DISEASES OF THE ADRENAL CORTEX

Hypercortisolism

The term hypercortisolism refers to the physiologic state of glucocorticoid excess. This disorder is rare,

with an estimated incidence of 10 per million population. The most common cause of hypercortisolism

is the administration of exogenous steroids as immunosuppressive therapy for inflammatory disorders or

after organ transplantation. Endogenous hypercortisolism, or Cushing syndrome, in all cases is caused

by increased adrenal production of cortisol, which may be ACTH dependent (ACTH elevated) or

independent (ACTH suppressed). Some patients with major depression or chronic alcoholism have

abnormally high cortisol secretion and may appear to have clinical and biochemical features of Cushing

syndrome. Pseudo-Cushing syndrome responds to treatment of the underlying disorder.

3 Cushing syndrome is ACTH dependent in 80% to 90% of cases. Such ACTH-dependent

hypercortisolism is most often (80% to 90% of cases) caused by an ACTH-secreting pituitary adenoma

(termed Cushing disease). Ectopic ACTH-producing nonendocrine tumors (mostly non–small-cell lung

cancer and bronchial carcinoids) represent 10% to 20% of cases of ACTH-dependent Cushing syndrome.

All causes of ACTH-dependent Cushing syndrome involve bilateral adrenal hyperplasia in response to

ACTH stimulation.

Of patients with endogenous Cushing syndrome, 10% to 25% have ACTH-independent disease caused

by a primary adrenal cause. A solitary adrenal adenoma is present in 80% to 90% of these patients and

is often associated with atrophy of both adjacent and contralateral adrenocortical tissue. Nodular

cortical hyperplasia of both glands causes the remaining cases of primary adrenal Cushing syndrome.

Although nodular hyperplasia represents a diffuse process, one or more distinct nodules may simulate

adenomas. Rarely tumors secrete CRH ectopically, leading to ACTH-independent (though ACTH is

elevated) Cushing syndrome with secondary adrenal hypertrophy.

Signs and Symptoms

Clinical features of cortisol excess are listed in Table 77-1. Truncal obesity (orange on toothpicks),

accumulation of fat around the head and neck (moon facies and buffalo hump), and muscle wasting are

present in most patients. Patients often have purple striae and purpura on the abdomen and extremities.

Hirsutism may be present in women. High blood pressure is common and is usually moderate, although

malignant hypertension has been observed. Bone pain and muscle weakness (caused by proximal muscle

wasting and hypokalemia) are also common. Osteoporosis is common and pathologic fractures are

observed in advanced cases. Neurologic symptoms, including headache, emotional lability, depression,

and even psychosis may be observed. Glucose intolerance is common but can often be managed by

alterations in diet alone. The serum potassium level may be low secondary to the weak

mineralocorticoid properties of cortisol. Autonomous glucocorticoid production without specific signs

and symptoms of Cushing syndrome is termed subclinical Cushing syndrome. This condition is being

diagnosed with increased frequency because of the detection of adrenal incidentalomas by routine CT. A

substantial percentage of incidentalomas are hormonally active, with 5% to 20% of the tumors

producing glucocorticoids. The estimated prevalence of subclinical hypercortisolism is 79 cases per

100,000 persons, substantially higher than classic Cushing syndrome. Depending on the amounts of

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glucocorticoids secreted by the tumor, the clinical spectrum ranges from slightly attenuated diurnal

cortisol rhythm to atrophy of the contralateral adrenal gland. Patients with subclinical Cushing

syndrome lack the classical stigmata of hypercortisolism but have a high prevalence of obesity,

hypertension, and type 2 diabetes.

Diagnosis

The investigation of suspected Cushing syndrome should answer two questions: (a) Does the patient

have hypercortisolism? (b) If the answer is yes, then what is the cause? It is worthwhile to emphasize

that the diagnosis of Cushing syndrome is biochemical. Radiologic investigations should not be

undertaken until Cushing syndrome has been confirmed and its likely etiology characterized

biochemically.

Hypercortisolism insensitive to suppression by administration of exogenous glucocorticoid is the sine

qua non of Cushing syndrome. The low-dose dexamethasone suppression test is the best test in patients

with suspected Cushing syndrome. For this test, 1 mg of dexamethasone is administered orally at 11 PM

and plasma cortisol is obtained at 8 AM the following day. Normal individuals suppress cortisol to below

5 μg/dL. Patients with Cushing syndrome fail to suppress below 5 μg/dL. False-positive test results

occur in 10% to 15% of cases with the overnight test and occur especially in patients with obesity or

alcoholism or in those taking estrogens or phenytoin. Measurement of free cortisol (not metabolites) in

three consecutive 24-hour collections of urine is also a good screening test for Cushing syndrome.

