Highlights
- The Primary Aldosteronism Severity Classification (PASC) significantly correlates with AVS-defined lateralization, with severity reflecting increasing unilateral aldosterone excess.
- Surgical and medical treatment outcomes vary by PASC severity; higher severity is associated with lower rates of complete clinical success despite similar biochemical remission rates.
- Emerging hormonal biomarkers (e.g., metanephrine, androstenedione) and imaging modalities (68Ga-pentixafor PET/CT) show promise in enhancing AVS accuracy and subtype diagnosis.
- Integration of PASC with AVS results may guide individualized diagnostic and therapeutic strategies, optimizing patient outcomes in PA.
Background
Primary aldosteronism (PA) represents the most common cause of secondary hypertension, characterized by autonomous aldosterone secretion leading to hypertension and increased cardiovascular risk. Precise diagnosis and subtype classification, particularly to differentiate unilateral from bilateral disease, is essential to tailor treatment—either surgical adrenalectomy or medical therapy with mineralocorticoid receptor antagonists.
Adrenal venous sampling (AVS) remains the gold standard for lateralization but poses procedural challenges and variable interpretation. The newly introduced PA Severity Classification (PASC), integrating biochemical and clinical features, aims to stratify lateralization risk and inform management pathways, as recommended in the 2025 clinical guideline.
Key Content
Association of PASC with AVS-defined Lateralization
Lee et al. (2026) conducted a large retrospective multicenter cohort study involving 833 PA patients undergoing AVS across eight tertiary centers, classifying PA severity as mild, moderate, or severe per PASC criteria. They demonstrated a stepwise increase in unilateral AVS-defined lateralization rates across severity categories: 19.2% (mild), 48.0% (moderate), and 76.1% (severe) (p < 0.001). This robust association supports PASC’s role in predicting lateralized aldosterone excess and could refine indications for AVS referral.
Complementing this, Wachtel et al. (2025) showed that cosyntropin stimulation during AVS reveals aldosterone reserve in the nondominant adrenal, highlighting a physiological basis for lateralization variability and surgical outcomes prediction. The contralateral aldosterone reserve ratio was higher in patients with residual PA post-adrenalectomy and bilateral disease.
Treatment Outcomes Stratified by PASC Severity
Within the cohort analyzed by Lee et al., treatment outcomes using PASO and PAMO criteria differed by severity. For unilateral PA managed surgically, complete clinical success rates were 40.2% in moderate and 31.3% in severe cases (p = 0.002), while partial clinical success markedly increased in severe PA (55.1%). Biochemical remission was consistent across severity groups (p = 0.389). Conversely, bilateral PA treated medically exhibited decreasing complete clinical response rates from mild (36.8%) to severe (8.8%) disease (p = 0.005) with comparable biochemical outcomes (p = 0.993).
These findings align with prior observations that clinical hypertension resolution post-adrenalectomy is less frequent in severe disease despite biochemical normalization (Funder et al., 2016; Ku et al., 2022). Arterial stiffness, a marker of vascular damage, assessed by baPWV, correlates inversely with clinical cure rates in lateralized PA (Chang et al., 2020), possibly explaining diminished clinical success in severe cases.
Methodological Advances in AVS and Diagnostic Modalities
Several studies highlight innovations to improve AVS accuracy and subtype diagnosis. Li et al. (2025) demonstrated that measuring alternative hormones such as metanephrine, normetanephrine, androstenedione, and 17α-hydroxypregnenolone during AVS can enhance cannulation success and lateralization assessment, potentially surpassing cortisol-based indices.
Additionally, contemporary nuclear medicine tools like 68Ga-pentixafor PET/CT have demonstrated superior diagnostic performance compared to adrenal CT in identifying surgically eligible PA patients with adrenal micronodules (Zhang et al., 2024). This noninvasive approach showed higher concordance with surgical outcomes than AVS in a subset of patients, indicating a promising role for complementary imaging.
