Discussion
Our study found the prevalence of thal minor (carrier) to be nearly half
of the infant population (47%). It appeared to be higher than
previously reported, which had been ranges of
30-40%.8,10 One of the main reasons was the DNA
testing used in our current study was far more comprehensive than the
approach used (cord blood hemoglobin studies, hemoglobin typing, etc.)
some 20 years ago. This finding was consistent with the recent thal
prevalence reported by Viprakasit V et al . in
200941 with Hb E trait being the most common type of
thal minor9,10,41. In Thailand with its frequency up
to 50-60% in Southeast Asia,9 we found no individuals
with thal disease and this might result from the effectiveness of our
prevention and control program that screens for thal carriers in
pregnant women and their partners in order to identify couples with
genetic risk of severe thal syndromes.11 Therefore,
our studied population would simply represent ‘healthy’ infants who had
received routine care in our health system and were a primary target for
the iron supplementation program endorsed by the MOPH.
A study of β-thal traits showed mildly increased erythropoiesis,
evidenced by elevated erythropoietin levels.42Besides, adults with α- or β-thal traits have shown increases in soluble
transferrin receptors or erythropoietin concentrations, indicating
ineffective erythropoiesis and increased erythropoietic drive leading to
hepcidin suppression and upregulated iron
absorption.17 Previous studies in India and Iran
examining the iron status of adults with β-thal traits concluded that
β-thal traits had higher serum ferritin than the controls, representing
an advantage in iron balance.43,44 These findings were
discordant with others, which had stated that ID might commonly coexist
with thal traits.17,45,46 These conflicting results
caused uncertainty in iron supplementation strategies for areas with a
high prevalence of hemoglobinopathy. A universal iron supplementation
program has raised concern since it might increase the risk of iron
overload in individuals with thal minors.
A recent community study of 1821 Sri Lanka schoolchildren aged 8-18
years (48.3% males) from the Oxford group has shown that this might be
the case for those with β-thal traits.25 Eighty-two
β-thal carriers with iron-replete had evidence of increased
erythropoiesis, a slight but significant reduction in hepcidin, and
suppression of hepcidin out of proportion to their iron stores:
hepcidin-ferritin ratio compared with non-carrier controls (n=176 with
normal MCV and MCH). In another recent cross-sectional study of 2273
children (aged 12–19 years) from a total of 7526 students, also in Sri
Lanka, this effect was also observed in the iron-replete α‐thal carriers
as compared to the non‐iron deficient controls without thal minor (4.8
ng/mL vs. 5.3 ng/mL, P = 0.02).47 However, they
did not identify such findings in those with Hb E traits from both
cohorts.25,47 Based on these results, it has been
proposed the hepcidin cutoff of < 3.2 ng/mL might be used to
select cases for iron supplementation in countries with high rates of
thal carriers.47 Both studies were conducted in
primary and secondary school students; this is the age group in which
iron supplementation is given in Sri Lanka. However, the effect of thal
carriers on hepcidin suppression and risk of iron accumulation in
younger thal minor remains unclear.
Our study, for the first time, determined this iron supplement issue in
infants with thal minor. While we could not find a significant hepcidin
suppression in our infant thal minors compared to previous studies, our
results were somewhat in line with such findings. Most of our thal
minors were Hb E traits, and this condition did not show a significant
enough globin imbalance leading to ineffective erythropoiesis and
subsequent hepcidin suppression. Moreover, even for individuals with
homozygous Hb E, we found no evidence of such an effect. Our infants
with α-thal carriers also demonstrated no effects of hepcidin
suppression, differing from the previous study.47 It
might be possible our studied population was younger with remaining Hb F
expression (Table 1 and 2 ) and have less globin imbalance and
ineffective erythropoiesis per se . It is, therefore, possible the
erythropoietic drive that suppresses hepcidin was not fully operative
yet.
In addition, the normal physiology of hepcidin expression, especially
within the first year of life, might be more dynamic. A recent study in
late preterm infants (32-36 weeks gestation) described a physiologic
decrease of hepcidin levels during the first 4 months of life to
increase iron availability.48 A recent longitudinal
study that followed 140 Spanish healthy and full-term infants found
hepcidin levels to increase from 6 to 12 months of age with the levels
of hepcidin positively correlated with iron status.49These findings suggested that, in normal babies, a regulation of
hepcidin production is under development during the first year of life;
this might also be true for infants with thal. Therefore, the effects of
ineffective erythropoiesis on hepcidin suppression in thal traits might
not be fully apparent during the first year of their life. This result
warrants further study to define at what age this effect would be first
identified.
As a result, we still found our infants with thal minor having a high
proportion of iron depletion (57.7%), similar to infants without thal
(61.5%); the number of thal infants with IDA was even significantly
higher than infants without thal minor (32 vs. 20.2%). Thus, the
likely causes and possible risk factors of ID need to be further
identified (P. Surapolchai, manuscript in preparation). Nevertheless,
infants with thal minor who have IDA or ID would benefit from proper
iron supplementation. Interestingly, infants with a coexisting thal
minor and IDA had significantly reduced Hb, MCV, MCH, and MCHC with
increased RDW versus those having thal minor with normal iron or with ID
(Table 2 ). These findings were consistent with previous studies
in India where MCV and MCH were significantly lower in adults with
combined thal traits and IDA than with either of these
conditions.45 To the best of our knowledge; this is
the first time RBC indices have been comprehensively analyzed in thal
carriers at this age group (6-12-month-old). Our findings could be used
for future reference.
Among 36 thal minor infants with anemia, we found 5 cases who did not
have coexisting IDA, including infants with two α-thal traits
(-α3.7/αα and –SEA/αα), one
β-thal trait, one Hb E trait and one homozygous Hb E. This suggested
that α- and β-thal traits might be the cause of mild anemia in some
infants. Accordingly, anemic infants unresponsive to oral iron therapy
certainly should be investigated for thal, rather than continuously
undergoing long-term iron therapy by default, as toxicity or other side
effects may develop. Familial history of anemia or thal as shown herein,
was found to be strongly associated with thal minor in offspring and
could be used to diagnose future cases early.
In conclusion, our study showed infants (aged 6-12 months) with thal
minor in Thailand, in which the majority had Hb E and α-thal traits, are
at similar risk of having IDA as the general population and this may
partially be due to a lack of hepcidin suppression at this age or the
type of mutations found in our study. Therefore, a universal short-term
period of iron supplementation in infants would be not too harmful since
more than half of the population could benefit from this strategy.
However, beyond this age group, particularly for school children, a
proper measurement of serum hepcidin and using a cut-off as described
earlier would be an alternative approach for the selection of those who
should genuinely receive iron supplementation; this would minimize the
chance of overtreating individuals with thal minor in areas of a high
prevalence of thal and hemoglobinopathies.47