Etiology

mutations in SERPINA1 gene

• M is the normal allele.
• S mutation causes a moderate decrease in AAT production.
• Z mutation causes a significant decrease in AAT production.
• The severity of disease depends on the specific genotypic expression, which correlates with the amount of α1-antitrypsin protein synthesis
  • PiMM: 100% expression of normal protein and therefore normal serum levels of AAT
  • PiMS: 80% of normal serum levels of AAT
  • PiSS, PiMZ, PiSZ: 40–60% of normal serum levels of AAT
  • PiZZ: 10–15% of normal serum levels of AAT (severe AAT deficiency)

Pathophysiology

• Alpha-1 antitrypsin: a protease inhibitor that is synthesized in the liver and protects cells from breakdown by neutrophil elastase
• Gene mutation induces a conformational change in the structure of AAT protein → dysfunctional (or absent) AAT
  • Effect on the liver: accumulation of AAT in hepatocellular endoplasmic reticulum → hepatocyte destruction → hepatitis and liver cirrhosis
  • Effect on the lungs: deficient AAT → uninhibited neutrophil elastase activity → destruction of the pulmonary parenchyma → panacinar emphysema

Clinical features

• Pulmonary manifestations
  • Cough, wheezing
  • Dyspnea
  • Diminished breath sounds
  • Barrel chest

• Hepatic manifestations
  • Prolonged neonatal jaundice
  • Hepatitis
  • Cirrhosis
  • Increased risk of hepatocellular carcinoma (HCC)
    • Patients with AAT deficiency are at risk of developing liver cirrhosis with subsequent HCC. HCC can also develop in the absence of cirrhosis.

Diagnostics

• Serum: decreased antitrypsin protein levels
• Electrophoresis: decreased alpha-1 peak
• Chest x-ray
  • Low and flat diaphragm
  • Widened intercostal spaces
  • Hyperinflation and increased basilar radiolucency of both lungs with rarification of peripheral pulmonary vessels
• Chest CT
  • Panacinar emphysema (in contrast to centriacinar emphysema in smoking-related emphysema)
  • Bronchiectasis
  • Bullae
• Liver biopsy
  • PAS-positive, spherical inclusion bodies in periportal hepatocytes
  • Signs of cirrhosis

Treatment