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α‎1-Antitrypsin deficiency and the serpinopathies 

α‎1-Antitrypsin deficiency and the serpinopathies

Chapter:
α‎1-Antitrypsin deficiency and the serpinopathies
Author(s):

David A. Lomas

DOI:
10.1093/med/9780199204854.003.1213_update_001

July 30, 2015: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

Update:

New and emerging treatments—discussion of use of carbamazepine, genomically corrected fibroblasts, and strategies to ‘knock down’ the expression of mutant Z α‎1-antitrypsin within hepatocytes.

Updated on 28 Nov 2012. The previous version of this content can be found here.
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date: 27 March 2017

α‎1-Antitrypsin is an acute phase glycoprotein synthesized by the liver that functions as an inhibitor of a range of proteolytic enzymes, most importantly neutrophil elastase. Severe plasma deficiency of α‎1-antitrypsin results from homozygocity for the Z allele, which causes the protein to undergo a conformational transition and form ordered polymers that are retained within hepatocytes as PAS-positive inclusions.

Clinical features—(1) Liver—all adults with the Z allele of α‎1-antitrypsin have slowly progressive hepatic damage that is often subclinical and only evident as a minor degree of portal fibrosis, but up to 50% of Z homozygotes present with clinically evident cirrhosis and occasionally with hepatocellular carcinoma. (2) Lung—patients with Z α‎1-antitrypsin deficiency develop panlobular emphysema that tends to affect the bases rather than the apices of the lungs and is greatly exacerbated by smoking; cor pulmonale and polycythaemia are late features.

Diagnosis and management—severe genetic deficiency of α‎1-antitrypsin is readily diagnosed by low plasma levels and the virtual absence of the α‎1-band on protein electrophoresis. Patients should be very strongly advised to abstain from smoking, and to avoid agents that cause hepatic injury (such as excessive alcohol and obesity). Treatment otherwise involves conventional trials of bronchodilators and inhaled corticosteroids, pulmonary rehabilitation and—where appropriate—assessment for long-term oxygen therapy and lung transplantation. α‎1-Antitrypsin replacement therapy is widely used in North America, but its value is uncertain.

Other serpinopathies—the polymerization that underlies α‎1-antitrypsin deficiency is found in other members of the serine protease inhibitor (or serpin) superfamily to cause diseases as diverse as thrombosis (antithrombin), angioedema (C1 inhibitor), and dementia (neuroserpin).

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