Alpha-1-Antitrypsin Deficiency - AAT

  • Diagnosis
  • Screening
  • Background
  • Lab Tests
  • References
  • Related Content

Indications for Testing

  • American Thoracic Society/European Respiratory Society (2003)
    • Adult with early-onset COPD or emphysema without recognized risk factors
    • Unexplained necrotizing panniculitis or liver disease
    • Family history of emphysema, alpha-1-antitrypsin (AAT), bronchiectasis, liver disease, panniculitis
    • Bronchiectasis with no known etiology
    • ANCA vasculitis (anti-PR3 type)
  • Other
    • Newborns with bleeding disorder or prolonged jaundice

Laboratory Testing

  • Initial testing
    • Serum AAT – <60 mg/dL signifies substantial risk for AAT deficiency-related disorders
      • AAT is also an acute phase reactant and may be elevated by other disease processes
        • Up to fourfold increase observed in inflammatory conditions, cancer, and liver disease
      • Plasma concentration can be elevated into the normal range in PI MZ heterozygotes
  • Phenotyping and genotyping
    • Phenotyping
      • Identify AAT protein variants if AAT concentration is <90 mg/dL
      • Phenotyping by isoelectric focusing that is performed by a reliable laboratory is the gold standard for diagnosing AAT deficiency
    • Genotyping
      • Molecular testing of SERPINA1 gene for S and Z alleles can identify 95% of deficiency phenotypes in the general population

Histology

  • Immunohistochemistry – alpha-1-antitrypsin (AAT)
    • Homozygosity for Z allele confirms AAT severe phenotype
    • Homozygosity for S allele confirms AAT intermediate phenotype
    • SZ compound heterozygosity confirms AAT intermediate phenotype

Differential Diagnosis

  • Screening tests to perform prior to testing for alpha-1-antitrypsin (AAT) levels
    • Pulmonary function studies (irreversible airflow obstruction)
    • Chest x-ray/CT scan
  • Population-based screening not recommended even though disease recognized as being underdiagnosed

Alpha-1-antitrypsin (AAT, alpha-1-protease inhibitor) is the chief protease inhibitor in human serum. The loss of this protease inhibitor results in the degradation of the connective protein elastin in lung alveoli and increases the risk for developing severe lung disease during early adulthood.

Epidemiology

  • Prevalence
    • AAT deficiency affects ~2-3% of the 2-3 million patients with chronic obstructive pulmonary disease (COPD) in the U.S.
    • Severe deficiency – 1/6,000 in Caucasian populations; less frequent in other ethnicities
  • Incidence – 1/3,000-5,000 individuals of European ancestry
  • Age
    • Smokers develop disease in 40s
    • Nonsmokers develop disease in 50s

Risk Factors

  • Genetics – SERPINA1
    • Autosomal recessive
    • Isoelectric focusing (PI typing) has identified >100 AAT allelic variants classified according to electrophoretic mobility; most variants have no clinical significance
      • Mutations in the AAT glycoprotein gene on chromosome 14q31-q32.3; homozygosity for the Z allele is the most common cause
    • Most common normal phenotype is PI MM (100% AAT activity)
      • PI MM is found in 95% of Caucasians
    • Other common phenotypes and percentage of AAT activity include PI MS (80%), PI SS (60%), PI MZ (57.5%) and PI ZZ (15%)
      • S and Z alleles represent 95% of deficiency phenotypes in the general population
        • PI ZZ is associated with severe liver and lung disease
        • PI SS is associated with milder lung disease
      • Heterozygotes (PI MS and PI MZ) are at slightly increased risk for AAT deficiency-related disorders
  • Tobacco use
    • Tobacco smoke contains oxidants capable of inactivating AAT protein, further impairing reduced AAT function
    • Increases risk of developing severe lung disease; symptoms begin ≥10 years earlier than nonsmokers

Pathophysiology

  • AAT is a glycoprotein mainly synthesized by the liver
  • AAT deficiency results in uninhibited free neutrophil elastase which leads to degradation of the connective protein elastin in the alveoli
  • Oxidants in cigarette smoke inactivate AAT protein, causing further AAT impairment
  • Hepatic disease is secondary to accumulation of unsecreted AAT in hepatocytes

