Alpha-1-Antitrypsin Deficiency - AAT


Indications for Testing

  • American Thoracic Society/European Respiratory Society (2003)
    • Adult with early-onset COPD or emphysema without recognized risk factors
    • Necrotizing panniculitis (unexplained)
    • Family history of emphysema, alpha-1-antitrypsin (AAT), bronchiectasis, liver disease, panniculitis
    • Bronchiectasis with no known etiology
    • Unexplained liver disease
    • 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 accepted 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


  • 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

Clinical Background

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.


  • 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
  • Age 
    • Smokers develop disease in 40s
    • Nonsmokers develop disease in 50s

Risk Factors

  • Genetics – SERPINA1
    • Autosomal codominant
    • 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


  • 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


  • 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
Test Name and Number Recommended Use Limitations Follow Up
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

Primary test to identify AAT deficiency and causative DNA mutations or protein variants

Reflex pattern – reflexes to phenotyping when protein concentration <90 mg/dL and not homozygous or compound heterozygous for the S or Z deficiency alleles by genotyping

Mutations other than those targeted in S allele (c.791A>T) and Z allele (c.1024G>A) are not detected

95% clinical sensitivity

AAT-deficient patients may have falsely normal AAT concentrations

Rare diagnostic errors may occur due to probe-site mutations

Rare diagnostic errors may occur due to probe-site mutations

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

Order to determine type of AAT protein/variant in individual with decreased concentration of AAT (<90 mg/dL)

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

Alpha-1-Antitrypsin 0050001
Method: Quantitative Immunoturbidimetry

May use to identify AAT deficiency

Only determines AAT plasma concentration

Does not determine phenotype or genotype

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

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

Aid in histologic diagnosis of AAT

Stained and returned to client pathologist; if consultation required, contact anatomic pathology, surgical consult or hematopathology