Aldosteronism

1. Aldosteronism Armed Forces Academy of Medical Sciences

2. Outline • Review normal physiology of RAAS system • Review normal physiology of Aldosterone • Primary hyperaldosteronism • Types • Symptoms • Diagnosis • Treatment

3. Normal Structure of Nephron

4. Renin-Angiotensin-Aldosterone System (RAAS) • Controls water reabsorption through the manipulation of sodium reabsorption • Renin release by kidney in response to • Fluid loss • Hypotension • Low Sodium intake • Systemic Vasoconstriction • These factors are sensed by • Baroreceptors (stretch receptors) • Afferent arteriole • Cardiac and arterial baroreceptors • Macula Densa • Early Distal Convoluted Tubule

5. RAAS Physiology Stimulus Angiotensinogen Arterial Constriction Renin Angiotensin II Angiotensin I Sodium Retention Angiotensin Converting Enzyme (ACE)

6. RAAS Physiology • Effects of Angiotensin II • Increases Na Retention • Through direct stimulation of the Proximal Convoluted Tubule (PCT) • Increases Aldosterone secretion • Aldosterone increases sodium retention in corticol collecting tubule • Increased Na retention leads to increased water reabsorption • Direct systemic arterial vasoconstriction • Increased blood pressure

7. RAAS Physiology www.uptodate.com

8. Aldosterone Synthesis • Synthesized in adrenal cortex • Zona glomerulosa

9. Normal Mechanism of Aldosterone Action • Increase number of open sodium channels in the luminal membrane of the principal cells in the cortical collecting tubule • Increased sodium reabsorption • Removal of Na makes lumen electronegative • Potassium is secreted from the cells into the electronegative urine to even out charge

10. Primary Aldosteronism • Conn’s syndrome • Aldosterone-producing adenoma (30-60%) • Bilateral idiopathic Hyperaldosteronism • Unilateral adrenal hyperplasia • Bilateral macronodular adrenal hyperplasia • Familial hyperaldosteronism • Type 1 • Type 2 • Pure aldosterone-producing adrenocortical carcinomas • Ectopic aldosterone-secreting tumors

11. Clinical Features of Primary Aldosteronism • Hypertension • Hypokalemia • Metabolic Alkalosis • Other electrolyte abnormalities • Lack of edema

12. Clinical Features of Primary Aldosteronism: Hypertension • Frequently substantially elevated (> 160 / 100) • Generally resistant to multiple antihypertensive medications • Hypervolemia • Markedly reduces renin secretion • Persistent hypervolemia leads to increased systemic vascular resistance (SVR) • Aldosterone is potent hypertensive agent • Even high normal levels of aldosterone associated with hypertension

13. Clinical Features of Primary Aldosteronism: Hypokalemia • Increased urinary potassium wasting • Serum potassium remains stable for the short term • Aldosterone induced potassium wasting counterbalanced by potassium retaining effect of hypokalemia • Progressive hypokalemia only occurs if another factor is added • Increased aldosterone production • Initiation of diuretic medication

14. Clinical Features of Primary Aldosteronism: Hypokalemia • Patients with primary aldosteronism due to adrenal hyperplasia often do NOT have hypokalemia • Phenomenon not understood • Symptoms of hypokalemia • Mild cases are asymptomatic • Mild elevation of blood pressure • Muscle weakness, cramps, myalgias • ECG changes

15. Clinical Features of Primary Aldosteronism: Other Effects • Metabolic Alkalosis • Due to increased urinary hydrogen ion excretion as a result of aldosterone stimulating Na-H transporter • Mild Hypernatremia • Often between 143 – 147 mEq/L • Hypomagnesemia • Urinary magnesium wasting • Not well understood

16. Hyperaldosteronism and Cardiac Risk • Patients with primary hyperaldosteronism have higher risk of cardiovascular complications then patients with hypertension • Retrospective study of 124 patients with primary aldosteronism to 465 patients with essential hypertension • Two groups matched for age, gender, degree of BP elevation • Higher rates of stroke, myocardial infarction, atrial fibrillation in hyperaldosteronism group Journal American College Cardiology 2005; 45 (8): 1243

