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