Introduction
Anemia is a global health problem; an estimated 300-million children worldwide had anemia in 2011.1 Iron deficiency anemia (IDA) is the most common cause of anemia in childhood. Thus, the WHO has recommended an international anemia control guideline: all children and women living in settings where the prevalence of anemia exceeds 20% should receive supplemental iron.2 In Thailand, this recommendation has been adopted by the Department of Health, Ministry of Public Health (MOPH) and incorporated into our routine childcare. It is fully subsidized by the Thai government through the National Health Security Office (NHSO). The MOPH recommends a universal iron supplement in Thai infants over 6 months old for IDA prevention when these babies come for routine vaccination. Iron supplementation continues until 24 months of age, with 12.5 mg of elemental iron weekly.3This age group has been selected as infants over 6 months who have a high prevalence of IDA, which can impair physical, behavioral, and cognitive functions and result in persistent neurocognitive defects, despite later iron therapy.4 However, local practitioners, in particular pediatricians, are concerned about this policy since there is a high prevalence of thalassemia and hemoglobin disorders in Thailand (P. Surapolchai et al., manuscript in preparation). It is widely accepted thalassemia disease could significantly increase the risk of iron overload (IOL), leading to iron toxicity in later life.5-6
Thalassemia (thal) is characterized by inherited mutations of α and β globin genes causing decreased globin synthesis. At least 5.2% of the world population carries one allele of globin gene variants (carrier or trait).7 For α-thal, there are two types based on molecular defects: α0-thal caused by deletions of two linked α-globin genes in cis (–/αα) and α+-thal caused by deletions of one α-globin gene (-α/αα) or nucleotide mutations (αTα/αα or αα/ααT). Coinheritance of two affected alleles (in autosomal recessive mode) leads to chronic hemolytic anemia and ineffective erythropoiesis known as thalassemia disease (thal disease).8 Hemoglobinopathy, on the other hand, is mainly caused by mutations of coding sequences, leads to qualitative defects. Several hemoglobinopathies are innocuous and do not lead to any clinical consequences.9 However, some mutations such as hemoglobin E (Hb E) at codon 26 of the β-globin genes (GAG >AAG) also have quantitative effects and interaction of Hb E with β-thal mutations leads to Hb E/β-thalassemia (Hb E/β-thal) syndrome with heterogeneous clinical severity. In Thailand, 30 to 40 percent of Thais possess thal carriers including α-thal, β-thal and Hb E. Due to the high prevalence of all genotypes, it is not uncommon to find individuals with combined α and β-globin abnormalities.10-13 Collectively, these thal traits, either simple or in combination, are asymptomatic and do not require specific treatment; they are then classified as thalassemia minor (thal minor). In addition, individuals with homozygous Hb E (Hb E/E), although carry two defective β-globin genes, they are benign with milder forms of anemia without hepatosplenomegaly or blood transfusion required.14
Several previous studies have extensively examined iron status in thal patients15-18, but little is known about thal minor in comparison to normal populations19, particularly in infants. Iron overload is one of the most common complications in thal patients due to blood transfusions and increased iron absorption5-6. Intestinal iron intake in thal has been shown to be enhanced due to hepcidin suppression by the upregulation of erythropoietic markers, such as GDF-11, GDF-15, and Erfe, in response to chronic anemia and erythropoietin drive.20-22 Hepcidin generally controls iron intake through duodenal enterocytes by limiting the expression of ferroportin: an intestinal iron gateway into our circulation. Recent studies have consistently shown hepcidin suppression in thal patients.23,24 More recently, a study from Sri Lanka has demonstrated β-thal carriers had mildly suppressed hepcidin concentrations out of proportion to their iron stores. It has been suggested that widespread distribution of iron supplementation could possibly increase the risk of harmful iron overload in β-thal carriers.25 In Thailand, there has been no data on the iron status and hepcidin levels in the young Thai population with our common thal traits; α-thal and Hb E and homozygous HbE, especially infants who would receive supplementation through our national program.
Our main objective in this study was to determine the iron status in infants aged 6 to 12 months at our Well Baby Clinic and identify the prevalence of iron deficiency (ID) and IDA among those with or without thal. In addition, we evaluated the clinical and laboratory characteristics of each group to identify which factors, including hepcidin levels, would significantly influence iron status. Our work aimed to illustrate whether infants with thal are at similar or lower risk of ID or IDA compared to the general population at this age and supply evidence regarding safe universal iron supplementation for Thai infants in the future.