Histopathologic Correlations and Long-term Outcomes
Immunohistochemistry (IHC) with CYP11B2 staining offers detailed adrenal histopathologic classification, revealing aldosterone-producing nodules or micronodules (Helgadottir et al., 2023). IHC reclassified 23% of cases compared to standard histology and linked with higher lateralization indices and contralateral suppression on AVS.
Long-term follow-up reinforces PASC and AVS’s prognostic value, emphasizing the importance of aldosterone and renin measurements post-treatment to monitor disease control and relapse risk.
Expert Commentary
The integration of PASC into PA diagnostic algorithms provides a nuanced framework that complements AVS, improving lateralization risk stratification and potentially minimizing unnecessary invasive procedures. The strong positive correlation between PA severity and AVS lateralization underscores the value of incorporating clinical and biochemical severity indices in clinical decision-making.
However, the paradoxical finding of lower complete clinical success with increasing severity—despite stable biochemical remission rates—raises questions about the pathophysiology of hypertension persistence. Vascular remodeling, arterial stiffness, and irreversible end-organ damage may limit clinical recovery even after correction of aldosterone excess, warranting adjunctive vascular and cardiorenal assessments to guide prognostication and management.
Emerging AVS biomarker panels and advanced imaging techniques promise to refine lateralization diagnosis and surgical candidacy further but require validation in larger, prospective cohorts. Immunohistochemical profiling deepens pathophysiological understanding and aids in individualizing postoperative follow-up.
Guideline recommendations should adapt dynamically to these advances, incorporating PASC and novel tools to optimize patient-centered care. Limitations remain, including retrospective design biases, heterogeneous AVS protocols, and variable follow-up durations in current studies.
Conclusion
The 2025 introduction of the Primary Aldosteronism Severity Classification marks a critical advance in refining diagnostic and therapeutic pathways for PA. The robust association of PASC severity with AVS-defined lateralization and differential treatment outcomes supports a severity-informed approach integrated with AVS findings.
While biochemical remission appears consistently achievable across severity strata, clinical response diminishes with increasing disease severity, highlighting unmet needs in management of advanced PA. Novel hormonal markers and imaging adjuncts complement AVS, potentially enhancing lateralization accuracy and therapeutic decision-making.
Future research should focus on prospective validation of PASC in diverse populations, integration with novel biomarkers and imaging, and strategies to mitigate residual hypertension and end-organ sequelae in severe PA. This paradigm fosters precision medicine tailored to disease severity and individual patient profiles.
References
- Lee JH et al. Association of the Primary Aldosteronism Severity Classification with Lateralization and Treatment Outcomes. J Clin Endocrinol Metab. 2026 Jun 30;doi: 10.1210/clinem/dgag259. PMID: 42375012.
- Wachtel H et al. Cosyntropin-Stimulated Aldosterone Reserve of the Nondominant Adrenal Predicts Surgical Outcomes in Primary Aldosteronism. Hypertension. 2025 Oct;82(10):1687-1695. PMID: 40755305.
- Li L et al. An exploratory study on new indicators of AVS in the typing diagnosis of primary aldosteronism. Zhonghua Xin Xue Guan Bing Za Zhi. 2025 Sep 24;53(9):1033-1038. PMID: 40953988.
- Zhang F et al. Clinical Value of 68Ga-Pentixafor PET/CT in Subtype Diagnosis of Primary Aldosteronism Patients with Adrenal Micronodules. J Nucl Med. 2024 Jan;65(1):117-124. PMID: 38050127.
- Helgadottir A et al. Immunohistochemical staining seems mandatory for individualizing and shortening follow-up in unilateral primary aldosteronism. Clin Endocrinol (Oxf). 2023 Nov;99(5):441-448. PMID: 37525427.
- Ku EJ et al. Prognostic value of contralateral suppression for remission after surgery in patients with primary aldosteronism. Clin Endocrinol (Oxf). 2022 Jun;96(6):793-802. PMID: 35060161.
- Chang C et al. Arterial Stiffness Is Associated with Clinical Outcome and Cardiorenal Injury in Lateralized Primary Aldosteronism. J Clin Endocrinol Metab. 2020 Nov 1;105(11):dgaa566. PMID: 32835357.
- Funder JW et al. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(5):1889-1916.