Treatment of Unilateral PA by Adrenalectomy: Potential Reasons for Incomplete Biochemical Cure

AbstractThe importance of an early diagnosis and appropriate management of patients with primary aldosteronism (PA) has become increasingly clear because of the adverse impact of the disorder on cardiovascular and cerebrovascular events and target organ damage. Adrenalectomy potentially cures patients with unilateral PA resulting in normalisation of blood pressure or significant clinical improvements in the majority of patients. Different criteria have been used to evaluate outcomes of unilateral adrenalectomy. Clinical remission (cure of hypertension) is observed in 6% to 86% of patients and clinical benefits from surgery are seen in the majority. Several factors have been identified that predict clinical success after surgery such as age, sex, anti-hypertensive medication dosage and known duration of hypertension. Biochemical remission of PA after unilateral adrenalectomy, characterised by the resolution of hyperaldosteronism and correction of pre-surgical hypokalaemia, is observed in 67% to 100% of patients with unilateral PA. In only a small proportion of patients, adrenalectomy fails to resolve hyperaldosteronism and inappropriate aldosterone production persists after surgery. In this review we discuss the potential reasons for failing to cure hyperaldosteronism after unilateral adrenalectomy for unilateral primary aldosteronism.

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Adrenal Venous Sampling in Young Patients with Primary Aldosteronism. Extravagance or Irreplaceable?

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab047 ◽

2021 ◽

Author(s):

Eleftheria Gkaniatsa ◽

Augustinas Sakinis ◽

Magnus Palmér ◽

Andreas Muth ◽

Penelope Trimpou ◽

...

Keyword(s):

Primary Aldosteronism ◽

Clinical Guidelines ◽

Clinical Success ◽

Adrenal Adenoma ◽

Young Patients ◽

Adrenal Venous Sampling ◽

Imaging Studies ◽

Venous Sampling ◽

Unilateral Adrenalectomy ◽

Aldosterone Production

Abstract Context Current clinical guidelines suggest that adrenal venous sampling (AVS) may not be mandatory in young patients with primary aldosteronism (PA) and a solitary adrenal adenoma on imaging. Objective The aim of this study was to further elucidate whether conventional imaging alone is sufficient to distinguish unilateral from bilateral PA among patients aged 40 years or younger. Methods This was a retrospective study where data from 45 patients with PA, aged between 26 and 40 years, who underwent successful AVS between 2005 and 2019, were analyzed. Results concerning laterality on imaging studies and AVS were recorded. Outcome in surgically treated patients was assessed according to the Primary Aldosteronism Surgical Outcomes criteria. Results In 4 of 25 patients with unilateral aldosterone production according to AVS, computed tomography inaccurately suggested bilateral disease. Following unilateral adrenalectomy, all 4 patients showed complete clinical success. Five of 20 patients with bilateral aldosterone production according to AVS had a solitary adrenal nodule (8-19 mm) on imaging. Two of these 5 patients were treated with unilateral adrenalectomy, neither having complete biochemical and/or clinical success postoperatively. Two of 16 patients younger than 35 years had discordant results, 1 with unilateral and 1 with bilateral aldosterone production, according to AVS. Conclusion Imaging studies inaccurately predicted laterality in a significant number of young patients with PA. In contrast to current clinical guidelines, our results support AVS for subtype evaluation in young adults with PA, including patients 35 years or younger.

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Nomogram-Based Preoperative Score for Predicting Clinical Outcome in Unilateral Primary Aldosteronism

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa634 ◽

2020 ◽

Vol 105 (12) ◽

pp. e4382-e4392

Author(s):

Yi Yang ◽

Tracy Ann Williams ◽

Ying Song ◽

Shumin Yang ◽

Wenwen He ◽

...

Keyword(s):

