Adrenal Gland Disorders

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[edit] Adrenal Gland Disorders

Melanie J. Brunt

James C. Melby

[edit] ADRENAL ANATOMY AND PHYSIOLOGY

In the adrenal cortex, which constitutes 80% of the total adrenal weight, three zones are responsible for corticosteroid synthesis. The outermost layer, the zona glomerulosa, synthesizes aldosterone, which is the predominant mineralocorticoid responsible for sodium retention and potassium excretion. The middle and inner layers, the zona fasciculata and the zona reticularis, produce glucocorticoids (principally cortisol) and the sex steroids and their precursor, dehydroepiandrosterone (DHEA). Cortisol functions to promote protein and lipid catabolism and gluconeogenesis. Catecholamines are synthesized in the adrenal medulla, and they are regulated via the autonomic nervous system.

All corticosteroids are derived from cholesterol, which is found in abundance in the adrenal cortex. Regulatory systems for cortisol and aldosterone are outlined in Fig. 98-1. Cortisol is subject to negative feedback regulation via the hypothalamic-pituitary axis (HPA). The majority of the daily cortisol production of 15 to 25 mg is produced between 5 and 9am. Metabolic stress such as sepsis or myocardial infarction can raise production levels to 250 mg per day. Aldo sterone is regulated via the renin-angiotensin feedback loop, through which low renal perfusion pressure stimulates increased aldosterone production. Extracellular potassium concentration also affects aldosterone secretion, and the HPA plays a small role as well, regulating about 15% of aldosterone production via adrenocorticotropic hormone (ACTH) stimulation.

Figure 98-1 Regulatory systems for cortisol and aldosterone. CRH, Corticotropin-releasing hormone;ACTH, adrenocorticotropic hormone;DHEA, dehydroepiandrosterone.

[edit] ADRENOCORTICAL HYPOFUNCTION

[edit] Pathophysiology

Adrenocortical hypofunction can result from primary destruction of the adrenal cortex, with consequent loss of all corticosteroid hormone production. It may also be secondary, due to diminished ACTH production by the pituitary. In the latter disorder only glucocorticoid and androgen production are affected. Mineralocorticoid production remains largely intact because ACTH plays only a small role in aldosterone regulation. Angiotensin II and potassium are the principal factors affecting aldosterone production, and the renin-angiotensin II-aldosterone regulatory axis is independent of regulation by the pituitary. In both disorders the clinical consequences related to loss of cortisol, a hormone essential for survival, are paramount. Cortisol is essential for the maintenance of vascular tone and cardiovascular output due to its positive inotropic effects; thus hypotension may be present in either disorder. Hypoglycemia also occurs due to the loss of the permissive effects of cortisol on glycogenolysis and gluconeogenesis. Hypercalcemia may be present due to the loss of cortisol inhibition of intestinal absorption and renal reabsorption of calcium. Hyponatremia can also occur. In primary adrenal insufficiency this is due to loss of thesodium-retentive properties of aldosterone. In secondary insufficiency it can occur despite normal aldosterone levels due to (1) decreased cortisol-mediated renal free water clearance and (2) compensatory elevations of antidiuretic hormone (ADH).

Hyperpigmentation is seen only in primary adrenal insufficiency and is due to increased secretion of β-lipotropin, a component of the precursor peptide that also contains ACTH. Also in primary insufficiency, the loss of aldosterone, the principal regulator of potassium excretion in the body, can result in potentially life-threatening hyperkalemia. Increased sodium excretion in the absence of aldosterone can result in profound volume depletion.

[edit] History and Physical Findings

Adrenal insufficiency often fails to be diagnosed because the clinical presentation can be quite nonspecific. Key clinical features include weakness, fatigue, anorexia, nausea/vomiting, weight loss, and symptoms of volume depletion.Box 98-1 lists the predominant clinical features of primary adrenal insufficiency, or Addison's disease, which is the most common type. Skin changes in this disease include diffuse hyperpigmentation with accentuation in palmar folds, scars, and oral mucosa (Fig. 98-2); longitudinal pigmented bands under nails; vitiligo in up to 15% of patients; and decreased pubic and axillary hair in females. Associated problems include weakness, fatigue, nausea and vomiting, and a craving for salt. It may be associated with other endocrine insufficiencies, such as hypothyroidism and hypoparathyroidism, pernicious anemia, thyroiditis, and alopecia areata. Treatment is to replace adrenal hormones. Secondary adrenal insufficiency most commonly occurs in the setting of panhypopituitarism; thus most patients have clinical signs and symptoms suggestive of secondary hypothyroidism and hypogonadism in addition to evidence of cortisol deficiency (see Chapter 99 ). Rarely secondary adrenal insufficiency is due to isolated ACTH deficiency. In this disorder symptoms and signs of cortisol deficiency such as hypotension, hyponatremia, malaise, and fatigue are present without concomitant evidence of secondary thyroid and gonadal failure.

Figure 98-2 Hyperpigmentation of almar folds (A) and gums in Addison's disease (B).

The following cases illustrate the difficulty in making a diagnosis of adrenal insufficiency: Case 1 A 50-year-old U.S. citizen living overseas in a tropical climate developed malaise, weakness, intermittent abdominal pain, and diarrhea a few months after a brief febrile illness. Physicians prescribed antibiotics without effect. During a visit to the United States he saw his internist, who referred him to a gastroenterologist. Several radiographic studies were performed, no diagnosis was found, and he was treated symptomatically. The patient continued to experience the same symptoms and became depressed, for which he pursued counseling. Upon his permanent return to the United States over a year later, he sought furthercounseling and was started on a tricyclic antidepressant. A few weeks thereafter he experienced two falls, the second of which was associated with a loss of consciousness. He was brought to an emergency ward, where laboratory data revealed a sodium level of 110 mEq/L. Hyperpigmentation in sun-exposed areas was noted; the patient attributed this to frequent sun exposure. A workup revealed low cortisol levels with absent response to synthetic ACTH (cosyntropin) injection. A purified protein derivative (PPD) test was positive, and calcification was noted in the area of the right adrenal gland on computed tomographic (CT) scan of the abdomen. All symptoms resolved promptly with glucocorticoid replacement.

