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Blood First Edition
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2003;
DOIuse
10.1182/blood-2003-10-3564
1
Hemochromatosis mutations in the general population:
iron overload progression rate
Running head: Hemochromatosis mutations in the general population
Rolf Værn Andersena, M.Sc., Ph.D., Anne Tybjærg-Hansenc,d, M.D., D.M.Sc., Merete Appleyardd,
Henrik Birgensb, M.D., D.M.Sc., and Børge Grønne Nordestgaarda,d, M.D., D.M.Sc.
a
Dept. Clinical Biochemistry, and bDept. Hematology, Herlev University Hospital, cDept. Clinical
Biochemistry, Rigshospitalet, Copenhagen University Hospital, and dThe Copenhagen City Heart
Study, Bispebjerg University Hospital, University of Copenhagen, Denmark.
Scientific heading: Clinical observations, Interventions, and Therapeutic trials
Word count: 2959 (excluding tables, figure legends and references), 202 (abstract).
Corresponding author: Børge G. Nordestgaard, M.D., D.M.Sc.
Dept. Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev,
Denmark. Phone: +45 44883297; Fax: +45 44883311. E-mail: [email protected]
Financial support:
Supported financially by the Danish Heart Foundation and Chief Physician Johan Boserup’s and
Lise Boserup’s Fund.
1
Copyright (c) 2003 American Society of Hematology
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Abstract
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 two subjects each of five other HFE genotypes with respect to gender,
age, and alcohol consumption. As a function of biological age, transferrin saturation increased from
50-70% from 25-85 years and from 70-80% from 35-80 years in female and male C282Y
homozygotes, respectively. Equivalently, ferritin levels increased from 100-500 µg/L and decreased
from 800-400 µg/L in female and male C282Y homozygotes. As a function of 25 years follow-up
irrespective of age, transferrin saturation and ferritin 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, 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 10-20 years.
2
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3
Hereditary hemochromatosis is a disease caused by iron accumulation in the body due to excess iron
absorption from the intestinal tract1. 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 gene2.
Hereditary hemochromatosis may be one of the most common genetic disorders among
people of Northern European descent3,4. Therefore, hereditary hemochromatosis could be an ideal
condition for population screening5,6; however, penetrance of C282Y homozygosity remains
controversial7-19. Accordingly, before such screening procedures can be recommended we need to
know in individuals from the general population the iron overload progression rate among healthy
C282Y homozygotes.
We genotyped 9174 individuals from the Danish general population, The Copenhagen
City Heart Study20. 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.
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4
Experimental procedures
Subjects
The basis for this study was 9174 subjects from The Copenhagen City Heart Study (3rd examination,
1991-94)20,21. These individuals were selected after age and gender stratification based on the
Danish Central Population Register code to represent the Danish general population.
More than 99% were Whites of 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 ethical 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 two subjects each
of wild type/wild type, H63D/wild type, H63D/H63D, C282Y/wild type and C282Y/H63D
genotypes, respectively, with respect to gender, age (in 10-year groups), and alcohol consumption
(in gender-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; we followed each individual for up to 25 years comprising four
investigations between 1976 and 2001. Plasma samples from 1976-78 and 1981-83 stored at -20°C,
serum samples from 1991-94 stored at -80°C, as well as newly drawn serum samples from 2001,
were used.
To study life-time penetrance, we conducted a 4th examination in 2001 comprising the
20 C282Y homozygotes still alive. During this examination, blood samples were obtained and in
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addition patients were questioned about possible illnesses and examined physically by a
hemochromatosis specialist (HB). 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 genotyping was as described20. Transferrin was measured on a Nephelometer
Analyzer II (Behring), while follicle-stimulating hormone, luteinizing hormone and ferritin was
determined on a Technicon Immuno 1TM System (Bayer). Ferritin >250 µg/L in men and >200 µg/L
in women was chosen as indication of iron overload. Aspartate aminotransferase was measured on a
Hitachi 705 autoanalyser. Albumin, alkaline phosphatase, bilirubin and iron (except for the 1976-78
and 1981-83 samples) were measured on a Vitros 950 autoanalyser (Johnson & Johnson). Because
plasma samples from the 1976-78 and 1981-83 investigations contained EDTA, iron contents of
these samples were measured by atomic absorption photometry on a Perkin-Elmer 403 photometer.
Statistical analyses
Statistical analyses were performed using SPSS22. A p-value <0.05 on a two-sided test was
significant. Correction for multiple comparisons was not performed. A priori we stratified by
gender. We used Mann-Whitney U-test for two-genotype comparisons. The smoothed relation
between age and transferrin saturation and ferritin (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.
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Results
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%;19.7-21.3%), 158 were H63D/H63D (1.7%;1.52.0%), 846 were C282Y/wild type (9.2%;8.6-9.9%), 131 were C282Y/H63D compound
heterozygous (1.4%;1.2-1.7%) and 23 were homozygous for C282Y (0.25%;0.16-0.38%)20.
