The primary precursor of adrenal steroid hormones is cholesterol, which is stored in the adrenal cortex. Multiple enzymatic steps produce the steroid hormones along three pathways, producing mineralocorticoids, glucocorticoids, and androgens.

ADRENAL INSUFFICIENCY

Less-common causes of adrenal cortical loss include metastatic disease, although adrenal failure is rare. This can occur in up to 40% to 60% of women with breast or lung cancer, 30% of those with malignant melanoma, and 14% to 20% of patients with gastric or colon cancer. Other infiltrating diseases, such as amyloidosis, sarcoidosis, or hemochromatosis, can lead to loss of adrenal cortical function. Familial disorders, including X-linked or autosomal recessive metabolic disorders, adrenoleukodystrophy, and the milder adrenomyeloneuropathy, all cause adrenal deficiency; these disorders primarily affect 1 in 20,000 males (Moser, Raymond, & Dubey, 2005).

History and Physical Examination

In adrenal hemorrhage, there is a precipitous drop in the hematocrit while the number of white blood cells increases (leukocytosis; Baker et al., 2012). Hyponatremia and hyperkalemia with renal insufficiency (azotemia) and acidosis are also seen.

The lack of response of the adrenal gland to ACTH stimulation may help confirm the diagnosis of adrenal insufficiency. Random cortisol levels may not distinguish patients with mild disease from the normal population, but morning cortisol levels >25 mcg/dL (>525 nmol/L) are likely to indicate normal function, whereas patients with 8 to 9 a.m. cortisol levels <4 mcg/dL (83 nmol/L) probably have adrenal insufficiency. The ACTH stimulation test can be done at any time and consists of giving 250 mcg (85 nmL, or 40 international units) of synthetic ACTH (cosyntropin) intravenously or intramuscularly. To differentiate primary from secondary disease, an ACTH level is drawn 30 minutes before the synthetic ACTH is given and 60 minutes after the injection; the minimum value is 18 to 20 mcg/dL or 500 to 550 nmol/L (before or after the injection). Measurement of ACTH in the basal sample will be high in primary disease (>100 pg/mL or 22 pmol/L) and low in secondary disease. Alternatively, serum aldosterone could be measured; if low, it is indicative of primary disease, whereas its level is normal in secondary disease (Deutschbein, Unger, Mann, & Petersenn, 2009).

IMAGING STUDIES

In patients with primary adrenal insufficiency from autoimmune disease, imaging of the adrenal glands is not necessary. In other cases, CT of the adrenal glands should be done to diagnose fungal disease or cancer. In patients with secondary disease from a pituitary or hypothalamic process, MRI of the pituitary and hypothalamic regions is done.

Treatment Options, Expected Outcomes, and Comprehensive Management

The usual replacement is cortisone, 12 to 15 mg/m²/d, usually given as 25 mg in the morning and 12.5 mg in the evening to try to mimic the natural circadian rhythm of higher steroid production in the morning (Nieman, 2013). If other steroids are used, dosages are adjusted according to the relative potency of the drug. For example, prednisone is about four times as potent as hydrocortisone, so replacement is given as 5 mg in the morning and 2.5 mg in the evening. Because steroids can cause gastritis, weight gain, and osteoporosis, the goal is to give the lowest dosage that relieves symptoms; this can be as low as 15 to 20 mg/d of hydrocortisone. The steroid replacement dose may be adjusted based on 24-hour measurements of urinary cortisol. Mineralocorticoids are necessary in 75% of patients with primary adrenal insufficiency to prevent sodium loss, intravascular volume depletion, and hyperkalemia; the dosage is usually 50 to 200 mcg 9-alpha-fludrocortisol (Florinef) given each morning with a liberal-salt diet. This aldosterone substitute can be adjusted by measuring blood pressure, potassium, and plasma renin activity (PRA), which should be in the upper end of the normal range (Fitzgerald, 2008).

Teaching and Self-Care

Concern about causing iatrogenic alterations in the pituitary–adrenal axis is widespread because of the common use of glucocorticoids to treat chronic diseases such as arthritis, inflammatory bowel disease, asthma, and emphysema.

