• Information
  1. alpha1-Antitrypsin
  2. Clinical Symptoms of A1AT Deficiency
  3. Treatment

A. alpha1-Antitrypsin (A1AT)

1. Function
   1. Serine protease (trypsin) inhibitor ("serpin")
   2. Acute phase reactant
2. Synthesized primarily in liver, protects lungs and other organs from neutrophil proteases
3. Serum Levels of A1AT
   1. Serum levels A1AT in normal persons (usually genotype MM) are >2.5 g/L
   2. Levels >0.8 g/L are associated with normal function
   3. Most common polymorphisms leading to disease result in levels <10% of normal
4. A1AT Gene
   1. Most common normal allele designated "M"
   2. Normal allele designated X has Gly363Lys substitution, normal phenotype
   3. Over 100 mutations causing disease have been identified [3]
   4. Most mutations lead to polymerization and sequestration inside liver cells
   5. Other mutations lead to enhanced intracellular degradation
   6. Most common disease mutation (~95%) is designated "Z", codes for Gly342Lys mutant
   7. Gly342Lys mutant polymerizes and accumulates in and is toxic to liver cells
   8. Leads to both lung and liver pathology
   9. "S" allele, Glu264Val, leads to enhanced degradation of A1AT inside liver cells
5. Effect of Mutant A1AT Alleles
   1. Risk of emphysema increases greatly at serum levels below about 800 mg/L [4]
   2. MZ has slightly greater reduction in FEV1 with aging than MM [5]
   3. Heterozygotes (MZ genotype) have 30% increased risk of developing COPD than MM [5]

B. Clinical Symptoms of A1AT Deficiency

1. ~2% of COPD/emphysema is caused by severe A1AT deficiency
2. Some 10-15% of persons with A1AT deficiency develop (early onset) emphysema [6]
   1. Risk of emphysema increases greatly at serum levels below about 0.8 g/L [4]
   2. Emphysema occurs with any mutation that leads to reduced levels or loss of A1AT function
   3. Emphysema characterized by panacinar pathology
   4. Emphysema usual begins age 30-45 (early onset)
   5. A1AT deficiency may also predispose to bronchiectasis
3. Check A1AT for emphysema <50 years of age with little or no smoking history
4. Chronic Hepatitis and Cirrhosis
   1. Uncommon cause of hepatitis due to toxicity of accumulated mutant A1AT
   2. Most commonly associated with "Z" alleles
   3. ALT (SGPT) and AST (SGOT) elevations initially
   4. May be exacerbated by viral infections [7]
   5. May progress to cirrhosis
5. Diagnosis
   1. Determination of A1AT levels in serum
   2. For levels <0.8 g/L, mutation analysis can be undertaken
   3. Family patterns should be determined in patients abnormally low levels
   4. Commercial test kits for detecting Z or S alleles are available
6. Evaluation
   1. Lung and liver are the main target organs
   2. CT scan of the lung often shows basilar emphysema most prominant
   3. Pulmonary function tests may show reversible component ("asthma")
7. Causes of Death
   1. Respiratory ~65%
   2. Cirrhosis ~10%
   3. Overall annual mortality ~2.5% following diagnosis

C. Treatment [1]

1. Standard Treatments for COPD
   1. Smoking cessation
   2. Bronchodilators
   3. Preventive vaccinations
   4. Oxygen as needed
2. Liver Disease
   1. No specific treatments
   2. comorbid conditions should be evaluated and treated if possible
   3. Liver transplant may be considered
3. Replacement (Augmentation) Therapy
   1. Intravenous infusion of A1AT raises serum and alveolar levels, may slow disease [8,9]
   2. Three A1AT products produced from pooled human plasma approved in USA
   3. Include: Prolastin®, Aralast®, Zemaira® typically given at 4 week intervals
   4. Mortality benefit not yet definitive with replacement therapy

References

1. Stoller JK and Aboussouan LS. 2005. Lancet. 365(9478):2225
2. Carrell RW and Lomas DA. 2002. NEJM. 346(1):45
3. 22. Norman MR, Mowat AP, Hutchison DC. 1997. Ann Clin Biochem. 34(3):230
4. 24. Wiedemann HP and Stoller JK. 1996. Curr Opin Pulm Med. 2(2):155
5. 23b. Dahl M, Tybjaerg A, Lange P, et al. 2002. Ann Intern Med. 136(4):279
6. 23. Knight KR, Burdon JG, Cook L, et al. 1997. Respirology. 2(2):91
7. 18. Propst T, Propst A, Dietze O, et al. 1992. Ann Intern Med. 117(8):641
8. 25. Seersholm N, Wencker M, Banik N, et al. 1997. Eur Respir J. 10(10):2260
9. Stoller JK, Rouhani F, Brantly M, et al. 2002. Chest. 122:66