Clinical Outcome ◽

Primary Aldosteronism ◽

Validation Cohort ◽

Clinical Success ◽

Characteristic Curve ◽

Target Organ Damage ◽

Asian Population ◽

Unilateral Adrenalectomy ◽

Training Cohort ◽

Preoperative Score

Abstract Context More than half of patients diagnosed with unilateral primary aldosteronism (UPA) suffer from persisting hypertension after unilateral adrenalectomy. Objective The objective of this work is to develop and validate a nomogram-based preoperative score (NBPS) to predict clinical outcomes after unilateral adrenalectomy for UPA. Design and Setting The NBPS was developed in an Asian cohort by incorporating predictors independently associated with remission of hypertension after unilateral adrenalectomy for UPA and validated in a Caucasian cohort. Participants Participants comprised patients with UPA achieving complete biochemical success after unilateral adrenalectomy. Main Outcome Measure Measurements included the predictive performance of the NBPS compared with 2 previously developed outcome prediction scores: aldosteronoma resolution score (ARS) and primary aldosteronism surgical outcome (PASO) score. Results Ninety-seven of 150 (64.7%) patients achieved complete clinical success after unilateral adrenalectomy in the training cohort and 57 out of 165 (34.5%) in the validation cohort. A nomogram was established incorporating sex, duration of hypertension, aldosterone-to-renin ratio, and target organ damage. The nomogram showed good C indices and calibration curves both in Asian and Caucasian cohorts. The area under the receiver operating characteristic curve (AUC) of the NBPS for predicting hypertension remission in the training cohort was 0.853 (0.786-0.905), which was superior to the ARS (0.745 [0.667-0.812], P = .019) and PASO score (0.747 [0.670-0.815], P = .012). The AUC of the NBPS in the validation cohort was 0.830 (0.764-0.884), which was higher than the ARS (0.745 [95% CI, 0.672-0.810], P = .045), but not significantly different from the PASO score (0.825 [95% CI, 0.758-0.880], P = .911). Conclusion The NBPS is useful in predicting clinical outcome for UPA patients, especially in the Asian population.

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Re-Evaluating Absent Clinical Success After Adrenalectomy in Unilateral Primary Aldosteronism

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.605 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A298-A298

Author(s):

Troy Puar ◽

Yvonne Chan ◽

Lih-Ming Loh ◽

Roger Foo ◽

Peng Chin Kek

Keyword(s):

Diabetes Mellitus ◽

Primary Aldosteronism ◽

Clinical Success ◽

Significant Proportion ◽

Antihypertensive Medications ◽

Unilateral Adrenalectomy ◽

Recommended Treatment ◽

Post Surgery ◽

Biochemical Cure

Abstract Introduction: Adrenalectomy cures unilateral primary aldosteronism (PA), and improves or cures hypertension. However, a significant proportion of patients are classified with absent clinical success post-surgery, suggesting that surgery was ineffective. Methods: We assessed all patients 6–12 months after unilateral adrenalectomy for clinical outcomes using Primary Aldosteronism Surgical Outcomes (PASO), AVIS-2 and CONNsortium criteria. We estimated blood pressure (BP) changes after adjustment for changes in defined daily dosages (DDD) of antihypertensive medications. Finally, patients were reassessed using PASO at their most recent clinical visit. Results: 104 patients with unilateral PA underwent adrenalectomy at two tertiary centres from 2000–2019. 24 (23%), 31(30%) and 54 (52%) patients were classified with absent clinical success using PASO, AVIS-2 and CONNsortium criteria respectively. Amongst 24 patients with absent clinical success using PASO criteria, 10 had complete biochemical cure, 3 partial, 2 absent, and 9 had resolution of hypokalemia. On multivariate analysis, absent clinical success was associated with presence of hyperlipidemia, diabetes mellitus and lower DDD at baseline. After adjustment for changes in DDD, 7 of 24 patients showed BP improvement ≥20/10mmHg. After follow-up of mean 5.6 years, 12 of 24 patients showed partial or complete clinical success when reassessed using PASO criteria. Only 6 of 104 (5.8%) patients failed to show any clinical improvement after surgery. Conclusions: Although some patients may be classified with absent clinical success post-surgery, majority demonstrate evidence of clinical benefit. Unilateral adrenalectomy remains the recommended treatment option for patients with unilateral PA.

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Aldosterone and Its Blockade: A Cardiovascular and Renal Perspective

The Scientific World JOURNAL ◽

10.1100/tsw.2006.68 ◽

2006 ◽

Vol 6 ◽

pp. 413-424 ◽

Cited By ~ 11

Author(s):

V. Lahera ◽

V. Cachofeiro ◽

G. Balfagon ◽

J.L. Rodicio

Keyword(s):

Heart Failure ◽

Target Organ Damage ◽

Organ Damage ◽

Dietary Salt ◽

Salt Diet ◽

Cardiovascular Damage ◽

Key Factor ◽

Clinical Benefits ◽

Species Production ◽

Cell Growth And Proliferation

Aldosterone not only contributes to salt and water homeostasis, but also exerts direct cardiovascular and renal effects. Numerous experimental and clinical studies indicate that aldosterone participate in cardiac alterations associated with hypertension, heart failure, diabetes and other pathological entities. It is important to mention that dietary salt is a key factor in aldosterone-mediated cardiovascular damage, since damage was moreevident in animals on a high-salt diet than animals on a low salt diet. A pathophysiological action of aldosterone involves development of extracellular matrix and fibrosis, inflammation, stimulation of reactive oxygen species production, endothelial dysfunction, cell growth and proliferation. Many studies showed local extra-adrenal production of aldosterone in brain blood vessel, and the heart, which contribute in an important manner to the pathological actions of this mineralocorticoid.Several studies such as RALES, EPHESUS, 4E and others, recently showed that mineralocorticoid-receptor (MR) antagonists, alone or in combination with ACE inhibitors or ARBs, reduced the risk of progressive target organ damage and hospitalization in patients with hypertension and heart failure. These clinical benefits support the therapeutic usefulness of MR antagonists.