Case 2 A 35-year-old non–English-speaking immigrant from the Caribbean had a medical history remarkable only for a motor vehicle accident involving a brief loss of consciousness 5 years previously. He was brought to an emergency ward on many occasions over a 3-year period by family members due to confusional episodes associated with violent behavior, recurrent fevers, weight loss, and malaise. The patient was admitted to the hospital from the emergency ward on several occasions. On some of these admissions infections were documented, including streptococcal pharyngitis, pneumococcal pneumonia, and urinary tract infection; on other occasions extensive sepsis evaluations were unrevealing. His mental status remained abnormal but no explanation was found. Electrolytes were consistently within normal limits, although potassium was usually ≥4.5 mEq/L, sodium ≤140 mEq/L, and blood glucose 60 to 70 mg/dl. A blood glucose level of 29 mg/dl finally prompted evaluation of the adrenal axis, and poor response to synthetic ACTH injection was documented.

In both cases primary adrenal insufficiency was finally diagnosed, but the delay led to significant morbidity.

[edit] Etiology and Differential Diagnosis

[edit] Primary Adrenal Insufficiency.

Idiopathic Addison's disease is the predominant cause of primary adrenal insufficiency (Box 98-2). This is thought in most cases to be an autoimmune disorder of the adrenal cortex characterized by lymphocytic infiltration on histologic examination. The prevalence of antiadrenal antibodies in patients with idiopathic Addison's disease is 70%; therefore the absence of antibodies does not rule out the diagnosis. Nearly half of Addison's disease patients develop associated endocrine disorders with organ-specific antibodies, such as pernicious anemia, gonadal failure, insulin-dependent diabetes mellitus, hypoparathyroidism, vitiligo, or thyroid disorders.

Tuberculosis once accounted for over 75% of all cases of Addison's disease. Although it is now less common, the emergence of resistant strains of tuberculosis among human immunodeficiency virus (HIV)-infected persons and increased immigration from countries with a high prevalence of tuberculosis may lead to a resurgence of this type of Addison's disease. Features of tuberculous adrenal insufficiency include adrenal enlargement in the early stages (within the first 5 years) followed by adrenal atrophy with calcification. Absence of these features does not rule out tuberculosis as a cause; thus skin testing for tuberculosis should be a standard part of the evaluation of patients with Addison's disease.

Metastatic disease frequently involves the adrenal gland. Cancer of the lung and breast are the two types of malignancies that most commonly metastasize to the adrenals. Adrenal metastases are found in 35% of patients with metastatic lung or breast cancer. Despite this high frequency, adrenal insufficiency can be documented biochemically in only about 20% of these patients. This is presumed to reflect the fact that over 90% of the adrenal gland must be destroyed to produce insufficiency. All patients with bilateral adrenal metastatic disease should be tested with short-acting synthetic α-1,24 ACTH (cosyntropin) to rule out insufficiency.

Acquired immunodeficiency syndrome (AIDS) can cause primary adrenal insufficiency. The etiology is usually infection with cytomegalovirus (CMV), Cryptococcus, tuberculosis, or atypical Mycobacterium. Although most HIV patients with evidence of adrenal infiltration by one of these organisms do not have adrenal insufficiency because there is sufficient adrenal function preserved, about 20% of patients with HIV have been found in some series to have a subnormal response to injected synthetic ACTH consistent with adrenal insufficiency.^[1] fs Also, medications such as ketoconazole, rifampin, and megestrol, which are commonly used in patients with HIV disease, can cause adrenal insufficiency. Ketoconazole inhibits adrenal steroidogenesis by blocking cholesterol desmolase, 11β-hydroxylase, and aldosterone synthase, which can result in primary insufficiency. Megestrol has glucocorticoid receptor agonist activity, which has resulted in both Cushing's syndrome and secondary adrenal insufficiency. Rifampin induces cortisol-metabolizing enzymes.

[edit] Secondary Adrenal Insufficiency.

Secondary adrenal insufficiency can be related to panhypopituitarism, isolated ACTH loss, or exogenous glucocorticoid suppression of the HPA (see Box 98-2). Panhypopituitarism is discussed in detail in Chapter 99 . Pituitary tumor, infiltration, and infarction are common etiologies. Cases have been reported in the literature of isolated ACTH loss due to selective failure of pituitary ACTH-producing cells. The etiology is unknown in most cases, but an association with other autoimmune endocrinopathies, the postpartum occurrence in some patients, and the measurement of serum antipituitary antibodies have suggested an autoimmune etiology. Exogenous suppression of the HPA during glucocorticoid therapy for nonendocrine disorders is common. This can occur up to 12 months after treatment of at least 3 weeks' duration with pharmacologic dosages of these medications. A pharmacologic dosage is defined as any dosage exceeding the 24-hour adrenal replacement dosage (Table 98-1). Although most cases of adrenal suppression follow prolonged use of oral or parenteral glucocorticoids, cases of adrenal suppression following the use of high dosages of inhaled or topical glucocorticoids have been reported as well. In general, the likelihood of suppression increases with dosage and duration of therapy and with use of longer acting agents. However, it is impossible to predict the exact dosage or duration of glucocorticoid use that will produce HPA suppression in an individual patient. Clinically some patients undergoing a taper from prolonged use of glucocorticoids can experience the glucocorticoid withdrawal syndrome, which includes fatigue, weakness, arthralgias, anorexia, nausea, abdominal pain, skin desquamation, and dizziness. This clinical syndrome may or may not be associated with evidence of endogenous adrenal suppression upon testing. In some cases testing is completely normal, suggesting that this syndromemay reflect physiologic and/or psychologic dependence on high doses of glucocorticoids.

Table 98-1 Glucocorticoid Characteristics

✢Refers to the dosage required to replace the 24-hour cortisol production of nonstressed adrenal glands.

†Refers to the dosage required to replace the 24-hour cortisol production of the adrenals in situations of severe metabolic stress.

‡Refers to the glucocorticoid potency of the medication as compared with cortisol (note the 1,4,5,25 rule may be a helpful way to recall relative potencies).

§Refers to the mineralocorticoid potency of the medication as compared with cortisol.

[edit] Laboratory Studies and Diagnostic Procedures

As shown in Box 98-1, hyperkalemia occurs in 66%, hyponatremia in 90%, and hypoglycemia in 40% of cases. However, as illustrated by Case 2, they can be mild and easily missed. Dynamic endocrine testing is necessary to establish a diagnosis, since random cortisol levels are usually not helpful. Indications for such testing, in addition to electrolyte abnormalities, may include repeated episodes of syncope or hypotension, significant weight loss, unexplained fevers, or fever disproportionate to the type of infection.Fig. 98-3 is an algorithm of the diagnostic evaluation.

