Use of the Wnt/β-catenin Activator Lithium Is Associated with Less Emphysema

Emphysema is defined by progressive alveolar destruction and impaired tissue repair, with diminished Wnt/β-catenin signaling implicated in its pathogenesis. Preclinical studies suggest that lithium, a pharmacologic activator of Wnt/β-catenin signaling, may attenuate emphysema. However, its effects in humans remain unknown.

To investigate whether individuals using lithium for neuropsychiatric conditions have reduced susceptibility to emphysema compared to users of other neuropsychiatric medications.

We analyzed cross-sectional data from two large cohorts - the UK Biobank and COPDGene - comprising over 800 individuals using oral lithium. Lithium users were compared to individuals using other neuropsychiatric medications. In the UK Biobank, outcomes included spirometry and self-reported physician-diagnosed emphysema. In COPDGene, outcomes included spirometry and quantitative CT measures of emphysema. Multivariable regression and propensity score matching accounted for demographics, smoking history, and psychiatric diagnoses.

In the UK Biobank, lithium use was associated with higher FEV₁ and FVC (% predicted) and ~50% lower adjusted odds of emphysema diagnosis. In COPDGene, lithium users exhibited significantly higher FEV₁, FVC, and FEV₁/FVC ratios, lower CT-measured emphysema (%LAA-950), and higher lung density. These associations persisted after multivariable adjustment and across sensitivity analyses.

Lithium use is associated with less emphysema in two independent cohorts. These findings align with preclinical evidence supporting Wnt/β-catenin activation as a protective mechanism and warrant further investigation of lithium and related agents as potential therapies for emphysema.