Alpha-1-Antitrypsin Deficiency - AAT

Alpha-1-antitrypsin (AAT) is the chief protease inhibitor (PI) in human serum. Alterations in the production of this PI may result in the degradation of the connective protein elastin in lung alveoli, which increases the risk for developing lung disease. Additionally, severe AAT deficiency may cause improper folding of the AAT protein leading to deposition in hepatocytes and corresponding liver disease.

Chronic obstructive pulmonary disease (COPD) caused by AAT deficiency (AATD-COPD) is the fourth most common factor associated with lung transplantation. Pooled plasma AAT infusions can be used to treat lung disease in patients with AATD-COPD; however, this treatment does not address liver disease caused by AAT deficiency (Sandhaus, 2016).


Indications for Testing

  • Chronic obstructive pulmonary disease (COPD) or unexplained bronchiectasis, regardless of age or ethnicity
  • Unexplained chronic liver disease
  • Necrotizing panniculitis or granulomatosis with polyangiitis
  • First-degree relative with 1 or 2 pathogenic alpha-1-antitrypsin (AAT) gene variants
  • Family history of AAT deficiency
  • Newborns with bleeding disorder or prolonged jaundice

Laboratory Testing

  • Diagnostic testing for symptomatic individuals
Testing for Symptomatic Individuals
  Protease Inhibitor (PI) Typing (Phenotyping) Genotyping of S and Z Alleles AAT Serum Concentration AAT Gene Sequencing (Expanded Genotyping)

Detect abnormal phenotypes

Identify causative S and Z DNA variants

Evaluate AAT protein concentration

  • <90mg/dL suggests patient is at least a carrier of AAT deficiency
  • <10-15% of normal suggests patient is affected

Identify rare pathogenic variants


Considered gold standard; identifies all abnormally migrating proteins

Identify 95% of affected individuals

Allow for prenatal diagnosis in at-risk pregnancies

Determine AAT enzyme plasma concentration for the initial evaluation of AAT deficiency

Identify variants other than S and Z alleles


May not be able to accurately identify rare deficiency alleles

Does not detect null alleles

Does not detect rare deficiency alleles including null alleles

Serum AAT concentration has low sensitivity for AAT deficiency because AAT is an acute phase reactant and may be elevated by other disease processes



Isoelectric focusing

Molecular testing of SERPINA1 gene

Quantification of AAT protein in serum

Molecular sequencing of SERPINA1

  • Testing of asymptomatic high-risk individuals
    • First-degree relatives of affected individuals
    • Molecular testing of known familial variant

Imaging Studies

  • Computed tomography (CT) scan of chest
    • Recommended in newly diagnosed patients who are symptomatic or have abnormal pulmonary function testing results (Sandhaus, 2016)

Differential Diagnosis


  • American Thoracic Society (ATS) and European Respiratory Society (ERS) Guidelines (2003)
    • Neonatal screening: not recommended despite high prevalence of deficiency in population
    • Screening in individuals >11 years: may be indicated in areas of high alpha-1-antitrypsin (AAT) deficiency prevalence or in areas of high smoking rates


  • Pulmonary disease (Sandhaus, 2016)
    • Measure lung function with baseline spirometry and annual spirometry follow-up
    • Computed tomography (CT) of chest not recommended for monitoring
  • Liver disease: monitor annually unless clinically indicated sooner (Sandhaus, 2016)
    • Laboratory monitoring
      • Aspartate aminotransferase (AST)
      • Alanine aminotransferase (ALT)
      • Gamma-glutamyl transferase (GGT)
      • Albumin, bilirubin
      • International normalized ratio (INR)
      • Platelets
    • Physical examination of abdomen
    • Liver ultrasound



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

Risk Factors

  • Tobacco use
    • Increases risk of developing severe lung disease; symptoms begin ≥10 years earlier than in nonsmokers
    • Oxidants in tobacco smoke inactivate AAT protein, causing further AAT impairment
  • Occupational dust/fumes
  • Liver insults


    • Gene located on chromosome 14q31-q32.3
    • Inheritance: codominant
    •  >100 variants identified: most are benign
    • Pathogenic variant (c.1024G>A; p.E324K), known as Z allele by phenotyping, is most common severe deficiency variant
    • Pathogenic variant (c.791A>T; p.E264V), known as S allele by phenotyping, is most common moderate deficiency variant
    • 95% of White individuals have the M allele by phenotyping (ie, no variants present in the AAT gene [wild type])
Genotype/Phenotype Interpretation
Allele Variants AAT Activity Emphysema Risk Liver Disease Risk






















Moderately high – high






  • AAT is a glycoprotein mainly synthesized by the liver
  • AAT deficiency results in uninhibited free neutrophil elastase, which leads to degradation of connective protein elastin in alveoli
  • Hepatic disease is secondary to accumulation of improperly folded, unsecreted AAT in hepatocytes

Clinical Presentation

  • Adults
    • Pulmonary: dyspnea, wheezing, cough, phlegm, and early onset emphysema (panacinar)
    • Hepatic: liver dysfunction, cirrhosis
      • Occurs more often in individuals with Z allele
      • Hepatitis with jaundice
      • Chronic liver disease
    • Skin: panniculitis
      • Necrotic areas with spontaneous suppuration
  • Neonates
    • Small percentage of affected newborns have hepatitis with cholestatic jaundice (prolonged jaundice with conjugated hyperbilirubinemia)
    • Low AAT levels are also found in neonatal respiratory distress syndrome and severe protein-losing disorders
  • Rare associated diseases
    • Granulomatosis with polyangiitis, necrotizing panniculitis, and aneurysms of aortic and brain arteries
  • Complications

ARUP Laboratory Tests

Primary Tests

Preferred test to identify alpha-1-antitrypsin (AAT) deficiency and causative DNA and protein variants

Only 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

Diagnostic errors may occur due to rare probe-site mutations

Determine specific AAT protein variant(s) in individual with decreased concentration of AAT (<90mg/dL)

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

Determine AAT enzyme plasma concentration for the initial evaluation of AAT deficiency

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

Aid in histologic diagnosis of AAT

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


Additional Resources

Medical Experts



Rong Mao, MD, FACMG
Professor of Pathology (Clinical), and Co-Director of Laboratory Genetics and Genomics Fellowship, University of Utah
Medical Director, Molecular Genetics and Genomics, ARUP Laboratories