Figure 98-3 Algorithm for adrenal insufficiency.

[edit] Plasma ACTH Level.

A plasma ACTH assay differentiates between primary adrenal insufficiency and insufficiency at a higher level when the rapid ACTH stimulation test yields abnormal results. Patients with primary failure have elevated ACTH levels, whereas patients with secondary failure have normal or low levels. A normal plasma ACTH level is 20 to 80 pg/ml. Careful attention must be paid to specimen collection, since falsely low results can occur.

[edit] Rapid ACTH Test.

The rapid ACTH stimulation test is highly accurate in establishing or excluding adrenal insufficiency. The test measures only adrenal response to injected synthetic ACTH and does not test for endogenous ACTH or corticotropin-releasing hormone (CRH) deficiency. However, the adrenal atrophy that occurs with chronic endogenous ACTH or CRH deficiency often results in poor adrenal response to injected ACTH. Correlation has been demonstrated between rapid ACTH testing results and results of direct testing at higher levels, so the test can be used to assess all levels of adrenal dysfunction. A bolus intravenous injection of 0.25 mg of synthetic α-1,24 ACTH (cosyntropin) is administered. Plasma cortisol levels are measured at 0 and 30 to 60 minutes. A 30- to 60-minute plasma cortisol level of greater than 18 to 20 μg/dl excludes the diagnosis of primary adrenal insufficiency and usually excludes chronicsecondary adrenal insufficiency as well. However, in acute secondary adrenal insufficiency, cortisol response to cosyntropin may be normal.

[edit] Other Tests.

These tests are usually reserved for endocrine/metabolic units and are not essential for diagnosis if the combined cortisol and ACTH test results establish the level of dysfunction. A long ACTH test involves the administration of 500 μg/dl cosyntropin as a continuous infusion over 48 hours, with measurement of urinary free cortisol and serum cortisol levels. An insulin tolerance test involves the administration of insulin to invoke hypoglycemia, which is a stimulus to pituitary ACTH secretion. Endogenous ACTH levels are measured as hypoglycemia occurs. This test requires close supervision by experienced personnel. The metyrapone test uses the drug metyrapone to block the final step in cortisol synthesis, thus stimulating an ACTH response to a temporary decrease in cortisol production. Those who are confirmed to have secondary adrenal insufficiency may require additional testing to rule out secondary thyroid or gonadal failure.

[edit] Radiologic Imaging.

If a biochemical diagnosis of primary adrenal insufficiency is established, imaging of the adrenal glands may be helpful in distinguishing etiology. CT scan may be preferable to magnetic resonance imaging (MRI) in this setting, because detection of calcification in the area of the adrenals by CT scan is suggestive of prior adrenal tuberculosis. Infiltrative disorders such as metastatic disease, sarcoidosis, and tuberculosis may cause adrenal enlargement detectable by CT or MRI in the early stages of disease. If antiadrenal antibodies are negative and calcification is present in the area of the adrenal glands, the presumed etiology is tuberculosis. Patients who have neither adrenal calcification nor positive tuberculin skin testing must be presumed to have idiopathic Addison's disease regardless of antibody status. There is no role for adrenal imaging in patients who have biochemical evidence of secondary adrenal insufficiency.

For patients who appear to have secondary adrenal insufficiency on biochemical testing, MRI of the brain with views of the pituitary is necessary to rule out a midline central nervous system (CNS) lesion.

[edit] Management

The emergency treatment of acute adrenal crisis is outlined in Box 98-3. Empiric treatment for adrenal crisis should be considered in all severely ill patients with shock refractory to volume expansion or pressor agents. Factors that would argue strongly for such treatment include risk factors for adrenal insufficiency such as anticoagulant therapy, bleeding diathesis, disseminated intravascular coagulation, disseminated tuberculosis, AIDS, sepsis, or a history of glucocorticoid therapy within the previous 12 months. Treatment is not likely to benefit patients whose refractory hypotension is clearly related to cardiogenic shock. Treatment should be continued until results of the diagnostic evaluation are available. The dosage of glucocorticoid can be tapered at a rate appropriate to the clinical condition of the patient. In patients who are clearly improving clinically, the dosage can be tapered by 50% daily, with a change to oral maintenance therapy within several days.

Maintenance therapy for adrenal insufficiency consists of daily oral glucocorticoid, most commonly hydrocortisone or prednisone, plus the mineralocorticoid fludrocortisone in primary adrenal insufficiency (see Table 98-1). For primary adrenal insufficiency, hydrocortisone may be a better choice than prednisone because of its higher mineralocorticoid activity. Thus, for some patients taking hydrocortisone, mineralocorticoid replacement with fludrocortisone may not be necessary. Prednisone is less expensive than hydrocortisone but often requires the concurrent use of fludrocortisone for mineralocorticoid replacement. The need for mineralocorticoid therapy can be monitored via electrolytes and postural blood pressure measurements. Plasma renin activity levels can also be used, since they are elevated if mineralocorticoid replacement is insufficient. Patients should be given the minimum amount of glucocorticoid and mineralocorticoid required to prevent symptoms and maintain normal electrolyte and blood pressure status.^[2] Care must be taken to ensure that the patient is indeed on the minimum required dosage, since even small excesses of glucocorticoid therapy can cause osteoporosis and metabolic complications such as hyperglycemia (see the discussion on iatrogenic Cushing's syndrome in this chapter). Excess mineralocorticoid therapy can cause hypertension and hypokalemia.

In secondary or tertiary adrenal insufficiency, only glucocorticoid replacement is required, unless any concurrent deficiencies of the other pituitary hormones are present.

Patients with adrenal insufficiency should wear some form of easily visible identification stating their diagnosis and therapy. They also must be instructed to increase their medication dosage if any significant illness occurs. Medication should be doubled for illnesses associated with vomiting and/or diarrhea. For milder febrile illnesses dosages should be increased somewhat less. Major medical stresses such as trauma or a surgical procedure require parenteral therapy. For surgery 100 mg of hydrocortisone should be given 8 hours preoperatively and repeated at 1 hour preoperatively. Hydrocortisone should also be added as a continuous infusion to the intravenous fluids at 5 mg/hour during the surgical procedure. A total of 150 to 200 mg should be given in the first 24 hours, with tapering of dosage by 50% per day assuming continued uneventful recovery.

