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HYPERALDOSTERONISM      DX  |  RX  | Primary Aldosteronism 2006 | hyperaldosteronism2008 | Hyperaldosteronism_Case2010.pdf     REF:  UpToDate 2006 | ACPMedicine 2006

Primary Aldosteronism
   - is a syndrome of hypertension and hypokalemia secondary to elevated plasma aldosterone
that occurs in 0.05 -2 % of hypertensive patients.
Diagnosis of Primary Hyperaldosteronism:
  • Hypokalemia & hypertension
    Increased bicarbonate (alkalosis), hypochloremia.
    - Be aware that in hypokalemia, >30 mmol/d of urinary potassium  (off diuretics and potassium supplement x 4 days) is indicative of potassium wastage, usually driven by mineralocorticoid excess.  
    - Ensure that urine sodium is >100 mmol/d, because potassium wastage is ameliorated by intense dietary sodium restriction and a urine creatinine of >800 mg/d to ensure a complete collection.  

  • Decreased 8 A.M. plasma renin (< 1-2 ng/ml/hr) after 1-2 hours of upright posture.

  • Elevated   8 A.M. plasma aldosterone concentration  (> 14-15 ng/dL) &

    Elevated 24 hours urine aldosterone level > 14 mcg after 3 days of high salt diet aldosterone suppression test.

    Orally administered high sodium chloride diet  (to achieve a 5000 mg sodium diet)  x 3 days and measurement of urine aldosterone excretion and measurement of PAC.
    - In circumstances of high sodium dietary intolerance, patients can be given oral sodium chloride tablets (eg, two 1 g sodium chloride tablets taken three times daily with food will provide approximately 90 meq of sodium). The risk of increasing dietary sodium in patients with severe hypertension must be assessed in each case. In addition, since sodium loading typically increases kaliuresis and hypokalemia, serum potassium should be measured daily and vigorous replacement of potassium chloride should be prescribed as indicated.
    - On the third day of the high sodium diet, serum electrolytes are measured and a 24-hour urine specimen is collected for measurement of aldosterone, sodium, and creatinine. The 24-hour urine sodium excretion should exceed 200 meq to document adequate sodium loading. Urine aldosterone excretion >14 µg/24 hours (39 nmol/day) in this setting is consistent with hyperaldosteronism.

    IV administration of two liters of isotonic saline over four hours (while the patient is recumbent). The PAC will fall below 6 ng/dL (166 pmol/L) in normal subjects, whereas values above 10 ng/dL (277 pmol/L) are consistent with primary hyperaldosteronism.

  • A single plasma aldosterone concentration/plasma renin activity (PAC/PRA) ratio > 20-25 as screening test.

  • Abnormal adrenal CT  or MRI scan to localize the adrenal lesion.
    - If unilateral adenoma >1.0 cm is located, surgery can be recommended.

  • Bilateral adrenal vein sampling for both aldosterone and cortisol.
    - To establish the need for surgery, recommend adrenal venous sampling in patients with ambiguous adrenal CT or MRI scans to establish the source of hyperaldosteronism.
    - Consider an increase in aldosterone-to-cortisol ratio (on the affected side compared to the presumed normal side) of at least two-fold to define lateralization.


Causes of Hyperaldosteronism                       

A. Primary Aldosteronism    

  1. Unilateral benign adrenal adenoma (in about 70 percent of such patients)
  2. Bilateral adrenal hyperplasia of the zoma glomerulosa idiopathic (in 20 to 30 percent)
    1. Idiopathic hyperplasia; and
    2. The rare glucocorticoid-remediable aldosteronism, which responds to the administration of exogenous glucocorticoid.
      Dexamethasone-suppressible hyperaldosteronism is a rare familial cause of hyperaldosteronism and is transmitted as an autosomal dominant trait. The aldosterone secretion becomes entrained to ACTH secretion and is “blind” to renin-angiotensin levels. Because ACTH secretion is not modulated by aldosterone, aldosterone secretion becomes independent of salt balance, blood potassium levels, and vascular volume.  Treatment for this disorder starts with the use of a potassium-sparing diuretic such as amiloride or triamterene. This regimen has the advantage of not suppressing the HPA axis. If it is unsuccessful, ACTH secretion can be suppressed with dexamethasone, usually 0.5 mg in a single daily dose.  
  3. Adrenocortical carcinoma, rarely.

