Laboratory evaluation of α(1)-antitrypsin (A1AT) deficiency involves measurement of circulating A1AT protein (quantitation) and characterization of A1AT genetic polymorphisms (phenotyping or genotyping). This study compared adult and pediatric A1AT reference ranges in patients with nondeficiency alleles and examined A1AT concentrations in multiple other phenotypes. A1AT phenotype and quantitation were retrospectively collected on adult (n = 21,444) and pediatric (n = 2,469) samples that were submitted for laboratory evaluation of A1AT deficiency. The 95% reference ranges for normal adult and pediatric populations with the M/M phenotype were determined to be 100 to 273 mg/dL (18.4-50.2 μmol/L) and 93 to 251 mg/dL (17.1-46.2 μmol/L), respectively (P < .0001). Decreased concentrations of A1AT correlated with heterozygosity and homozygosity for the S and Z alleles in both the adult and pediatric groups. Other rare alleles, such as I, were also associated with decreased concentrations of A1AT, particularly in the context of a Z allele, and may warrant monitoring for symptoms of deficiency.
"Previously reported overlapping between AAT concentrations corresponding to AATD carriers and patients with no AATD (3,6,13) was evidenced in the investigated patients. Through concomitant measurement of serum AAT concentration and genotyping for Z and S allele, integrative algorithm diminished the possibility that carriers remain undetected. "
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Alpha-1-antitrypsin deficiency (AATD), genetic risk factor for premature chronic obstructive pulmonary disease (COPD), often remains undetected. The aim of our study was to analyse the effectiveness of an integrative laboratory algorithm for AATD detection in patients diagnosed with COPD by the age of 45 years, in comparison with the screening approach based on AAT concentration measurement alone.
Subjects and methods:
50 unrelated patients (28 males/22 females, age 52 (24–75 years) diagnosed with COPD before the age of 45 years were enrolled. Immunonephelometric assay for alpha-1-antitrypsin (AAT) and PCR-reverse hybridization for Z and S allele were first-line, and isoelectric focusing and DNA sequencing (ABI Prism BigDye) were reflex tests.
AATD associated genotypes were detected in 7 patients (5 ZZ, 1 ZMmalton, 1 ZQ0amersfoort), 10 were heterozygous carriers (8 MZ and 2 MS genotypes) and 33 were without AATD (MM genotype). Carriers and patients without AATD had comparable AAT concentrations (P = 0.125). In majority of participants (48) first line tests were sufficient to analyze AATD presence. In two remaining cases reflex tests identified rare alleles, Mmalton and Q0amersfoort, the later one being reported for the first time in Serbian population. Detection rate did not differ between algorithm and screening both for AATD (P = 0.500) and carriers (P = 0.063).
There is a high prevalence of AATD affected subjects and carriers in a group of patients with premature COPD. The use of integrative laboratory algorithm does not improve the effectiveness of AATD detection in comparison with the screening based on AAT concentration alone.
[Show abstract][Hide abstract] ABSTRACT: Nosocomial pneumonia (NP) is the third most common hospital-acquired infection and the leading cause of death due to hospital-acquired infection in the US. During pneumonia and non-pneumonia severe illness, respiratory tract secretions become enriched with the serine protease neutrophil elastase (NE). Several NE activities promote onset and severity of NP. NE in the airways causes proteolytic tissue damage, augments inflammation, may promote invasion of respiratory epithelium by bacteria, and disrupts respiratory epithelial barrier function. These NE activities culminate in enhanced bacterial replication, impaired gas exchange, fluid intrusion into the airways, and loss of bacterial containment that can result in bacteremia. Therefore, neutralizing NE activity may reduce the frequency and severity of NP. We evaluated human alpha-1 antitrypsin (AAT), the prototype endogenous NE inhibitor, as a suppressor of bacterial pneumonia and pneumonia-related pathogenesis. In AAT(+/+) transgenic mice that express human AAT in lungs, mortality due to Pseudomonas aeruginosa (P.aer) pneumonia was reduced 90% compared to non-transgenic control animals. Exogenous human AAT given to non-transgenic mice also significantly reduced P.aer pneumonia mortality. P.aer-infected AAT(+/+) mice demonstrated reduced lung tissue damage, decreased bacterial concentrations in lungs and blood, and diminished circulating cytokine concentrations compared to infected non-transgenic mice. In vitro, AAT suppressed P.aer internalization into respiratory epithelial cells and inhibited NE or P.aer-induced disruption of epithelial cell barrier function. The beneficial effects of human AAT in murine P.aer pneumonia raise the possibility of AAT use as a prophylactic treatment for NP in humans, and suggest a role for AAT as an innate immune mediator.
Frontiers in Public Health 06/2013; 1:19. DOI:10.3389/fpubh.2013.00019
[Show abstract][Hide abstract] ABSTRACT: α(1)-Antitrypsin (AAT) deficiency leads to deterioration of the lungs that can be prevented with diagnosis and treatment. Isoelectric focusing (IEF) electrophoresis is the current biochemical gold standard for detecting AAT deficiency variants but involves complex interpretation. Variant AAT samples were collected over a 2-year period. Stability of AAT for phenotype determination was assessed in whole blood, dried blood spots, and dried serum spots. A compendium displaying 13 common and 5 rare AAT phenotypes was created, and a detailed methodology describing how to recognize AAT banding patterns and interpret a rare phenotype accompanied these visual data. AAT was stable for IEF phenotype analysis for at least 1 week in whole blood and for 24 hours on dried serum spots. In conclusion, a reference compendium of known AAT phenotypes was established that can serve as a resource for interpreting AAT phenotypes.
American Journal of Clinical Pathology 02/2013; 139(2):184-91. DOI:10.1309/AJCP6XBK8ULZXWFP · 2.51 Impact Factor
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