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

Treatment

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

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