1. Evaluation and Management of the Patient with Hypertension and Hypokalemia Stephen L. Aronoff, MD

2. When to Expect Mineralocorticoid Excess Hypertension Hypertension Hypokalemia Hypokalemia Metabolic alkalosis Metabolic alkalosis Less than 50% with Primary Aldosteronism are hypokalemia Less than 50% with Primary Aldosteronism are hypokalemia

3. Differential Diagnosis of Hypokalemia and normal BP Surreptitious vomiting Surreptitious vomiting Bartter’s Syndrome Bartter’s Syndrome Rare primary aldosteronism Rare primary aldosteronism

4. Other Causes of Hypertension and Hypokalemia Renovascular Disease Renovascular Disease Diuretic therapy Diuretic therapy Cushing’s Syndrome Cushing’s Syndrome Licorice ingestion Licorice ingestion CAH CAH Rare renin-secreting tumors Rare renin-secreting tumors

5. When to Screen Patient for Primary Aldosteronism Hypokalemia Hypokalemia Severe, resistant or relatively acute HT Severe, resistant or relatively acute HT Adrenal incidentaloma Adrenal incidentaloma Primary aldosteronism occurs in 1-2% up to 5-10% of all hypertensives – probably an over-estimate Primary aldosteronism occurs in 1-2% up to 5-10% of all hypertensives – probably an over-estimate

6. Consider screening Hypertensive patients under 30 for secondary causes With mild to severe hypertension With mild to severe hypertension No FH of hypertension No FH of hypertension Non-obese Non-obese

7. Initial Approach to Patient with HT and Hypokalemia Plasma renin activity Plasma renin activity Plasma aldosterone concentration Plasma aldosterone concentration

8. Plasma Renin Activity in Hypokalemia and HT Low Low Primary mineralocorticoid excess Primary mineralocorticoid excess High High Diuretic therapy Diuretic therapy Reno-vascular HT Reno-vascular HT Malignant HT Malignant HT Rare – renin-secreting tumor Rare – renin-secreting tumor

9. Plasma Aldosteronism/Plasma Renin Activity Test in AM Test in AM Un-interpretable with spironolactone or eplerenone RX – stop for 6 weeks Un-interpretable with spironolactone or eplerenone RX – stop for 6 weeks Other K+ diuretics OK Other K+ diuretics OK ACEI and ARB’s may falsely elevate PRA ACEI and ARB’s may falsely elevate PRA (undetectable PRA strongly suggestive) (undetectable PRA strongly suggestive)

10. Plasma Aldosteronism/Plasma Renin Activity Normal ratio 4 – 10 Normal ratio 4 – 10 Primary aldosteronism 30 – 50 Primary aldosteronism 30 – 50 PRA low in many with essential HT but high PAC (>15 ng/dl) and abnormal ratio are uncommon PRA low in many with essential HT but high PAC (>15 ng/dl) and abnormal ratio are uncommon Cut-off for high PAC/PRA is lab dependent. Thus increased PAC is part of dx requirement Cut-off for high PAC/PRA is lab dependent. Thus increased PAC is part of dx requirement

11. Other Lab Testing 24 hour urine Potassium – usually not necessary to demonstrate K+ wasting 24 hour urine Potassium – usually not necessary to demonstrate K+ wasting Unless PRA not suppressed Unless PRA not suppressed PAC not elevated PAC not elevated Clinical suspicion of surreptitious vomiting or laxative abuse Clinical suspicion of surreptitious vomiting or laxative abuse Inappropriate K+ wasting is > 30mg daily in hypokalemic patient Inappropriate K+ wasting is > 30mg daily in hypokalemic patient Urine Na+ > 50meq daily Urine Na+ > 50meq daily

12. Confirmation of Primary Aldosteronism Elevated PAC/PRA Elevated PAC/PRA Salt load (after control of HT and correction of K+) Salt load (after control of HT and correction of K+) Dietary for 3 days Dietary for 3 days 5000mg Na+ diet or 1gm NaCl tablets – 2 tid 5000mg Na+ diet or 1gm NaCl tablets – 2 tid Watch out for worsening HT and hypokalemia Watch out for worsening HT and hypokalemia

13. Confirmation of Primary Aldosteronism – Cont’d 3 rd day of high salt diet – collect 24 hr urine for aldosterone, sodium and creatinine 3 rd day of high salt diet – collect 24 hr urine for aldosterone, sodium and creatinine 24 hr urine Na+ should be > 200meq to show adequate Na+ loading 24 hr urine Na+ should be > 200meq to show adequate Na+ loading Urine aldosterone > 14 mcg/24 hrs consistent with primary hyperaldosteronism Urine aldosterone > 14 mcg/24 hrs consistent with primary hyperaldosteronism