B. Secondary aldosteronism
    - should be considered when both the PRA and PAC (plasma renin activity and aldosterone) are increased and the PAC/PRA ratio is <10 (as in renovascular disease); it may or may not be associated with hypertension. Patients with hypertension usually have underlying renal pathology, including renal artery stenosis, renin-secreting tumors, and chronic renal failure.Treatment should be directed at the underlying cause.

  1. With hypertension
    a. Unilateral renal hypertension
    b. Malignant hypertension
    c. Oral contraceptive related hypertension; Glucocorticoid-remediable aldosteronism (GRA)
    d. Renin secreting renal tumor (primary reninism)
    e. Licorice ingestion  induced hypertension and hypokalemia .
        - An alternate source of mineralocorticoid receptor stimulation (eg, hypercortisolism, licorice ingestion)
          should be considered when both the PRA and PAC are suppressed.
  2. Without hypertension
    a. Nephrotic syndrome
    b. Cirrhosis
    c. Congestive heart failure
    d. Bartter's synd juxtaglomerular cell hyperplasia
    e. Decreased effective plasma volume (diuretics, blood loss, salt depletion)

Differential Diagnosis of Hypertension with Hypokalemia

  1. Primary aldosteronism
  2. Renovascular disease (in which hypersecretion of renin leads sequentially to increased angiotensin II and then aldosterone secretion)
  3. Diuretic therapy, which may be surreptitious.
  4. Less common causes include Cushing's syndrome, licorice ingestion, certain forms of congenital adrenal hyperplasia, and rare renin-secreting tumors.

Causes of Increased Plasma Aldosterone and PRA (renin) levels:

  • Renal tubular acidosis
  • Bartter syndrome
  • Diuretic abuse
  • Heart failure
  • Chronic vomiting
  • Laxative abuse
  • Magnesium-losing enteropathy
  • Familial chloride diarrhea
  • Liver failure with ascites


Laborary Findings in Primary Hyperaldosteronism

Plasma aldosterone (PAC) to renin ratio (PAC/PRA) >20-25 ,more than 30-50 in most patients with primary aldosteronism.   
- is performed by measuring a morning (preferably 8 AM), ambulatory, paired, random PAC and PRA.  Most antihypertensive medications (except  aldosterone receptor antagonists, ACE inhibitors or ARB) can be continued and posture stimulation is not required.

  • It is impossible to interpret data obtained from patients treated with aldosterone receptor antagonists. Thus, spironolactone and eplerenone should not be initiated until the evaluation is completed and the final decisions about treatment are made. If primary aldosteronism is suspected in a patient already receiving spironolactone, therapy should be discontinued for at least six weeks.
  • Other potassium-sparing diuretics, such as amiloride and triamterene, usually do not interfere with testing unless the patient is on high doses.
  • Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) may "falsely elevate" the PRA in patients with primary aldosteronism. Thus, in a patient treated with an ACE inhibitor or ARB, a detectable PRA level or a low PAC/PRA ratio does not exclude the diagnosis of primary aldosteronism. On the other hand, a strong predictor for primary aldosteronism is an undetectable PRA in a patient taking an ACE inhibitor or ARB.