      CLINICAL WARNING:

The degree of suppression of the adrenal axis depends on many factors, such as the type of steroid used, the dosage, and the duration of treatment. Nonetheless, many studies show that suppression is not predictable in individual patients, and thus random cortisol levels are not helpful. Patients taking 20 mg or more of prednisone (or its equivalent) for more than 5 days should be suspected of having adrenal suppression, and thus are at risk of adrenal crisis if the medication is not appropriately weaned. Some patients have symptoms of adrenal insufficiency with normal cortisol and ACTH levels, probably from a sudden elevation in prostaglandin levels after steroid disuse (steroid withdrawal syndrome).

Alternate-day therapy is an approach used by many providers to minimize adrenal axis suppression and decrease side effects from glucocorticoids while sustaining therapeutic effects. This use of a short-acting steroid (prednisone or methylprednisolone) every 48 hours should be the regimen of choice in patients facing more than a few weeks of glucocorticoid therapy for conditions other than adrenal insufficiency. Those lacking cortisol or ACTH secretion must take replacement daily.

Because steroid-related gastritis can be a problem, patients should be encouraged to avoid smoking and the use of aspirin and ibuprofen and to limit caffeine and alcohol intake. They should be advised to take their steroid with food. Some patients may find that eating small, frequent meals helps their tolerance of steroid medication.

Self-care for bone loss and osteoporosis is covered in another chapter.

      CLINICAL WARNING:

      CLINICAL WARNING:

When a patient with known adrenal insufficiency must undergo emergency surgery, steroid coverage is increased and is given intravenously until oral medication can be reliably taken.

If patients have a history of steroid use, and in whom the length of steroid treatment, time since last use, or the dosage that was given is not clearly known, the safest and most practical clinical solution is to assume that they may be adrenal-insufficient.

      CLINICAL WARNING:

Additional Resources for Patients

Fatigue, weakness, irritability, polyuria, polydipsia, and increased frequency of skin and urinary tract infections from hyperglycemia also are common complaints. Altered protein metabolism can lead to easy bruising and striae wider than 1 cm on the abdomen or proximal extremities. Oligomenorrhea or amenorrhea occurs in premenopausal women; men report decreased libido (Toogood & Stewart, 2008). Depression and insomnia often occur; major depression is found in as many as 66% to 75% of patients.

The typical cushingoid appearance is that of a patient with a round face (moon facies) with plethora (telangiectasias), fat pads that bulge above the supraclavicular fossae, and central obesity with spindle-like extremities. An increased prominence of the dorsal fat pad (buffalo hump) is less specific for Cushing’s syndrome and can be found in patients with weight gain from any cause. There may be increased facial hair, thinning of the skin with petechiae and ecchymosis, and increased pigmentation of the skin, especially in the groin and palmar creases if the Cushing’s syndrome is ACTH dependent. There is proximal muscle wasting from protein catabolism, so the patient has difficulty rising from the seated position. There can also be osteoporosis or frank fractures with minimal trauma.

Pseudo-Cushing’s syndrome is a diagnosis given to the disorder in which patients appear to have the physical signs of Cushing’s syndrome, but the excess glucocorticoid is from secondary causes, such as alcoholism or depression. Patients with alcoholism have hormonal abnormalities that resolve with abstinence. Their hormonal abnormalities are probably caused by increased CRH or impaired hepatic metabolism of cortisol. Major depression can also lead to abnormally regulated cortisol metabolism, although hypersecretion of cortisol is minimal. The hormonal defect disappears on remission of the depression.

DIAGNOSTIC STUDIES

Laboratory Findings • Single cortisol values are not of value in diagnosing Cushing’s syndrome. There is, nonetheless, a loss of the usual diurnal variation in cortisol secretion and evening cortisol levels are equal to or higher than morning values. In a patient with the signs of Cushing’s syndrome, low cortisol values may indicate the previously unsuspected use of exogenous steroids.