14. Confirmation of Primary Aldosteronism – Cont’d IV sodium chloride IV sodium chloride Baseline plasma aldosterone level Baseline plasma aldosterone level 2 liters NS IV over 4 hours 2 liters NS IV over 4 hours Repeat plasma aldosterone level Repeat plasma aldosterone level Primary hyperaldosteronism – plasma aldosterone level does not suppress Primary hyperaldosteronism – plasma aldosterone level does not suppress

15. Nonaldosterone Mineralocorticoid Excess Suppressed PRA and low plasma or urine aldosterone value Suppressed PRA and low plasma or urine aldosterone value Causes Causes Some types of CAH or familial cortisol resistance Some types of CAH or familial cortisol resistance Chronic licorice ingestion Chronic licorice ingestion Severe cases of Cushing’s syndrome Severe cases of Cushing’s syndrome Deoxycorticosterone producing tumor Deoxycorticosterone producing tumor

16. Familial Hyperaldosteronism Type 1 – glucocorticoid-remediable aldosteronism Type 1 – glucocorticoid-remediable aldosteronism Secondary to ACTH stimulation of aldosterone secretion Secondary to ACTH stimulation of aldosterone secretion Type 2 – not ACTH dependent and not suppressible with dexamethasone Type 2 – not ACTH dependent and not suppressible with dexamethasone Genetic defect unknown Genetic defect unknown They can have APA or IPA or both They can have APA or IPA or both

17. Differentiating Adrenal Adenoma from Hyperplasia 30 – 60 % Adrenal adenomas 30 – 60 % Adrenal adenomas APA have higher aldosterone secretion rates APA have higher aldosterone secretion rates Adrenal hyperplasia less severe with less hypokalemia Adrenal hyperplasia less severe with less hypokalemia PAC/PRA > 32 had 100% sensitivity and 61% specificity for APA in one study PAC/PRA > 32 had 100% sensitivity and 61% specificity for APA in one study

18. Differentiating Adrenal Adenoma from Hyperplasia Patients with APA Patients with APA More severe HT More severe HT More profound hypokalemia - < 3.0 More profound hypokalemia - < 3.0 Higher plasma (>25 ng/dl) and urinary (>30 mcg/24 hrs) levels of aldosterone Higher plasma (>25 ng/dl) and urinary (>30 mcg/24 hrs) levels of aldosterone Younger - < 50 Younger - < 50

19. Differentiating Adrenal Adenoma from Hyperplasia Radiographic Tests Hypo-dense unilateral macroadenoma (>1 cm) likely APA Hypo-dense unilateral macroadenoma (>1 cm) likely APA Abnormality in both glands likely hyperplasia although both glands my appear normal on CT or MRI Abnormality in both glands likely hyperplasia although both glands my appear normal on CT or MRI

20. Differentiating Adrenal Adenoma from Hyperplasia Radiographic Tests Some investigators suggest low K+, nonsuppressible hyperaldosteronism, PAC/PRA ratio > 50 and a unilateral mass can go directly to surgery Some investigators suggest low K+, nonsuppressible hyperaldosteronism, PAC/PRA ratio > 50 and a unilateral mass can go directly to surgery But – in 3 studies of 32 pts. – 11 patients (1/3) had bilateral hyperplasia But – in 3 studies of 32 pts. – 11 patients (1/3) had bilateral hyperplasia Absence of mass does not exclude APA Absence of mass does not exclude APA Bilateral lesions do not exclude APA Bilateral lesions do not exclude APA CT may be accurate only 50% of time CT may be accurate only 50% of time

21. Differentiating Adrenal Adenoma from Hyperplasia Adrenal Vein Sampling Gold standard Gold standard APA - >4 fold step-up of PAC APA - >4 fold step-up of PAC Best performed with continuous infusion of ACTH (50 mcg per hour) Best performed with continuous infusion of ACTH (50 mcg per hour) Measure cortisol in same sample to be sure samples from adrenal veins Measure cortisol in same sample to be sure samples from adrenal veins Cortisol from right adrenal 25% higher and 10 times higher than peripheral vein Cortisol from right adrenal 25% higher and 10 times higher than peripheral vein

22. Differentiating Adrenal Adenoma from Hyperplasia Adrenal Vein Sampling Most useful when no adrenal abnormality Most useful when no adrenal abnormality Both adrenal glands abnormal but asymmetric Both adrenal glands abnormal but asymmetric One study – 41% with normal CT and 49% with bilateral micronodules on CT had unilateral APA One study – 41% with normal CT and 49% with bilateral micronodules on CT had unilateral APA In 203 pts. with primary aldosteronism – 51% with unilateral micro-nodule and 66% with unilateral macro-nodule had ipsilateral aldo hypersecretion In 203 pts. with primary aldosteronism – 51% with unilateral micro-nodule and 66% with unilateral macro-nodule had ipsilateral aldo hypersecretion