Editorial
Screening for Hemochromatosis
SEE ARTICLE ON PAGE 1160
Hereditary hemochromatosis is a disorder of iron metabo-
lism caused by an inappropriate increase in intestinal iron
absorption, which, if untreated, may result in the insidious
development of damage to various body organs including the
liver, pancreas, and heart. In 1996, Feder et al.1 identified a
novel gene, now termed HFE, on chromosome 6. Eighty-two
percent of iron-loaded subjects carried a G to A base
substitution resulting in a cysteine rather than a tyrosine
residue at position 282 of the hemochromatosis gene prod-
uct. In the United States, Northern Europe, and Australia,
approximately 90% of subjects with primary iron overload
are homozygous for the C282Y mutation.2-4 Population
studies based on phenotypic assessment of body iron stores
have consistently shown that the condition affects 1:200-300
persons of Caucasian ancestry and that it is possibly the most
common autosomal recessive disorder in this racial group.5,6
The clinical evolution of the disorder during life is well
understood. There is a lengthy stage of clinically insignificant
iron accumulation, followed by a period of iron overload with
reversible organ injury, and treatment by venesection therapy
during these periods restores life expectancy to normal.7 A
disease with these characteristics should be an ideal disorder
for widespread population screening.
In this edition of HEPATOLOGY, Adams et al. draw our
attention to the issue of screening for C282Y-associated
hemochromatosis by investigating the utility of the unsatu-
rated iron-binding capacity (UIBC) as the initial test in a
protocol for screening for iron overload in 5,211 blood
donors.8 They found 16 C282Y homozygotes in their study
population and claimed that UIBC performed better than
transferrin saturation and was cost effective in identifying
persons who should be genotyped. These findings should be
considered in the context of a recent report from our center in
which the cost per case detected using a similar strategy was
$AUS 2,268 (approximately $US 1,500).9 Despite confirming
the clinical and economic utility of UIBC as an initial
screening tool, there are aspects of the report by Adams et al.
that require further consideration.
First, we are concerned about imprecise and confusing
terminology with regard to transferrin saturation. The gold
Abbreviations: UIBC, unsaturated iron-binding capacity; TIBC, total iron-binding
capacity.
From the Departments of Gastroenterology and Hepatology, and Chemical Pathology,
Princess Alexandra Hospital, Brisbane, Australia.
Received March 8, 2000; accepted March 8, 2000.
Address reprint requests to: Darrell H. G. Crawford, Department of Gastroenterology
and Hepatology, Princess Alexandria Hospital, Ipswich Road, Woolloongabba, Brisbane
QLD 4102, Australia. E-mail: crawford@health.qld.gov.au; fax: (61) 7-3240-5111.
Copyright r 2000 by the American Association for the Study of Liver Diseases.
0270-9139/00/3105-0022$3.00/0
doi:10.1053/he.2000.7354
1192
standard method of measuring transferrin saturation requires
colorimetric measurement of iron and immunochemical
measurement of transferrin. Transferrin saturation can be
calculated because the molecular weight of transferrin is
precisely known. This assay, which has been carefully and
precisely standardized, was not the method of transferrin
saturation used in the current study. Rather, Adams et al.
measured TIBC saturation (i.e. serum iron/serum iron 1
UIBC) as a surrogate marker of transferrin saturation. TIBC
saturation may show considerable bias with respect to the
transferrin saturation due to inadequate standardization.10
If a screening program based on phenotype were under-
taken, the present choices for the initial screening strategy are
estimation of transferrin saturation, estimation of TIBC
saturation, or estimation of UIBC. The investigators claim
that UIBC was a considerably less expensive test than TIBC
saturation and performed better than TIBC saturation in
identifying C282Y homozygotes.8 It is difficult to understand
why there is such a cost advantage for UIBC over TIBC
saturation when the tests differ only by the measurement of
serum iron; the additional cost of measuring serum iron,
when a UIBC has already been requested, is only a few cents.
We also believe that it is questionable to extrapolate compari-
sons of test performance of UIBC and TIBC saturation in
predicting homozygosity for C282Y from blood donors to the
rest of the population because phlebotomy is the treatment of
the disease under consideration. Indeed, 4 of the 16 C282Y
homozygotes had TIBC saturations below 40%. We have
recently used the UIBC to screen a hospital population for
C282Y homozygous hemochromatosis and, although it per-
formed adequately, we did not identify as many persons as
anticipated from screening studies, even after correction for
racial admixture. We believe that this reflects that UIBC is
inferior to transferrin saturation as a screening strategy.
