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Accelerated spirometric decline in New York City firefighters with α₁-antitrypsin deficiency.

ABSTRACT: On September 11, 2001, the World Trade Center (WTC) collapse caused massive air pollution, producing variable amounts of lung function reduction in the New York City Fire Department (FDNY) rescue workforce. α₁-Antitrypsin (AAT) deficiency is a risk factor for obstructive airway disease.This prospective, longitudinal cohort study of the first 4 years post-September 11, 2001, investigated the influence of AAT deficiency on adjusted longitudinal spirometric change (FEV₁) in 90 FDNY rescue workers with WTC exposure. Workers with protease inhibitor (Pi) Z heterozygosity were considered moderately AAT deficient. PiS homozygosity or PiS heterozygosity without concomitant PiZ heterozygosity was considered mild deficiency, and PiM homozygosity was considered normal. Alternately, workers had low AAT levels if serum AAT was ≤ 20 μmol/L.In addition to normal aging-related decline (37 mL/y), significant FEV(1) decline accelerations developed with increasing AAT deficiency severity (110 mL/y for moderate and 32 mL/y for mild) or with low AAT serum levels (49 mL/y). Spirometric rates pre-September 11, 2001, did not show accelerations with AAT deficiency. Among workers with low AAT levels, cough persisted in a significant number of participants at 4 years post-September 11, 2001.FDNY rescue workers with AAT deficiency had significant spirometric decline accelerations and persistent airway symptoms during the first 4 years after WTC exposure, representing a novel gene-by-environment interaction. Clinically meaningful decline acceleration occurred even with the mild serum AAT level reductions associated with PiS heterozygosity (without concomitant PiZ heterozygosity).

SUBMITTER: Banauch GI

PROVIDER: S-EPMC2972627 | biostudies-other | 2010 Nov

REPOSITORIES: biostudies-other

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Project description:BACKGROUND:Alpha-1-antitrypsin (AAT) deficiency (AATD) of Z, Mmalton, Siiyama type is associated with liver storage of the mutant proteins and liver disease. The Z variant can be diagnosed on isoelectric focusing (IEF) while Mmalton and Siiyama may be missed or misdiagnosed with this technique. Therefore, molecular analysis is mandatory for their characterization. In particular, that holds true for the Mmalton variant as on IEF profile it resembles the wild M2 subtype. METHODS:This is a retrospective analysis involving review of medical records and of liver biopsy specimens from a series of Mmalton, Z and Siiyama Alpha-1-antitrypsin deficiency patients. The review has been implemented by additional histological stains, electron microscopic observations and 3-D modeling studies of the sites of the mutations. RESULTS:Z, Mmalton and Siiyama liver specimen contained characteristic intrahepatocytic PAS-D globules. The globules differed in the three variants as only Mmalton cases showed dark basophilic precipitates within the AAT inclusions. The precipitates were visualized in haematoxylin-eosin (H.E.) stained preparations and corresponded to calcium precipitates as demonstrated by von Kossa staining. On immunohistochemistry, ZAAT inclusions were stained by polyclonal as well as monoclonal noncommercial anti-AAT antibody (AZT11), whilst Mmalton and Siiyama inclusion bodies remained negative with the monoclonal anti-Z antibody. 3-D protein analysis allowed to predict more severe misfolding of the Mmalton molecule as compared to Z and Siiyama that could trigger anomalous interaction with endoplasmic reticulum chaperon proteins, namely calcium binding proteins. CONCLUSIONS:Mmalton AAT inclusion bodies contain calcium precipitates inside them that allow the differential diagnosis with Siiyama and ZAAT inclusions in routine histological sections. The study has confirmed the specificity of the monoclonal AZT11 for the Z mutant. Thus, the combination of these two features is crucial for the distinction between the three variants and for predicting the genotype, whose confirmation would definitely require molecular analysis. Our study provides new data on the pathomorphogenesis of Mmalton inclusion bodies whose mineralization could play a central role in disease pathogenesis of Mmalton that is distinct from the Z and Siiyama variants. Calcium is known to be a major effector of cell death either via the increased intracellular concentration or the alteration of homeostasis.

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Accelerated spirometric decline in New York City firefighters with α₁-antitrypsin deficiency.

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