Alpha-1-Antitrypsin Deficiency - AAT

  • Diagnosis
  • Screening
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics

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
  • Test

    Protease Inhibitor (PI) Typing (Phenotyping)

    Genotyping of S and Z Alleles

    AAT Serum Concentration

    AAT Gene Sequencing (Expanded Genotyping)

    Rationale

    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

    Strengths

    Considered gold standard – identify 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

    Limitations

    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

     

    Description

    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

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).

Epidemiology

  • Prevalence
    • AAT deficiency affects ~2-3% of the 2-3 million patients with COPD in U.S.
    • Severe deficiency – 1/6,000 in Caucasian 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

Genetics

  • SERPINA1
    • 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
    • No variants present in AAT gene (wild type), known as M allele by phenotyping – present in 95% of Caucasians
  • Genotype/phenotype interpretation
  • Allele Variants

    AAT Activity

    Emphysema Risk

    Liver Disease Risk

    MM

    100%

    Background

    Low

    MS

    80%

    Background

    Low

    MZ

    58%

    Background

    Low

    SS

    60%

    Background

    Low

    SZ

    38%

    20-50%

    Intermediate

    ZZ

    15%

    80-100%

    Moderately high – high

    Null-Null

    0%

    100%

    High

Pathophysiology

  • 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

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 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

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

Limitations 

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

Alpha-1-Antitrypsin 0050001
Method: Quantitative Immunoturbidimetry

Limitations 

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

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

Guidelines

Alpha-1 antitrypsin deficiency. National Institutes of Health. Bethesda, MD [Reviewed Jan 2013; Accessed: Jun 2017]

American Thoracic Society, European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003; 168(7): 818-900. PubMed

Global Strategy for Diagnosis, Management, and Prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease. [Accessed: Jun 2017]

Sandhaus RA, Turino G, Brantly ML, Higgins VS, Make BJ, Marvel J, Yu T, Wood R, Campos M, Cross CE, Goodman K, Hogarth K, Knight SL, Stocks JM, Stoller JK, Strange C, Teckman J. Clinical Guidelines for the Diagnosis and Management of Alpha-1 Antitrypsin Deficiency in the Adult. Chronic Obstr Pulm Dis. 2016; 3(3): 668-682. PubMed

General References

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

Ferrarotti I, Thun GA, Zorzetto M, Ottaviani S, Imboden M, Schindler C, von Eckardstein A, Rohrer L, Rochat T, Russi EW, Probst-Hensch NM, Luisetti M. Serum levels and genotype distribution of α1-antitrypsin in the general population. Thorax. 2012; 67(8): 669-74. 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

Marciniuk DD, Hernandez P, Balter M, Bourbeau J, Chapman KR, Ford GT, Lauzon JL, Maltais F, O'Donnell DE, Goodridge D, Strange C, Cave AJ, Curren K, Muthuri S, Canadian Thoracic Society COPD Clinical Assembly Alpha-1 Antitrypsin Deficiency Expert Working Group. Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: a Canadian Thoracic Society clinical practice guideline. Can Respir J. 2012; 19(2): 109-16. PubMed

McElvaney NG. Diagnosing α1-antitrypsin deficiency: how to improve the current algorithm. Eur Respir Rev. 2015; 24(135): 52-7. PubMed

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

Stoller JK, Lacbawan FL, Aboussouan LS. Alpha-1 Antitrypsin Deficiency. 2006 Oct 27 [updated 2014 May 01]. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Fong CT, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Bornhorst JA, Calderon FR, Procter M, Tang W, Ashwood ER, 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 JA, Greene DN, Ashwood ER, Grenache DG. α1-Antitrypsin phenotypes and associated serum protein concentrations in a large clinical population. Chest. 2013; 143(4): 1000-8. PubMed

Bornhorst JA, Procter M, Meadows C, Ashwood ER, 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 DN, Elliott-Jelf MC, Straseski JA, Grenache DG. Facilitating the laboratory diagnosis of α1-antitrypsin deficiency. Am J Clin Pathol. 2013; 139(2): 184-91. PubMed

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

Slev PR, Williams BG, Harville TO, Ashwood ER, Bornhorst JA. 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 BB, Procter M, Krautscheid P, Haas J, Kumar S, Mao R, Grenache DG. 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

Content Reviewed: 
June 2017

Last Update: September 2017