24-hour urine collection  of potassium and aldosterone secretion

  1. Increased Aldosterone excretion can also be measured, with high values (>14 µg/day [39 nmol/day]) on a high sodium diet (urine sodium excretion >200 meq/day) being consistent with primary aldosteronism if the PRA is low.
  2. Increased urinary potassium excretion (defined as more than 30 meq/day in a patient with hypokalemi). At present, we do not order a 24 hour urine collection unless the PRA is not suppressed, the PAC is not elevated, or there is a clinical suspicion of surreptitious vomiting or laxative abuse.

The patient must not have a low-sodium intake or hypovolemia (as evidenced by less than 50 meq of sodium being excreted per day), since the associated decrease in sodium and water delivery to the distal potassium secretory site can diminish potassium excretion even in patients with hyperaldosteronism. On the other hand, the degree of potassium wasting and therefore the diagnostic accuracy can be increased by a high-sodium diet, because the combination of increased distal flow and hypersecretion of aldosterone will maximize potassium losses.

A high-sodium diet can also be given as a provocative test in patients with an initial serum potassium concentration in the normal or low-normal range. Sodium-induced hypokalemia is strongly suggestive of nonsuppressible hyperaldosteronism. Normal subjects do not waste potassium during sodium loading, because the increase in distal flow is offset by reduced secretion of aldosterone.

Nonaldosterone mineralocorticoid excess — The combination of a suppressed PRA and a low plasma or urinary aldosterone value indicates the presence of some nonaldosterone mineralocorticoid. This can occur in patients with:

  • Some types of congenital adrenal hyperplasia or familial cortisol resistance, which has a similar presentation.
  • Chronic licorice ingestion, the rare genetic syndrome of apparent mineralocorticoid excess, and severe cases of Cushing's syndrome, in which cortisol acts as the primary mineralocorticoid. In the last setting, there may also be hypersecretion of other mineralocorticoids such as deoxycorticosterone and corticosterone.
  • A deoxycorticosterone-producing tumor, which can usually be detected by CT or magnetic resonance imaging (MRI).
  • Liddle's syndrome, a rare autosomal dominant condition in which there is a primary increase in sodium reabsorption in the collecting tubules and, in most cases, potassium secretion. This disorder is due to a genetic abnormality that increases the collecting tubule sodium channel, which is the effect produced by mineralocorticoids.


RX of Hyperaldosterosnism:
The treatment for unilateral adenomas is adrenalectomy. Idiopathic aldosteronism, bilateral hyperplasia, and bilateral adenomas are generally treated medically. The aldosterone antagonist spironolactone is generally used for women, whereas amiloride is used for men because spironolactone causes gynecomastia in some patients.

GOALS OF THERAPY for primary aldosteronism

  1. Normalization of blood pressure and hypokalemia,
  2. Normalization of plasma aldosterone concentrations or blockade of aldosterone activity with a mineralocorticoid receptor antagonist


  • A unilateral adrenal adenoma is responsible for the hypersecretion of aldosterone in 30 to 60 percent of cases.
  • Surgery (Unilateral adrenalectomy or adrenal enucleation) is the preferred therapy in this setting; alternatives include medical therapy with a potassium-sparing diuretic and, rarely, ablative procedures.
  • Laparoscopic adrenalectomy is the surgical procedure of choice.

1.  Surgery Rx  for unilateral adrenal adenoma
— Unilateral adrenalectomy or adrenal enucleation induces a marked reduction in aldosterone secretion, a fall in blood pressure, and correction of the hypokalemia in almost all patients. However, a lesser degree of hypertension persists in as many as 40 to 65 percent of cases. Resolution of hypertension after adrenalectomy is independently associated with a lack of family history of hypertension and preoperative use of two or fewer antihypertensive agents.