[edit] Management of Glucocorticoid Withdrawal

Sudden cessation of therapy following at least 3 weeks of supraphysiologic doses of glucocorticoids can precipitate acute adrenal insufficiency (see Table 98-1). Guidelines to prevent adrenal crisis during withdrawal from therapy are outlined in Box 98-4. Changing therapy to shorter acting agents and using alternate day therapy are features that allow HPA axis recovery. The rate of taper of a pharmacologic glucocorticoid dosage depends primarily on the underlying nonendocrine disorder for which the medication is being used. As noted, there may be significant adrenal suppression for up to 1 year after discontinuation of steroids. Major stresses, including surgery, require stress dose steroid therapy (see Box 98-4 and Chapter 13 ). If patients have symptoms of adrenal insufficiency on withdrawal of steroids, it may be reasonable to perform a cosyntropin stimulation test to assess adrenal responsiveness.

[edit] ADRENOCORTICAL HYPERFUNCTION (CUSHING'S SYNDROME)

[edit] Pathophysiology

Cushing's syndrome is a constellation of symptoms, signs, and biochemical abnormalities that result from prolonged exposure to excess levels of glucocorticoids. The principal glucocorticoid, cortisol, has primarily catabolic effects in most tissues. Collagen production is impaired, which reduces the tensile strength of dermal structures, including blood vessels, resulting in spontaneous ecchymoses, purple striae, and poor wound healing. Cortisol excess can also result in diffuse fine body hair growth, known as lanugo hair. Muscle wasting and weakness occur due to generalized protein catabolism. Catabolic effects on bone are also seen, since cortisol decreases intestinal calcium absorption, which in turn results in increased bone reabsorption and hypercalciuria, progressing to osteoporosis. Hyperglycemia results from the direct anti-insulin effect of cortisol and a cortisol-mediated increase in hepatic gluconeogenesis and glycogenolysis. Impaired immune and inflammatory response is seen due to a variety of immunologic effects, including impairment of polymorphonuclear cell phagocytosis; depletion of T lymphocytes, monocytes, and eosinophils; and decreased antibody formation. Cell-mediated immune response, vascular permeability, and histamine release are also impaired. The clinical result is an increased susceptibility to bacterial and fungal infections, most commonly with opportunistic organisms such as Pneumocystis carinii, Aspergillus, Nocardia, and Cryptococcus. Hypertension is also seen due to the permissive effect of cortisol on catecholamine activity and its positive inotropic effects on the heart. The increased catecholamine also has lipolytic effects, as does excess cortisol. This appears to affect adipocytes differentially. In the extremities fat wasting occurs, while fat deposition is increased centrally in the face, neck, and trunk, resulting in the typical Cushing's features of centripetal obesity, moon facies, and buffalo hump.

Clinical manifestations of androgen or mineralocorticoid excess may also be present, depending on the etiology of the syndrome. In the ACTH-dependent forms of Cushing's syndrome, in which excess pituitary or ectopic ACTH production is the primary pathologic feature, signs of androgen excess occur due to stimulation of adrenal androgen production by the excess ACTH. Androgen excess is clinically apparent only in women, resulting in coarse terminal hair growth in androgen-sensitive areas, such as the face, chest, and upper back. Acne, oligomenorrhea, temporal balding, and deepening of the voice may also occur. In the ACTH-independent forms of Cushing's syndrome primary overproduction of cortisol results in suppression of ACTH production, which in turn reduces adrenal androgen production, so that features of androgen excess do not occur.

Cushing's syndrome is also associated with accelerated atherosclerosis. In the years before effective treatment evolved, patients with Cushing's syndrome commonly experienced early death from myocardial infarction or stroke. Vascular endothelial cell damage and elevated serum lipid levels due to cortisol excess are thought to be the pathogenic factors.

Endogenous (noniatrogenic) Cushing's syndrome is a serious disorder with a 5-year mortality of 50% if left untreated. The majority of deaths are due to infection, cardiovascular disease, and suicide. Treatment confers a dramatically improved prognosis.

[edit] History and Physical Findings

Many of the features of Cushing's syndrome are seen with high frequency in the general population, as shown in Box 98-5. In particular, the triad of obesity, hypertension, and glucose intolerance or diabetes is commonly encountered in an outpatient general medical practice. Alternately, among patients with documented Cushing's syndrome, the presentation is often nonspecific, and typical clinical features may be absent. For example, among patients with pituitary Cushing's syndrome the prevalence of symptoms is obesity 79%, hypertension 77%, easy bruisability 77%, hirsutism 64%, proximal muscle weakness 48%, psychiatric disturbances 48%, abnormal glucose tolerance 39%, clinical diabetes 13%, and hypokalemia 24%. Psychiatric symptoms most frequently include affective changes (mania, depression) but may also present as toxic psychoses, often with paranoia. Symptoms are typically dose-related, although they occasionally follow use of low-dose steroids. Onset is usually within 5 days of starting glucocorticoid therapy, often in the setting of prior psychiatric problems. Resolution is typically within 1 week of discontinuation of glucocorticoids.

Rapid or subacute onset of obesity, hypertension, or other features of Cushing's syndrome is one clue that there is an underlying pathologic process that merits investigation.

[edit] Etiology and Differential Diagnosis

The differential diagnosis for Cushing's syndrome and the features unique to each type of the syndrome are outlined in Table 98-2.

Table 98-2 Cushing's Syndrome: Etiology and Differential Diagnosis

[edit] Iatrogenic Cushing's Syndrome.

Iatrogenic Cushing's syndrome is the most common type seen clinically. Any prolonged use of glucocorticoid at dosages above replacement (see Table 98-1) can result in the adverse metabolic effects and/or clinical features of Cushing's syndrome. Osteoporosis can be a serious problem, with an incidence of 30% to 50% among those treated chronically with glucocorticoids. Reductions in trabecular bone density have been measured after as little as 8 mg of prednisone daily for 4 months. At prednisone dosages of over 10 mg daily for at least 2 months, an increased prevalence of infection is seen. Atherosclerotic disease may also be increased and steroid myopathy may be very disabling (see Chapter 175 ). Several pathologic features of iatrogenic Cushing's syndrome are unique to exogenous glucocorticoid use and are not seen in other types of the syndrome. These include aseptic necrosis of the femoral or humeral heads (which can occasionally occur even with short-term steroid therapy), glaucoma, cataracts, benign intracranial hypertension, and pancreatitis. Signs of androgen excess are not a feature, since exogenous glucocorticoids cause HPA suppression, resulting in decreased ACTH-mediated adrenal androgen production.

[edit] Pituitary Cushing's Syndrome (Cushing's Disease).

