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Indian Pediatr 2010;47:
1011-1012 |
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Alpha- 1 Antitrypsin Deficiency Related Liver
Disease: Is It Worth a Search in India? |
Surender K Yachha and Anshu Srivastava
Department of Pediatric Gastroenterology, Sanjay Gandhi
Postgraduate Institute of Medical Sciences,
Lucknow, UP, India.
Email: [email protected]
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A lpha-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.
We appreciate the authors for studying a large number
of subjects including controls using phenotying/ genotyping. However it is
felt that there are some limitations: (a) details about the number
of subjects that were screened individually by different methods is
lacking; (b) serum levels and "cut off" value taken for defining
AAT deficiency are not provided; and (c) it is not clear whether
all the subjects amongst 1250 liver disease cases had liver biopsy and
also immunohistochemistry for AAT deposits. To support their conclusion
and to be precise, the authors should have given a detailed break up of
individual screening tests and their correlation with genotyping and
phenotyping. Although 840 CLD and 410 NC cases were screened but the focus
could have been directed towards children with unknown etiology (237 CLD
and 126 NC).
This study highlights the difficulties in making a
diagnosis of AATD. The measurement of serum/plasma levels of AAT is the
simplest test but it lacks both sensitivity and specificity and should not
be used to exclude AATD. The phenotyping (PI type) by isoelectric
focussing, though considered as the "gold standard" for diagnosis, is time
consuming, requires expertise for interpretation of gels and is best done
in a referral laboratory. The phenotyping also cannot identify null
alleles and variants which have similar or slightly different
electrophoretic mobility than the normal M alleles as was seen in two
cases described by Arora, et al.(2). Genotyping provides a
definitive diagnosis and helps in identification of new mutations(3).
Snyder, et al.(4) suggest that genotyping with
commercial assay for common alleles (S and Z) along with determination of
serum AAT to identify samples with rare deficiency alleles not recognized
by S and Z genotypes is a useful and simple approach to diagnosis of AATD.
Phenotyping and direct sequencing may then be done only for samples with
discordant results.
Only a small proportion of subjects with AATD ever
develop liver disease, this is believed to be determined by genetic
modifiers and/or environ-mental factors. Nearly 85-90% of all affected
children present with NC, and the remaining 10-15% present later in
childhood with hepatomegaly, failure to thrive, asymptomatic elevation of
transaminases or cirrhosis. NCS in AATD can be severe with acholic stools
and non- excretory hepatobiliary scan and often confused with biliary
atresia. Some infants may also present with serious hemorrhagic
complications. According to the landmark study of Sveger, et al.(5),
nearly 80% of PIZZ infants presenting with NC are free of CLD by 18 years
of age. Overall, the risk of progressive liver disease and poor quality of
life due to pruritus requiring transplantation in childhood ranges from
3-5%(6).
AATD generally requires supportive management as there
is no specific treatment. The diagnosis of AATD in childhood has the dual
advantage of predicting the prognosis and counselling. This study
highlights rarity of AAT despite best confirmatory tests applied in the
study. Since we do see a sizeable proportion of metabolic disorders
including AAT there is a need for developing a dedicated central
diagnostic facility in India. This would be a cost-effective and highly
valuable step in development of pediatric service and research.
Funding: None.
Competing interests: None stated.
References
1. Fairbank KD, Tavill AS. Liver disease in alpha
1-antitrypsin deficiency: a review. Am J Gastroenterol 2008; 103:
2136-2141.
2. Arora NK, Arora S, Ahuja A, Mathur P, Maheshwari M,
Das MK, et al. Alpha 1-antitrypsin deficiency in children with CLD
in North India. Indian Pediatr 2010; 47: 1015-1023.
3. Rachelefsky G, Hogarth DK. Issues in the diagnosis
of a1-antitrypsin
deficiency. J Allergy Clin Immunol 2008; 121: 833-838.
4. Snyder MR, Katzmann JA, Butz ML, Yang P, Dawson DB,
Halling KC, et al. Diagnosis of alpha-1-antitrypsin deficiency: an
algorithm of quantitation, genotyping and phenotyping. Clin Chem 2006; 52:
2236-2242.
5. Sveger T, Eriksson S. The liver in adolescents with
alpha 1-antitrypsin deficiency. Hepatology 1995; 22: 514–517.
6. Teckman JH. a1-antitrypsin
deficiency in childhood. Semin Liv Dis 2007; 27: 274-281.
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