A. Pathophysiology

1. Aldosterone is a potent mineralocorticoid
2. Produced by adrenal cortex (mainly glomerulosa)
3. Binds to receptors in renal collecting duct [2]
   1. Activates Na+/K+ pump [2]
   2. Na+ enters collecting duct principal cells through apical amiloride sensitive Na+ channel
   3. Na+ is pumped out by aldosterone sensitive Na+/K+ pump (ATPase)
4. Increased aldosterone drives increased Na+ (salt) resorption
   1. This leads to volume expansion and hypertension (HTN)
   2. In addition, K+ is lost in the urine, possibly leading to frank hypokalemia
   3. Mild hyperaldosteronism occurs in >11% of resistant HTN [3,9]
5. Pseudoaldosteronism (Liddle's Syndrome) [3]
   1. Activating mutations in ß or gamma subunits of amiloride sensitive Na+ channel
   2. In Liddle's syndrome, salt absorption is increased and hypertension results
   3. In general, K+ is lost due to shift in equilibrium driving Na+/K+ pump
   4. Resistant HTN may respond to Na+ channel inhibitor amiloride
6. Aldosterone Stimulation
   1. Aldosterone is stimulated by angiotensin II and by reduced pressures sensed in kidney
   2. Aldosterone is therefore part of the renin-angiotensin system
   3. This system evolved to retain fluid in setting of hemorrhage and/or dehydration
   4. Aldosterone levels are highly elevated in most fluid-overloaded states
   5. Sodium concentrations may be normal or slightly elevated

B. Etiology

1. Adrenal Mass (most common)
   1. Adrenal masses are fairly commonly detected on radiographic imaging for other issues
   2. These so-called "incidentalomas" rarely secrete significant aldosterone
   3. Aldosteronomas are more common in women than men
   4. Adrenal masses causing hyperaldosteronism are usually benign (adenomas)
   5. Adrenal carcinomas are uncommon (<2%) causes of hyperaldosteronism [4]
2. Adrenal Hyperplasia (common)
3. Idiopathic hyperaldosteronism
   1. Glands normal size
   2. Ectopic aldosterone secretion (very uncommon)
4. Glucocorticoid Remediable Aldosteronism
5. Primary hyperaldosteronism represents <1% of all cases of HTN
6. Mild hyperaldosteronism may be present in up to 20% of resistant HTN [3]

C. Signs and Symptoms

1. Symptoms of Hypokalemia
   1. Muscle Fatigue
   2. Cardiac Arrhythmias (especially bradycardia)
   3. Prominant U waves on ECG
2. HTN
   1. Often difficult to control: resistant HTN is blood pressure >140/90mm on three drugs
   2. Overall accounts for 1-2% of all cases of HTN and >11% of resistant HTN [9]
3. Weight Gain
4. Edema
5. Laboratory
   1. Hypokalemia and hyperkaliuria
   2. Reduced urinary sodium (particularly given patient's volume)
   3. Metabolic alkalosis
   4. Albuminuria and mildly increased glomerular filtration rate may be present [5]

D. Evaluation [1,2,6]

1. Baseline random renin and aldosterone levels (upright position)
   1. Normally, these should correlate within usual range
   2. In primary hyperaldosteronism, renin level is very low (aldosterone high normal or high)
   3. Aldosterone is secreted independently of the renin system
   4. Diagnosis requires aldosterone : renin ratio >65 and aldosterone level >416 pmol/L [9]
   5. Ratio of aldosterone to renin >20-30 should also precipitate further evaluation
   6. A basal (8 AM) plasma level of 18-hydroxycorticosterone >100ng/dL supports diagnosis
   7. Response to aldosterone antagonist (spironolactone, eplerenone) confirms diagnosis
2. Saline Infusion Test
   1. Baseline plasma renin and aldosterone
   2. Infuse saline should normally suppress both levels
   3. Infuse 2L isotonic saline over 4 hours and measure plasma aldosterone
   4. Plasma aldosterone level >10ng/dL is diagnostic of hyperaldosteronism
   5. Plasma aldosterone level 5-10ng/dL is borderline
3. Imaging: CT or MRI Scanning [7,8]
   1. Unilateral suggests adenoma (unilateral hyperplasia very uncommon)
   2. Bilateral suggests bilateral adrenal hyperplasia
   3. Accuracy ~75%
4. Adrenal Venous Aldosterone Sampling
   1. For determining aldosterone output with bilateral adrenal abnormalities
   2. Also useful when imaging and hormone studies disagree
   3. Hyperplasia tends to be bilateral, whereas adenomas are unilateral
   4. Hyperplasia and adenomas may be present together
   5. In situations where high aldosterone levels lateralize, surgery is very effective
5. Distinguishing Hyperplasia from Adenomas
   1. Urinary excretion of 18-oxocortisol and 18-hydroxycortisol
   2. Adrenal vein sampling
   3. Aldosterone blockade is most effective for bilateral hyperplasia
   4. Postural stimulation test - rarely done now
6. Rule out other components of MEN 2A
   1. MEN Type 2A is also called Sipple Syndrome
   2. Thyroid medullary tumors and pheochromocytomas are always found
   3. Adrenal Cortical Mass 5%
   4. Carcinoids <5%
7. If dexamethasone 2mg qd x 3 days lowers blood pressure and aldosterone levels, then glucocorticoid remediable hyperaldosteronism is likely cause
8. Renal function should be assessed at baseline and in follow up [5]