Pituitary Cushing's syndrome accounts for approximately 60% of cases of endogenous hypercortisolism. This is due to an ACTH-secreting pituitary adenoma. These adenomas are often small, resulting in sella turcica enlargement in only 10% of cases. Signs of androgen excess are often present in this disorder due to ACTH-mediated adrenal overproduction of androgen precursors. The HPA appears to be intact but has an abnormally high set point of ACTH feedback regulation. Thus circulating cortisol production can be suppressed with high-dose dexamethasone testing but not with low-dose or overnight testing.

[edit] Ectopic ACTH Syndrome.

Ectopic ACTH syndrome accounts for about 10% of endogenous hypercortisolism. Thesource of ectopic ACTH production is a thoracic tumor in 79% of patients. The most common thoracic tumors are small-cell carcinoma of the lung, bronchial carcinoid, and thymoma. Extrathoracic tumors such as pancreatic carcinoma can also produce ACTH. Both bronchial carcinoid and thymoma are usually benign tumors with a clinical course typical of Cushing's syndrome. The malignant tumors resulting in this syndrome often have a poor prognosis, and patients seldom live long enough to manifest the typical Cushing's stigmata. Metabolic features, such as severe hypokalemia, may predominate. Hyperpigmentation, leg edema, and weight loss may also be predominant features. These tumors are autonomously functioning; thus cortisol and ACTH production are not suppressed following the administration of high doses of the glucocorticoid dexamethasone. Symptomatic treatment may improve quality of life or prolong life and should be pursued.

[edit] Adrenal Neoplasms.

Adrenal tumors account for about 30% of cases of endogenous Cushing's syndrome. The majority of these are benign adenomas, which are autonomously functioning and secrete primarily cortisol. Excess cortisol suppresses pituitary production of ACTH; thus, clinically, signs of cortisol excess without androgen excess predominate. These tumors are autonomous and do not decrease cortisol production in response to dexamethasone.

Bilateral nodular adrenal hyperplasia is a poorly understood entity. It is characterized by autonomous cortisol overproduction, but production can be suppressed with high doses of dexamethasone. This may represent a variant of Cushing's disease in which a pituitary adenoma is not visible, since ACTH levels are often elevated.

Adrenal carcinomas are rare, accounting for only 0.2% of cancer deaths in the United States per year. The mean age of presentation is 46 years, with a female/male ratio of 2.5:1. In those cases with hormonal overproduction the majority present with clinical features of Cushing's syndrome. In one series 30% presented with pure glucocorticoid excess, 27% had combined glucocorticoid and androgen excess, 8% had androgen excess alone, 2% had mineralocorticoid excess, 1% had estrogen excess, and the remainder (32%) had no hormone overproduction. At diagnosis 50% had regional or distant metastases. Median survival was 21 months, with only 10% surviving for 5 years.

[edit] Alcoholic Pseudo-Cushing's Syndrome.

Chronic alcoholism may have many of the stigmata of Cushing's syndrome. Cortisol dynamics are abnormal and cortisol overproduction can be documented. Following abstinence the cortisol dynamics usually return to normal within 3 to 7 days.^[3]

[edit] Diagnostic Tests

An algorithm that outlines a diagnostic approach to Cushing's syndrome is outlined in Fig. 98-4. The initial step is to perform a screening test to confirm the presence of Cushing's syndrome.

Figure 98-4 Diagnostic algorithm for Cushing's syndrome. (Modified from Kaye TB, Crapo L:Ann Intern Med 112:434, 1990.)

[edit] Hormonal Tests.

The overnight dexamethasone suppression test (ONDST) is the most widely used screen for this disorder. It involves the oral administration of 1 mg of dexamethasone at 11pm, with measurement of plasma cortisol at 8am the following day. The normal cortisol response is suppression to less than 5 mg/dl. This test has an extremely low false-negative rate of <2%, but a high false-positive rate. Obesity, stress, psychiatric disease (especially depression), and medications that increase hepatic metabolism of cortisol and dexamethasone, such as antiseizure medications, estrogen, and rifampin, can falsely elevate the results of this test. If any of these conditions are present, the ONDST should not be performed, and either of the following two tests should be used as the initial screening maneuver (these tests are also used to confirm the diagnosis when the ONDST is positive): (1) the 24-hour urinary free cortisol test is a measurement of unbound, biologically available cortisol; (2) the low-dose dexamethasone suppression test (LDDST) is done by administering 0.5 mg of dexamethasone orally every 6 hours for 2 days. A serum cortisol measured at 8am after 48 hours of dexamethasone administration should be suppressed to less than 5 mg/dl. However the diagnostic accuracy of the LDDST is only 71%.^[4] A recent modification, which has been shown to increase diagnostic accuracy to 100%, is the LDDST-CRH, in which the dexamethasone is initiated at noon, so that the eighth dose is taken at 6am 2 days later. CRH (corticotropin-releasing hormone) as a 1 μg/kg IV bolus is injected at 8am after the last dose of dexamethasone, and a 15-minute serum cortisol is drawn. A cortisol result of >1.4 μg/dl is diagnostic of Cushing's syndrome.^[5] This modification of the LDDST can be performed in patients with positive ONDST results, whose LDDST is negative but in whom clinical suspicion is extremely high for Cushing's syndrome.

If Cushing's syndrome is confirmed, further testing is pursued to differentiate among the types of the syndrome. The high-dose dexamethasone suppression test in conjunction with an ACTH level is the first step. ACTH measured by immunoradiometric assay rather than by radioimmunoassay (RIA) more accurately identifies ACTH-independent forms of Cushing's syndrome. A single 8-mg dose of dexamethasone is given at 11pm following a baseline 8am cortisol measurement. The cortisol is then repeated the following morning. This test has a higher sensitivity of 70% to 90% compared with the traditional test in which dexamethasone is given every 6 hours for 2 days and urine and serum cortisols are monitored (60% to 70% sensitivity).^[4] Lack of suppression of the cortisol level, in conjunction with an undetectable to low ACTH level, is diagnostic of adrenal Cushing's syndrome. Suppression to 50% or less of the baseline cortisol level with normal to elevated ACTH is diagnostic of pituitary Cushing's syndrome. Lack of suppression of cortisol in conjunction with a normal to elevated ACTH suggests the ectopic ACTH syndrome.

