Alpha-1 antitrypsin (AAT) deficiency
AAT = protease inhibitor (PI), synthesized in hepatocytes
Emphysema results from an imbalance between neutrophil elastase in the lung (destroys elastin), and the elastase inhibitor AAT = “toxic loss of function”
- Lung degradation occurs with increased elastase burden in the lungs (smoking)
Liver disease: “toxic gain of function”; accumulation within the hepatocytes of unsecreted variant AAT protein; almost always PI*ZZ
Genetics: autosomal co-dominant; 150 alleles of AAT
- Normal = M -> PI*MM
- AAT = Z (most common) -> PI*ZZ
- AAT = S (compound heterozygote) -> PI*SZ
- Heterozygotes (PI*MZ): conflicting data re emphysema risk
AAT phenotypes: protective threshold 11 micromol/L (57 mg/dL)
- Normal: MM
- Deficient: AAT level < 35% normal
- Null: no detectable AAT (rare, most severe lung disease, no liver disease)
- Dysfunctional: normal levels but dysfunctional (PI*F)
Epidemiology: 2-3% of patients with COPD; 80-100K individuals in the US
Clinical manifestations:
- Emphysema onset at young age, basilar-predominant (although substantial variability), PTX, bronchiectasis
- Hepatitis, cirrhosis, HCC, panniculitis, IBD, intracranial and inta-abdominal aneurysms, fibromuscular dysplasia, glomerulonephritis
From: https://radiopaedia.org/cases/alpha-1-antitrypsin-deficiency-15?lang=us
Diagnosis: screen all adults with persistent airflow obstruction, emphysema, FH or emphysema/liver disease, adult onset asthma, panniculitis, unexplained liver disease
- Send Alpha-1 Antitrypsin Phenotype and Quant
Monitoring:
- Asymptomatic with normal spiro: spiro Q6-12 mths; augment if/when FEV1 < 80%
- LFTs annually, +/- CBC (Plts) and liver US Q6-12 mths
- Lung function decline strongly affected by smoking
Treatment (i.e., Augmentation)
- Pooled human AAT intravenous infusion (weekly) -> goal is to slow disease progression
- Never or ex-smokers, > 18 y/o, with low serum AAT and high-risk genetic variant
- FEV1 35-65% (other societies suggest FEV1 25-80%); uncertainty regarding a lower limit of FEV1 – probably protecting additional lung function decline is favorable although study do not demonstrate clinical improvement
- Check pre-treatment IgA levels, vaccinate for Hep A and B
- Efficacy: modest effect in slowing lung function decline (23% slower decline); greatest benefit for those with moderate obstruction. Achieving a “protective” serum threshold is not necessary.
- Cost: > $100,000 per year
Screening of Family:
- Genotype first-degree relatives: siblings, parents, children of PI*ZZ individuals; first degree relatives of individulas with other PI*MZ can be offered testing
Good reference: https://www.alpha1.org/alphas-friends-family/resources/find-an-alpha-1-specialist/
Thank you, Dr. Schroedl, our fearless Program Director, for summarizing!
Clara Schroedl, MD, MSc, Medicine – Pulmonary/Critical Care