Obscure pathogenesis of primary iron overload in Indians warrants more focused research.

Cirrhosis of liver is one of the common clinical conditions encountered in gastroenterology and hepatology practice, and is associated with significant morbidity and mortality. A varied etiology of the condition necessitates detailed history taking, thorough clinical examination as well as a set of laboratory investigations for confirmation. An uncommon etiology of cirrhosis is primary iron overload, generally due to hereditary hemochromatosis for which a high index of suspicion amongst physicians is required for diagnosis. Hereditary hemochromatosis is commonly inherited as an autosomal recessive disorder, leading to progressive iron overload in several organs and eventual iron toxicity. It is caused by an inappropriate increase in iron absorption in the duodenum and upper small intestine due to malfunction of one of the proteins in iron homeostasis. The disease is relatively commonly encountered in the Caucasians and is associated with mutations in the locus, Histone Family E1 (HFE). Among populations of north European origin, two mutations have been identified in the HFE gene, viz. substitution of cysteine for tyrosine at position 282 (C282Y, nucleotide 845) in the alpha 3-domain of the HFE protein and aspartate replacing histidine at amino acid 63 (H63D, nucleotide 187) [1]. The mutation C282Y is the predominant Caucasian mutation with over 90% of patients in north Europe being homozygous for this mutation [2]. In this issue of the Journal, Jain et al. from a center in northern India, report their experience of the common HFE gene mutation in primary iron overload and liver cirrhosis in adult Indian subjects [3]. In their study comprising 496 patients with cirrhosis of various etiologies, they found only 13 with primary iron overload with near absence of C282Y mutation, and only two of them with heterozygous H63D mutation in HFE gene. Frequency of the risk allele at H63D was similar in patients and normal subjects. Neither the patients with heterozygous H63D mutation, nor the lone compound heterozygote individual (C282Y/H63D) had primary iron overload. These observations are in concordance with previous studies from India where C282Y has not been identified except for a single individual from Punjab in northern India, and a more widespread distribution of H63D mutation has been reported [4–8]. The H63D mutation is widely distributed in nearly all populations with a variable allele frequency and haplotype analysis suggests that it has occurred earlier to the C282Y mutation. Its frequency varies from 9.1% to 13.9% in different studies from India [5–8] and several studies have showed that even H63D homozygotes have no evidence of iron overload. An independent role of H63D mutation in causing hereditary hemochromatosis is not established yet. It is therefore difficult to propose any important role for this mutation in Indians as the frequency is similar to the reported frequency in the western population, and the overall frequency of 63D allele in patients and controls is also similar. This raises the question, “what is the pathogenesis of primary iron overload in Indians”. Though it is a much underrated problem locally, in the few well-characterized patients, it is difficult to understand why and how the increased iron absorption fails to correct despite the patients being put on a R. Das Department of Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India