Screening tests for Cushing’s syndrome involve either the collection of two or three 24-hour urine samples for free cortisol measurement, or the overnight dexamethasone suppression test, because ACTH secretion is episodic in Cushing’s syndrome. To verify the completeness of a 24-hour urine collection, urine creatinine is also measured in the sample, as its level should not vary by more than 10%. Both tests can have false-negative and false-positive results, but a morning serum cortisol >5 mcg/dL after an 11 p.m. dose of 1 mg dexamethasone or a urine-free cortisol value >80 mcg/dL warrants referral for further investigation. Stress can lead to false-positive results. Testing is best done in the outpatient setting.

The ideal time to screen a patient for Cushing’s syndrome is between midnight and 2 a.m., when cortisol and ACTH levels are usually low because of circadian rhythms. For patient convenience, this can be done after 4 p.m., and an ACTH level >15 pg/mL (>3.3 pmol/L) in the face of a cortisol level >15 mcg/dL (>415 nmol/L) suggests ACTH-dependent Cushing’s, either Cushing’s disease or ectopic ACTH syndrome. If ACTH levels are under 5 pg/mL (1.1 pmol/L) with elevated cortisol levels, a primary adrenal lesion may be present.

Pseudo-Cushing’s syndrome can be differentiated from Cushing’s syndrome by checking evening cortisol levels. Cortisol concentrations in the blood have a diurnal rhythm, high in the morning and low between 10 p.m. and 2 a.m. This evening nadir is preserved in pseudo-Cushing’s syndrome and not in Cushing’s syndrome, so patients with the fomer should demonstrate a low midnight cortisol value (<5 mcg/dL or 138 nmol/L).

IMAGING STUDIES

Before the advent of MRI, pituitary tumors were identified in <50% of those with Cushing’s disease, because Cushing’s disease is often caused by a microadenoma (a lesion <1 cm). Now, with MRI scanning, pituitary tumors can be identified in up to 75% of those with Cushing’s disease. In some patients, there are signs that the defect originates in the hypothalamus rather than in the pituitary.

Patients with adrenal adenomas have an equal chance of having benign or malignant tumors. MRI imaging, although it is more expensive than CT, can occasionally differentiate benign from malignant masses. With the advent of better CT and MRI scanners, small adrenal lesions (<0.5 cm) are being identified that are nonfunctional; these are called adrenal incidentalomas. Seventy percent to 94% of adrenal masses found incidentally are nonsecretory and benign adenomas (Musella et al., 2013). Minimally invasive or laparoscopic adrenalectomy is now the procedure of choice for benign appearing adrenal tumors ≤6 cm in diameter and weighing <100 g (Conzo et al., 2013). A cancerous lesion is suspected if the tumor is >6 cm.

If no pituitary tumor is seen on MRI and the patient has non-suppressible cortisol secretion, bilateral inferior petrosal vein catheterization and sampling for ACTH during stimulation with CRH can differentiate pituitary from ectopic ACTH-dependent disease. This catheterization procedure is expensive and invasive and can produce dire complications, including brainstem damage; thus, it cannot be recommended as a routine procedure.

      CLINICAL WARNING:

Treatment Options, Expected Outcomes, and Comprehensive Management

SURGICAL TREATMENT

The treatment of Cushing’s syndrome depends on the cause. If Cushing’s disease is found, the pituitary adenoma should be removed by transsphenoidal surgery. The surgery is curative in 60% to 90% of cases.

For larger tumors (macroadenomas), total hypophysectomy is required. If the symptoms of Cushing’s syndrome are very pronounced, bilateral adrenalectomy may be preferred, as this stops the organ damage from hyperglycemia, hypertension, and protein catabolism. In up to 25% of patients treated in this fashion, there is a risk of developing Nelson’s syndrome (a state created by the lack of feedback of exogenous steroid replacement on the pituitary tissue; Barber et al., 2010), because removal of the adrenal glands allows pituitary secretion of ACTH to increase. This is more likely to occur if the original pituitary lesion was an adenoma rather than hyperplasia, and if there was a high level of pretreatment urinary cortisol.

