Introduction
Background
Conn syndrome is characterized by increased aldosterone secretion from the adrenal glands, suppressed plasma renin activity (PRA), hypertension, and hypokalemia. It was first described in 1955 by JW Conn in a patient who, as in the image below, had an aldosterone-producing adenoma (ie, Conn syndrome). Later, many other cases of adrenal hyperplasia with increased aldosterone secretion were described, and now the term primary hyperaldosteronism is used to describe Conn syndrome and other etiologies of primary hypersecretion of aldosterone (eg, adrenal hyperplasia). Currently, primary hyperaldosteronism, especially Conn syndrome, seems to be the most common form of secondary hypertension.
Magnetic resonance imaging (MRI) scan in a patient with Conn syndrome showing a left adrenal adenoma.
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Magnetic resonance imaging (MRI) scan in a patient with Conn syndrome showing a left adrenal adenoma.
Pathophysiology
Primary hyperaldosteronism is caused by increased aldosterone excretion from the adrenals, which results primarily from 2 major subtypes: (1) unilateral aldosterone-producing adenoma (APA) or Conn syndrome (50-60% of cases) and (2) idiopathic hyperaldosteronism (IHA) or bilateral adrenal hyperplasia (40-50% of cases).
A rare subtype is renin-responsive adenoma, which morphologically and in response to adrenalectomy appears as APA, but it responds to physiologic maneuvers, as do hyperplastic glands of IHA. Another rare subtype is primary adrenal hyperplasia, in which a hyperplastic adrenal morphologically resembles that in IHA but mimics the APA response to physiologic maneuvers and unilateral adrenalectomy. The last rare subtype is glucocorticoid-remediable aldosteronism (GRA), which is autosomal dominant in inheritance and is associated with variable degrees of hyperaldosteronism that are suppressible with exogenous glucocorticoids. Rarely, aldosterone can be secreted by adrenocortical carcinomas and ovarian tumors.
Frequency
United States
Prevalence estimates for primary hyperaldosteronism, specifically Conn syndrome, are, respectively, 0.05-2% and 0.03-1.2% of the population with hypertension.
Mortality/Morbidity
The morbidity and mortality associated with primary hyperaldosteronism, especially Conn syndrome, are primarily related to hypertension and hypokalemia.1,2
Hypertension, especially if left untreated for many years, can lead to many complications, including heart disease (eg, coronary artery disease, congestive heart failure), stroke, and intracerebral hemorrhage (with very high blood pressure).
Hypokalemia, especially if severe, causes cardiac arrhythmias, which can be fatal.
Sex
Primary hyperaldosteronism is twice as common in women as in men.
Age
Peak incidence occurs in the third to sixth decades of life.
Clinical
History
Few symptoms are specific, and mostly they result from hypokalemia and alkalosis. Aldosterone, by inducing renal distal tubular reabsorption of sodium, enhances secretion of potassium and hydrogen ions, causing hypernatremia, hypokalemia, and alkalosis.
Patients with severe hypokalemia report fatigue, muscle weakness, cramping, headaches, and palpitations. They can also have polydipsia and polyuria from hypokalemia-induced nephrogenic diabetes insipidus.
As mentioned previously, long-standing hypertension may lead to cardiac and neurologic problems, with all the associated symptoms.
Physical
No specific physical findings are evident.
Patients with congestive heart failure, stroke, or cerebral hemorrhage from hypertension have physical examination findings related to these conditions.
Causes
Primary aldosteronism can be divided into many subtypes.
The most common subtype is Conn syndrome, an APA that is usually small (<3 cm), unilateral, and renin-unresponsive. This means that aldosterone secretion is not affected by changes in posture. Rarely, the adenoma is renin-responsive (ie, aldosterone levels increase with standing). Conn syndrome occurs in 50-60% of cases.
The remaining 40-50% of cases are due to bilateral adrenal hyperplasia or IHA, in which aldosterone increases in response to postural studies. Rarely, patients are hyperplastic (ie, primary adrenal hyperplasia), and the response of aldosterone to standing is similar to renin-unresponsive APA.
Rarely, adrenocortical carcinomas secrete aldosterone. Usually, the tumors are large (>4 cm).
Aldosterone can be ectopically secreted by adrenal embryologic rest neoplasms within the kidney and ovary.
