Dissociation of the Hepatic and Pulmonary Axes in Alpha-1 Antitrypsin Deficiency: Independent Trajectories of Organ-Specific Disease
Juan Luis Rodríguez Hermosa, Soha Esmaili, Iman Esmaili, Maria Torres-Duran, Hanan Tanash, Alice M. Turner, Carlota Rodríguez-García, Miriam Barrecheguren, Jens-Ulrik Stæhr Jensen, Vincent Bunel, Angelo Guido Corsico, Kenneth R. Chapman, Jean-François Mornex, Eva Bartošovská-Klinková, Beatriz Lara, José Luis López-Campos, Christian F. Clarenbach, Emily F. A. van ’t Wout, Mariano Fernandez-Acquier, Myriam Calle RubioThe 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.