1. Introduction

• Definition: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder characterized by low levels of alpha-1 antitrypsin (AAT), a protein produced by the liver that protects the lungs from neutrophil elastase, an enzyme that can damage lung tissue.
• Prevalence: AATD is one of the most common inherited disorders among Caucasians, particularly in Northern Europe. The estimated prevalence is 1 in 2,000 to 1 in 5,000 individuals.

2. Pathophysiology

• Genetics: AATD is inherited in an autosomal codominant manner. The SERPINA1 gene on chromosome 14 encodes AAT. The most common pathogenic alleles are the Z and S alleles.
  • Normal Genotype: MM (produces normal levels of AAT).
  • Deficient Genotypes:
    • ZZ: Most severe deficiency (10-15% of normal AAT levels).
    • SZ: Moderate deficiency.
    • MZ: Typically asymptomatic carriers with slightly reduced AAT levels.
• Lung Disease: In the lungs, AAT neutralizes neutrophil elastase. Deficiency allows elastase to damage alveolar walls, leading to early-onset emphysema, particularly in the lower lobes.
• Liver Disease: Mutant AAT proteins can accumulate in hepatocytes, causing liver damage, leading to cirrhosis, neonatal hepatitis, or hepatocellular carcinoma.

3. Clinical Manifestations

• Pulmonary Symptoms:
  • Early-Onset Emphysema: Symptoms typically present in the third to fifth decades of life, especially in smokers. Symptoms include dyspnea, wheezing, chronic cough, and sputum production.
  • Bronchiectasis: Some patients may develop this condition, characterized by chronic cough, sputum production, and recurrent infections.
• Hepatic Symptoms:
  • Neonatal Cholestasis: Presents in infancy with jaundice, hepatomegaly, and failure to thrive.
  • Chronic Hepatitis and Cirrhosis: May present later in life with symptoms of liver dysfunction.
  • Hepatocellular Carcinoma: Increased risk in individuals with cirrhosis.
• Other Manifestations:
  • Panniculitis: A rare skin condition characterized by painful, inflamed nodules, usually on the lower extremities.

4. Diagnosis

• Serum AAT Levels: A low serum AAT level is the first indication of AATD.
• Genotyping: Determines the specific SERPINA1 alleles, confirming the diagnosis and helping assess the risk for lung and liver disease.
• Pulmonary Function Tests (PFTs): Typically show obstructive patterns in affected individuals, with reduced FEV1/FVC ratio.
• Liver Function Tests (LFTs): May be abnormal in patients with liver involvement.
• Imaging Studies:
  • Chest X-Ray and CT Scan: Reveal hyperinflation, basal emphysema, or bronchiectasis.
  • Liver Ultrasound/CT/MRI: Used to assess liver disease severity and screen for hepatocellular carcinoma.

5. Management

• Smoking Cessation: Crucial to slowing the progression of lung disease.
• Augmentation Therapy:
  • Indicated for: Individuals with ZZ or SZ genotypes and evidence of emphysema.
  • Agents: Weekly or bi-weekly intravenous infusions of purified AAT.
  • Outcome: Slows the progression of emphysema but does not reverse existing lung damage.