Alpha-1 antitrypsin deficiency related liver disease: Is it worth a search in India?

Abstract

Alpha-1-antitrypsin deficiency (AATD) is the commonest genetic cause of liver disease in children from the West and also a major cause of emphysema and chronic obstructive pulmonary disease in adults. The mechanism of lung and liver injury are distinct and unique. The liver disease appears to involve a “gain of function” mechanism in which the retained mutant AAT molecule in the endoplasmic reticulum triggers a series of events which lead to programmed hepatocyte death, inflammation, fibrosis and cirrhosis. More than 100 mutant alleles have been identified, but only few are associated with liver disease. The commonest deficiency phenotypes are PIZZ, PISS and PISZ. Other rare alleles account for 5% of PI variants and include Mmalton and MDuarte among others(1). In this issue of the Journal, Arora, et al.(2) have evaluated 1250 children (840 chronic liver disease [CLD], 410 neonatal cholestasis [NC]) and 450 controls for AATD. Authors carried out investi-gations of screening and phenotyping (PI) with isoelectric focussing (IEF) in all the subjects (n=1700). On screening 7.8% (98/1700) subjects were shown to be deficient (low serum AAT level or absent/faint alpha-1 globulin band on serum agarose electrophoresis or PAS positive diastase resistant globules on liver histology). Phenotyping was normal (MM) in 99.8% (n=1697) children and the other 3 subjects had other variants (MIE, MP, MC: one each), none of which are known to be associated with liver disease. Fifty subjects (CLD 34, NC 16) of the 98 screen positive were subjected to genotype sequencing; none had PIZ or PIS genotypes. However two children had a novel mutation at position 333 in exon V; both having cryptogenic CLD, low serum AAT levels and positive globules on liver biopsy on immune histochemistry, all pointing towards a diagnosis of AATD. The study suggests that the commonest AAT deficiency alleles of PIZ and PIS as described in the West are not seen in Indian children. Thus AATD is a rare cause of liver diseases in India.