If results do not localize the source of the excess cortisol production, further testing must be performed via inferior petrosal sinus sampling. This consists of measuring ACTH levels in blood drawn directly from the petrosal sinuses, which receive the venous drainage from the pituitary. A central/peripheral ACTH ratio of 2:1 or greater indicates a pituitary source of ACTH hypersecretion. A ratio of 1.5:1 or less supports an ectopic cause. If a pituitary source is evident from petrosal sinus sampling, levels may also help to indicate whether it is located on the right or left side of the pituitary.

[edit] Radiologic Studies.

Radiologic studies are performed after localization of the site of excess cortisol production. It iscritical that imaging studies be deferred until hormonal studies have been completed, since incidental adrenal or pituitary adenomas are common, occurring in 1% to 8% of normal individuals. If hormonal studies indicate an adrenal source of cortisol overproduction, adrenal imaging is performed. CT scanning of the adrenal has a sensitivity of almost 100% and is generally the preferred initial imaging modality.^[4] MRI or adrenal scintigraphy with¹³¹I- iodomethylnorcholesterol (NP-59) may be helpful in localizing adenomas not seen by CT scan.

If hormonal studies indicate that cortisol overproduction is localized to the pituitary, MRI has higher sensitivity for pituitary imaging than CT scan and should be the diagnostic study of choice. When gadolinium contrast is used, pituitary MRI has approximately 80% sensitivity.^[4]

[edit] Management

The treatment of iatrogenic Cushing's syndrome once it has occurred is to taper the dosage of glucocorticoid as tolerated by the underlying disease. Some of the metabolic effects of excess glucocorticoid use, such as the loss of bone mass, are not reversible. Thus prevention by minimizing dosage and duration of glucocorticoid therapy is critical. Principles of glucocorticoid use and withdrawal are outlined in Box 98-4. Use of the shortest acting preparation for the shortest time possible is a key feature. Additionally, to minimize bone loss,calcium and vitamin D supplementation should be given to those in whom glucocorticoid use is expected to exceed 1 month. Calcium intake from all sources should total at least 1000 mg per day, and vitamin D, 400 IU per day, should also be administered. Also, pharmacologic prevention of glucocorticoid-induced osteoporosis should be strongly considered; regimens demonstrated to be effective include alendronate 5 mg qd, etidronate 400 mg/day for 14 days every 3 months, and risedronate 5 mg/day.^[6] For women who are estrogen deficient due to menopause, other disorders, or the effects of the glucocorticoid therapy, estrogen therapy should be strongly considered.

The treatment of choice for pituitary Cushing's syndrome is surgery. A transsphenoidal microsurgical approach is used. The surgery is safe and effective, with tumor localization and removal occurring in approximately 90% of patients without subsequent pituitary hypofunction in most. If no adenoma is visible at operation, total or partial hypophysectomy is sometimes recommended, because very small tumors can be found on careful sectioning of the pituitary. Tumor lateralization with inferior petrosal sinus sampling can be used to guide hemihypophysectomy if no tumor is seen on MRI. Surgical cure rates are high, and surgical morbidity and mortality are low. For pituitary microadenomas (under 10 mm), the 10-year cure rate is over 90%, while for macroadenomas, 10-year cure rates are lower at 55%, but survival rates remain high due to a variety of adjunctive therapies to control hypercortisolism, including medications, irradiation, and bilateral adrenalectomy.^[7][8]

For Cushing's syndrome due to adrenal adenoma, surgical resection is the treatment of choice and is usually curative. Surgery may have to be delayed for a few months while medical adrenolytic agents (see below) are administered to avoid problems with poor wound healing or with metabolic derangement. Surgical resection after medical preparation is also used for adrenal carcinoma, even if metastases are documented preoperatively. If metastatic disease is present, postoperative medical therapy is usually necessary on an indefinite basis to control symptoms and metabolic manifestations. Similarly, the hypercortisolism of ectopic ACTH syndrome is usually controlled with medical therapy, even if the ACTH-secreting malignancy confers a poor prognosis. Medical therapy can substantially improve the quality of life in terminally ill patients by ameliorating the myopathy, hypokalemia, and catabolism of Cushing's syndrome.

Options for medical therapy of Cushing's syndrome include ketoconazole, the most commonly used medication, which reduces or normalizes cortisol levels in about 40% of patients. Other drugs that may be effective in lowering cortisol overproduction include mitotane, an adrenolytic agent, and aminoglutethimide, a more rapidly acting adrenolytic agent that blocks the conversion of cholesterol to pregnenolone, a cortisol precursor. This is extremely effective for the rapid reduction of cortisol overproduction. Metyrapone, another effective drug sometimes used in conjunction with aminoglutethimide, is an inhibitor of the adrenocortical enzyme 11β-hydroxylase. Physiologic doses of hydrocortisone must usually be administered with these drugs to avoid adrenal insufficiency. In Cushing's syndrome caused by ectopic ACTH production or adrenal carcinoma, mifepristone (RU 486) is effective. In Cushing's disease cyproheptadine, an antiseratoninergic agent, has been shown to induce clinical and biochemical remission in a small number of patients. Bromocriptine, a dopaminergic agonist, has also produced temporary remission in Cushing's disease.

Finally, alcoholic pseudo-Cushing's syndrome is best treated by detoxification from alcohol. Calcium and vitamin D supplementation should also be considered as osteoporosis prophylaxis in all alcoholics, and estrogen replacement should be considered in amenorrheic alcoholic women.

[edit] MINERALOCORTICOIDS

Aldosterone is the major mineralocorticoid produced by the adrenal gland. Its production is affected primarily by angiotensin II and extracellular potassium, with ACTH playing a small role as well (see Fig. 98-1). Angiotensin II, the predominant factor controlling aldosterone secretion, is in turn responsive to renin, which is secreted by the renal juxtaglomerular apparatus in response to low renal perfusion pressure and low extracellular sodium concentration. Renin stimulates hepatic conversion of angiotensinogen to angiotensin I, which is in turn converted in the lungs to angiotensin II. Stimulation of this axis results in increased aldosterone production, resulting in distal tubular sodium retention and in renal potassium excretion. Disorders of aldosterone may result from excess production, as in primary hyperaldosteronism, or inadequate production, as in hypoaldosteronism.

[edit] Primary Hyperaldosteronism

[edit] Pathophysiology.

