Alpha1-antitrypsin deficiency, cirrhosis and emphysema

Emphysema is a chronic progressive lung disease characterised by abnormal permanent enlargement of airspaces as a result of destruction of alveolar walls. 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 á1-antitrypsin. The two common deficiency variants of á1-antitrypsin, S and Z, result from point mutations in the á1-antitrypsin gene 2–4 and are named on the basis of their slower electrophoretic mobility on isoelectric focusing analysis compared with the normal M allele. S á1-antitrypsin ( Glu→Val) is found in up to 28% of Southern Europeans and, although it results in plasma á1-antitrypsin levels that are 60% of the M allele, it is not associated with any pulmonary sequelae. The Z variant (Glu→Lys) results in a more severe deficiency that is characterised, in the homozygote, by plasma á1-antitrypsin levels of 10% of the normalM allele and by levels of 60% in theMZ heterozygote (50% from the M allele and 10% from the Z allele). The Z mutation results in the accumulation of á1-antitrypsin in the rough endoplasmic reticulum of the liver (fig 1A) and predisposes the homozygote to juvenile hepatitis, cirrhosis, and hepatocellular carcinoma. Z á1-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. 8 The role of á1-antitrypsin is to protect the tissues against enzymatic digestion by neutrophil elastase. The low circulating levels are unable to inhibit this proteinase and predispose the Z homozygote to early onset panlobular emphysema, bronchiectasis, and vasculitis. Alpha1-antitrypsin deficiency related emphysema is predominantly panlobular and basal compared with the centrilobular upper lobe disease seen in smokers. Patients usually present with increasing dyspnoea and weight loss, with cor pulmonale and polycythaemia occurring late in the course of the disease. Chest radiographs and high resolution CT scans typically show bilateral basal emphysema with paucity and pruning of the basal pulmonary vessels (fig 1B). Upper lobe vascularisation is relatively normal and ventilation perfusion radioisotope scans and angiography also show abnormalities with a lower zone distribution. Lung function tests are typical for emphysema with a reduced FEV1/FVC ratio, evidence of air trapping and a low gas transfer factor.