Direct immunochemical measurement of transferrin satura-
tion is now possible on some large laboratory analyzers, but it
is still more expensive than colorimetric measures of TIBC.
Carefully standardized TIBC assays may yet be the best front-
line test for C282Y hemochromatosis screening, but this
requires further study.
An alternative to the phenotypic screening strategy out-
lined by Adams et al. is initial testing for the C282Y mutation.
If this were conducted in adults, both iron loaded and
nonexpressing homozygotes (see below) would be detected.
Because up to 30% of women homozygous for C282Y do not
express the disease, this would raise difficult social, voca-
tional, and insurance issues. If screening for the genotype
were undertaken in the neonatal population, further difficult
ethical issues would arise, and mechanisms that provide
long-term follow-up would need to be established. At pres-
ent, the cost of genotype analysis precludes its use as an
initial screening instrument.11 However, new technology may
reduce the cost of genotype analysis and the role of screening
on the basis of genotype may have to be revisited in the
future.
HEPATOLOGY Vol. 31, No. 5, 2000
Which population(s) should be screened? Before this
question can be categorically answered, the question of
precisely what is the disease burden associated with hemochro-
matosis needs to be resolved. The discordance between the
prevalence of iron overload or HFE mutations in the popula-
tion and death statistics and the paucity of patients with
C282Y-associated hemochromatosis undergoing liver trans-
plantation suggests that the disease burden is modest.12 We
know that end organ damage is related to the severity of iron
overload and reduces life expectancy,13,14 but we do not know
with confidence what proportion of C282Y homozygotes will
develop end organ damage if left untreated. There is, how-
ever, emerging data that define the clinical implications of
homozygosity for the C282Y mutation. Fifteen to 20% of
patients homozygous for the C282Y mutation have a normal
serum ferritin concentration.15 This observation is supported
in the report by Adams et al. because 3 patients (all of whom
donated less than 5 units of blood) had normal or low serum
ferritin concentrations. Furthermore, in a study of 3,011
subjects, Olynyk et al.16 identified 12 new subjects homozy-
gous for the C282Y mutation. Three of these cases had serum
ferritin concentrations less than 60 ng/mL and were asymp-
tomatic. Nonexpressing subjects are usually women of child-
bearing age, reflecting the effect of physiological blood loss
on disease expression. However, genetic factors—probably in
the HFE gene region—can also influence disease expression
as evidenced by the concordance of disease expression
between siblings and the association of the ancestral haplo-
type with a more severe phenotype.17-19 Olynyk et al.16
identified a further 3 patients with established fibrosis or
cirrhosis who were clearly at risk of future liver-related
complications. The cost effectiveness of screening for hemo-
chromatosis is within acceptable guidelines even if only 20%
of patients develop life-threatening complications. Thus, the
report by Olynyk et al. provides strong support for screening
in Caucasian populations, and the results of further studies of
the clinical expression of the disease are eagerly awaited.
We believe that national screening programs for hemochro-
matosis are unlikely to develop in most countries in the
foreseeable future. In the absence of such programs, we
suggest that healthy ambulant primary care populations are
the most appropriate group to be screened. In our opinion,
whether the most appropriate initial test will be transferrin
saturation, TIBC saturation, or UIBC still requires further
evaluation. Nevertheless, Adams et al. outline a sensible
screening strategy using a relatively low-cost phenotypic
marker to identify those subjects who may consider undergo-
ing genotypic analysis.
DARRELL H. G. CRAWFORD, MD, FRACP
PETER HICKMAN, PHD, MBBS, FRCPA
Department of Gastroenterology and Hepatology
Department of Chemical Pathology
Princess Alexandra Hospital,
Brisbane, Australia
CRAWFORD AND HICKMAN 1193
REFERENCES
1. Feder JN, Gnirke A, Thomas W, Tsuchibashi Z, Ruddy DA, Basava A,
Dormishlan F, et al. A novel MHC class-I like gene is mutated in patients
with hereditary haemochromatosis. Nat Genet 1996;13:399-408.
