Primary Aldosteronism: an update on the management Dr Man Chi Mei Vivian Queen Mary Hospital

Content Background information Diagnostic algorithms Localization and subtype differentiation Management

Case Scenario 60/M , good past health Blood test confirmed primary aldosteronism 17mm right adrenal nodule 7mm left adrenal nodule

What should be the management? Adrenalectomy Right adrenalectomy? Left adrenalectomy? Bilateral adrenalectomy? Medical therapy with aldosterone receptor antagonist

Background First described in 1954 Group of disorders in which aldosterone production is inappropriately high, relatively autonomous, and non-suppressible by sodium loading1 Estimated prevalence of 11.2% in hypertensives2 Hypokalemia not always present 52% aldosterone-producing adenoma 83.1% bilateral adrenal hyperplasia Jerome W. Conn (1907-1994) Dr Jerome W. Conn: American endocrinologist Presented his index patient in the Clinical research meeting in 1954 1 J Clin Endocrinol Metab 93:3266-3281, 2008 2 Rossi et al. JACC vol. 48, No. 11. 2006: 2293-300

Types of Primary Aldosteronism Approximate prevalence % Aldosterone-producing adenoma 30 Bilateral idiopathic hyperaldosteronism 65 Primary adrenal hyperplasia <2 Aldosterone-producing adrenocortical carcinoma 1 Aldosterone-producing ovarian tumor <1 Familial hyperaldosteronism Role for adrenal venous sampling in primary aldosteronism. Young WF et al. Surgery. December 2004.

Diagnosis of primary aldosteronism Screening Aldosterone/ renin ratio (ARR) Plasma aldosterone concentration (PAC) Elevated ARR >20ng/dl per ng/ml/h and PAC >10ng/dL Confirmation Intravenous saline load/ oral salt load Captopril challenge test Fludro-cortisone suppression test Screening test SI unit pmol/L x 27.7, pmol/L/min x 12.8 = 550pmol/L per ng/ml/h No standard cutoff value Higher cut-off results in higher false negative values can be influenced by most antihypertensive drug therapy Diagnostic test Collaboration with endocrinologists No consensus on the optimal test

Lateralization and subtype differentiation Computed tomography (CT) Adrenal scintigraphy Adrenal venous sampling (AVS)

Computed tomography Young WF et al. The incidentally discovered adrenal mass. New England Journal of Medicine 2007; 356: 601-10

Adrenocortical carcinoma Adrenocortical adenoma Young WF et al. The incidentally discovered adrenal mass. New England Journal of Medicine 2007; 356: 601-10

Lateralization and subtype differentiation Computed tomography (CT) Adrenal scintigraphy Adrenal vein sampling (AVS)

Adrenal Scintigraphy Provides functional information 131I-6β-iodomethyl-19-norcholesterol (NP-59) Marker of adreno-cortical uptake Resolution problem Previous study suggested that the detection rate was related to adenoma size. It failed to detect adenoma size <1cm Huang YE et al. Role of 131I-NP-59 Adrenal Imaging in Patients of ACTH-Independent Cushing’s Syndrome. Ann Nucl Med Sci 2001;14:75-83

Chen YC et al. Use of NP-59 SPECT/ CT imaging in atypical primary aldosteronism. Q J Med (2013)

Lateralization and subtype differentiation Computed tomography (CT) Adrenal scintigraphy Adrenal venous sampling (AVS)

Adrenal vein sampling First proposed in 1967 as a test to distinguish between aldosterone-producing adenoma and idiopathic hyperaldosteronism Gold standard for lateralization of disease Femoral venous access Simultaneously left and right adrenal venous sampling Blood aldosterone and cortisol level Kahn SL et al. Adrenal vein sampling. Techniques in vascular and interventional radiology 13: 110-125

Interpretation Confirmation of correct position of adrenal catheters: Cortisol level from adrenal catheters being 5-10 times the value obtained from peripheral sheath Asymmetrical aldosterone: cortisol values on the affected side being 3-5 times the value obtained from the unaffected side Kahn SL et al. Adrenal vein sampling. Techniques in vascular and interventional radiology 13: 110-125