Estimates of the incidence of primary hyperaldosteronism in the hypertensive population of the United States vary from 0.05% to 2%. Excess mineralocorticoid results in hypokalemia, metabolic alkalosis, and sodium retention. Sodium retention in turn leads to volume expansion and hypertension. Hypokalemia and sodium retention occur because aldosterone acts on the cortical collecting tubules within the kidney to retain sodium and increase potassium excretion. The mechanism is increased aldosterone-mediated synthesis of sodium-potassium-ATPase, which in turn increases the activity of the sodium-potassium pump that draws sodium into the tubular cells and secretes potassium into the lumen. Excess secretion of hydrogen ion into the tubular lumen, resulting in metabolic alkalosis, occurs in the renal medullary collecting tubules under aldosterone's influence as well. Renin and angiotensin II levels are both suppressed due to primary overproduction of aldosterone.

[edit] History and Physical Findings.

This disorder presents between the third and fifth decades and is more common in women. The hypertension is clinically indistinguishable from essential hypertension in most cases, since most patients with this disorder are asymptomatic. When symptoms occur, the most commonly reported are headache, easy fatigability, and weakness. The most consistent and overt biochemical manifestation is hypokalemia, which results from renal potassium wastage. More than 50% of hypertensive patients with spontaneous hypokalemia are found to have primary aldosteronism; thus hypokalemia in the absence of diuretic therapy should prompt testing for aldosterone excess, even if the hypokalemia is mild (3.4 to 3.5 mEq/L). It should also be suspected in patients who become severely hypokalemic with the administration of diuretics and who remain so after diuretics are stopped. The hypokalemia causes no symptoms in a substantial proportion of patients. In others, nocturnal polyuria and polydipsia and neuromuscular manifestationssuch as weakness, paresthesias, intermittent paralysis, and frank tetany can occur. The degree of hypokalemia is related in part to sodium intake. Sodium restriction leads to potassium retention, whereas sodium excess promotes further renal potassium wastage.

[edit] Etiology and Differential Diagnosis.

The causes of primary hyperaldosteronism and their frequencies are illustrated in Box 98-6. An aldosterone-producing adenoma (APA) of the adrenal, also known as Conn's syndrome, is the most common cause. These adenomas are usually unilateral, more commonly on the left, and less than 2 cm in size. Aldosterone excess is more pronounced than in other forms of primary hyperaldosteronism. Although plasma renin is completely suppressed by the excess aldosterone, synthesis of aldosterone is only partly autonomous. In about 80% of patients, plasma levels still exhibit a circadian rhythm that parallels the plasma cortisol and ACTH levels (corticotropin-responsive). About 20% maintain some response to angiotensin II and postural changes (renin-responsive). The latter is also true of idiopathic hyperaldosteronism (IHA), which is due to bilateral nodular hyperplasia of the adrenal cortex. The histologically normal but hypertrophic adrenal glands found in this condition are thought to result from stimulation by an abnormal secretagogue or an amplifier of angiotensin II that has yet to be identified. There is partial suppression of plasma renin, and there is no parallel between cortisol and aldosterone levels. Rarely, primary hyperaldosteronism is due to production of aldosterone by an adrenal carcinoma. Another unusual etiology is glucocorticoid-suppressible hyperaldosteronism, a rare hereditary autosomal dominant trait in which there is ACTH-mediated hypersecretion of aldosterone and little or no regulation of aldosterone by angiotensin II.^[9] This disorder often presents in children or young adults as hypertension, with or without a family history. Typically, hypokalemia is mild or absent. APA is more common in young adult to middle-aged females, and IHA more typically occurs in middle-aged males.

[edit] Diagnostic Tests.

Screening for primary hyperaldosteronism can be performed in the outpatient setting. Currently, the most widely recommended screening test is the ratio of the plasma aldosterone level to plasma renin activity.^[10] Patients should be off all antihypertensive medications for at least 2 weeks (calcium channel blockers can be continued until 3 days prior to testing). Hypertension can be controlled with prazosin, doxazosin, or clonidine during this time if diastolic blood pressures exceed 110 mm. The blood should be drawn in the morning, with the patient in the upright position, preferably after 2 hours of ambulation. An aldosterone:renin ratio of >30 is an indication for further evaluation. Definitive diagnosis is best established by the saline infusion test, in which 1.25 L over 2 hours, or 2 L of normal saline over 4 hours, is infused and plasma aldosterone is measured. An aldosterone level of <8.5 ng/dl (240 pmol/L) rules out all types of primary aldosteronism.

Once a diagnosis of primary hyperaldosteronism is established, the cause must be determined (Fig. 98-5). The renin-aldosterone stimulation test (posture test) results can be helpful in differentiating IHA from APA in 90% of cases of confirmed primary hyperaldosteronism. Starting at 7:30am the patient remains recumbent for 30 minutes. Plasma renin and aldosterone levels are drawn at 8am. The patient then remains upright for 4 hours, and the levels are repeated. Whereas most patients with APA have a decline in aldosterone levels at 4 hours, patients with IHA experience a normal rise in levels. Additional testing may be necessary to identify those patients who have corticotropin-responsive APA or glucocorticoid-remediable hyperaldosteronism.

Figure 98-5 Diagnostic approach to primary hyperaldosteronism. (Modified from Melby JC:J Clin Endocrinol Metab 69:697, 1989.)

Bilateral adrenal venous sampling continues to be the most accurate test. Normal adrenal venous aldosterone concentration is from 100 to 400 ng/dl. In APA the ipsilateral adrenal venous aldosterone concentration is usually 1000 to 10,000 ng/dl, and the ratio of ipsilateral to contralateral aldosterone levels is usually greater than 10:1. Correct placement of the catheter in the adrenal vein is essential and can be verified by administration of synthetic ACTH with subsequent bilateral cortisol measurements. An aldosterone ratio greater than 10:1 in the presence of a symmetric ACTH-induced cortisol response is diagnostic of APA.

[edit] Radiologic Studies.

CT scanning can detect most aldosterone-producing adenomas. Another promising radiologic maneuver in those unable to undergo adrenal venous sampling is adrenal scanning with¹³¹I-iodomethylnorcholesterol (NP-59). Patients are pretreated with dexamethasone to suppress normal adrenal functioning, and radioisotope is administered. Imaging is deferred for 5 days, since adrenal uptake and concentration of the isotope are maximal at that time. APA is manifested as lateralization of isotope to one adrenal gland. Accuracy may be as high as 90%, but false-negative results have been reported, so this test has not supplanted adrenal venous sampling.

[edit] Management.