Primary hyperaldosteronism can be inherited in an autosomal dominant fashion in patients with GRA, in whom activation of aldosterone secretion is induced by corticotropin and is suppressible with glucocorticoids. The involved gene is on chromosome Differential Diagnoses
C-11 Hydroxylase Deficiency
C-17 Hydroxylase Deficiency
Cushing Syndrome
Hypertension
Hypertension, Malignant
Renovascular Hypertension
Other Problems to Be Considered
Liddle syndrome - This is a rare autosomal dominant disorder resulting in a continuously activated sodium channel with excessive sodium reabsorption in the renal distal tubule. Levels of renin and aldosterone are low.
Renin-secreting tumor - These are rare tumors arising from the juxtaglomerular apparatus.
Exogenous mineralocorticoid
Excessive licorice intake - In this situation, the glycyrrhizinic acid component inhibits 11beta-hydroxysteroid dehydrogenase, impairing conversion of cortisol to cortisone in the kidneys; hence, cortisol binds to mineralocorticoid receptors and acts as a mineralocorticoid.
Workup
Laboratory Studies
Routine laboratory studies can show hypernatremia, hypokalemia, and metabolic alkalosis resulting from the action of aldosterone on the distal tubule of the kidney (ie, enhancing sodium reabsorption and potassium and hydrogen ion excretion).
Almost 20% of patients have impaired glucose tolerance resulting from the inhibitory affect of hypokalemia on insulin action and secretion; however, diabetes mellitus is rare.
Normokalemia does not exclude primary hyperaldosteronism. Several studies have shown that 7-38% of patients with primary hyperaldosteronism have baseline serum levels of potassium that are in the reference range. The hypokalemia becomes evident with liberalization of dietary sodium intake.
Typically, renin levels are suppressed to less than 1 ng/mL/h in patients with primary hyperaldosteronism, and levels do not stimulate above 2 ng/mL/h with diuretics and upright posture.
Because of this finding, some experts suggest that suppressed renin levels should be used as a screen for detecting primary hyperaldosteronism. However, in a 1993 series by Bravo, 30% of patients had renin levels that rose to greater than 2 ng/mL/h when appropriately stimulated by sodium deprivation.3
Thus, a nonsuppressed renin level in the setting of diuretic administration does not exclude a diagnosis of primary aldosteronism.
Furthermore, a subnormal renin level (<2 ng/mL/h) can be found in 30% of patients with essential hypertension; thus, a low renin level is not specific for primary aldosteronism.
In order to improve the sensitivity of a screening test for primary hyperaldosteronism, a ratio of plasma aldosterone (PA) activity to PRA can be calculated.
PA/PRA ratio (obtained in the morning) 20 or greater (with a PA ≥15 ng/dL) provide a sensitivity of 100% and a specificity of 80%, indicating the need for further study.
Others use a ratio greater than 30 and a PA level greater than 20 ng/dL, with a sensitivity of 90% and a specificity of 91%.
Note, however, that this ratio should be calculated when the patient is not taking interfering medications. Spironolactone should be stopped for 6 weeks prior to testing. Eplerenone, another aldosterone receptor antagonist, can also interfere with testing and should be stopped for at least 2 weeks before.
Alpha blockers, such as doxazosin, do not interfere with the PA/PRA ratio. Beta blockers and calcium channel blockers do not affect the diagnostic accuracy of the ratio in most cases.
Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) can falsely elevate PRA, leading to a lower PA/PRA ratio; therefore, the presence of suppressed PRA in a patient treated with a diuretic or, especially, an ACE inhibitor or ARB, is a strong predictor for primary hyperaldosteronism.
Because of limited specificity, a positive screening test result should be followed by a confirmatory test.
When the PA/PRA ratio is 20 or greater with a PA 15 ng/dL or greater, confirmatory tests need to be performed. The most commonly used confirmatory test is a 24-hour urine aldosterone level obtained after 3 days of salt loading. The patient can be instructed to maintain a sodium intake of at least 200 mEq/d (1 teaspoon of salt 3 times daily) for 3 days.
Care must be taken to ensure that potassium stores are replete and that the patient is normokalemic at the time of testing, because hypokalemia can inhibit aldosterone release and salt loading can exacerbate hypokalemia.
A 24-hour aldosterone excretion rate of greater than 14 mcg (with a concomitant 24-h urine sodium >200 mEq) is diagnostic of primary hyperaldosteronism.