Left adrenal vein catheterization Right adrenal vein catheterization Kahn SL et al. Adrenal vein sampling. Techniques in vascular and interventional radiology 13: 110-125 Lau JHG et al . Clinical Endocrinology (2010) 76; 182-188

Diagnostic values and accuracy 203 patients were selected for AVS from 1990-2003 194 patients underwent successful adrenal vein cannulation Success rate 95.6% Computed tomography, AVS and histopathological findings were compared Young WF et al. Role of adrenal venous sampling in primary aldosteronism. Surgery 2004; 136: 1227-35

Discordant between CT and AVS 110 patients (56.7%) had unilateral source for aldosterone hyper-secretion Normal CT scan 24 Bilateral micronodule 16 Bilateral macronodule 2 Unilateral micronodule 7/31 contralateral gland Unilateral macronodule 1/22 contralateral gland Combination of micronodule and macronodule 11/18 macronodule 4/18 micronodule Young WF et al. Role of adrenal venous sampling in primary aldosteronism. Surgery 2004; 136: 1227-35

Discordant between CT and AVS 21.7% (42 patients) would have been incorrectly excluded as candidates for adrenalectomy 24.7% (48 patients) might have unnecessary or inappropriate adrenalectomy Young WF et al. Role of adrenal venous sampling in primary aldosteronism. Surgery 2004; 136: 1227-35

Discordant between CT/MRI and AVS Systematic review of 38 studies, 950 patients included 37.8% discordance between CT/MRI and AVS 14.6% inappropriate adrenalectomy 19.1% inappropriate exclusion from adrenalectomy 3.9% adrenalectomy on wrong side Kempers MJE et al. Systematic Review: Diagnostic Procedures to Differentiate Unilateral From Bilateral Adrenal Abnormality in Primary Aldosteronism. Annals of Internal Medicine, 09/2009, Volume 151, Issue 5, pp. 329 - 337

Adrenal venous sampling NP-59 adrenal scintigraphy Computed tomography Adrenal venous sampling NP-59 adrenal scintigraphy Easily available Technically demanding expertise required Requirement of radio-labeled material 3-5 day test Non-invasive Invasive complication rate ~2.5%3 Good resolution Limited spatial resolution Improved with NP-59 SPECT/CT Sensitivity 77%1 Specificity 80%1 Accuracy improved if discrete unilateral macronodule Sensitivity 95%4 Specificity 100%4 Planar scintigraphy sensitivity as low as 40%2 Sensitivity increased to 81.8% when combined with CT2 Lau JHG et al . Clinical Endocrinology (2010) 76; 182-188 Yen RF et al. The Journal of Nuclear Medicine (2009) 50; 10: 1631-1637 Young WF et al. Surgery (2004) 136; 6; 1227-1234 Tsai YS et al. Formos J Endocrin Metab 2011; 2(2): 38-43

Kahn SL et al. Adrenal vein sampling Kahn SL et al. Adrenal vein sampling. Techniques in vascular and interventional radiology 13: 110-125

Management Bilateral idiopathic hyperaldosteronism Medical treatment: aldosterone receptor antagonist Intolerance/ refractory cases: bilateral adrenalectomy Aldosterone producing adenoma Primary adrenal hyperplasia Adrenalectomy (laparoscopic/ open) Emerging therapies: Acetic acid injection Radiofrequency ablation Moo TA et al. Prediction of Successful Outcome in Patients with Primary Aldosteronism. Current treatment options in oncology (2007) 8:314-321

Back to our patient Adrenal to peripheral cortisol level: Right side: 3.6 versus left side: 3.2 Lateralization index 7.4 Right side: 42 versus left side: 5.7 Right adrenalectomy performed and Conn’s adenoma confirmed Improvement in ARR one month after operation

Conclusion Primary aldosteronism is frequently under-diagnosed in hypertensives Aldosterone producing adenoma and bilateral idiopathic hyperaldosteronism are two commonest causes of primary aldosteronism Lateralization is important for identification of surgically-amendable causes