17. Diagnosis of Primary Hyperaldosteronism • First step is to measure Plasma Renin Activity (PRA) and Plasma Renin Concentration (PRC) • PRA and PRC levels affected by diuretic use • PRA and PRC should be LOW in primary aldosteronism • Measure the Plasma Aldosterone Concentration • Calculate PAC/PRA ratio

18. Calculating the PAC/PRA ratio • Measure levels at 0800 • Test can be done while patient takes most of his antihypertensive medications • Must hold spironolactone or eplerenone • Will falsely elevated PRA • ACE inhibitor and ARBs will also affect PRA • Normal value of PAC/PRA 4-10 • Primary aldosteronism average 30-50

19. Interpreting the PAC/PRA ratio • Primary Aldosteronism: PRA suppressed, PAC increased (usually > 15 ng/dL) • PAC > 20 and PAC/PRA > 30 is 90% specific for primary aldosteronism • Secondary Aldosteronism(renovascular disease): PRA and PAC increased, PAC/PRA < 10 • Other (hypercoritsolism, licorice root ingestion): both PRA and PAC suppressed

20. Establishing Subtype • Adrenal CT • Differentiates adenoma from hyperplasia • Normal adrenal glands does not exclude hyperplasia • Adrenal carcinoma suspected with > 4 cm adrenal mass

21. Confirming Diagnosis • Adrenal vein sampling • Interventional radiologist obtains aldosterone levels from each adrenal vein • Differentiates bilateral from unilateral disease • Indications for adrenal vein sampling • Confirm unilateral disease in anyone considering surgery • When PAC/PRA is abnormal but CT scan normal

22. Treatment of Primary Hyperaldosteronism • Treatment or primary aldosteronism is based on whether aldosteronehypersecretion is • Unilateral • Bilateral • Goal of therapy is to prevent morbidity and mortality associated with • Hypertension • Hypokalemia • Increased cardiovascular risk

23. Treatment of Unilateral Adenoma or Hyperplasia • Surgery: Unilateral adrenalectomy • Unilateral adenoma • Unilateral hyperplasia • Partial adrenalectomy inadequate • Laparoscopic better than open • Shorter hospital stay • Less complications 2008 Endocrine Society Guidelines

24. Post-Op Management of Unilateral Adrenalectomy • Hypertension and hypokalemia controlled medically • Spironolactone or Eplerenone • Plasma aldosterone should be measured the day after surgery to asses for cure • Patients monitored for hyperkalemia as spironolactone, potassium supplements and anti-hypertensives are discontinued

25. Medical Therapy for Unilateral Adrenal Hyperplasia or Adenoma • Surgical treatment is preferred method • Medical therapy with aldosterone antagonists is effective • 50 point reduction in systolic BP • 30 point reduction in diastolic BP • Increase in serum potassium of > 1.0 mEq/L • Also include low salt diet, regular exercise • No efficacy difference between spironolactone and eplerenone

26. Precautions with Spironolactone • Monitor serum potassium and creatinine frequently during first 6 weeks of therapy • Spironolactone will increase half life of digoxin • Concurrent NSAID use will blunt anti-hypertensive effects of aldactone • Patients may develop breast tenderness, decreased libido, gynecomastia

27. Treatment of Bilateral Adrenal Hyperplasia • Generally milder disease than adrenal adenoma • Less aldosterone secretion • Less severe hypertension and hypokalemia • Patients should be treated with long term aldosterone antagonist • Aldosterone or Eplerenone • May need thiazide diuretic or ACE inhibitor • Partial Adrenalectomy has been tried and failed

28. Conclusions • Primary hyperaldosteronism is one of the more common causes of hypertension • It often presents as hypertension and hypokalemia • It causes increased cardiovascular morbidity and mortality beyond it’s hypertension • There are many subtypes • Must diagnosis each subtype as treatment varies