Biomarkers for subtype stratification in primary aldosteronism: current and future perspectives

Primary aldosteronism, the most common endocrine cause of secondary hypertension, requires accurate differentiation of lateralised from bilateral subtypes to guide therapy: adrenalectomy for surgically curable lateralising forms vs lifelong mineralocorticoid receptor antagonist treatment for bilateral disease. Despite advances, conventional subtype classification remains challenging. Cross-sectional imaging has limited sensitivity and may misclassify lateralisation due to discordance between anatomical findings and functional aldosterone secretion. Although adrenal vein sampling remains the gold standard for subtype differentiation, its technical complexity, cost, and lack of standardised protocols limit widespread implementation and contribute to inconsistent diagnostic outcomes across centres. The advent of molecular imaging tracers exemplifies the shift towards non-invasive diagnostics; however, their routine clinical adoption is restricted by limited availability, concerns regarding specificity, and lack of harmonisation. Circulating and urinary biomarkers remain promising non-invasive alternatives. Advances in steroid profiling via liquid chromatography-mass spectrometry-based detection of hybrid steroids or steroid panels demonstrate encouraging diagnostic accuracy. While these biomarker approaches may assist subtype differentiation, anatomical localisation for surgical decision-making ultimately requires concordant imaging. Machine learning-driven approaches offer a promising solution by integratively analysing multidimensional datasets, including clinical features, imaging findings, and comprehensive biomarker profiles such as steroid profiles, circulating proteins, and microRNAs, to refine lateralisation predictions and overcome the limitations of individual diagnostic modalities. Nonetheless, implementation of these innovations into clinical practice remains hindered by analytical variability, insufficient population-specific validation, and economic barriers, especially in resource-limited settings. This review summarises current evidence and explores future directions for biomarker-driven stratification in primary aldosteronism.