Makindo Medical Notes

Note: Screen for Alpha-1 Antitrypsin (AAT) deficiency in anyone with COPD under the age of 40. AAT deficiency is inherited in an autosomal recessive pattern, contributing to emphysema and cirrhosis, with a prevalence of 1 in 2500. It accounts for about 1% of emphysema cases. Patients who manifest disease usually have the PiZZ genotype.

About

• Alpha-1 Antitrypsin (AAT) deficiency is a genetic disorder that results in a reduced ability to inhibit neutrophil elastase, leading to tissue damage.
• The deficiency primarily affects the lungs, causing emphysema, and the liver, leading to cirrhosis, depending on the genetic variant.
• Normal genotype is PiMM, while the most severe form is PiZZ.

Aetiology

• AAT is produced in the liver and acts as an inhibitor of the proteolytic enzyme elastase, which is released by neutrophils.
• The AAT gene is located on chromosome 14.
• The PiZZ genotype is present in about 1 in 2500 people in Europe.

Pathophysiology

• Neutrophil elastase can cause damage to lung tissue when not adequately inhibited.
• AAT neutralizes elastase, preventing excessive breakdown of elastin in the lung's alveolar walls.
• In AAT deficiency, the reduced levels of AAT lead to unopposed elastase activity, resulting in increased tissue destruction and emphysema.
• Genotypes include:
  • Normal: PiMM
  • Intermediate Deficiency: PiSS (50% of normal AAT levels)
  • Severe Deficiency: PiZZ (10% of normal AAT levels)

Genetics

• AAT phenotypes are defined by electrophoresis, indicating the speed of enzyme movement.
• Alleles include M (normal), S (intermediate), and Z (severe decrease).
• Common genotypes:
  • Best: MM, MS, MZ
  • Intermediate: SZ
  • Worst: ZZ

Clinical Features

• Lungs: Panacinar emphysema, primarily affecting the lung bases, often with associated bronchiectasis.
• Liver: Cirrhosis and hepatocellular carcinoma in adults; neonatal cholestasis in children.
• Onset typically occurs at ages 30-40 in smokers and 50-60 in non-smokers.
• Approximately 10% of patients develop liver disease.

Investigations

• Serum AAT Levels: Typically low, with levels below 50 to 80 mg/dL (11 µmol/L).
• Genotyping: Determines the presence of severe deficiency genotypes like PiZZ.
• Liver Biopsy: May show PAS-positive, diastase-resistant globules, indicative of AAT accumulation in hepatocytes and cirrhosis.

Management

• Lifestyle: Smoking cessation and reducing alcohol intake are critical.
• Standard Treatment: Manage as per standard guidelines for emphysema and cirrhosis.
• AAT Replacement Therapy: Infusions of pooled human AAT (alpha-1 antiprotease) are considered in moderate disease.
• Future Therapies: Gene therapy is a potential future treatment option.
• Transplantation: Lung and liver transplantation can be considered for advanced cases. A liver transplant can cure the deficiency, as the new liver produces normal levels of AAT.

References

• NICE Guidelines on Chronic Obstructive Pulmonary Disease
• American Thoracic Society Guidelines on Alpha-1 Antitrypsin Deficiency