α1-antitrypsin (α1-AT)
deficiency
Dr. Ahmed Hussein Jasim F.I.C.M.S (resp)
This is an inherited condition that is associated with the early development of
emphysema.
Genetics
α1-AT deficiency is inherited as an autosomal co-dominant disorder. So far,
>100 different alleles have been identified for this gene (SERPINA 1) on the long arm of
chromosome . The commonest alleles are the M allele (normal), the partially defective S
allele, and the almost fully defective Z allele (
lysine is substituted for glutamic acid at
position 342
, leading to abnormal folding, preventing post-translational processing with
retention within cells)
• MM, the normal phenotype. Background population risk of emphysema
• MS, MZ have 50–70% of normal α1-protease inhibitor (Pi) levels. Background risk of
emphysema
• SZ, SS have 35–50% of normal levels. 20–50% risk of emphysema
• Homozygous ZZ has only 10–20% of normal levels. 80–100% risk of emphysema.
Pathophysiology
α1-AT is a glycoprotein protease inhibitor produced by the liver. It is secreted via the
bloodstream into the lungs and opposes neutrophil elastase, which destroys alveolar wall
connective tissue. Elastase is produced in increased levels by pulmonary neutrophils and
macrophages in response to smoking and lung infections. If α1-AT is deficient, the elastase
cannot be opposed, and subsequently basal emphysema develops.
The disease is worse in smokers and can cause COPD at a young age (40s and 50s). There
may also be associated liver dysfunction, chronic hepatitis, cirrhosis, and hepatoma, as
abnormal protein secretion accumulates in the liver. Predisposition also to skin disease
(panniculitis) and vasculitis (especially AnCA +ve).
Screening
should be carried out, especially in patients <40 with COPD or minimal smoking history or
family history. Also patients with unexplained liver disease should be screened. Send blood
for α1-AT concentrations and genotyping if levels are low. Siblings should be screened and
the particular importance of not smoking and avoiding passive smoking emphasized. non-
smokers are usually asymptomatic.
Treatment
Specialist centre involvement recommended. Specific treatment is known as augmentation
therapy, with ideally weekly, but also 2-weekly or monthly infusions, of purified α1-AT from
pooled human plasma.
Thoracic Society (ATS) and European Respiratory Society (ERS), for those with moderate (FEV1
35–60% predicted) emphysema due to α1-AT deficiency, who are non-/ex-smokers, but not
those with mild disease (optimal therapy unclear) or severe disease (less clinical efficacy) or
those post-lung transplant for α1-AT deficiency, except during episodes of acute rejection
and infection (when inflammation causes free elastase activity).