Collections should include concurrent creatinine measurement to evaluate the completeness of the

collection. A 24-hour urinary-free cortisol level greater than 100 μg is diagnostic of Cushing syndrome.

This test may be less sensitive than the low-dose dexamethasone suppression test in mild

hypercortisolism. Plasma cortisol levels can normally vary considerably during a 24-hour period, so a

single random plasma cortisol level is not helpful in establishing a diagnosis of Cushing syndrome.

Once the presence of hypercortisolism is established, the next task is to determine ACTH-dependent

(pituitary or ectopic source) from ACTH-independent (primary adrenal) causes. Measurement of basal

ACTH by immunoradiometric assay is the best test to make this distinction. Plasma ACTH levels are

normally between 10 and 100 pg. Suppression of the absolute level of ACTH below 5 pg/mL is nearly

diagnostic of adrenocortical neoplasms, which secrete high levels of cortisol and inhibit ACTH release

by the pituitary. Patients with pituitary neoplasms and secondary bilateral adrenocortical hyperplasia

have ACTH levels that may range from the upper limits of normal (15 pg/mL) to 500 pg/mL. The

highest plasma levels of ACTH (more than 1,000 pg/mL) are in patients with ACTH-producing

nonendocrine tumors, such as non–small-cell lung cancer.

Although 80% to 90% of patients with ACTH-dependent Cushing syndrome have Cushing disease, a

high dose dexamethasone suppression test may be required to exclude ectopic ACTH syndrome.

Hypercortisolism caused by ACTH-secreting pituitary adenomas is suppressed at least partially by high

dexamethasone, whereas hypercortisolism caused by adrenal tumors and ectopic ACTH-producing

tumors is not suppressed. For this test 2 mg dexamethasone is administered orally every 6 hours for 2

days, and a 24-hour urine collection for free cortisol is taken during the second day. About 90% of

patients with pituitary source Cushing disease have a 50% reduction in urine-free cortisol. The

specificity of the test can be improved to 100% for diagnosing pituitary disease if more than 90%

suppression in urinary-free cortisol is used.

Algorithm 77-1. Diagnosis of hypercortisolism. ACTH, adrenocorticotropic hormone; IRMA, immunoradiometric assay; CT,

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computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography.

Biochemical testing of suspected Cushing syndrome is followed by radiologic studies. Pituitary

adenomas are best imaged with gadolinium-enhanced magnetic resonance imaging (MRI) of the sella

turcica, which has a sensitivity approaching 100%, although small pituitary microadenomas may be

missed. Patients with ACTH-independent Cushing syndrome require thin-section CT or MRI of the

adrenal, which identifies adrenal abnormalities with more than 95% sensitivity. CT or MRI of the chest

may identify a source of ectopic ACTH and should be undertaken in patients with elevated ACTH and

hypercortisolism that cannot be suppressed by high-dose dexamethasone.

Despite the accuracy of biochemical testing and radiographic localization, a pituitary versus ectopic

source of ACTH sometimes cannot be determined. Bilateral inferior petrosal sinus sampling is the best

test to settle this issue. Simultaneous bilateral petrosal sinus and peripheral blood samples are obtained

before and after peripheral intravenous injection of 1 μg/kg CRH. An inferior petrosal sinus to

peripheral plasma ACTH ratio of 2.0 at basal stimulated or of 3.0 after CRH administration is 100%

sensitive and specific for pituitary adenoma. Comparison of right and left inferior petrosal sinus ratios

may also lateralize the adenoma.

The laboratory approach to the diagnosis of Cushing syndrome is summarized in Algorithm 77-1. A

careful history and physical examination form the basis for suspecting this condition. A low-dose

dexamethasone suppression test and/or urinary-free cortisol measurement provide initial evidence for

the diagnosis. Plasma ACTH determination and the high-dose dexamethasone suppression test are then

used to identify the underlying cause of excess cortisol production by the adrenal cortex. Imaging

studies support the cause of Cushing syndrome suggested by biochemical testing and localize the site for

subsequent treatment.

