
treatment for hemochromatosis (in 2001), which therefore will not
affect the results of the present study. Before the study, only 1 of 23
homozygotes was treated with phlebotomy, but this person did not
suffer from hemochromatosis.
Potential limitations
First, the low penetrance of C282Y homozygosity in this study
most likely was not due to selection bias, since all individuals were
randomly selected from the general population of Copenhagen.21
Second, since clinical manifestations in hereditary hemochromatosis will not appear before 40 years of age,24 we could have studied
individuals who were too young; however, median ages at investigation were 66 and 62 years in female and male C282Y homozygotes, making this possibility unlikely. Third, since women develop
manifestations of hemochromatosis later in life than men and
usually in a milder form,24 the minority of men in our study could
have influenced the result in favor of lesser iron overload.
However, this was probably not the case, since our results agree
with 2 large population-based studies and a study of blood donors
evaluating the clinical penetrance of C282Y homozygosity.7-9 A
similar low penetrance was also suggested by a large necropsy
study of patients with liver cirrhosis.25 Fourth, as we found fewer
male (7 homozygotes among 4096 participants ⫽ 0.17%; 95% CI,
0.07%-0.35%) than female C282Y homozygotes (16 among 5078
participants ⫽ 0.32%; 95% CI, 0.18%-0.51%), the former could
have died at an earlier age or not been able to participate in The
Copenhagen City Heart Study; however, the average age of male
C282Y homozygotes was similar to that of men with other
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BLOOD, 15 APRIL 2004 䡠 VOLUME 103, NUMBER 8
HEMOCHROMATOSIS MUTATIONS IN GENERAL POPULATION
genotypes. Furthermore, the C282Y genotype frequencies in our
study did not differ from that predicted from the Hardy-Weinberg
equilibrium (women and men, P ⫽ .35; women, P ⬎ .9; men,
P ⫽ .10). Fifth, it seems unlikely that we underdiagnosed the
282Y allele, because C282Y genotype frequencies did not differ
from the Hardy-Weinberg equilibrium and because the 95%
confidence interval for the allele frequency for 282Y in our study of
5.3% to 5.9% overlapped that reported for 219 Danish newborns
of 5.5% to 10.9%.26
Regarding progression with age, the main objective of the
present study, the relatively small number of C282Y homozygotes,
represents a limitation. Of the 23 patients only 7 were men, the
most critical subgroup in the study, and only 3 of these men were
younger than 50 years of age at the last analysis. This is a rather
small group to reach firm conclusions regarding age-related
changes in patients ranging from 35 to 80 years of age. Therefore,
to increase the statistical power, iron load progression rate was
examined according to the length of follow-up as well as a function
of biologic age. Concerning transferrin saturation, the conclusion
was similar from the 2 different plots, namely that transferrin
saturation increased slightly with age in both female and male
C282Y homozygotes. This was also the case for ferritin levels in
female C282Y homozygotes; both plots demonstrated moderate
increases with age. Progression in ferritin levels in male C282Y
homozygotes differed in the 2 plots. As a function of increasing
biologic age, ferritin levels seemed to decrease; however, this most
likely was caused by the 2 relatively young males with very high
ferritin levels (Figure 2). Thus, as a function of follow-up time,
ferritin levels increased slightly even in male C282Y homozygotes
(Figure 3).
2919
Regarding phenotype, the work up was not completely satisfactory. A rough clinical evaluation is not enough to determine
conclusively that clinical disease is negligible. Three of the 23
homozygotes had serum ferritin levels greater than 1000 up to 2433
␮g/L and many had transferrin saturation greater than 75%. In such
patients we cannot totally exclude liver fibrosis or cirrhosis.
Therefore, initially we considered whether we should perform liver
biopsies on these participants; however, for ethical reasons we
abstained from performing liver biopsy because these persons
appeared healthy. All C282Y homozygous individuals were referred for further control for hemochromatosis.
In conclusion, the average individual in the general population with
C282Y homozygosity at most demonstrates modest increases in transferrin saturation and ferritin during 25 years follow-up and rarely
develops clinically overt hemochromatosis. Therefore, C282Y homozygotes identified during population screening, and not because of
clinically overt hemochromatosis, at most need to be screened for
manifestations of hemochromatosis every 10 to 20 years.
The future challenge will be to identify the few C282Y
homozygotes who will develop serious progressive iron accumulation leading to organ damage. Other genetic and environmental
factors that regulate iron absorption and thus may modulate the
phenotype of C282Y homozygotes need to be identified.
Acknowledgments
We thank Vibeke Wohlgehagen, Hanne Damm, and Nina Kjersgaard for excellent technical assistance and Niels Fogh-Andersen
for introduction to atomic absorption photometry.
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From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
2004 103: 2914-2919
doi:10.1182/blood-2003-10-3564 originally published online
December 4, 2003
Hemochromatosis mutations in the general population: iron overload
progression rate
Rolf Værn Andersen, Anne Tybjærg-Hansen, Merete Appleyard, Henrik Birgens and Børge Grønne
Nordestgaard
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