Alpha1-antitrypsin deficiency

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Can be associated with cirrhosis. Severe deficiency (phenotype PiZZ) is also liable to develop emphysema, especially in smokers.

Partial deficiency can occur (phenotypes PiMS and MZ - normal is PiMM). PiMZ genotype does not appear to predispose to chronic liver disease, but is found more often in patients with decompensated LD (of any cause) and particularly in Hepatitis C infection or non-alcoholic fatty liver disease. [1]


Alpha1-antitrypsin (ATT, PI) is a protein coded by the SERPINA1 (PI) gene at 14q32.1. It is a serine protease inhibitor, in particular of neutrophil elastase (human leukocyte elastase, HLE). It also inhibits trypsin, chymotrypsin and plasminogen activator with a moderate affinity for plasmin and thrombin. Its structure has a reactive center loop (RCL) which extends out from the protein body and directly binds to proteases. The reactive center of alpha-1-antitrypsin is methionine 358, which acts as a 'bait' for elastase. The bond protease cleaves the serpin at the reactive site in the reactive center loop and establishs a covalent linked inactive serpin-protease complex which is very stable.

There are 3 isoforms. Subclassification is complex due to multiple symbol systems with most based on relative electrophoretic mobility of the allele product.

Multiple mutational variants are known and all are not routinely screened for so if a phenotype of alpha1-antitrypsin deficiency is suspected a combination of functional and genetic analysis is often required for accurate diagnosis. One in ten Europeans are heterozygous for either the Z or S variants and this explains about 1% of European chronic lung disease. Note that up to 17% of lung disease is associated with PI Kalshheker-Poller which has fully functional ATT but is a polymorphism of the 3-prime flanking sequence of the AAT gene[2].

The mutations might produce:

  • No change in function
    • PI Kalshheker-Poller
  • Deficiency of ATT
    Photomicrograph showing magenta/purple globules of defective α1-antitrypsin protein that accumulates within hepatocytes. (Diastase/periodic acid-Schiff staining)
    • PI Z
      • Disease-producing glu342-to-lys mutation and val213-to-ala substitution
      • Causes intracellular aggregation which can be seen in the liver on histological staining
      • Caucasian gene estimated as about 6000 years old with Scandinavian predominance
      • ZZ associated with both liver and pulmonary disease risk
      • Z null associated with pulmonary disease risk
      • MZ probably increase in both liver and pulmonary disease risk
      • Smoking markedly increases risk of lung damage (demonstrated from identical twin studies)
    • PI M(Malton)
      • Deletion of the codon for 1 of the 2 adjacent phenylalanine residues (amino acid 51 or 52)
      • Associated with both liver and pulmonary disease risk
    • PI S associated with pulmonary disease risk
      • Common in Southern Europeans (10%) and while normal phenotype in combination with Z (ie SZ genotype) associated with emphysema and probable increased risk hepatic disease.
    • M(Heerlen) associated with pulmonary disease risk
      • Substitution of leucine for proline at codon 369
    • M(Mineral Springs) associated with pulmonary disease risk
      • Black race inheritance
      • GGG-to-GAG change in codon 67 leds to substitution of glutamic acid for glycine
    • M(Procida) associated with pulmonary disease risk
      • Substitution of proline for leucine at position 41
    • M(Nichinan) associated with pulmonary disease risk
    • I associated with pulmonary disease risk
    • P(Lowell) compound heterozygotes with a Z or null allele have a mildly increased pulmonary disease risk
      • GAT (aspartic acid at residue 256) in the M protein is converted to GTT (valine at that position) in the P protein
  • Null mutations with no ATT
    • Usually associated with pulmonary disease risk
    • PI Null(Devon)
      • Associated with increased risk of both emphysema and liver disease
      • Due to a substitution of serine for glycine at AA 115
  • Altered function of ATT
    • PI Pittsburgh (missing AA 382) causes antithrombin activity.
      • This is because it takes up function of antithrombin III which is a genetically related protase (common ancestral protein some 500 million years ago).
    • PI W(Bethesda) associated with both liver and pulmonary disease risk
      • Change in codon 336 from GCT to ACT

The most frequent gene alleles are:

  1. M1V (44 - 49%)
  2. M1A (20 - 23%) probably in fact the base allele
  3. M3 (14 to 19%)
  4. M2 (10 - 11%)


This article is a work in progress. Please feel free to contribute to it.