RADIATION THERAPY

Pituitary irradiation can be used, although the cure rate is not high. Relapse of Cushing’s syndrome in adults is less likely when unsuccessful pituitary surgery is followed by radiation.

PHARMACOTHERAPY

Teaching and Self-Care

Patients with obesity often present to the primary care provider for evaluation of pituitary or adrenal function to determine if a hormonal imbalance has led to difficulty in losing weight. The patient may know a friend or relative with Cushing’s syndrome or may have seen information in the press, on television, or on the Internet about adrenal gland disorders. It can be difficult to separate patients with syndrome X, a genetic tendency for weight gain, hypertension, type 2 diabetes, gout, and (in women) hyperandrogenism (hirsutism), from those with early Cushing’s syndrome. This is especially true if the patient with syndrome X is depressed. Laboratory findings discussed previously and serial examinations can be helpful, along with the recognition that Cushing’s syndrome is rare and obesity, type 2 diabetes, hypertension, and depression are more common.

Hypersecretion of CRH can occur in depression, stress, anorexia nervosa, excessive exercise, panic disorders, chronic alcoholism or drug withdrawal, diabetes mellitus with neuropathy, and central obesity. There may be higher levels of glucocorticoids in hyperthyroidism and premenstrual tension syndrome and in survivors of childhood sexual abuse. Lower levels of CRH or HPA axis dysregulation and “hypoarousal” may be found in patients with hypothyroidism and seasonal depression and chronic fatigue syndromes, including fibromyalgia. The weight gain, depression, and fatigue in Cushing’s syndrome from chronic hypercortisolism might then be attributed to suppression of CRH secretion.

The primary care provider can assist the patient with Cushing’s syndrome by encouraging regular exercise and stress management. Other healthy lifestyle choices have been previously discussed, including diet and tobacco, alcohol, and caffeine management. The provider should also discuss the benefits of limiting refined carbohydrates in the diet.

      CLINICAL WARNING:

INCREASED PRODUCTION OF MINERALOCORTICOIDS

Hyperaldosteronism

Excessive production of mineralocorticoids can occur as the result of primary disease (overproduction of aldosterone) or secondary disease from excessive stimulation by the renin–angiotensin system. In both instances, glucocorticoid production is normal.

Primary hyperaldosteronism can be caused by an aldosterone-producing adenoma, bilateral adrenal hyperplasia (sometimes referred to as idiopathic hyperaldosteronism), or aldosterone-producing carcinoma. In bilateral hyperplasia, it is thought that the adrenals may be stimulated by a pituitary or hypothalamic factor, causing the overstimulation of aldosterone secretion (Nieman, 2013).

EPIDEMIOLOGY

Primary aldosteronism is a rare cause of hypertension, accounting for 1% of patients with hypertension. It should be suspected in patients with unexplained hypertension and hypokalemia even with low-dose diuretics. In those patients, the incidence is increased to 50%. It affects women more often than men, and the peak age of diagnosis is between 30 and 50 years. More than 60% of cases are caused by benign adenomas; 30% of patients have idiopathic hyperaldosteronism.

HISTORY AND PHYSICAL EXAMINATION

Patients with hyperaldosteronism may have no specific symptoms, but could have some complaints caused by mild hypokalemia; a low potassium level is found in up to 90% of patients. These complaints include polyuria, polydipsia, and muscle weakness. When the loss of potassium is severe, there may be paresis or tetany. The loss of potassium will also bring out glucose intolerance. Edema is not seen unless there is coexistent congestive heart disease or nephrotic syndrome. Hypertension (blood pressure >140/90 mmHg) is almost always seen in hyperaldosteronism, although there are some rare patients who are normotensive but have hypokalemic alkalosis caused by hyperaldosteronism.

Some patients with hyperaldosteronism have hypokalemia but no hypertension; this is called Bartter syndrome and is caused by excessive renin production from hyperplasia of the renal juxtaglomerular apparatus. There is also increased excretion of prostaglandins and the hypokalemia responds to treatment with prostaglandin inhibitors such as indomethacin. Nonetheless, potassium supplementation is often used as the sole therapy because of the undesirable long-term side effects of NSAIDs.

