α1-antitrypsin is an enzyme inhibitor which inactivates the proteases released by inflammatory cells particularly neutrophils. α1-antitrypsin measurement is usually carried out to detect genetic deficiency of the molecule. Although α1-antitrypsin is a slow-reacting acute phase protein whose concentration increases during inflammation, infection or malignancy, measurement in these situations is seldom of value.
There are many different forms of α1 antitrypsin deficiency associated with different genetic mutations, producing proteins which can be identified by isoelectric focussing – the phenotype. Some of these phenotypic variations lead to lower levels of α1-antitrypsin, some lead to normal levels of less active functional variants. α1-antitrypsin deficiency can have serious clinical implications, for example in chronic obstructive airways disease, emphysema or liver disease, often occurring later in life (age 30-40) In most serious deficiencies clinical symptoms can occur in neonates and young children. Measurement of α1-antitrypsin should be considered in investigation of emphysema, unexplained lung disease, unexplained liver disease in adults and always in neonatal/juvenile jaundice.
Low levels of α1-antitrypsin may be detected inadvertently during serum immunoelectrophoresis which is most commonly being used to investigate immunoglobulin levels. Where the electrophoresis pattern suggests that α1-antitrypsin levels are low, the levels will automatically be quantitated by the laboratory.
Patients with low α1 antitrypsin will be phenotyped (by isoelectric focussing) to detect homozygous (2 identical alleles) or heterozygous (2 different alleles) deficiency states. There are many phenotypes which lead to low serum levels of the protein. Some rarer phenotypes give normal serum levels of an inactive α1-antitrypsin. The different deficiency phenotypes have varying risks for clinical problems. In general patients with two immunodeficiency alleles are more likely to have significant clinical problems that those with only one deficiency allele. Severe genetic deficiencies of α1-antitrypsin (usually less than 0.6g/L) occur in UK with an incidence of 1 in 2,000.
Note that because α1-antitrypsin is an acute phase protein which can increase in concentration 2-3 fold, inflammatory conditions might mask deficiency. Increased levels also occur in malignancy, pregnancy and during oestrogen treatment. Smoking markedly exacerbates the effects of any α1-antitrypsin deficiency and all deficient individuals must be advised to stop smoking.
There are >59 protein variants which result in varying levels of α1-antitrypsin and are associated with different degrees of severity of symptoms. Phenotypes are designated as PI phenotypes termed M, S, Z, F etc. PIMM is the commonest phenotype; PIMM is often referred to as the “normal” phenotype. Individuals show no deficiency. PIMZ heterozygous individuals have 40% reduction in levels, PIZZ homozygous individuals have 85% reduction. PI*S and PI*Z are the commonest deficiency alleles in UK.
Phenotyping should be performed in adults if quantitative result below age related median result. The phenotype should be determined in all children with liver disease irrespective of α1-antitrypsin concentration. The frequency of different alleles is different in different racial groups
In all cases where deficiency phenotypes are identified, the result will be given with appropriate interpretive comments.
When clinically important phenotypes are detected, (family studies) genotyping (DNA studies) might be required for patients with severe deficiencies and their relatives.