Current and Novel Biomarkers for Diagnosis and Subtyping of Primary Aldosteronism.

Primary aldosteronism is a common and potentially curable cause of secondary hypertension, yet it remains substantially underdiagnosed. Current diagnostic pathways rely on the aldosterone-to-renin ratio, confirmatory tests, and subtype classification by imaging and adrenal venous sampling. However, these approaches are limited by assay variability, medication effects, imperfect diagnostic accuracy, and the absence of a true reference standard, particularly for bilateral disease. Recent molecular imaging and histopathologic data further challenge the traditional binary distinction between unilateral and bilateral primary aldosteronism and instead support a biological continuum of renin-independent aldosteronism. In this context, novel biomarkers may improve both detection and biological subtyping. Steroidomics is currently the most clinically advanced approach, with plasma and urinary steroid profiles showing promise for primary aldosteronism detection, identification of KCNJ5-mutated adenomas, and subtype prediction. Proteomics and circulating microRNAs provide complementary information on systemic effects, upstream regulation, and lesion biology, while multiomics strategies increasingly demonstrate that integrated models outperform single-modality approaches. Nevertheless, translation into clinical practice remains constrained by small and selected cohorts, heterogeneous analytical platforms, inconsistent reference standards, and limited external validation. Future progress will depend on standardized assays, interpretable machine learning models, and prospective multicenter implementation studies linking biomarker-guided diagnosis to improved clinical outcomes.