Clinical Presentation

Treatment

  • Early diagnosis is crucial in order to begin enzyme-replacement therapy

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations.
Click on number for test-specific information in the ARUP Laboratory Test Directory

Alpha-1-Antitrypsin (SERPINA1) Enzyme Concentration and 2 Mutations with Reflex to Alpha-1-Antitrypsin Phenotype 0051256
Method: Immunoturbidimetry/Polymerase Chain Reaction/Fluorescence Monitoring/Isoelectric Focusing

Limitations

Only the Z (c.1024G>A, p.E342K) and S (c.791A>T, p.E264V) alleles are detected by genotyping

AAT-deficient patients may have falsely normal AAT concentrations

Rare diagnostic errors may occur due to probe-site mutations

Alpha-1-Antitrypsin Phenotype (Includes Alpha-1-Antitrypsin) 0080500
Method: Qualitative Isoelectric Focusing/Immunoturbidimetry

Limitations

Only the Z (c.1024G>A, p.E342K) and S (c.791A>T, p.E264V) alleles are detected by genotyping

Acutely ill, AAT-deficient patients may have falsely normal AAT concentrations

Rare diagnostic errors may occur due to probe-site mutations

Alpha-1-Antitrypsin 0050001
Method: Quantitative Immunoturbidimetry

Limitations

Only the Z (c.1024G>A, p.E342K) and S (c.791A>T, p.E264V) alleles are detected by genotyping

Does not determine phenotype or genotype

Acutely ill, AAT-deficient patients may have falsely normal AAT concentrations

Rare diagnostic errors may occur due to probe-site mutations

Alpha-1-Antitrypsin (AAT) by Immunohistochemistry 2003424
Method: Immunohistochemistry

General References

Bals R. Alpha-1-antitrypsin deficiency. Best Pract Res Clin Gastroenterol. 2010; 24(5): 629-33. PubMed

Fregonese L, Stolk J. Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. Orphanet J Rare Dis. 2008; 3: 16. PubMed

Köhnlein T, Welte T. Alpha-1 antitrypsin deficiency: pathogenesis, clinical presentation, diagnosis, and treatment. Am J Med. 2008; 121(1): 3-9. PubMed

Stoller J, Aboussouan L. A review of α1-antitrypsin deficiency. Am J Respir Crit Care Med. 2012; 185(3): 246-59. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Bornhorst J, Calderon F, Procter M, Tang W, Ashwood E, Mao R. Genotypes and serum concentrations of human alpha-1-antitrypsin "P" protein variants in a clinical population. J Clin Pathol. 2007; 60(10): 1124-8. PubMed

Bornhorst J, Greene D, Ashwood E, Grenache D. α1-Antitrypsin phenotypes and associated serum protein concentrations in a large clinical population. Chest. 2013; 143(4): 1000-8. PubMed

Bornhorst J, Procter M, Meadows C, Ashwood E, Mao R. Evaluation of an integrative diagnostic algorithm for the identification of people at risk for alpha1-antitrypsin deficiency. Am J Clin Pathol. 2007; 128(3): 482-90. PubMed

Greene D, Elliott-Jelf M, Straseski J, Grenache D. Facilitating the laboratory diagnosis of α1-antitrypsin deficiency. Am J Clin Pathol. 2013; 139(2): 184-91. PubMed

Greene D, Procter M, Krautscheid P, Mao R, Lyon E, Grenache D. α1-antitrypsin deficiency in fraternal twins born with familial spontaneous pneumothorax. Chest. 2012; 141(1): 239-41. PubMed

Slev P, Williams B, Harville T, Ashwood E, Bornhorst J. Efficacy of the detection of the alpha1-antitrypsin "Z" deficiency variant by routine serum protein electrophoresis. Am J Clin Pathol. 2008; 130(4): 568-72. PubMed

Suh-Lailam B, Procter M, Krautscheid P, Haas J, Kumar S, Mao R, Grenache D. Challenging identification of a novel PiISF and the rare PiMmaltonZ α1-antitrypsin deficiency variants in two patients. Am J Clin Pathol. 2014; 141(5): 742-6. PubMed

Medical Reviewers

Last Update: December 2015