Treatment

ACTH-dependent Cushing syndrome is best treated by removing the source of ACTH excess. In the case

of Cushing disease, transsphenoidal resection of the pituitary microadenoma is successful in 80% or

more of cases. If a microadenoma is not found, then hemihypophysectomy may be performed with the

understanding that fertility may be impaired. Pituitary irradiation is a good treatment option when

fertility is desired, when a tumor is not found or is unresectable, or cure is not achieved by

transsphenoidal resection of a tumor. Debulking of unresectable primary lesions or recurrences with or

without bilateral adrenalectomy may provide palliation in some patients. Treatment of ectopic ACTH

syndrome involves removal of the primary lesion. Medical adrenalectomy with metyrapone,

aminoglutethimide, and mitotane has been used to suppress production of corticosteroid in inoperable

cases for both pituitary and ectopic sources of ACTH. Bilateral adrenalectomy is a good option for

patients intolerant of mitotane.

ACTH-independent Cushing syndrome is best treated by removal of the adrenal tumor and affected

gland. Small lesions, less than 6 cm in diameter, may be resected laparoscopically. Lesions larger than 6

cm or those suspected of being carcinoma require an anterior open approach. Resection of cortisolproducing benign adrenal adenomas is curative and prognosis is good following resection. Cortisolproducing adrenocortical carcinomas recur frequently following adrenalectomy, heralded by the

reemergence of hypercortisolism. Micronodular pigmented hyperplasia and macronodular adrenal

hyperplasia may involve both adrenal glands. These conditions are cured only by bilateral

adrenalectomy. Medical adrenalectomy with mitotane or agents interfering with cortisol production is

not currently recommended.

Whether patients with subclinical Cushing syndrome should undergo adrenalectomy is unclear.

Several small series have demonstrated weight loss, an improvement in hypertension and glucose

control following adrenalectomy for subclinical Cushing syndrome. Furthermore, patients with

subclinical Cushing syndrome may progress to overt Cushing syndrome as frequently as 12.5% at 1

year. Accordingly, adrenalectomy for subclinical Cushing syndrome may be beneficial and is reasonable

in young patients, patients with suppressed plasma ACTH, and patients with a recent weight gain,

substantial obesity, arterial hypertension, diabetes mellitus, and osteopenia. Truly asymptomatic

patients with normal plasma ACTH concentrations and the elderly or unfit may be observed.

Demonstration of the benefits of surgery versus conservative treatment in patients with subclinical

Cushing syndrome will require a randomized prospective trial.

All patients who undergo adrenalectomy for Cushing syndrome require perioperative and

postoperative glucocorticoid replacement, since the contralateral gland is suppressed. Replacement

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therapy with hydrocortisone, 12 mg/m2 per day, may be required as long as 2 years postoperatively.

Adequacy of replacement is monitored clinically. The duration of replacement therapy is guided by

normalization of the ACTH stimulation test.

Hyperaldosteronism

Hyperaldosteronism is a syndrome of hypertension and hypokalemia caused by autonomous adrenal

secretion of the mineralocorticoid aldosterone. Hyperaldosteronism may be primary, as a result of an

adrenal neoplasm with suppressed plasma renin, or may be secondary, as a result of elevated plasma

renin. Primary hyperaldosteronism is twice as common in women as in men, and it usually occurs

between the ages of 30 and 50 years. Screening of hypertensive patients with plasma aldosterone and

plasma renin activity (PRA) has suggested that primary hyperaldosteronism may be the underlying

cause of up to 15% of cases of essential hypertension.

Algorithm 77-2. Diagnosis and management of hyperaldosteronism. PRA, plasma renin activity; PAC, plasma aldosterone

concentration; CT, computed tomography; AVS, bilateral adrenal venous sampling.

4 An aldosterone-producing adrenal adenoma (Conn syndrome) is the source of primary

hyperaldosteronism in 60% to 70% of cases. Idiopathic bilateral adrenal hyperplasia causes the

remaining cases of primary hyperaldosteronism. Adrenocortical carcinoma is a rare cause of primary

hyperaldosteronism. Autosomal dominant glucocorticoid-suppressible hyperaldosteronism is a rare cause

of hyperaldosteronism resulting from the fusion of the ACTH-responsive 11-beta hydroxylase gene

promoter to the aldosterone synthase gene in cells of the adrenal cortex.

Secondary hyperaldosteronism is a physiologic response of the renin–angiotensin system to decreased

renal perfusion due to renal artery stenosis, cirrhosis, congestive heart failure, and normal pregnancy.

The adrenal cortex functions normally and secretes aldosterone in response to the elevated plasma renin

and angiotensin caused by these conditions. Secondary hyperaldosteronism responds to treatment of the

underlying cause.

