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Editorials |

α1-Antitrypsin Deficiency Therapy : Pieces of the Puzzle

Robert A. Sandhaus, MD, PhD, FCCP
Author and Funding Information

Affiliations: Denver, CO 
 ,  Dr. Sandhaus is Clinical Professor of Medicine at the University of Colorado Health Sciences Center and National Jewish Medical and Research Center, Denver, CO. He is also Medical Director of the Alpha One Foundation, Miami, FL, and co-director of the University of Colorado Center for Genetic Lung Disease.

Correspondence to: Robert A. Sandhaus, MD, PhD, FCCP, Division of Pulmonary and Critical Care Medicine, UCHSC, Mail drop C272, 4200 E. Ninth Ave, Denver, CO 80262



Chest. 2001;119(3):676-678. doi:10.1378/chest.119.3.676
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The article by Marion Wencker et al in this issue of CHEST (see page 737) fits another piece within the yet-unfinished jigsaw puzzle of the pathophysiology and treatment ofα 1-antitrypsin (AAT) deficiency. The molecular and cellular mechanisms leading to this deficiency are among the best understood of the genetic conditions leading to an increased risk for organ dysfunction. The single amino-acid substitution seen in the most common form of AAT deficiency leads to an altered conformation of this protein as it is translated in the hepatocyte.1 This provokes insertion of the reactive loop of one Z mutation AAT molecule into the A-sheet of another Z mutation AAT molecule, resulting in polymerization and accumulation of AAT within the hepatocyte cytoplasm.2 This, in turn, leads to the characteristic periodic acid-Schiff–positive, diastase-resistant hepatocyte granules and a low serum level of this important serine proteinase inhibitor. Lowered levels of AAT bathing the lungs leads to the possibility of connective tissue degradation by phagocyte proteinases, normally inhibited by physiologic concentrations of AAT.3 The insights gained from studying AAT deficiency have provided the basis for our growing comprehension of the mechanisms leading to COPD in general.

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