Biomolecules · 2026
Dissociation of the Hepatic and Pulmonary Axes in Alpha-1 Antitrypsin Deficiency: Independent Trajectories of Organ-Specific Disease.
СтатьяМногоцентровое исследованиеНаблюдательное исследованиеНазвание и аннотация: Перевод пока не подготовлен
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Rodríguez Hermosa Juan Luis, Esmaili Soha, Esmaili Iman, Torres-Duran Maria, Tanash Hanan, Turner Alice M, Rodríguez-García Carlota, Barrecheguren Miriam, Stæhr Jensen Jens-Ulrik, Bunel Vincent, Corsico Angelo Guido, Chapman Kenneth R, Mornex Jean-François, Bartošovská-Klinková Eva, Lara Beatriz, López-Campos José Luis, Clarenbach Christian F, van 't Wout Emily F A, Fernandez-Acquier Mariano, Calle Rubio Myriam
Аннотация
UNLABELLED: The interindividual phenotypic heterogeneity in Alpha-1 Antitrypsin Deficiency (AATD), despite a shared genetic etiology (the Z-allele of SERPINA1), is explained by the interaction of dual pathogenic mechanisms (gain-of-function vs. loss-of-function), additional genetic modifiers, and environmental or metabolic factors. Building on recent evidence suggesting divergent disease trajectories, we investigated whether pulmonary and hepatic impairments represent coupled manifestations or independent clinical dimensions within a large European cohort.
METHODS: This international multicenter study utilized the European Alpha-1 Research Collaboration (EARCO) registry (n = 1217). Pulmonary and hepatic severities were quantified using concurrent 0.0-10.0 composite indices. Independence was evaluated via partial Spearman correlations, multivariable multinomial regression, and geometric mapping across a continuous phenotypic space.
RESULTS: Cross-domain correlations between respiratory metrics and liver stiffness were near zero (r = -0.03), demonstrating statistical independence. Phenotypic dominance classification isolated distinct profiles; the lung-dominant group exhibited a higher age (57.0 vs. 54.0 years; p < 0.001) and tobacco exposure, while the liver-dominant group registered a higher body mass index (25.8 vs. 24.4 kg/m2; p < 0.001). Multivariable models identified age (OR 1.03; 95% CI 1.02-1.05) and smoking as independent predictors of lung dominance, whereas body mass index was independently associated with liver dominance (OR 1.04; 95% CI 1.01-1.07). Geometric mapping revealed advanced disease clusters at orthogonal margins rather than forming a systemic continuum.
CONCLUSIONS: Hepatic and pulmonary impairments in AATD operate as independent clinical dimensions modulated by distinct metabolic and environmental factors. Risk stratification must transition toward organ-specific prognostic models.
METHODS: This international multicenter study utilized the European Alpha-1 Research Collaboration (EARCO) registry (n = 1217). Pulmonary and hepatic severities were quantified using concurrent 0.0-10.0 composite indices. Independence was evaluated via partial Spearman correlations, multivariable multinomial regression, and geometric mapping across a continuous phenotypic space.
RESULTS: Cross-domain correlations between respiratory metrics and liver stiffness were near zero (r = -0.03), demonstrating statistical independence. Phenotypic dominance classification isolated distinct profiles; the lung-dominant group exhibited a higher age (57.0 vs. 54.0 years; p < 0.001) and tobacco exposure, while the liver-dominant group registered a higher body mass index (25.8 vs. 24.4 kg/m2; p < 0.001). Multivariable models identified age (OR 1.03; 95% CI 1.02-1.05) and smoking as independent predictors of lung dominance, whereas body mass index was independently associated with liver dominance (OR 1.04; 95% CI 1.01-1.07). Geometric mapping revealed advanced disease clusters at orthogonal margins rather than forming a systemic continuum.
CONCLUSIONS: Hepatic and pulmonary impairments in AATD operate as independent clinical dimensions modulated by distinct metabolic and environmental factors. Risk stratification must transition toward organ-specific prognostic models.