What is the significance of decreased Alpha one anti-trypsin (A1AT) levels?

Significance of Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin (A1AT) deficiency is a common genetic disorder that significantly increases risk for developing pulmonary emphysema, liver disease, and rarely skin conditions like panniculitis, with decreased A1AT levels disrupting the protease-antiprotease balance in the lungs and potentially leading to premature disability and death. 1

Clinical Manifestations

• Pulmonary emphysema of the panacinar type is the most prevalent clinical consequence of A1AT deficiency and represents the major cause of disability and death 1
• Symptomatic obstructive lung disease typically presents between ages 32 and 41 in individuals with a history of smoking 1
• Liver disease is the second most frequent clinical complication, which may present in infancy as cholestasis that usually resolves by adolescence, but can also lead to cirrhosis in adulthood 1
• Rare manifestations include necrotizing panniculitis and secondary vasculitis 2
• A1AT deficiency has also been associated with chronic urticaria, particularly cold urticaria and acquired idiopathic angioedema 2

Genetic Basis and Classification

• A1AT deficiency is caused by mutations in the SERPINA1 gene and is inherited as an autosomal recessive trait 3
• The most common severe deficiency allele is the Z mutation (p.E342K), which causes the A1AT protein to fold aberrantly, accumulate in hepatocytes, and significantly reduce circulating levels 2
• The S allele (p.E264V) is another common variant that causes intermediate deficiency 2
• Null mutations lead to complete absence of circulating A1AT and greater susceptibility to emphysema, though without liver accumulation 2
• Different phenotypes include:
  • PI*ZZ (severe deficiency, highest risk)
  • PI*SZ (moderate deficiency)
  • PI*MZ (mild/intermediate deficiency)
  • PI*MM (normal) 2

Diagnostic Approach

• Testing should be considered in individuals with:

  • Early-onset emphysema (regardless of smoking history)
  • All subjects with COPD or asthma with persistent airflow obstruction
  • Adults with bronchiectasis without evident etiology
  • Liver disease of unknown cause
  • Family members of known A1AT-deficient patients 1, 2

• Diagnostic testing involves:

  • Measuring serum or plasma A1AT levels (primary screening test)
  • In moderate clinical suspicion cases, an A1AT level ≥ 23 mmol/L (≥ 1.2 g/L) rules out severe A1AT deficiency
  • In high clinical suspicion cases, DNA sequencing of the SERPINA1 gene is recommended as the initial test 2

Clinical Implications of Different A1AT Levels

• Severe deficiency (<11 μmol/L or <0.57 g/L): High risk for emphysema, especially in smokers; may qualify for augmentation therapy 2, 4
• Intermediate deficiency (11-23 μmol/L or 0.57-1.2 g/L): Increased risk for lung disease, especially with environmental exposures 2
• MZ phenotype (typically ~60% of normal levels): Slightly increased risk of COPD compared to the general population, with a relative risk of 2.2 for hospitalization due to COPD 5
• Normal levels (>23 μmol/L or >1.2 g/L): No increased risk 2

Management Approaches

• Early diagnosis is crucial as late diagnosis has been associated with reduced functional status, quality of life, and worse overall survival 2
• Preventive measures include:
  • Smoking cessation and avoidance of environmental irritants
  • Maintaining up-to-date vaccination status
  • Exercise, healthy diet, and pulmonary hygiene 1
• Augmentation therapy with purified A1AT protein should be considered for patients with severe deficiency and emphysema 4
• For MZ individuals:
  • Confirm phenotype through qualitative testing
  • Perform baseline pulmonary function tests and liver function tests
  • More frequent monitoring if risk factors are present 5

Prognosis and Monitoring

• Without treatment, A1AT deficiency can lead to premature disability and death, with 72% of deaths due to emphysema 1
• Long-term surveillance for early detection of lung and liver diseases is recommended 1
• Family screening should be encouraged to identify relatives who may be affected 2
• The panel strongly supports offering genetic counseling and A1AT testing for first-degree relatives of individuals identified with abnormal A1AT genes 2

Pitfalls and Caveats

• A1AT deficiency is significantly underdiagnosed with an average diagnostic delay of approximately 5.6 years 6
• Some genetic variants of A1AT deficiency are associated with normal circulating levels but represent actual deficiency because the circulating A1AT is nonfunctional (e.g., Pi*F variant) 2
• Serum A1AT levels can be falsely elevated during acute inflammation as A1AT is an acute phase reactant 2
• Relying solely on A1AT levels without genetic testing may miss rare variants 2
• Patients with novel mutations should be referred to expert reference centers for proper characterization and clinical implications assessment 2