Signs and Symptoms

Clinical manifestations of primary hyperaldosteronism are attributable to hypersecretion of aldosterone

by the adrenal gland (Table 77-2). Aldosterone-mediated retention of sodium and excretion of potassium

and hydrogen ion by the kidney causes moderate diastolic hypertension. Edema is absent. Hypokalemia

occurs spontaneously in 80% to 90% of patients with primary hyperaldosteronism but may be normal.

Hypokalemia is easily provocable in the remaining patients. Potassium depletion frequently causes

symptoms of muscle weakness and fatigue, polyuria and polydipsia, as well as impaired insulin

secretion and fasting hyperglycemia. Primary hyperaldosteronism should be suspected in hypertensive

patients with spontaneous hypokalemia (serum concentration <3.5 mEq/L), moderate hypokalemia

(serum potassium concentration <3.0) during diuretic therapy despite concomitant use of oral

potassium or potassium-sparing diuretics, or refractory hypertension without explanation.

Diagnosis

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The clinical hallmarks of primary hyperaldosteronism are (a) diastolic hypertension without edema; (b)

suppression of plasma renin in the face of volume depletion; and (c) hypersecretion of aldosterone that

fails to suppress with intravascular volume expansion. Diagnostic evaluation must establish primary

hyperaldosteronism, discern surgically correctable adrenal adenoma from medically treatable idiopathic

hyperplasia, and localize an adrenal tumor (Algorithm 77-2).

Demonstration of an elevated plasma aldosterone concentration (PAC) in the setting of suppressed

PRA is the best test to establish primary hyperaldosteronism. The ratio in normal subjects and patients

with essential hypertension is 4:10 compared with more than 30 in most patients with primary

hyperaldosteronism. A PAC of greater than 20 ng/dL and a PAC/PRA ratio of greater than 30 are

diagnostic for aldosteronoma with almost 90% sensitivity. A serum potassium value less than 3.5 mEq/L

and urinary potassium excretion greater than 30 mEq/day also support a diagnosis of primary

hyperaldosteronism. Before biochemical evaluation, patients need to be potassium repleted and have an

adequate sodium intake. Medications including ACE inhibitors and spironolactone should be withheld

for at least 4 weeks before study.

An elevated PAC/PRA ratio alone does not establish the diagnosis of primary hyperaldosteronism,

which must be confirmed by demonstrating inappropriate aldosterone secretion with salt loading. This

involves a 24-hour urine collection for sodium and aldosterone after 3 days of a high-sodium diet. The

24-hour urinary excretion of aldosterone should be greater than 14 μg per 24 hours after a high-salt diet

for patients with primary hyperaldosteronism. An intravenous saline infusion test or captopril challenge

test is also a reliable method to confirm primary hyperaldosteronism. These tests are not usually

required.

After the diagnosis of primary hyperaldosteronism is made, distinction must be made between an

aldosteronoma and idiopathic adrenal hyperplasia. The first test measures aldosterone in blood collected

at 8 AM from a patient who has been supine overnight. Laboratory studies are repeated 4 hours later

after the patient has been upright. Aldosterone secretion in patients with an aldosteronoma is unaffected

by postural changes (<20 ng/dL), whereas, in patients with idiopathic adrenal hyperplasia, plasma

aldosterone levels are elevated 33% (>20 ng/dL) or more by postural changes.

Figure 77-6. Computed tomography scan of right adrenal aldosteronoma. Short arrow shows aldosteronoma. Long arrow shows

normal contralateral adrenal gland.

High-resolution adrenal computed tomography (CT) is the best test for localization of an adrenal

tumor (Fig. 77-6). CT will detect an aldosterone-producing adenoma in 90% of cases overall. The

presence of a unilateral adenoma greater than 1 cm on CT and supportive biochemical evidence of an

aldosteronoma are generally all that is needed to make the diagnosis in most patients under 40 years of

age. MRI is less effective and more costly but may be useful during pregnancy or in situations in which

intravenous contrast medium injection is undesirable. The test of 6-[beta](131-I)-iodo-methyl-19-

norcholesterol (NP-59) scintigraphy identifies functional tumors and discriminates aldosteronoma from

adrenal hyperplasia with an overall accuracy of approximately 75%, but requires a tumor of sufficient

size (>1 cm) for imaging to be dependable.

Adrenal vein sampling to lateralize the source of aldosterone production is useful in patients with

hyperaldosteronism when there is no adrenal abnormality on CT or MRI or when both adrenal glands

are abnormal but asymmetric. Further, patients older than 40 years, in whom the possibility of a

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