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Chapter 25 - α1-Antitrypsin deficiency

from Section IV - Metabolic liver disease

Published online by Cambridge University Press:  05 March 2014

By
David H. Perlmutter
Edited by
Frederick J. Suchy ,
Ronald J. Sokol  and
William F. Balistreri
David H. Perlmutter
Affiliation:
Department of Pediatrics, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA
Frederick J. Suchy
Affiliation:
University of Colorado Medical Center
Ronald J. Sokol
Affiliation:
University of Colorado Medical Center
William F. Balistreri
Affiliation:
University of Cincinnati College of Medicine
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Summary

Introduction

Homozygous (PiZZ phenotype) α1-antitrypsin (α1-AT) deficiency is a relatively common genetic disorder, affecting 1 in 3000 live births [1]. It is an autosomal codominant disorder associated with 85–90% reduction in serum concentrations of α1-AT. A single amino acid substitution results in an abnormally folded protein that is unable to traverse the secretory pathway. The mutant α1-antitrypsin Z (α1-ATZ) protein is retained in the endoplasmic reticulum (ER) rather than secreted into the blood and body fluids.

α1-Antitrypsin is an approximately 55kDa secretory glycoprotein that inhibits destructive neutrophil proteases, elastase, cathepsin G, and proteinase 3. Plasma α1-AT is derived predominantly from the liver and increases three- to five-fold during the host response to tissue injury or inflammation. It is the archetype of a family of structurally related circulating serine protease inhibitors called serpins.

Nationwide prospective screening studies by Sveger and coworkers [2,3] in Sweden have shown that only 8–10% of the PiZZ population develops clinically significant liver disease over the first 20 years of life. Nevertheless, this deficiency is the most frequent genetic cause of liver disease in children and the most frequent genetic disease for which children undergo orthotopic liver transplantation. It also causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma in adults [4].

Type
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Information
Liver Disease in Children , pp. 400 - 418
Publisher: Cambridge University Press
Print publication year: 2014

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References

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