Hyperaldosteronism
1. What is hyperaldosteronism?
Hyperaldosteronism is a disorder with a characteristic set of signs and symptoms resulting from excessive effects of aldosterone or a similar mineralocorticoid agent, which typically include:
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Hypertension: usually unresponsive to angiotensin converting-enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or direct renin inhibitors
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Intravascular volume expansion
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Hypokalemia
2. Describe the most common subtypes or causes of hyperaldosteronism.
Hyperaldosteronism can be either primary or secondary. As a result of an autonomously functioning adrenal adenoma, it is called Conn syndrome, after Jerome William Conn (1907 to 1994). More common is bilateral adrenal hyperplasia (sometimes called idiopathic hyperaldosteronism), in which both glands oversecrete aldosterone. Glucocorticoid-remediable hyperaldosteronism results from a chimeric gene on chromosome 8 that crosses the regulatory sequence for corticotropin, 11β-hydroxylase, with the enzyme coding sequences for aldosterone synthase. Hyperaldosteronism from an adrenal carcinoma is rare (∼30 cases worldwide) and usually presents as a large tumor.
Secondary hyperaldosteronism includes obstructive sleep apnea (OSA). OSA is one of the more common causes of resistant hypertension. Renovascular hypertension is another example of secondary hyperaldosteronism causing hypertension.
3. How common is hyperaldosteronism?
The prevalence of hyperaldosteronism depends on where and how one looks for it. Some referral centers report a prevalence of hyperaldosteronism related to sleep apnea at about 20%, similar to the original estimate for aldosterone-secreting adenomas proposed by Conn in 1954. Other population-based studies suggest that such a high prevalence is a result of a lack of specificity of the aldosterone-renin ratio that is often used to screen for the condition. In a consecutive series from the Mayo Clinic, about 10% of community-dwelling hypertensives had an “abnormal” ratio, but no tumors suggestive of adrenal adenomas were detected by computed tomography (CT) scanning. Small (often bilateral) tumors are occasionally seen in patients with bilateral hyperplasia but not with OSA.
4. What is the most appropriate test to screen for hyperaldosteronism?
After total body potassium stores have been repleted, the ratio of plasma aldosterone to renin measured in (optimally, untreated) patients in the seated position at 8 am is the most widely recommended test. A plasma aldosterone/renin activity ratio >20 ng/dL per ng/mL per hour and the plasma aldosterone level >15 ng/dL is a positive screen for primary hyperaldosteronism. Potential confounders of the test are listed in Box 65.1 .
Decrease ARR (higher likelihood of a false-negative test)
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Diuretics
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Angiotensin-converting enzyme inhibitors
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Angiotensin receptor antagonists
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Dihydropyridine calcium antagonists (smaller effect)
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Hypokalemia
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Pregnancy
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Renovascular hypertension
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Hypertensive emergency (formerly, “malignant hypertension”)
Increase ARR (higher likelihood of a false-positive test)
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Beta-adrenergic antagonists
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Alpha-1 adrenergic agonists
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Nonsteroidal antiinflammatory drugs
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High-potassium diet (or “potassium loading”)
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Older age
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Chronic kidney disease
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Pseudohypoaldosteronism, type 2
Changes in dietary sodium and potassium consumption can also affect the ARR, but the magnitude and direction of the changes depend on many other factors.
ARR , Aldosterone-renin ratio.
5. What additional tests may be useful in identifying patients with hyperaldosteronism?
Many different tests have been proposed to distinguish between an aldosterone-producing adenoma and bilateral adrenal hyperplasia, including an assay of blood or urine for aldosterone (and/or other mineralocorticoids) before and after infusion of 2 L of saline, after a high-sodium diet, postural change, either an ACE inhibitor or an ARB, or an assay of serum 11- or 18-oxo-aldosterone. None of these are perfect discriminators, but the updated 2016 Endocrine Society guidelines suggest usually performing one of these confirmatory tests before imaging the adrenals. A CT scan of the abdomen, with thin (5 mm) cuts through the adrenals, is usually selected. If a unilateral hypodense mass >1 cm is found, particularly in a patient younger than 40 years, a surgeon is often consulted for laparoscopic removal (see later). Some physicians prefer a magnetic resonance imaging (MRI) scan, again with thin cuts through the adrenals, but this is less sensitive (because of the higher spatial resolution of CT scans).