Iron status cross-sectionally
Transferrin saturation levels were increased in C282Y homozygotes (p<0.001), C282Y/H63D
compound heterozygotes (p<0.001), C282Y/wild type (p<0.05) and H63D/H63D (p<0.01) when
compared with wild type/wild type (Figure 1). 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 to 70% at 85 years in female C282Y
homozygotes and from 70% at 35 years to 80% at 80 years 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
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(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, ferritin levels increased from 120 to 500 µg/L in female C282Y
homozygotes, from 30 to 150 µg/L in female C282Y/H63D compound heterozygotes and from 25
to 80 µg/L in female wild type/wild type individuals (Figure 2). From 35 to 80 years, ferritin levels
declined from 800 to 400 µg/L in male C282Y homozygotes, was stable around 150 µg/L in male
C282/H63D compound heterozygotes, but increased in male wild type/wild type individuals from
40 to 150 µg/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 at most modestly (Figure 3). This was also the case for
ferritin levels.
Life-time penetrance
Of the 23 C282Y homozygotes, 14 women and 6 men with median ages of 66 years (range 35-85)
and 62 years (range 45-81) were alive in 2001 (Table 1). Only 4 of these had been blood donors, and
only one gave more than 50 units. Three patients died from lung cancer, atherosclerotic heart
disease, and malignant melanoma, respectively.
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 of 452 µg/L, and the
subsequent finding of C282Y homozygosity without clinically overt hemochromatosis (No.17).
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Among C282Y homozygotes, 13 of 16 women and 5 of 7 men developed transferrin saturation >50
%. Iron-overload defined as ferritin >200 µg/L was found in 10 of 16 women and defined as ferritin
>250 µg/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 age 72 years (Table 1, No.13). Lack of secondary hypogonadism was demonstrated by
normal age-adjusted values of follicle-stimulating hormone and luteinizing hormone in all C282Y
homozygotes (Table 1). Levels of aspartate aminotransferase, follicle-stimulating 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 age 55 years (No.21) and age 68 years (No.13). Two C282Y homozygotes had
universal arthralgias (Table 1, No.1&7), but none had clinical signs of arthritis at physical
examination. None of the homozygotes had skin darkening.
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Discussion
Iron overload progression rate
Transferrin saturation increased from 50-70% from 25-85 years and from 70-80% from 35-80 years
in female and male C282Y homozygotes, respectively, a phenomenon not observed for other
genotypes. Within the same age ranges, ferritin levels increased from 100-500 µg/L and decreased
from 800-400 µg/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 cross-sectional studies8-15.
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
Olynyk et al16, where 5 of 12 C282Y homozygotes had static or decreasing ferritin levels during a 4
years observation period. We have no explanation for why one patient dropped from over 1000 µg/L
to less than half the initial value. He was not phlebotomized or loosing blood in another manner.
Life-time penetrance
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 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
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10
ferritin >2000 µg/l and aspartate aminotransferase at the upper limit of normal, suggesting that he
might have hepatic fibrosis23. In addition, one woman had been blood donor >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 two C282Y homozygotes who suffered from non-specific
arthralgias had ferritin levels of only 280 and 330 µg/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 0-5 %
at age 64 years, which is supported by three previous studies7-9. 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 one 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
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Copenhagen21. Second, since clinical manifestations in hereditary hemochromatosis will not appear
before age 40 years24, we could have studied too young individuals; however, median ages at
investigation was 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 form24, 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 two
large population-based studies and a study of blood donors evaluating the clinical penetrance of
C282Y homozygosity7-9. A similar low penetrance was also suggested by a large necropsy study of
patients with liver cirrhosis25. 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%; 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 genotypes. Furthermore, the C282Y genotype
frequencies in our study did not differ from that predicted from the Hardy-Weinberg equilibrium
(women+men: p=0.35; women: p>0.9; men: p=0.10). 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 below 50 years age at the last
analysis. This is a rather small group to reach firm conclusions regarding age-related changes
ranging from 35 to 80 years of age. Therefore, to increase the statistical power iron load progression
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rate was examined according to the length of follow-up as well as a function of biological age.
Concerning transferrin saturation the conclusion was similar from the two 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 two plots. As a function of increasing biological age ferritin levels seemed to decrease; however,
this most likely was caused by the two relatively young males with very high ferritin levels (see
Figure 2). Thus, as a function of follow-up time ferritin levels increased slightly even in male
C282Y homozygotes (see Figure 3).
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 over 1000 up to 2433 µg/L and many had transferrin saturation
over 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 10-20
years.
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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.
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Acknowledgements
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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References
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Beutler E, Bothwell TH, Charlton RW, Motulsky AG. Hereditary hemochromatosis. In: Scriver
CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease.
8th ed. New York, NY: McGraw-Hill, 2001:3127-61.
2. Feder JN, Gnirke A, Thomas W , et al. A novel MHC class I-like gene is mutated in patients
with hereditary haemochromatosis. Nat Genet. 1996;13:399-408.
3. Barton JC, Bertoli LF. Hemochromatosis: the genetic disorder of the twenty-first century. Nat
Med. 1996;2:394-5.
4. Smith BN, Kantrowitz W, Grace ND , et al. Prevalence of hereditary hemochromatosis in a
Massachusetts corporation: is Celtic origin a risk factor? Hepatology. 1997;25:1439-46.
