Abstract
BackgroundIndividuals with severe Z α1-antitrypsin (AAT) deficiency have a considerably increased risk of developing chronic obstructive lung disease (COPD). It has been hypothesized that compensatory increases in levels of other protease inhibitors mitigate the effects of this AAT deficiency. We analysed plasma levels of AAT, α1-antichymotrypsin (ACT) and secretory leukocyte protease inhibitor (SLPI) in healthy (asymptomatic) and COPD subjects with and without AAT deficiency.MethodsStudied groups included: 71 asymptomatic AAT-deficient subjects (ZZ, n = 48 and SZ, n = 23, age 31 ± 0.5) identified during Swedish neonatal screening for AAT deficiency between 1972 and 1974; age-matched controls (MM, n = 57, age 30.7 ± 0.6); older asymptomatic ZZ (n = 10); healthy MM (n = 20, age 53 ± 9.6); and COPD patients (ZZ, n = 10, age 47.4 ± 11 and MM, n = 10, age 59.4 ± 6.7). Plasma levels of SLPI, AAT and ACT were analysed using ELISA and immunoelectrophoresis.ResultsNo significant difference was found in plasma ACT and SLPI levels between the healthy MM and the ZZ or SZ subjects in the studied groups. Independent of the genetic variant, subjects with COPD (n = 19) had elevated plasma levels of SLPI and ACT relative to controls (n = 153) (49.5 ± 7.2 vs 40.7 ± 9.1 ng/ml, p < 0.001 and 0.52 ± 0.19 vs 0.40 ± 0.1 mg/ml, p < 0.05, respectively).ConclusionOur findings show that plasma levels of ACT and SLPI are not elevated in subjects with genetic AAT deficiency compared MM controls and do not appear to compensate for the deficiency of plasma AAT.
Highlights
Individuals with severe Z α1-antitrypsin (AAT) deficiency have a considerably increased risk of developing chronic obstructive lung disease (COPD)
Severe AAT deficiency in the homozygous Z variant, which differs from the wild type M variant in the substitution of Glu-342 by Lys, was first recognized as a hereditary condition predisposing to COPD on the basis of low plasma levels (10% of normal) of AAT [6]
Plasma levels of serine protease inhibitors in older healthy and COPD subjects with and without severe Z AAT deficiency We found no significant difference in plasma levels of secretory leukocyte protease inhibitor (SLPI) and ACT between deficiency and normal AAT subjects in the absence of COPD (Table 2A)
Summary
Individuals with severe Z α1-antitrypsin (AAT) deficiency have a considerably increased risk of developing chronic obstructive lung disease (COPD). Severe AAT deficiency in the homozygous Z variant, which differs from the wild type M variant in the substitution of Glu-342 by Lys, was first recognized as a hereditary condition predisposing to COPD on the basis of low plasma levels (10% of normal) of AAT [6]. This single amino acid mutation perturbs the folding and tertiary structure of AAT, leading to spontaneous polymerization and cellular retention. These Z-AAT polymers are hypothesized to be cytotoxic and cause liver damage with variable clinical presentation ranging from neonatal cholestasis to liver cirrhosis and hepatocellular carcinoma in adults [911]
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