Imaging Studies
Computed tomography (CT) scanning4
Once the diagnosis of primary hyperaldosteronism is confirmed, the next step is to differentiate the subtypes and to identify surgically curable disease. For practical purposes, this means distinguishing between an adrenal adenoma and bilateral hyperplasia.
In general, patients with adenomas are younger, have more severe hypertension and hypokalemia, and have higher urinary aldosterone levels than patients with hyperplasia. However, these clinical parameters are not reliable enough to accurately distinguish unilateral disease from bilateral disease.
Abdominal CT scanning is considered the procedure of choice.
Some investigators suggest that when a solitary unilateral macroadenoma (>1 cm) is detected in the setting of unequivocal hyperaldosteronism in a young patient, unilateral adrenalectomy is indicated.
Because of the age-dependent risk that a solitary unilateral adrenal macroadenoma may be a nonfunctioning adenoma, some experts believe that adrenal vein sampling4 should be performed in patients older than 40 years.
The problem arises with lesions that are smaller than 1 cm, which may be missed by CT scanning. Furthermore, bilateral lesions are not always diagnostic of adrenal hyperplasia because of the high incidence of adrenal incidentaloma. In these cases, adrenal vein sampling is the only way to make a firm diagnosis.
Overall, CT scanning has a sensitivity of 67-85% in patients with primary hyperaldosteronism.
Scanning with iodine I-131 iodocholesterol (NP-59, a precursor of aldosterone): This has also been used to detect unilateral functional adrenal lesions. In experienced hands, NP-59 scanning has a sensitivity of 88%. However, this procedure is not widely available, requires careful patient preparation, is very expensive, and rarely detects lesions larger than 1.5 cm. See the image below.
Scintigram obtained by using iodine-131-6β-iodomethylnorcholesterol (NP-59) in a 59-year-old man with hypertension shows fairly intense radionuclide uptake in the right adrenal tumor. At surgery, a Conn tumor was confirmed.
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Scintigram obtained by using iodine-131-6β-iodomethylnorcholesterol (NP-59) in a 59-year-old man with hypertension shows fairly intense radionuclide uptake in the right adrenal tumor. At surgery, a Conn tumor was confirmed.
Magnetic resonance imaging (MRI) - MRI is not more sensitive than CT scanning. See the image below.
Magnetic resonance imaging (MRI) scan in a patient with Conn syndrome showing a left adrenal adenoma.
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Magnetic resonance imaging (MRI) scan in a patient with Conn syndrome showing a left adrenal adenoma.
Other Tests
Postural studies are cumbersome to perform in most office settings and have proven less useful since the recognition of a renin-responsive subtype of adrenal adenoma. They are rarely used in current practice.
Procedures
Because of the difficulties in distinguishing hyperplastic lesions from adenomatous lesions, adrenal venous sampling4 has become the preferred diagnostic approach in patients with equivocal findings after CT scanning.
The adrenal veins are catheterized via a percutaneous femoral venous approach.
Right and left venous catheters should be placed in the ipsilateral adrenal veins to prevent errors in handling the samples.
Blood is obtained from both adrenal veins and the inferior vena cava and is then assayed for aldosterone and cortisol. Cannulation of the right adrenal vein is technically difficult because of the short length of this vessel. The left adrenal vein is longer, allowing for more stable catheter placement.
In order to document placement of the catheters within the adrenal veins, an adrenal-to – vena cava cortisol ratio (post-corticotropin) is obtained and should be greater than 5-10. Because the secretion of aldosterone from either an adenoma or hyperplasia may be pulsatile, samples are obtained under maximum stimulation following cosyntropin (corticotropin) infusion. Several different protocols have been used. In a 1996 article, Doppman and Gill recommended a 250-mcg bolus of corticotropin (Cortrosyn) followed by a corticotropin infusion, with samples collected at baseline and 15 minutes following the infusion.5 An aldosterone-to-cortisol ratio, post-corticotropin, can then be calculated for each sampling site. Most patients with a unilateral source of aldosterone have adrenal-to-adrenal aldosterone-to-cortisol ratios greater than 4. Ratios less than 3 suggest hyperplasia, and values of 3-4 are indeterminate results.
Treatment
Medical Care
In patients with primary hyperaldosteronism, the goal of treatment is to prevent the morbidity and mortality associated with hypertension and hypokalemia. The appropriate treatment depends on the cause (Conn syndrome vs IHA). Although hypertension is frequently cured after unilateral adrenalectomy in patients with Conn syndrome, the mean cure rate is only 19% after unilateral or bilateral adrenalectomy in patients with IHA, in whom treatment mainly is medical.
