a1 Antitrypsin Phenotyping

Clinical use: Severe genetic deficiencies of AAT (less than 0.6 g/L) occur in the UK with an incidence of about 1:2,000. Typical clinical presentations include chronic obstructive airway disease with severe lower lobe panlobular emphysema occuring between 30-40 years of age; neonatal cholestasis and progressive juvenile cirrhosis; some cases of unexplained micronodular cirrhosis in adults; and some cases of necrotising angiitis. A causal relationship with these varied clinical presentations is not established but the reduction in plasma tryptic inhibitory capacity and the failure to inhibit elastase and macrophage lysosmal enzymes increases the tissue damage of the inflammatory process.

Smoking and atmospheric pollution contribute to the severity of the lung disease in deficient subjects. There does not, however, seem to be a similar association between smoking and the heterozygous state. AAT deficiency is reputed to account for 6% of all cases of emphysema in Western Europe and for up to 20% of all cases of neonatal cholestasis where congenital anomalies of the biliary tract can be excluded.

Other genetic associations have been described. Heterozygous deficiency (AAT 0.6-1.5 g/L) may allow increased tissue damage in chronic inflammatory disorders with phagocytic overload. There are loose associations between PI*Z allelle and galactosaemia and membranoproliferative glomerulonephritis. PI*S and PI*Z alleles are associated with increases in serum angiotensin converting enzyme.

The confirmation of PI*Z and PI* S can be achieved by genotype studies using PCR technology and DNA extracted from EDTA blood or from buccal washings. Whilst it is expected that phenotyping by isoelectric focusing will remain the first line investigation of PI genetic status, the genotype by DNA analysis is required for admission of an individual to the national AAT deficiency register.

The present genotype identification method will identify the PI*Z and PI*S gene products, but assumes that all non-S and non-Z are PI*M. It will, therefore, incorrectly classify both a PI*Z- and a PI*FZ as a PI*MZ if used in isolation. For this reason the test should not be used as a first-line investigation, but should always be used in confirmation of isofocusing phenotype identification and AAT quantitation.

Sample requirement: 2 mL serum for phenotype identification and 5 mL EDTA blood for genotype determination.

Centres offering this assay: 
Sheffield Northern General’s PRU Diagnostic Service

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