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Subclinical target organ damage in primary aldosteronism

Journal of Hypertension ◽

10.1097/hjh.0000000000001642 ◽

2018 ◽

Vol 36 (3) ◽

pp. 701 ◽

Cited By ~ 2

Author(s):

Konstantinos Stavropoulos ◽

Konstantinos P. Imprialos ◽

Michael Doumas ◽

Vasilios G. Athyros ◽

Asterios Karagiannis

Keyword(s):

Primary Aldosteronism ◽

Target Organ Damage ◽

Organ Damage ◽

Target Organ

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Does Contralateral Suppression at Adrenal Venous Sampling Predict Outcome Following Unilateral Adrenalectomy for Primary Aldosteronism? A Retrospective Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2014-3676 ◽

2015 ◽

Vol 100 (4) ◽

pp. 1477-1484 ◽

Cited By ~ 47

Author(s):

Martin J. Wolley ◽

Richard D. Gordon ◽

Ashraf H. Ahmed ◽

Michael Stowasser

Keyword(s):

Retrospective Study ◽

Primary Aldosteronism ◽

Median Number ◽

Antihypertensive Medications ◽

Unaffected Side ◽

Unilateral Adrenalectomy ◽

Contralateral Suppression ◽

Biochemical Cure ◽

Lateralization Index

Context: In primary aldosteronism (PA), adrenal vein sampling (AVS) distinguishes unilateral and bilateral disease by comparison of aldosterone/cortisol (A/F) ratios. There is controversy about the criteria for interpretation, however, and in particular it is not clear whether contralateral suppression (CS) (defined as A/Fadrenal ≤ A/Fperipheral on the unaffected side) is important. We therefore performed a retrospective study to determine whether CS in surgically treated unilateral PA was associated with blood pressure (BP) and biochemical outcomes. Setting and Design: Patients who underwent unilateral adrenalectomy for PA after successful AVS were included if the lateralization index (A/Fdominant:A/Fnondominant) was ≥2. Cases were reviewed at 6 to 24 months follow-up for outcomes with respect to the presence and degree of CS. Results: Sixty-six of 80 patients had CS. Baseline characteristics were similar. At postoperative follow-up, those with CS had lower systolic BP (SBP) (128 mm Hg vs 144 mm Hg, P = .001), a greater proportion with cure or improvement of hypertension (96% vs 64%, P = .0034), a greater proportion with biochemical cure of PA on fludrocortisone suppression testing (43 of 49 [88%] vs 4 of 9 [44%], P = .002) and were taking a lower median number of antihypertensive medications (0 vs 1.5, P = .0032). In a multivariate model, the degree of CS and preoperative SBP were both significantly correlated with postoperative SBP, but the lateralization index, sex, and age were not. Conclusion: In this study, the presence of CS correlated with good BP and biochemical outcomes from surgery. This finding suggests that CS should be a factor in deciding whether to offer surgery for treatment of PA.

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A case of primary aldosteronism with a negative aldosterone-to-renin ratio

BMC Cardiovascular Disorders ◽

10.1186/s12872-021-02162-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Fengyi Liu ◽

Liang Wang ◽

Yanchun Ding

Keyword(s):

Blood Pressure ◽

Primary Aldosteronism ◽

Antihypertensive Drugs ◽

Target Organ Damage ◽

Screening Method ◽

Organ Damage ◽

Secondary Hypertension ◽

Cardiovascular Damage ◽

Aldosterone To Renin Ratio ◽

Clinical Conditions

Abstract Background Primary aldosteronism (PA), as a cause of secondary hypertension, can cause more serious cardiovascular damage than essential hypertension. The aldosterone-to-renin ratio (ARR) is recommended as the most reliable screening method for PA, but ARR screening is often influenced by many factors. PA cannot be easily excluded when negative ARR. Case presentation We report the case of a 45-year-old Chinese man with resistant hypertension. Three years ago, he underwent a comprehensive screening for secondary hypertension, including the ARR, and the result was negative. After that, the patient's blood pressure was still poorly controlled with four kinds of antihypertensive drugs, the target organ damage of hypertension progressed, and hypokalaemia was difficult to correct. When the patient was hospitalized again for comprehensive examination, we found that aldosterone levels had significantly increased, although the ARR was negative. An inhibitory test with saline was further carried out, and the results suggested that aldosterone was not inhibited; therefore, PA was diagnosed. We performed a unilateral adenoma resection for this patient, and spironolactone was continued to control blood pressure. After the operation, blood pressure is well controlled, and hypokalaemia is corrected. Conclusion When the ARR is negative, PA cannot be easily excluded. Comprehensive analysis and diagnosis should be based on the medication and clinical conditions of patients.