Dexamethasone-suppressible hyperaldosteronism is an autosomal dominant disorder with features identical to those of primary aldosteronism, but the excessive aldosterone secretion can be eliminated by giving steroids such as dexamethasone.

Excessive ingestion of licorice can cause hypertension and laboratory findings of mineralocorticoid excess.

Secondary aldosteronism that also leads to hypokalemia is caused by elevated renin levels. Hyperreninemic hyperaldosteronism can occur in malignant hypertension, unilateral renal artery stenosis, and renin-secreting tumors of the kidney’s juxtaglomerular apparatus.

DIAGNOSTIC STUDIES

Laboratory Findings • For an accurate evaluation of the renin–aldosterone axis, many patients have to discontinue drugs known to affect hormones in the pathway. Spironolactone and estrogens should be stopped for 6 weeks. Prostaglandin inhibitors (NSAIDs), calcium channel blockers, ACE inhibitors, sympathomimetics, and adrenergic inhibitors should be withheld for 2 weeks. If patients experience hypertension after discontinuing these drugs, prazosin or other alpha-1 adrenergic inhibitors can be substituted during this period.

Laboratory testing in patients with hyperaldosteronism demonstrates a low potassium level (3–3.5 mEq/L) with alkalosis. The potassium value may be normal if the patient has been eating a low-sodium diet, so these tests should be done after 2 or 3 days of sodium loading (>200 mEq or 120 mM Na). Primary aldosteronism is suspected if there are borderline or low potassium levels, low stimulated PRA, and high aldosterone levels. Aldosterone values are high in the serum (>14 ng/dL), and urinary aldosterone and potassium levels are also high (K >30 mEq). In secondary hyperaldosteronism, the major distinguishing feature is elevation of PRA. In contrast to secondary hyperaldosteronism, the PRA is suppressed in primary aldosteronism and does not increase in response to an upright position (standing for 4 hours) or volume depletion after a 40-mg dose of furosemide.

      CLINICAL WARNING:

An initial evaluation for hyperaldosteronism is to check the plasma aldosterone level and the ratio of plasma aldosterone to PRA before and 90 minutes after administration of captopril (25–50 mg), an ACE inhibitor. This test does not require dietary preparation and does not expose the patient to salt loading. Those with secondary hyperaldosteronism, like normal patients, show a rise in PRA and a fall in aldosterone levels.

Single Adenoma Versus Bilateral Adrenal Hyperplasia. Once the diagnosis of primary aldosteronism is confirmed, it is important to then distinguish between causative factors: either a single adrenal adenoma or bilateral adrenal hyperplasia.

IMAGING STUDIES

CT scanning can distinguish adrenal hyperplasia from a benign adenoma and can also exclude adrenocortical carcinoma. If the CT is normal or reveals bilateral abnormalities or a unilateral abnormality in a patient older than 40 years, then an adrenal venous sampling is recommended to rule out unilateral disease and assess readiness for surgical management if needed. Aldosterone should be measured the day after surgery to assess cure. Potassium and spironolactone should be discontinued and antihypertensive medications decreased.

OTHER STUDIES

Hypokalemia (K <3 mEq/L) can be seen on electrocardiogram tracings as depression of the ST segment and inversion of the T wave. As potassium levels continue to fall, a prominent U wave is seen in the anterior leads.

Treatment Options, Expected Outcomes, and Comprehensive Management

In patients with a benign adenoma, surgical removal of the adrenal gland that contains the adenoma is curative in more than 70% of patients. Surgery is not indicated in idiopathic hyperaldosteronism (bilateral hyperplasia), which is treated with a potassium-sparing diuretic, ACE inhibitors, or calcium channel blockers, which inhibit aldosterone secretion.

Spironolactone (50–200 mg/d) is the most effective agent for hyperaldosteronism that cannot be treated surgically, as it is a competitive antagonist. It can create side effects because of its antiandrogenic activity, leading to decreased libido, breast pain, and gynecomastia in more than 50% of men treated. In women, breast pain and irregular menstrual bleeding can occur. If spironolactone is not tolerated, calcium channel blockers with potassium-sparing diuretics can be used.

