Alpha-1-Antitrypsin Deficiency - AAT

Alpha-1-Antitrypsin Deficiency - AAT

 

Alpha-1-antitrypsin (AAT, alpha-1-protease inhibitor) is the major protease (trypsin, chymotrypsin and elastase) inhibitor in human serum. The loss of this protease increases the risk for developing emphysema in early adulthood.

Epidemiology

  • Prevalence
    • Estimated that 2-3% of 2-3 million patients with chronic obstructive pulmonary disease (COPD) in the U.S. have AAT deficiency
    • 1/3,000 for severe deficiency
  • Ethnicity – highest prevalence in Caucasians of North American and European descent
  • Age – 30s-40s with early onset COPD

Risk Factors

  • Genetics
    • Over 100 AAT allelic variants have been classified according to their electrophoretic mobility using isoelectric focusing; most have no clinical significance
    • Common phenotypes include: MM, MS, SS, MZ and ZZ, associated with 100, 80, 60, 57.5 and 15% AAT activity, respectively
    • MM, present in 95% of Caucasians, is considered the normal phenotype
    • 95% of deficiency alleles in the general population are either S or Z
    • Z allele is associated with severe liver and lung disease, and the S allele is associated with milder lung disease
    • Heterozygotes for a deficiency allele are only at slightly increased risk for AAT deficiency-related disorders
  • Concomitant smoking increases the risk of emphysema and decreases the age of onset

Pathophysiology

  • AAT is an acute phase reactant synthesized by the liver; its inherited deficiency is associated with liver and lung disease
    • Most important role is inhibition of protease neutrophil elastase
  • Decreased quantities of AAT allow elastase to degrade lung parenchyma
  • Hepatic disease is secondary to accumulation of unsecreted AAT in hepatocytes

Clinical Presentation

  • Adults
    • Emphysema
      • Early onset
      • Panacinar
    • Liver dysfunction
      • Occurs more often in individuals with a Z allele
      • Hepatitis with jaundice
  • Neonates
    • 10% of affected newborns have hepatitis with cholestatic jaundice
    • Low AAT levels are also found in neonatal respiratory distress syndrome and severe protein-losing disorders
  • Rare associated diseases
    • Wegener’s granulomatosis, necrotizing panniculitis, aneurysms of aorta and brain arteries

Diagnosis

  • Indications for testing
    • Adult with early onset COPD (<45 years of age)
    • Necrotizing panniculitis (unexplained)
    • Sibling or family member with known AAT deficiency
    • Bronchiectasis without known etiology
    • Unexplained liver disease
    • ANCA vasculitis (anti-PR3 type)
  • Screening tests – prior to measuring levels
    • Pulmonary function studies (irreversible airflow obstruction)
    • Chest X-ray/CT scan
  • Laboratory testing
    • Serum AAT concentrations will be low in disease
    • Phenotype determination to identify AAT protein variants if concentration is <100mg/dL
    • Molecular DNA genotyping for common disease alleles

Treatment

  • Enzyme replacement treatment is available, so early diagnosis is crucial

See Also