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Analysis of Unilateral Adrenal Hyperplasia with Primary Aldosteronism from the Aspect of Messenger Ribonucleic Acid Expression for Steroidogenic Enzymes: A Comparative Study with Adrenal Cortices Adhering to Aldosterone-Producing Adenoma

Endocrinology ◽

10.1210/en.2005-0765 ◽

2006 ◽

Vol 147 (2) ◽

pp. 999-1006 ◽

Cited By ~ 15

Author(s):

Kazuto Shigematsu ◽

Kioko Kawai ◽

Junji Irie ◽

Hideki Sakai ◽

Osamu Nakashima ◽

...

Keyword(s):

Primary Aldosteronism ◽

Zona Glomerulosa ◽

Adrenal Hyperplasia ◽

Steroidogenic Enzymes ◽

Unilateral Adrenalectomy ◽

Messenger Ribonucleic Acid ◽

Unilateral Adrenal Hyperplasia ◽

Aldosterone Production ◽

Long Term Follow Up ◽

Aldosterone Producing Adenoma

Unilateral adrenal hyperplasia with primary aldosteronism is very rare and shows similar endocrine features to aldosterone-producing adenoma and bilateral adrenal hyperplasia. In this study, the mRNA expression of steroidogenic enzymes in unilateral adrenal hyperplasia was examined by in situ hybridization. We found subcapsular micronodules composed of spironolactone body-containing cells, which showed intense expression for 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, 18-hydroxylase, and 21-hydroxylase but not 17α-hydroxylase, indicating aldosterone production. This expression pattern was the same as that in unilateral multiple adrenocortical micronodules, reported recently. Additionally, it was noted that a nodule with active aldosterone production was closely adjacent to one showing intense 17α-hydroxylase expression. In the adrenal cortices adhering to aldosterone-producing adenoma, the majority of hyperplastic zona glomerulosa and hyperplastic nodules demonstrated a decreased steroidogenic activity. However, minute nodules indicative of active aldosterone production were found at high frequency. These results suggest that the subcapsular micronodules observed might be the root of aldosterone-producing adenoma. Furthermore, we emphasize the need for long-term follow-up after unilateral adrenalectomy or enucleation of the adenoma because of the possibility that buds with autonomous aldosterone production may still be present in the contralateral or remaining adrenal tissue.

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Salt Appetite and its Effects on Cardiovascular Risk in Primary Aldosteronism

Hormone and Metabolic Research ◽

10.1055/a-1116-2407 ◽

2020 ◽

Vol 52 (06) ◽

pp. 386-393

Author(s):

Christian Adolf ◽

Holger Schneider ◽

Daniel A. Heinrich ◽

Laura Handgriff ◽

Martin Reincke

Keyword(s):

Cardiovascular Risk ◽

Primary Aldosteronism ◽

Salt Intake ◽

Target Organ Damage ◽

Organ Damage ◽

Target Organ ◽

World Health ◽

Salt Appetite ◽

Dietary Salt ◽

Dietary Salt Intake

AbstractFirst described in 1955 by Jerome W. Conn, primary aldosteronism (PA) today is well established as a relevant cause of secondary hypertension and accounts for about 5–10 % of hypertensives. The importance of considering PA is based on its deleterious target organ damage far beyond the effect of elevated blood pressure and on PA being a potentially curable form of hypertension. Aside the established contributory role of high dietary salt intake to arterial hypertension and cardiovascular disease, high salt intake is mandatory for aldosterone-mediated deleterious effects on target-organ damage in patients with primary aldosteronism. Consequently, counselling patients on the need to reduce salt intake represents a major component in the treatment of PA to minimize cardiovascular damage. Unfortunately, in PA patients salt intake is high and far beyond the target values of 5 g per day, recommended by the World Health Organization. Insufficient patient motivation for lifestyle interventions can be further complicated by enhancing effects of aldosterone on salt appetite, via central and gustatory pathways. In this context, treatment for PA by adrenalectomy results in a spontaneous decrease in dietary salt intake and might therefore provide further reduction of cardiovascular risk in PA than specific medical treatment alone. Furthermore, there is evidence from clinical studies that even after sufficient treatment of PA dietary salt intake remains a relevant prognostic factor for cardiovascular risk. This review will focus on the synergistic benefits derived from both blockade of aldosterone-mediated effects and reduction in dietary salt intake on cardiovascular risk.

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