E. Treatment [2]

1. Surgical Therapy
   1. Removal of adenoma is most effective and often curative (unilateral)
   2. Response to medical therapy suggests that surgical cure is possible
   3. However, not all surgically treated patients have complete remission
   4. Therefore, adjunctive medical therapy may be required
   5. Normalized blood pressure after surgery associated with no family history of HTN [10]
2. Overview of Medical Therapy [11]
   1. Most effective for bilateral hyperplasia
   2. May also be used as adjunct to surgical therapy
   3. Combination of diuretic (potassium sparing) and blood pressure medication required
   4. Careful monitoring of potassium levels and blood pressure essential
3. Diuretics [11]
   1. Potassium sparing diuretics are drugs of choice
   2. The aldosterone analog spironolactone acts as a receptor blocker (see below)
   3. Amiloride - potassium sparing diuretic better tolerated than spironolactone
   4. Amiloride doses of 20-40mg / day well tolerated (mild muscle cramping)
   5. Addition of furosemide or other loop diuretic to reduce edema is often required
4. Aldosterone Receptor Blockers [12]
   1. Spironolactone (Aldacton®) and Eplerenone (Inspra®)
   2. Direct aldosterone receptor antagonists
   3. Spironolactone doses: 25-400mg/d (usually divided)
   4. Spironolactone >100mg/d are usually required
   5. Spironolactone >100mg/d are poorly tolerated in long term however
   6. Side effects include gynecomastia, impotence, fatigue, and gastrointestinal symptoms
   7. Eplerenone is a more specific aldosterone receptor blocker
   8. Eplerenone dose 50mg po qd to start, up to 100mg po bid
   9. Main risk for either agent is hyperkalemia; monitoring is required
   10. Spironolactone has higher risk of gynecomastia than eplerenone
   11. Impotence and menstrual disturbances are uncommon with both agents
5. Control of HTN [11]
   1. The HTN associated with hyperaldosteronism is often difficult to treat
   2. ACE inhibitors or angiotensin 2 receptor blockers have poor efficacy alone alone
   3. Combinations of aldosterone receptor blockers and other agents are effective
   4. Potassium (and sodium) levels must be monitored carefully
   5. Dexamethasone 2mg/d for glucocorticoid remediable hyperaldosteronism
6. Renal dysfunction at baseline is usually at least partially reversible [5]

Resources

Serum Osmolality

References

1. Ganguly A. 1998. NEJM. 339(25):1828
2. Herbert SC. 1998. Am J Med. 104(1):87
3. Oparil S, Zaman A, Calhoun DA. 2003. Ann Intern Med. 139(9):761
4. Rossi GP, Vendraminelli R, Cesari M, Pessina AC. 2000. Lancet. 356(9241):1570
5. Sechi LA, Novello M, Lapenna R, et al. 2006. JAMA. 295(22):2638
6. Bornstein SR, Stratakis CA, Chrousos GP. 1999. Ann Intern Med. 130(9):759
7. Abdelhamed S, Muller-Lobeck H, Pahl S, et al. 1996. Arch Intern Med. 156(11):1190
8. Cook DM and Loriaux L. 1996. Am J Med. 101(1):88
9. Douma S, Petidis K, Doumas M, et al. 2008. Lancet. 371(9628):1921
10. Sawka AM, Young WF Jr, Thompson GB, et al. 2001. Ann Intern Med. 135(4):258
11. Ghose RP, Hall PM, Bravo EL. 1999. Ann Intern Med. 131(2):105
12. Eplerenone. 2003. Med Let. 45(1156):39