Alpha-1-Antitrypsin Deficiency - AAT

Clinical Background

Alpha-1-antitrypsin (AAT, alpha-1-protease inhibitor) is the chief protease inhibitor in human serum. The loss of this protease inhibitor results in the degradation of the connective protein elastin in lung alveoli and increases the risk for developing severe lung disease during early adulthood.

Epidemiology 

• Prevalence
  • AAT deficiency is estimated to affect 2-3% of the 2-3 million patients with chronic obstructive pulmonary disease (COPD) in the U.S.
  • Severe deficiency – 1/6,000  in Caucasian populations; less frequent in other ethnicities
• Age 
  • 50s for early-onset COPD (nonsmokers)
  • Tobacco smokers usually become symptomatic in their 40s
• Ethnicity – highest prevalence in Caucasians of North American and European descent

Risk Factors

• Genetics
  • Isoelectric focusing (PI typing) has identified >100 AAT allelic variants classified according to electrophoretic mobility; most variants have no clinical significance
  • Most common normal phenotype is PI MM (100% AAT activity)
    • PI MM is found in 95% of Caucasians
  • Other common phenotypes and percentage of AAT activity include PI MS (80%), PI SS (60%), PI MZ (57.5%) and PI ZZ (15%)
  • S and Z alleles represent 95% of the deficiency phenotypes in the general population
    • PI ZZ is associated with severe liver and lung disease
    • PI SS is associated with milder lung disease
  • Heterozygotes (PI MS and PI MZ) are at slightly increased risk for AAT deficiency-related disorders
• Tobacco use
  • Tobacco smoke contains oxidants capable of inactivating AAT protein, further impairing reduced AAT function
  • Increases risk of developing severe lung disease with symptoms beginning ≥10 years earlier than nonsmokers

Pathophysiology

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

Clinical Presentation

• Adults
  • Pulmonary – early onset emphysema (panacinar)
  • Hepatic – liver disfunction, cirrhosis 
    • Occurs more often in individuals with Z allele
    • Hepatitis with jaundice
    • Chronic liver disease
  • Skin – panniculitis
    • Necrotic areas with spontaneous suppuration
• Neonates
  • 10% 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
  • Wegener granulomatosis, necrotizing panniculitis, aneurysms of aortic and brain arteries
• Complications
  • Hepatocellular carcinoma and cholangiocarcinoma

Treatment

• Early diagnosis is crucial in order to begin enzyme-replacement therapy

Diagnosis

Indications for Testing

• Adult with early-onset COPD (<45 years)
• Necrotizing panniculitis (unexplained)
• Sibling or family member with known AAT deficiency
• Bronchiectasis with no known etiology
• Unexplained liver disease
• Newborns with bleeding disorder or prolonged jaundice
• ANCA vasculitis (anti-PR3 type)

Laboratory Testing

• Initial testing
  • Serum AAT – concentrations usually low in symptomatic disease
    • AAT is also an acute phase reactant and may be elevated by other disease processes
      • Up to 4-fold increase observed in inflammatory conditions, cancer, and liver disease
      • Plasma concentration can be elevated into the normal range in PI MZ heterozygotes
• Phenotyping and genotyping
  • Phenotype testing to identify AAT protein variants if AAT concentration is <100 mg/dL
  • Molecular testing of SERPINA1 gene for S and Z alleles if phenotype is abnormal

Differential Diagnosis

• Adults
  • Non-AAT COPD
  • Cirrhosis from other etiologies
• Pediatric
  • Viral infection
  • Hemochromatosis
  • Wilson disease
  • Autoimmune hepatitis
  • Inborn errors of metabolism

Screening

Indications for Laboratory Testing

• 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