Alpha(1)-antitrypsin deficiency, liver disease and emphysema.
alpha(1)-Antitrypsin is a member of the serine proteinase inhibitor (serpin) superfamily and a potent inhibitor of neutrophil elastase. The most important deficiency variant of alpha(1)-antitrypsin arises from the Z mutation (Glu342Lys). This mutation perturbs the protein's tertiary structure to promote a precise, sequential intermolecular linkage that results in polymer formation. These polymers accumulate within the endoplasmic reticulum of the hepatocyte forming inclusion bodies that are associated with neonatal hepatitis, juvenile cirrhosis and adult hepatocellular carcinoma. The resultant secretory defect leads to plasma deficiency of alpha(1)-antitrypsin. This exposes lung tissue to uncontrolled proteolytic attack from neutrophil elastase, culminating in alveolar destruction. Thus, the Z alpha(1)-antitrypsin homozygote is predisposed to developing early onset basal, panacinar emphysema. In this review, we summarise the current understanding of the pathobiology of alpha(1)-antitrypsin deficiency and the associated liver cirrhosis and emphysema. We show how this knowledge has led to the development of novel therapeutic approaches to treat this condition.
Parfrey
Helen
H
Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, UK. hp226@cam.ac.uk
Mahadeva
Ravi
R
Lomas
David A
DA
D022781:Hepatocytes / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology* / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011656:Pulmonary Emphysema / Q000209:etiology* / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000235:genetics*; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications*
D000515:alpha 1-Antitrypsin