• AAT encoded by SERPINA1 gene located on chromosome 14 (Methods Mol Biol 2017;1639:9, Trends Mol Med 2014;20:116)
• Multiple genetic variants:
  • "M" = wild type allele
  • "Z" and "S" = most common mutant alleles (Methods Mol Biol 2017;1639:9)
    • "Z" mutant allele accounts for 90% of disease (Methods Mol Biol 2017;1639:9)
  • Numerous other rare alleles (J Biol Chem 1995;270:16864)
    • Mmalton, etc.
• 4 phenotypes (Methods Mol Biol 2017;1639:9, Orphanet J Rare Dis 2008;3:16):
  • Normal = normal function and plasma levels of AAT
    • "M" phenotype (PiMM)
    • Present in > 99% of world population
  • Deficient = abnormal function and low plasma levels of AAT
    • Mutant phenotype with "Z" or "S" alleles (PiSZ, PIZZ, etc.)
    • Present in < 1% of world population
  • Null = no detectable AAT in plasma
    • Proteins are truncated or unstable; leads to degradation
    • Very rarely causes liver disease and no hepatocyte inclusions will be present
    • Does cause lung disease
    • Present in < 0.1% of world population
  • Dysfunctional = normal plasma levels of AAT
    • AAT does not function correctly
    • Present in < 0.1% of world population

• Low serum concentration of AAT (Methods Mol Biol 2017;1639:9, Mutat Res 2017 Jul;773:14)
  • < 50% of the normal reference range = no further tests needed (Mutat Res 2017 Jul;773:14)
  • Caution: AAT is an acute phase reactant and so may show small elevations with systemic inflammatory states
• Absence of alpha-1 band on serum protein electrophoresis (Methods Mol Biol 2017;1639:9)
• Genotype analysis (Mutat Res 2017 Jul;773:14, Clin Liver Dis 2018;22:643)
• Phenotype of AAT protein (Clin Liver Dis 2018;22:643)
  • Either genotype or phenotype analysis can be used as gold standard

Contributed by Avani Pendse, M.D., Ph.D.

Contributed by Avani Pendse, M.D., Ph.D.

Which of the following is true of alpha-1 antitrypsin (AAT) deficiency in the liver?

1. Electron microscopy would show intramitochondrial fibrillary inclusions
2. Globules are negative for PASD and positive for AAT immunohistochemistry
3. Globules represent misfolded protein within the endoplasmic reticulum
4. Intracytoplasmic globules are the diagnostic feature
5. Number of globules correlates with disease severity

C. Globules represent misfolded protein within the endoplasmic reticulum. Although the intracytoplasmic globules are highly suggestive of alpha-1 antitrypsin deficiency, they are not diagnostic. In fact, there are no definitive diagnostic criteria for this disease (Answer D). Additionally, the globules are variably present and may be absent in some cases. There is also no correlation between the number of globules and disease severity (Answer E). When present, the globules are positive for both PASD and AAT (Answer B). These globules represent collections of misfolded protein. On electron microscopy the fibrillary inclusions are located within the endoplasmic reticulum, not within the mitochondria (Answer A).

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Reference: Alpha-1 antitrypsin deficiency

Which of the following additional findings is most often seen associated with alpha-1 antitrypsin (AAT) deficiency in the liver of adult patients?

1. Early onset cirrhosis
2. Elevated tissue concentration of AAT
3. High AST and low ALT
4. Mild steatosis
5. No detectable AAT in plasma

A. Early onset cirrhosis. Although AAT does indeed collect in the hepatocytes due to its inability to be released from the ER, tissue levels are not routinely tested (Answer B). Rather, AAT levels are measured in the plasma. An AAT deficient phenotype is most common and would have a low but still detectable plasma level of AAT. This phenotype has the mutant "z" or "s" alleles. A null phenotype is much rarer and no AAT can be detected in the plasma of such patients due to degradation of the protein entirely (Answer E). A dysfunctional phenotype is also rare, but although the protein does not function properly there are normal plasma levels of AAT. Other laboratory abnormalities would be elevations in both AST and ALT (Answer C) indicating hepatocyte stress. A sole elevation in AST would be more consistent with alcoholic liver injury. Histologically, hepatic steatosis may be present but this finding is variable and much less common than fibrosis or cirrhosis (Answer D). In fact, early onset cirrhosis should prompt suspicion and testing for alpha-1 antitrypsin deficiency.

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Reference: Alpha-1 antitrypsin deficiency