Teaching and Self-Care

Potassium can be replaced orally as a liquid or as a slow-release tablet, which is usually preferred because of the unpleasant taste of liquid potassium. The slow-release tablets must be taken with a copious amount of water to avoid gastric irritation. Most patients taking diuretics do not need routine potassium replacement. Patients who have potassium levels <3 mEq/L, those with coexistent cardiac disease (especially those who take cardiac glycosides [digoxin, digitalis]), those with chronic liver disease, and those at risk for diuretic-induced glucose intolerance (diabetes) should take oral potassium while taking commonly used diuretics.

Self-care management includes maintaining a healthy lifestyle. The provider can counsel the patient about diet, including sources of potassium. Exercise as well as stress-relieving activities can be important parts of the self-care plan. Balancing exercise and activities with adequate sleep and quiet recreation can round out a successful self-management regimen.

      CLINICAL WARNING:

HYPOALDOSTERONISM

Hypoaldosteronism should be suspected in any patient with persistent hyperkalemia with no kidney failure and no potassium supplement therapy. Hypoaldosteronism can be a primary disease or can occur secondary to low renin levels. Usual causes of hypoaldosteronism include primary adrenal insufficiency, salt-wasting forms of congenital adrenal hyperplasia, or the use of drugs. Primary loss of aldosterone secretion can also be caused by genetic mutations of enzymes in the synthetic pathway for mineralocorticoids. Hyperreninemic hypoaldosteronism can also occur in critically ill patients as a likely response to chronic stress, ischemia in the zona glomerulosa, or a reaction to pyrogenic factors (e.g., interleukin-1, tumor necrosis factor). Secondary hypoaldosteronism from low levels of renin (hyporeninemic hypoaldosteronism) is a common cause of hyperkalemia. It often occurs in patients with mild renal insufficiency, and most of these patients have diabetes mellitus. Drugs known to inhibit aldosterone secretion or interfere with its actions include heparin, cyclosporin A, calcium channel blockers, beta-blockers, NSAIDs, ACE inhibitors, spironolactone, and aminoglutethimide.

Epidemiology

Primary deficiency of aldosterone (hyperreninemic hypoaldosteronism) is usually caused by adrenal insufficiency and was described earlier. Secondary aldosterone deficiency caused by hyporeninemic hypoaldosteronism is also called type IV renal tubular acidosis. It most often occurs in middle-aged men, and chronic renal insufficiency is found in 80% of cases. Diabetes mellitus occurs in 50% of patients. Persons with diabetes are predisposed to hyperkalemia because of hyperglycemia and low insulin levels, which produce an extracellular flux of potassium. Autonomic neuropathy may also be a factor in the acquisition of the hyporeninemic state.

History and Physical Examination

The clinical signs of hypoaldosteronism are caused by salt wasting and hyperkalemia. The hyperkalemia can lead to muscle weakness, muscle cramps, and cardiac arrhythmias. Salt wasting can cause orthostatic blood pressure changes and hyponatremia, which can lead to mental confusion.

Diagnostic Studies

LABORATORY FINDINGS

The diagnosis of hypoaldosteronism is made by measuring the PRA and the aldosterone level in the blood during a period of salt restriction. If PRA is high, then hypoaldosteronism is an isolated defect; if PRA is low, hypoaldosteronism is secondary to the low renin level.

OTHER STUDIES

Hyperkalemia, when the potassium level is >5.5 mEq/L, can be seen on the electrocardiogram as peaked T waves. With further increases in the plasma potassium level >7 mEq/L, the P wave disappears, the ST segment is depressed, and the QRS complex widens, becoming sinusoidal. Untreated patients with severe hyperkalemia will present with ventricular fibrillation or cardiac standstill, unresponsive to electrical cardioversion, unless hypokalemia is corrected.

