Aetiology

Alpha-1 antitrypsin (AAT) deficiency is caused by decreased circulating plasma levels of AAT, due to the inheritance of variant alleles of the SERPINA1 gene.[30] The inheritance pattern is autosomal, and expression of the alleles is codominant. This means that all individuals have twos AAT alleles, and it is the expression of both alleles that contributes to the phenotypic variance. Specifying genotype in the form PI*[allele A][allele B] provides greater precision when referring to the condition of individual patients.[5]

Inflammation of the lung in AAT deficiency is exacerbated by cigarette smoking, which initiates degradation of the extracellular matrix by neutrophil-secreted elastases in the absence of an antiprotease counterbalance. Characterisation of inflammation in transgenic mice and in explanted human lungs has shown that ZZ-phenotype polymers invoke a pro-inflammatory response, suggesting that emphysematous changes in AAT deficiency are the result of more than merely an imbalance between AAT and elastases.[31]

The effect of smoking in heterozygous AAT individuals was quantified in a family-based study in which lung function of PI*MZ individuals was compared with that of PI*MM individuals. There was no difference in lung function (FEV1 % predicted, FEV1/FVC ratio) between PI*MM and PI*MZ never-smokers. Among ever-smokers, lung function was significantly worse in PI*MZ subjects (FEV1/FVC ratio 0.71 versus 0.77, P=0.001; FEV1 % predicted: 84.6 versus 96.4, P=0.0006). These data suggest an important influence of smoking on lung function in heterozygote individuals.[32] In two large cohorts of patients with COPD, those with the PI*MM phenotype had higher FEV1/FVC than those with the PI*MZ phenotype. Furthermore, among those with low smoking exposure (<20-pack-years), PI*MZ individuals had more severe emphysema on CT scan than PI*MM individuals.[33] 

There are limited data on smoking of non-tobacco products and 'vaping' on lung function in people with AAT deficiency, but given the mechanism of inflammation imbalance caused by smoking, they are presumed to carry the same risk for PI*MZ and PI*ZZ individuals.

Pathophysiology

AAT deficiency results from allele mutations in the SERPINA1 gene at the protease inhibitor (PI) locus.[1]​ Allele mutations cause ineffective activity of the specific protease inhibitor AAT. The mechanism by which AAT plasma levels are decreased depends upon the specific mutation of the protease inhibitor allele.

The Z allele is characterised by a point mutation causing beta-sheet polymerisation of the protein and subsequent aggregation in the liver, where most of the enzyme is produced.[34] In severe deficiency alleles (including the Z allele and the rare Siiyama and Mmalton alleles), approximately 70% of the mutant AAT is degraded within hepatocytes, 15% is secreted, and 15% forms ordered polymers.[30] Retention of polymers in the liver can cause jaundice, hepatitis, cirrhosis and, in severe cases, hepatocellular carcinoma, and death in the first decade of life.

The failure to secrete functional AAT into the circulation also decreases the amount of AAT available for protease activity in the lung, causing unopposed lung damage by neutrophil elastase and other matrix metalloproteinases.[35][36][37]

The S allele (the other common abnormal allele) also occurs through a point mutation, but pathogenesis results from the failure of sufficient post-translational processing resulting in intracellular proteolysis and reduced circulating plasma levels.[5]

Reduced serum levels, by whichever mechanism, cause inflammatory responses within the lung to be less controlled, which increases susceptibility to infection and structural damage.[30] This is often initiated by cigarette smoking and involves degradation of the extracellular matrix of the lung by neutrophil-secreted elastases in the absence of an antiprotease counterbalance. Emphysematous changes result.

Classification

Level of functioning AAT enzyme

Serum AAT level measured using the purified standard developed by the US National Institutes of Health (the most common testing method in the US) is classified as follows.[6][7]

  • Normal: normal levels of circulating plasma AAT (>20 micromol/L).

  • Deficiency: decreased circulating plasma AAT (<20 micromol/L).

  • Null: no detectable circulating plasma AAT.

  • Dysfunctional: normal levels of circulating plasma AAT, but the enzyme has reduced activity.

  • Protective threshold: AAT levels <11 micromol/L are considered to confer inadequate protection against inflammatory lung disease.

Exact threshold values vary depending on testing method and regional guidance; appropriate regional guidelines should be consulted for interpretation of serum AAT levels.[6][8][9][10]

Alphabetic labelling of alleles[5][11]

All individuals have two AAT alleles. Each allele, normal or abnormal, has a letter designation between A and Z. The letter assigned to each allele is an indication of migration rate on electrophoresis gel with respect to the other >120 known AAT alleles. "A" represents the fastest-moving variant on electrophoresis gel and "Z" represents the slowest. Specifying phenotype in the form PI*[allele A][allele B] provides greater precision when referring to the condition of individual patients.

The normal allele is designated 'M', so two normal copies would be MM. An example of a carrier phenotype is PI*MZ, and an example of a patient with AAT deficiency is PI*ZZ.

Given the large number of possible alleles, there are hundreds of possible genotypes and phenotypes. The allele most widely associated with clinical AAT deficiency is allele Z. The S allele is another common variant that results in decreased functional AAT expression, although not as severe as with the Z allele.

Clinical AAT deficiency

Any combination of alleles whose expression results in AAT levels below the protective threshold in the lung has an increased likelihood of contributing to pulmonary disease. The PI*ZZ phenotype is one particular manifestation well known to cause pulmonary disease. However, intermediate phenotypes also predispose to disease. For example, PI*MZ individuals have one allele with normal expression of AAT, but one allele that results in significantly decreased amount of functioning protein. The codominant nature of AAT alleles means that the resulting phenotype lies between that expected of a patient with normal AAT levels and that expected of a patient with severe AAT deficiency as seen with PI*ZZ. The Z allele is also the cause of liver disease in AAT deficiency (due to variant protein accumulation). Little evidence exists to support the contribution of other variant AAT proteins to liver disease, except for the rare Mmalton and Siiyama mutations.[12]

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