Genetics and respiratory disease bullet  2: Alpha1-antitrypsin deficiency, cirrhosis and emphysema

Abstract

Emphysema is a chronic progressive lung disease characterised by abnormal permanent enlargement of airspaces as a result of destruction of alveolar walls.1 Most patients develop emphysema as a consequence of smoking but 1–2% of patients with emphysema develop the condition as a result of a genetic deficiency of the plasma proteinase inhibitor α1-antitrypsin. The two common deficiency variants of α1-antitrypsin, S and Z, result from point mutations in the α1-antitrypsin gene2-4 and are named on the basis of their slower electrophoretic mobility on isoelectric focusing analysis compared with the normal M allele.5 S α1-antitrypsin (264Glu→Val) is found in up to 28% of Southern Europeans and, although it results in plasma α1-antitrypsin levels that are 60% of the M allele, it is not associated with any pulmonary sequelae. The Z variant (342Glu→Lys) results in a more severe deficiency that is characterised, in the homozygote, by plasma α1-antitrypsin levels of 10% of the normal M allele and by levels of 60% in the MZ heterozygote (50% from the M allele and 10% from the Z allele). The Z mutation results in the accumulation of α1-antitrypsin in the rough endoplasmic reticulum of the liver (fig 1A) and predisposes the homozygote to juvenile hepatitis, cirrhosis,6 and hepatocellular carcinoma.7 Z α1-antitrypsin inclusions are associated with abnormal liver function tests in over 90% of Z homozygotes in the first year of life but only 10–15% of these develop the prolonged cholestatic jaundice that can progress to cirrhosis and the requirement for hepatic transplantation.6 8 Figure 1 (A) Electron micrograph of a hepatocyte from the liver of a child with Z α1-antitrypsin deficiency. The arrow shows the accumulation of α1-antitrypsin …