In the case of APA, medical therapy is used preoperatively to control blood pressure and correct hypokalemia, thus decreasing surgical risk. Medical therapy is administered to patients with persistent hypertension postoperatively, poor surgical candidates, and those who refuse surgery.
A sodium-restricted diet (<80 mEq or <2 g of sodium per d), maintenance of ideal body weight, and regular aerobic exercise contribute substantially to the success of pharmacologic treatment.
Frequently, hypertension and hypokalemia can be controlled with a potassium-sparing agent (first-step agent), such as spironolactone.6 Hypokalemia is promptly corrected, but hypertension may take as long as 4-8 weeks to correct. Potassium supplementation should not be routinely administered with spironolactone because of the potential for the development of hyperkalemia. If hypertension persists despite titration, a second-step agent is added to the treatment.
Second-step agents include thiazides diuretics, ACE inhibitors, calcium channel antagonists, and angiotensin II blockers.7
GRA is treated with physiologic doses of glucocorticoid, which correct the hypertension and hypokalemia.
Surgical Care
Surgery is the main therapy for Conn syndrome. A laparoscopic adrenalectomy is favored, when possible.6,4
In patients with Conn syndrome, the blood pressure response to spironolactone preoperatively is a predictor of the blood pressure response to unilateral adrenalectomy.
Surgical risk can be decreased by correcting the hypokalemia and controlling the blood pressure by administering spironolactone for at least 1-2 weeks, preferably 6 weeks, before surgery.
Hypertension typically does not resolve immediately postoperatively but, rather, over 3-6 months; however, almost all patients have improved control of blood pressure after surgery. Long-term cure rates with unilateral adrenalectomy for Conn syndrome average 69%. A retrospective study of 168 patients with primary hyperaldosteronism who underwent an adrenalectomy found that hypertension was cured or controlled in 77% of patients with a unilateral adenoma and in 68% of patients with hyperaldosteronism but no adenoma.8 Persistent hypertension may be related to resetting of baroreceptors, established hemodynamic changes, structural changes in the blood vessels, or coincidental essential hypertension.
Medication
As mentioned previously, potassium-sparing agents, especially spironolactone, are useful for patients with primary hyperaldosteronism. They act as specific antagonists of aldosterone.
Antihypertensives/diuretics
Treat hypertension, edematous conditions, and hypokalemia.
Spironolactone (Aldactone)
Competes with aldosterone for receptor sites in distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions. May block effects of aldosterone on arteriolar smooth muscles.
DosingInteractionsContraindicationsPrecautionsAdult
100 mg PO qd initially, increase to 400 mg/d prn for control of blood pressure
Pediatric
Not established
DosingInteractionsContraindicationsPrecautionsBlocks testosterone biosynthesis and peripheral androgen action, causing impotence, decreased libido, and gynecomastia; may cause menstrual irregularities in women; high doses increase half-life of digoxin (adjust digoxin dose); avoid concomitant therapy with salicylates because they decrease effectiveness; concomitant therapy with ACE inhibitors or indomethacin has been associated with severe hyperkalemia
DosingInteractionsContraindicationsPrecautionsDocumented hypersensitivity; anuria; renal failure; hyperkalemia
DosingInteractionsContraindicationsPrecautionsPregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Not recommended during pregnancy because may cross placenta; in male fetus, may cause pseudohermaphrodism; not recommended in nursing mothers because of excretion in breast milk; caution in renal and hepatic impairment
Eplerenone (Inspra)
Indicated for hypertension. Selectively blocks aldosterone at mineralocorticoid receptors in epithelial (eg, kidney) and nonepithelial (eg, heart, blood vessels, brain) tissues; thus, decreases blood pressure and sodium reabsorption.
DosingInteractionsContraindicationsPrecautionsAdult
50 mg PO qd; may increase dose after 4 wk, not to exceed 100 mg/d
Miscellaneous
Medicolegal Pitfalls
Failure to perform testing without withdrawal of interfering medications, which can lead to false results
Failure to wait until the diagnosis is confirmed by laboratory testing before obtaining adrenal imaging because the high incidence of adrenal incidentaloma can lead to unnecessary surgery
