¹Department of Pediatrics, Cell Biology and Physiology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, 3705 Fifth Avenue, Pittsburgh, PA 15213-2583, USA

Correspondence: DH Perlmutter, Department of Pediatrics, Cell Biology and Physiology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, 3705 Fifth Avenue, Pittsburgh, PA 15213-2583, USA. Tel: +412 692 8071; Fax: +412 692 5946; E-mail: david.perlmutter@chp.edu

Received 31 March 2008; Revised 3 June 2008; Accepted 12 June 2008; Published online 11 July 2008.

Abstract

-1-Antitrypsin (AT) deficiency is a relatively common autosomal co-dominant disorder, which causes chronic lung and liver disease. A point mutation renders aggregation-prone properties on a hepatic secretory protein in such a way that the mutant protein is retained in the endoplasmic reticulum of hepatocytes rather than secreted into the blood and body fluids where it ordinarily functions as an inhibitor of neutrophil proteases. A loss-of-function mechanism allows neutrophil proteases to degrade the connective tissue matrix of the lung causing chronic emphysema. Accumulation of aggregated mutant AT in the endoplasmic reticulum of hepatocytes causes liver inflammation and carcinogenesis by a gain-of-toxic function mechanism. However, genetic epidemiology studies indicate that many, if not the majority of, affected homozygotes are protected from liver disease by unlinked genetic and/or environmental modifiers. Studies performed over the last several years have demonstrated the importance of autophagy in disposal of mutant, aggregated AT and raise the possibility that predisposition to, or protection from, liver injury and carcinogenesis is determined by the balance of de novo biogenesis of the mutant AT molecule and its autophagic disposal.