2.  Medical therapy for unilateral adrenal adenoma

  1. A mineralocorticoid receptor antagonist is an effective alternative in patients who refuse or are not candidates for surgery.
    12.5 to 50 mg twice daily with food (The maximum of 200 mg twice daily.)
    - often not well tolerated, since it also blocks the androgen and progesterone receptors. These effects can result in impotence, decreased libido, gynecomastia (the incidence of gynecomastia was dose-dependent: 6.9 percent at doses below 50 mg/day and 52 percent at doses above 150 mg/day) , menstrual irregularities, and minor gastrointestinal tract symptoms.
    25 mg twice daily (The maximum dose approved for hypertension is 100 mg daily.)
    - Eplerenone has equal to 25 to 50 percent less mg per mg potency than spironolactone. 
    - a highly selective mineralocorticoid receptor antagonist that is associated with a low incidence of endocrine side effects.
    - It has been approved for the treatment of uncomplicated essential hypertension [21,22] and for heart failure after myocardial infarction.

    If the hypertension persists, we titrate back to the dose that normalized the plasma potassium and add another antihypertensive drug (eg, 12.5 to 25 mg of hydrochlorothiazide daily).
  2. Dietary sodium restriction (<100 meq/day), maintenance of ideal body weight, avoidance of alcohol, and regular aerobic exercise contribute significantly to the success of pharmacologic therapy.
  3. Potassium-sparing diuretics that block the aldosterone-sensitive sodium channel in the collecting tubules (amiloride, triamterene) can block the renal effects of aldosterone, lowering the blood pressure and raising the plasma potassium concentration. However, these drugs are not recommended for first-line therapy because of persistence of hyperaldosteronism with its possible deleterious effect on the heart.
    is the drug of choice for men and women intolerant of spironolactone and eplerenone.
    - Amiloride dosing may be started at 5 mg twice daily and increased up to 15 mg twice daily if needed to correct the hypokalemia.
    - Amiloride is not an effective antihypertensive agent and, if hypertension persists, a second-step drug should be added. Low doses of a thiazide diuretic (eg, 12.5 to 25 mg of hydrochlorothiazide daily) are preferred because hypervolemia is a major reason for resistance to amiloride.

3.  Ablative procedures — Although published data are limited, some centers have advocated percutaneous ablative therapy, including percutaneous acetic acid injection and radiofrequency ablation, for unilateral adrenal adenomas.  
Percutaneous ablative therapy requires overnight hospitalization. It is also associated with a variety of adverse effects, including abdominal pain, hematuria, pancreatitis, pneumothorax, bleeding, adrenal abscess formation, tumor tracking, and incomplete ablation. In the era of laparoscopic adrenalectomy and selective aldosterone receptor antagonists, it is difficult to justify the uncertainties of adrenal percutaneous ablative therapy.



There are two forms of primary aldosteronism due to adrenal hyperplasia:

  1. idiopathic hyperplasia; and
  2. the rare glucocorticoid-remediable aldosteronism, which responds to the administration of exogenous glucocorticoid.

Subtotal adrenalectomy
has generally been disappointing in idiopathic hyperplasia, as only a minority of patients have a clinically significant hypotensive response. This observation has led to the hypothesis that idiopathic adrenal hyperplasia may be a variant of essential hypertension in which enhanced sensitivity of the zona glomerulosa to angiotensin II is responsible for the aldosteronism and hypokalemia, which are typically milder than in patients with an adrenal adenoma.

Medical Therapy
Thus, optimal treatment of idiopathic adrenal hyperplasia consists of mineralocorticoid receptor blockade with spironolactone or eplerenone as described above for medical therapy of a unilateral adrenal adenoma. The goals of therapy are normalization of the plasma potassium in hypokalemic patients, normalization of the blood pressure, reversal of the effects of hyperaldosteronism on the heart, which cannot be determined clinically.

After initial higher doses, low doses (such as 12.5 to 25 mg twice daily of spironolactone) are often effective in maintaining control of hypertension and potassium levels [15]. A thiazide diuretic or an angiotensin converting enzyme (ACE) inhibitor can be added if the hypertension persists. The efficacy of an ACE inhibitor in the low plasma renin state may in part reflect the role of even low concentrations of angiotensin II as an aldosterone secretagogue in adrenal hyperplasia.