If hyperkalemia is mild, restriction of dietary potassium and avoidance of drugs that exacerbate hyperkalemia are useful. If dietary restrictions do not correct the hyperkalemia, mineralocorticoid replacement with 100 to 200 mcg/d of 9-alpha-fludrocortisol (Florinef) should be given. This therapy may promote edema from sodium retention and coexisting congestive heart failure or renal failure; hence, a balance between salt retention and fluid overload must be individualized. If Florinef cannot be tolerated, kaliuresis can be promoted using appropriate diuretics, such as chlorthalidone or hydrochlorothiazide. Sodium polystyrene sulfonate (Kayexalate), a cation exchange resin, removes potassium, but it also increases the sodium load, is expensive, and is difficult to use in the outpatient setting.

Teaching and Self-Care

Patients with hypertension often consume products advertised as being low in sodium. Nonetheless, patients with hyperkalemia or mild renal insufficiency should avoid low-sodium foods because they often contain high amounts of potassium. A healthy lifestyle, as previously described, should be encouraged.

      CLINICAL WARNING:

      CLINICAL WARNING:

PHEOCHROMOCYTOMA

Catecholamine-secreting tumors of the adrenal medulla, and rarely from extra-adrenal sites, are called pheochromocytomas. Extra-adrenal pheochromocytomas are referred to as catecholamine-secreting paragangliomas. Pheochromocytoma is a rare cause of hypertension. Most cases are sporadic, but some are associated with the familial syndromes of multiple endocrine neoplasia, where pheochromocytoma is found with hyperparathyroidism and medullary thyroid cancer. Pheochromocytomas can also be associated with neurofibromatosis and Von Hippel-Lindau disease.

Anatomy, Physiology, and Pathology

The medulla of the adrenal gland is formed from cells that migrate from the fetal neural crest; thus, they are related to the cells that form the sympathetic nervous system. These cells are called neuroendocrine cells and form catecholamines from the amino acid precursor tyrosine.

Because plasma catecholamines are labile, samples must be taken fasting, resting, and supine (with the needle placed 20–30 minutes before sample taking) and processed rapidly. Urinary catecholamines are greater in magnitude and give a more integrated function over 24 hours, but use of certain drugs can give false-positive and false-negative results. Methyldopa, terbutaline, and isoproterenol will give falsely elevated catecholamine values.

Epidemiology

Pheochromocytomas arise in the adrenal gland 90% of the time. They can be bilateral in 10%, especially in those with multiple endocrine neoplasia syndrome. When the tumor is located outside the adrenal gland, it is called a paraganglioma. Pheochromocytomas are the cause in <0.2% of patients with hypertension. When patients are hypertensive and have an adrenal mass or present with hypertension, episodic headaches, palpitations, and sweating, the yield increases to about 6%. Tumors are equally common in men and women and can occur at any age, although most are found in patients 30 to 40 years old, and 50% of tumors are found on autopsy and are clinically silent during life (Young & Kaplan, 2014).

History and Physical Examination

The main sign of pheochromocytoma is either sustained hypertension or paroxysmal hypertensive crises on a background of mild hypertension, and occurs in up to 90% of symptomatic patients. The classic triad of symptoms is:

Diagnostic Studies

LABORATORY FINDINGS

The diagnosis of pheochromocytoma is based on the finding of elevated catecholamine levels, usually measuring the urinary metabolites norepinephrine and normetanephrine in a 24-hour period. Vanillylmandelic acid (VMA) levels can be elevated but are not as specific as normetanephrine levels (65% vs. 84%; Agha, Tomlinson, Clark, Holder, & Stewart, 2006; Annane, Sébille, Charpentier et al., 2002; Eckstein et al., 2007). In recent literature, where high-performance liquid chromatography (HPLC) assays were used, collection of urinary free catecholamines was as sensitive as catecholamine metabolites such as normetanephrine, and may be more sensitive (>95%) for smaller lesions with rapid catecholamine turnover (Annane, Sébille, Charpentier et al., 2002).