Reference Galati SJ et al. Primary aldosteronism: emerging trends. Trends in Endocrinology and Metabolism. September 2013, Vol.24, No. 9 Role for adrenal venous sampling in primary aldosteronism. Young WF et al. Surgery. December 2004. Schwatz et al. Screening for primary aldosteronism in essential hypertension: Diagnostic accuracy of the ratio of plasma aldosterone concentration to plasma renin activity. Clinical Chemistry. 51:2. 386-394 Young WF et al. The incidentally discovered adrenal mass. New England Journal of Medicine 2007; 356: 601-10 Kahn SL et al. Adrenal vein sampling. Techniques in vascular and interventional radiology 13: 110-125 Huang YE et al. Role of 131I-NP-59 Adrenal Imaging in Patients of ACTH-Independent Cushing’s Syndrome. Ann Nucl Med Sci 2001;14:75-83 Chen YC et al. Use of NP-59 SPECT/ CT imaging in atypical primary aldosteronism. Q J Med (2013)

Rossi GP et al. A Prospective Study of the Prevalence of Primary Aldosteronism in 1125 Hypertensive Patients. JACC vol 48, No 11, 2006 Moo TA et al. Prediction of Successful Outcome in Patients with Primary Aldosteronism. Current treatment options in oncology (2007) 8:314-321 Stowasser M et al. Update in Primary aldosteronism. J Clin Endocrinol Metab (2009) 94: 3623-3630 Liu SYW et al. Radiofrequency ablation for benign aldosterone-producing adenoma: a scarless technique to an old disease. Annals of Surgery 256(6): 1058-1064 Kempers MJE et al. Systematic Review: Diagnostic Procedures to Differentiate Unilateral From Bilateral Adrenal Abnormality in Primary Aldosteronism. Annals of Internal Medicine, 09/2009, Volume 151, Issue 5, pp. 329 - 337 American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas The Endocrine Society’s Clinical Guidelines. J Clin Endocrinol Metab 93: 3266-3281, 2008

Thank you Questions?

Who should be screened? Moderate to severe hypertension Resistant hypertension Hypertension with a family history of early-onset disease Hypertension with an adrenal incidentaloma History of cerebrovascular accident occurring before age 40 years First-degree relative with primary aldosteronism Galati SJ et al. Primary aldosteronism: emerging trends. Trends in Endocrinology and Metabolism. September 2013, Vol.24, No. 9

Sequelae of primary aldosteronism Galati SJ et al. Primary aldosteronism: emerging trends. Trends in Endocrinology and Metabolism. September 2013, Vol.24, No. 9

Protocol Interpretation Intravenous saline load Infusion of 2L of 0.9% normal saline over 2 hours In recumbent position PAC > 10ng/dL post-infusion is highly suggestive of PA Oral salt load Sodium intake >6g/day for 3 days with diet and sodium chloride tabs 24 hour urinary aldosterone excretion >12μg/day consistent with PA Captopril challenge test 25-50mg oral captopril after sitting or standing for 1 hour ARR >30-50 PAC remained elevated (>8.5ng/dL or greater) Renin remained suppressed Fludro-cortisone suppression test 0.1mg of fludro-cortisone every 6 hours for 4 days PAC > 6 ng/dL confirms PA Renin suppressed to <1ng/mL/h Cortisol measured 10am lower than measured 7-8am Galati SJ et al. Primary aldosteronism: emerging trends. Trends in Endocrinology and Metabolism. September 2013, Vol.24, No. 9

Drug therapy Drug free Optimum ratio 95%CI 12.4 (7.1 – 16.6) 14.9 (14.2 – 20.9) Sensitivity 95%CI 73 87 Specificity 95%CI 74 75 Schwatz et al. Screening for primary aldosteronism in essential hypertension: Diagnostic accuracy of the ratio of plasma aldosterone concentration to plasma renin activity. Clinical Chemistry. 51:2. 386-394