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).

Diagnosis

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)
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

Screening

  • 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

Monitoring

  • 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

Background

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  

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

  • 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
  • Complications

ARUP Lab 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

Medical Experts

Contributor

Genzen

Jonathan R. Genzen, MD, PhD
Associate Professor of Clinical Pathology, University of Utah
Chief Operations Officer, Medical Director of Automated Core Laboratory, ARUP Laboratories
Contributor
Contributor

Mao

Rong Mao, MD, FACMG
Professor of Clinical Pathology, University of Utah
Section Chief, Molecular Genetics and Genomics, ARUP Laboratories
Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®