2. Jouanolle AM, Gandon G, Jezequel P, Blayau M, Campion ML, Yaouanq
J, Mosser J, et al. Haemochromatosis and HLA-H. Nat Genet 1996;14:251-
252.
3. Beutler E, Gelbart T, West C, Lee P, Adams M, Blackstone R, Pockros P, et
al. Mutational analysis in hereditary hemochromatosis. Blood Cells Mol
Dis 1996;22:187-194.
4. Jazwinska EC, Cullen LM, Busfield F, Pyper WR, Webb SI, Powell LW,
Morris CP, et al. Haemochromatosis and HLA-H [letter]. Nat Genet
1996;14:249-251.
5. Leggett BA, Halliday JW, Brown NN, Bryant S, Powell LW. Prevalence of
haemochromatosis amongst asymptomatic Australians. Br J Haematol
1990;74:525-530.
6. Smith BN, Kantrowitz W, Grace ND, Greenberg MS, Patton TJ, Ookubo
R, Sorger K, et al. Prevalence of hereditary hemochromatosis in a
Massachusetts Corporation: is Celtic origin a risk factor? HEPATOLOGY
1997;25:1439-1446.
7. Williams R, Smith PM, Spicer EJ, Barry M, Sherlock S. Venesection
therapy in idiopathic hemochromatosis. An analysis of 40 treated and 18
untreated patients. Q J Med 1969;38:1-16.
8. Adams PC, Kertesz AE, McLaren CE, Barr R, Bamford A, Chakrabarti S.
Population screening for hemochromatosis: a comparison of unbound
iron binding capacity, transferrin saturation and C282Y genotyping in
5,211 voluntary blood donors. HEPATOLOGY 2000;31:1160-1164.
9. Hickman PE, Hourigan LF, Powell LW, Cordingley F, Dimeski G,
Ormiston B, Shaw J, et al. Automated measurement of unsaturated iron
binding capacity is an effective screening strategy for C282Y homozy-
gous haemochromatosis. Gut 2000;46:405-409.
10. Gambino R, Desvarieux E, Orth M, Matan H, Acattupathil T, Lijoi E,
Wimmer C, et al. The relation between chemically measured total
iron-binding capacity concentrations and immunologically measured
transferrin concentrations in human serum. Clin Chem 1997;43:2408-
2412.
11. Adams PC, Valberg LS. Screening blood donors for hereditary haemochro-
matosis: decision analysis model comparing genotyping to phenotyping.
Am J Gastroenterol 1999;94:1593-1600.
12. Burke W, Franks AL, Bradley L. Screening for hereditary hemochromato-
sis: are DNA-based tests the answer? Mol Med Today 1999;5:428-430.
13. Bassett ML, Halliday JW, Powell LW. Value of hepatic iron measurements
in early hemochromatosis and determination of the critical iron level
associated with fibrosis. HEPATOLOGY 1986;6:24-29.
14. Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D,
Strohmeyer G. Long-term survival in patients with hereditary hemochro-
matosis. Gastroenterology 1996;110:1107-1119.
15. Crawford DHG, Jazwinska EC, Cullen LM, Powell LW. Expression of
HLA-linked hemochromatosis in subjects homozygous or heterozygous
for the C282Y mutation. Gastroenterology 1998;114:1003-1008.
16. Olynyk JK, Cullen DJ, Aquilia S, Rossi E, Summerville L, Powell LW. A
population-based study of the clinical expression of the hemochromato-
sis gene. N Engl J Med 1999;341:718-724.
17. Crawford DH, Halliday JW, Summers KM, Bourke MJ, Powell LW.
Concordance of iron storage in siblings with genetic hemochromatosis:
evidence for a predominantly genetic effect on iron storage. HEPATOLOGY
1993;17:833-837.
18. Crawford DH, Powell LW, Leggett BA, Francis JS, Fletcher LM, Webb SI,
Halliday JW, et al. Evidence that the ancestral haplotype in Australian
hemochromatosis patients may be associated with a common mutation
in the gene. Am J Hum Genet 1995;57:362-367.
19. Pratiwi R, Fletcher LM, Pyper WR, Do K-A, Crawford DHG, Powell LW,
Jazwinska EC. Linkage disequilibrium analysis in Australian haemochro-
motosis patients indicates bipartite association with clinical expression.
J Hepatol 1999;31:39-46.