Although challenged by the results of a randomized trial, adrenal venous sampling is recommended by the updated 2016 Endocrine Society guidelines for all surgical candidates over age 40 years, because CT scans have only 78% sensitivity and 75% specificity for unilateral adrenal adenomas. The procedure is complex and is typically done only at large, experienced centers, but it can help avoid removing an enlarged but nonfunctioning adrenal gland.
Glucocorticoid-remediable hyperaldosteronism can be detected by genetic testing of leukocyte DNA.
6. List of treatments for hyperaldosteronism.
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Conn adenoma: Unilateral adrenalectomy, now often by laparoscopic surgery.
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Bilateral adrenal hyperplasia: Chronic therapy with an aldosterone antagonist. Spironolactone had superior efficacy in lowering blood pressure compared to eplerenone in one international clinical trial, but the latter has fewer adverse effects.
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For hyperaldosteronism related to sleep apnea: Spironolactone (or eplerenone) is effective in the vast majority of cases; continuous positive airway pressure is recommended for the signs and symptoms of sleep apnea.
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For glucocorticoid-suppressible hyperaldosteronism: Low-dose glucocorticoid.
7. What are the short- and long-term challenges after surgery?
Strict attention to eukalemia is important, particularly in the first few days after the operation. Most patients receive normal saline, without potassium, during the immediate postoperative period. A day after the procedure, a plasma aldosterone level is measured, potassium supplements and aldosterone antagonists are discontinued, and the patient is counseled to consume more dietary sodium than usual, to minimize the risk of hyperkalemia while the contralateral adrenal gland recovers function. Hyperkalemia is more common in patients with chronic kidney disease (albuminuria, increased serum creatinine, or both). Long-term resolution of hypokalemia is common, but about 50% of patients remain hypertensive (and require antihypertensive medications), even after a successful operation. Persistent hypertension is more common in older patients and those with a longer duration of hypertension before the diagnosis was made.
Cushing syndrome and congenital adrenal hyperplasia
8. What is cushing syndrome?
Cushing syndrome is a characteristic set of signs and symptoms resulting from excessive effects of cortisol, initially attributed to a basophilic pituitary adenoma (Cushing disease) by Harvey Cushing in 1932.
9. Describe the most common clinical features of cushing syndrome.
Cushing syndrome is characterized by progressive physical changes, which are often best appreciated in serial photographs:
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Central (truncal) obesity
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Moon facies
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Dorsocervical fat pad (buffalo hump)
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Purple abdominal striae may be the most specific physical sign if >2.5 cm wide
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Plethora
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Ecchymoses
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Hypertrichosis
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Muscle weakness and atrophy, which are typically noted when climbing stairs or arising from a chair.
Other features of Cushing syndrome include emotional and cognitive changes, menstrual irregularity, glucose intolerance, and hypertension. Growth restriction is universal in children with Cushing syndrome.
10. How common is hypertension in cushing syndrome?
About 80% of patients with Cushing syndrome have hypertension.
11. Explain the mechanism of hypertension in patients with cushing syndrome.
Hypertension in patients with hypercortisolism is multifactorial:
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Excessive cortisol exposure increases systemic vascular resistance by:
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Enhancing the effects of catecholamines and angiotensin II
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Suppressing synthesis of endogenous vasodilatory agents, including nitric oxide and prostaglandins
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Cortisol also stimulates sodium reabsorption in the distal nephron, and to a lesser extent in the proximal nephron
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Synthesis of certain mineralocorticoids are increased in corticotropin (formerly adrenocorticotropic hormone [ACTH])-dependent Cushing syndrome
12. List the most common causes of cushing syndrome.
Corticotropin-dependent:
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Pituitary microadenoma (∼68% of endogenous hypercortisolemia)
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Ectopic corticotropin production (∼12%, from other tumors, typically small-cell lung cancer)
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Ectopic corticotropin-releasing hormone secretion (<1%)
Corticotropin-independent:
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Exogenous glucocorticoid administration (iatrogenic causes are the most common in the United States)
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Adrenal adenoma (∼10%)
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Adrenal adenocarcinoma (∼8%)
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Primary pigmented nodular adrenal hyperplasia (<1%)
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McCune-Albright syndrome (<1%)
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Macronodular adrenal disease (<1%)
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Hyperfunction of adrenal rest tissue (<1%)
13. What is the difference between cushing syndrome and cushing disease?
Cushing syndrome includes all patients with hypercortisolism. Cushing disease refers to that subset of patients with Cushing syndrome due to a corticotropin-secreting pituitary microadenoma.