The 24-hour collection of the urine is done in a jug containing acid, and creatinine should also be measured to ensure that the sample is adequate. Patients need not follow a special diet for detection of pheochromocytoma, but most antihypertensive medications should be stopped if possible. If the patient is severely hypertensive after discontinuing medication, hydralazine, minoxidil, calcium channel blockers, diuretics, or ACE inhibitors can be used. Drugs that are more apt to cause false elevations or to interfere with the collections are to be avoided, including:

VMA collections can also be affected by monoamine oxidase inhibitors and clofibrate.

Plasma catecholamines are usually not collected as an initial screening test for two reasons: tumors can have episodic secretion that would be missed, and in some patients, the stress of testing or pain during the procedure can lead to false-positive results. Nonetheless, plasma norepinephrine levels >2,000 pg/L are highly suggestive of a pheochromocytoma during a hypertensive crisis. The catabolic effects of excessive catecholamines and decreased tissue perfusion promote lactic acidosis, and a lactate level >5 mmol/L should increase the suspicion of a pheochromocytoma (Eisenhofer et al., 2005).

Giving clonidine (0.3 mg) orally can be useful in separating patients with baseline plasma catecholamine levels above normal into those likely to have a pheochromocytoma and those with elevations caused by stress. Pheochromocytoma is suspected when, 3 hours after clonidine dosing, the plasma catecholamine levels are >500 ng/L. Provocative testing can be done with glucagon, histamine, or metoclopramide, but is not advised because these drugs can cause life-threatening cardiac responses in those with pheochromocytomas.

Special Laboratory Staining • Cells that produce catecholamines stain for neuron-specific enolase and chromogranin. In patients with pheochromocytoma, blood levels of chromogranin are often elevated.

IMAGING STUDIES

Most pheochromocytomas are found within the adrenal gland. Adrenal tumors can usually be seen by CT examination, but if there is concern that the iodine contrast material could trigger a hypertensive crisis or paroxysm, MRI also can be used. Metaiodobenzylguanidine (MIBG) is a nuclear tracer that can locate these tumors in 80% to 95% of patients, but it is not available at many sites. Isotope-labeled octreotide (Sandostatin) can also detect pheochromocytomas and is more widely available than MIBG, but it is expensive. Using MIBG or octreotide scanning, whole-body images can be obtained, so that pheochromocytomas outside the adrenal area can be detected. If nuclear scanning to locate extra-adrenal sites of pheochromocytoma is not feasible, MRI scans of the chest, abdomen, and pelvis should be done to find those rarer tumor sites (e.g., the bronchial tree, pancreatic tissue, bladder wall, or sympathetic–parasympathetic ganglia). Fludeoxyglucose-positron emission tomography (FDG-PET) is more sensitive than 1231-MIBG and CT/MRI for detection of metastatic disease.

Treatment Options, Expected Outcomes, and Comprehensive Management

      CLINICAL WARNING:

Patients need preparation before surgery to avoid hypertensive crises and cardiac arrhythmias during anesthesia and hypotension on removal of the lesion. This preparation is ideally managed by an endocrine specialist. Hypertension lasting a month after surgery indicates multifocal disease or metastases or renal vasculature changes from the prior disease (discussion of surgical management is outside the bounds of this text).

Teaching and Self-Care

It may prove a diagnostic challenge to differentiate symptoms of a pheochromocytoma from those of thyrotoxicosis, drug withdrawal, anxiety disorders and panic attacks, carcinoid syndrome, paroxysmal tachycardia, mitral valve prolapse, migraine headaches, or hypoglycemia. Many patients with pheochromocytomas are asymptomatic, but those with short episodes of throbbing headache, palpitations, and sweating are more likely to have these tumors than those with a history of long-lasting headaches and incapacitation.

The body’s ability to respond to stress involves the HPA and the efferent sympathetic nervous system. Women may experience irregular or missed menstruation during stress. Stress can cause alterations in thyroid hormones, such as euthyroid sick syndrome. Thus, stress management, relaxation techniques, and regular aerobic exercise can help reduce hormonal alterations and decrease symptoms and signs associated with excessive catecholamine release in the absence of a known adrenal tumor.

      CLINICAL WARNING:

Community Resources