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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/9780198746690.003.0242
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date: 25 February 2021

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 in the lung. Ninety-five per cent of severe plasma deficiency of α‎1-antitrypsin results from homozygosity for the Z allele (Glu342Lys), which causes the protein to undergo a conformational transition and form ordered polymers that are retained within hepatocytes as periodic acid–Schiff-positive, diastase-resistant inclusions. Clinical features— all adults homozygous for the Z allele of α‎1-antitrypsin have a minor degree of portal fibrosis that is often subclinical, but up to 50% have clinically evident cirrhosis and occasionally hepatocellular carcinoma. They also develop panlobular emphysema that typically affects the lung bases 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 abstain from smoking and avoid agents that cause hepatic injury, such as excessive alcohol and obesity. Emphysema is treated along conventional lines. α‎1-Antitrypsin replacement therapy is widely used in North America to slow the progression of the lung disease and has recently been licensed by the European Medicines Agency, but its clinical efficacy remains contentious and it has no effect on liver disease. Clinical trials are underway to ‘knock down’ the expression of mutant Z α‎1-antitrypsin within hepatocytes to try to prevent cirrhosis. 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), angio-oedema (C1 inhibitor), and dementia (neuroserpin).

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