14. What are the best tests to screen for cushing syndrome?
Plasma cortisol levels >15 μg/dL in the afternoon or evening (in an unstressed patient) are suggestive of hypercortisolism; British endocrinologists prefer a midnight cortisol level, which can be measured noninvasively in saliva.
Urinary free cortisol values >100 μg/day are abnormal, and values >400 μg/day (more than four times the upper limit of the reference range) are suggestive of Cushing syndrome.
Many clinicians use the overnight dexamethasone suppression test (which is more convenient than the classical “low-dose” test) as a screen for Cushing syndrome. Morning (8 am ) plasma cortisol levels >5 μg/dL are suggestive of Cushing syndrome; patients with levels >1.8 μg/dL are candidates for further testing. Table 65.1 summarizes the usual test results for patients with Cushing syndrome.
| PATHOLOGY | PLASMA/URINARY CORTISOL LEVELS | CORTICOTROPIN LEVEL | CORTISOL LEVEL AFTER LOW-DOSE DEXAMETHASONE SUPPRESSION TEST | CORTISOL LEVEL AFTER HIGH-DOSE DEXAMETHASONE SUPPRESSION TEST |
|---|---|---|---|---|
| Pituitary microadenoma (Cushing disease) | Elevated | Elevated | Not suppressed a | Suppressed b |
| Ectopic source of corticotropin | Elevated | Elevated | Not suppressed | Not suppressed |
| Ectopic source of corticotropin-releasing hormone | Elevated | Elevated | Not suppressed | Variable, but usually suppressed |
| Adrenal tumor or hyperplasia | Elevated | Suppressed | Not suppressed | Not suppressed |
| Pseudo-Cushing syndrome | Normal or slightly elevated, often with deranged circadian variation | Variable, but often suppressed | Usually suppressed; formerly used as an “objective” indicator of severity of depression | Suppressed |
15. What additional tests may be useful in identifying the cause of cushing syndrome?
Classically, the high-dose dexamethasone suppression test (2 mg every 6 hours for eight doses) suppresses the production of cortisol by >90% (and its urinary metabolites) in patients with Cushing disease, because pituitary microadenomas remain sensitive to high levels or activity of circulating corticosteroids. A more convenient “high-dose” test measures plasma cortisol at bedtime, followed by one 8 mg dose of dexamethasone and another cortisol level test 8 hours later; “suppression” is diagnosed if the cortisol level drops by 50% compared to baseline. This test does not distinguish between Cushing disease and the far less common ectopic corticotropin secretion, so a chest x-ray is usually scrutinized for evidence of a tumor that is secreting corticotropin.
Head and abdominal CT scans may identify a pituitary or adrenal tumor; MRI is slightly less sensitive for adrenal tumors than a CT with thin cuts (5 mm) through the adrenals. Sometimes a chest x-ray and/or a chest CT is done because the most common source of ectopic corticotropin secretion is lung cancer, usually small cell.
16. List of treatment options for the various etiologies of cushing syndrome.
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Pituitary adenoma resection for Cushing disease
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Adrenalectomy, particularly unilateral adrenalectomy, but occasionally bilateral adrenalectomy if the pituitary tumor cannot be resected
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Resection of the corticotropin-secreting tumor
17. Is there a role for medical therapy for cushing syndrome?
Agents that modulate corticotropin release (cyproheptadine, bromocriptine, valproic acid) or inhibit cortisol synthesis and/or production (mitotane, trilostane, ketoconazole, aminoglutethimide, and metyrapone) may be useful preoperatively or for patients who are not surgical candidates.
18. Should all patients with hypertension who are obese be evaluated for cushing syndrome?
No. Testing should be considered for patients with hypertension who present with the characteristic clinical features of Cushing syndrome.
19. Define congenital adrenal hyperplasia (CAH).
CAH is a diverse family of autosomal-recessive disorders characterized by deficient function of one of the enzymes necessary for cortisol synthesis ( Fig. 65.1 ).