5. Edwards CQ, Griffen LM, Ajioka RS, Kushner JP. Screening for hemochromatosis: phenotype
versus genotype. Semin Hematol. 1998;35:72-6.
6. Adams PC. Population screening for hemochromatosis. Hepatology. 1999;29:1324-7.
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7. Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845G A (C282Y) HFE
hereditary haemochromatosis mutation in the USA. Lancet. 2002;359:211-8.
8. Åsberg A, Hveem K, Krüger Ø, Bjerve KS. Persons with screening-detected haemochromatosis:
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10. Åsberg A, Hveem K, Thorstensen K, et al. Screening for hemochromatosis: High prevalence
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11. Beaumont C, Simon M, Fauchet R, et al. Serum ferritin as a possible marker of the
hemochromatosis allele. N Engl J Med. 1979;301:169-174.
12. Meyer T, Baynes R, Bothwell T, et al. Phenotypic expression of the HLA linked iron-loading
gene in males over the age of 40 years: a population study using serial serum ferritin
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13. Milman N, Clausen JO, Jordal R. Iron status in young Danish men and women: A population
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14. Bassett ML, Halliday JW, Ferris RA, Powell LW. Diagnosis of hemochromatosis in young
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15. Beutler E, Felitti V, Gelbart T, Ho N. The effect of HFE genotypes in patients attending a health
appraisal clinic. Ann Intern Med. 2000;133:329-337.
16. Olynyk JK, Cullen DJ, Aquilia S, Rossi E, Summerville L, Powell LW. A population-based
study of the clinical expression of the hemochromatosis gene. N Engl J Med. 1999;341:718-24.
17. Crawford DH, Jazwinska EC, Cullen LM, Powell LW. Expression of HLA-linked
hemochromatosis in subjects homozygous or heterozygous for the C282Y mutation.
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19. Bulaj ZJ, Ajioka RS, Phillips JD , et al. Disease-related conditions in relatives of patients with
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20. Ellervik C, Mandrup-Poulsen T, Nordestgaard BG , et al. Prevalence of hereditary
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21. Schnohr P, Jensen G, Lange P, Scharling H, Appleyard M. The Copenhagen City Heart Study:
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SPSS Inc., 1998.
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24. Bothwell TH, MacPhail AP. Hereditary hemochromatosis: etiologic, pathologic, and clinical
aspects. Semin Hematol. 1998;35:55-71.
25. Willis G, Wimperis JZ, Lonsdale R, Fellows IW, Watson MA, Skipper LM, Jennings BA.
Incidence of liver disease in people with HFE mutations. Gut. 2000;46:401-4.
26. Merryweather-Clarke AT, Simonsen H, Shearman JD, Pointon JJ, Norgaard-Pedersen B,
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Legends
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 gender, age and alcohol
consumption with two persons each of the five other genotypes. Due to technical error, the sample
from one of the 23 C282Y homozygotes was not measured, and consequently the two 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=0.05, **p=0.01, ***p=0.001.
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 gender, age and alcohol consumption with two 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.
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 gender, age and alcohol consumption with two 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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Figure 4. Average levels with standard error of aspartate aminotransferase (ASAT), folliclestimulating hormone (FSH) and luteinizing hormone (LH) as a function of HFE genotype.
Twenty-three C282Y homozygotes were each matched for gender, age and alcohol consumption
with two persons each of the five other genotypes. Levels in mutation carriers were tested against
wild type/wild type (WT/WT) levels using Mann-Whitney U-tests: none were significant.
20
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Fig. 1
21
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Fig. 2
22
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Fig. 3
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Fig. 4
24
Table 1. Characteristics of C282Y homozygotes at the 2001 investigation
Subject
no.
Age at
Previous
Blood
Transferrin
investi-
hemochroma-
donor
saturation
gation
tosis diagnosis
(units)
(%)
Ferritin
Liver
disease¤
Diabetes
Hypo-
Cardio-
mellitus^
§
myopathy
gonadism
Arthritis
(µg/L)
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
45
**Yes
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
*Subjects no. 5, 8 and 18 died before 2001; their data are from the 1991-94 examination.**Subject no.17 was diagnosed with subclinical haemochromatosis in late 1999; all his data refer to this timepoint.¤Based on symptoms; aspartate aminotransferase >50 IU/L; alkaline phosphatase >275 IU/L;
coagulation factors II+VII+X <70%; bilirubin >17 µmol/L. ^Based on symptoms; non-fasting glucose >8.3 mmol/L; HbA1c >0.063. Subject no. 13 was
on insulin. §Based on symptoms; follicle-stimulating hormone <24 IU/L for post-menopausal women, <1.3 IU/L for others; luteinizing hormone
<13.5 IU/L for post-menopausal women, <1.3 IU/L for others.
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
Women
From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
Prepublished online December 4, 2003;
doi:10.1182/blood-2003-10-3564
Hemochromatosis mutations in the general population: iron overload
progression rate
Rolf Vaern Andersen, Anne Tybjaerg-Hansen, Merete Appleyard, Henrik Birgens and Borge Gronne
Nordestgaard
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