Surgery is the treatment of choice once APA is identified. Hypokalemia resolves permanently following surgery in all patients, but hypertension may persist. One year after surgery over 70% of patients are normotensive, whereas only 50% remain so at 5 years. With IHA fewer than 30% of patients are cured by surgery, so this approach, which invariably results in permanent adrenal insufficiency, is not indicated. Potassium-sparing diuretics are quite effective in IHA. Normokalemia is restored with spironolactone, amiloride, or triamterene/hydrochlorothiazide, although additional antihypertensives may be required to control blood pressure.

[edit] Secondary Hyperaldosteronism

Secondary hyperaldosteronism describes renin-mediated aldosterone excess, which is characterized by high renin and aldosterone levels. This can occur in edematous statessuch as congestive heart failure (CHF) or cirrhosis, in which intravascular volume depletion stimulates the renin-angiotensin axis. It also can occur in association with hypertension, in disorders such as renal artery stenosis, malignant hypertension, and juxtaglomerular cell tumor.Box 98-7 outlines the causes of secondary hyperaldosteronism. Hypokalemia may not be a prominent feature. Other unusual causes of secondary hyperaldosteronism include Bartter's syndrome. In this disorder chloride absorption is impaired in the ascending limb of the loop of Henle. Impaired chloride reabsorption in turn increases distal tubular delivery of sodium, resulting in increased sodium exchange for potassium in the distal tubule, with loss of potassium. This disorder can be mimicked by diuretic abuse or by chronic self-induced vomiting. Surreptitious vomiting can be recognized from a low urinary chloride level, and diuretics can be detected by a urine screen. Excess ingestion of true licorice, which contains substances that have mineralocorticoid-like effects, can also cause a metabolic picture that mimics endogenous aldosterone excess.

[edit] Disorders of Mineralocorticoid Deficiency

[edit] Pathophysiology.

In hypoaldosteronism there is a decrease in aldosterone-mediated synthesis of sodium-potassium ATPase in renal tubular cells; thus the activity of the renal tubular sodium-potassium pump is diminished.Hyperkalemia and sodium wasting are the result. The hyperkalemia can be severe, causing arrhythmias and even sudden death. The sodium wasting is more modest. Although decreased effective blood volume, mild hyponatremia, and postural hypotension may be present, there is often no clinical evidence of volume depletion. Metabolic acidosis may also be present due to decreased aldosterone-mediated renal tubular secretion of hydrogen ion.

[edit] Etiology and Clinical Findings.

Box 98-8 outlines the etiologies of this syndrome, which can occur at several levels of the renin-angiotensin axis. Hyporeninemic hypoaldosteronism, previously known as type IV renal tubular acidosis, is the most common of these disorders, usually presenting as unexplained hyperkalemia in a patient with diabetes, hypertension, and mild renal insufficiency, occurring spontaneously or with use of ACE inhibitors or administration of a potassium load. Hypochloremic acidosis may also be present. The production of renin by the renal juxtaglomerular apparatus is permanently diminished or absent, presumably due to local tissue damage.

Hyperreninemic hypoaldosteronism is seen when renin production by the kidney is intact and the defect is either in the biosynthesis or action of angiotensin II or in aldosterone biosynthesis. This may be due to a genetic disorder of aldosterone production. It is also the mechanism of action of ACE inhibitors, which interfere with angiotensin II synthesis. Heparin and lead induce hypoaldosteronism as well by interfering with aldosterone synthesis at the level of the adrenal gland. This pattern of elevated renin and low aldosterone is also sometimes seen in critically ill patients with hypotension.

Pseudohypoaldosteronism is characterized by renal resistance to aldosterone, despite high aldosterone and renin levels. The pharmacologic antagonist spironolactone has this effect by interfering with the effect of aldosterone at the receptor level. Less commonly it is caused by a renal resistance to aldosterone seen in association with interstitial nephritis, systemic lupus erythematosus, or amyloidosis. Type 2 pseudohypoaldosteronism is a rare syndrome characterized by the features of hyporeninemic hypoaldosteronism, including low renin and aldosterone levels, but with a normal glomerular filtration rate. A distal tubule defect in chloride reabsorption that increases distal sodium chloride reabsorption and a collecting tubule defect in potassium secretion have both been postulated.

[edit] Diagnosis and Management.

In most cases the clinical setting points to the diagnosis. The level of the defect can be confirmed, however, with the previously described renin-aldosterone stimulation test. Low stimulated renin and aldosterone levels point to a diagnosis of hyporeninemic hypoaldosteronism. Treatment consists of avoidance of potassium loads or inciting pharmacologic agents such as ACE inhibitors or potassium-sparing diuretics. A low-potassium diet with liberalization of sodium intake, potassium-wasting diuretics, or fludrocortisone 100 to 500 μg (0.01 to 0.05 mg) per day may be necessary in some patients. High stimulated renin and low aldosterone levels point to a defect at the level of the adrenal, and high stimulated renin and aldosterone levels point to end-organ refractoriness to aldosterone's effects. Treatment options are the same for these disorders as for hyporeninemic hypoaldosteronism, although treatment of pseudohypoaldosteronism may not be as effective due to renal insensitivity.

[edit] ADRENAL MEDULLA

The adrenal medulla has a different embryologic origin from the adrenal cortex, being composed of chromaffin tissue derived from neural crest ectoderm. Its location next to the adrenal cortex appears to be critical to the synthesis of its major catecholamine, epinephrine. The enzyme critical toepinephrine formation is inducible by high levels of glucocorticoids, delivered from the cortex to the medulla by a rich blood supply. The adrenal medulla is the source of all epinephrine, whereas norepinephrine is produced by extraadrenal chromaffin cells.

[edit] Pheochromocytoma

Pheochromocytoma is the most important disease of the adrenal medulla. It is a tumor of the chromaffin cells that is an uncommon but serious cause of hypertension, with an incidence of 0.1% to 0.4% among hypertensive patients. Autopsy series indicate that it may be substantially underdiagnosed, since about 40% of all pheochromocytomas detected at autopsy in patients with a history of hypertension are not identified during life. About 90% of pheochromocytomas are found in the adrenal medulla, and 10% are extraadrenal. In general, once spread occurs to outside the chromaffin tissue, the tumor is considered malignant. This occurs in fewer than 10% of the cases. Intraadrenal tumors are usually unilateral. In the 10% of the cases in which adrenal pheochromocytoma is bilateral, patients often are found to have polyglandular multiple endocrine neoplasia (MEN) type II. Most extraadrenal pheochromocytomas are intraabdominal and can be found anywhere along the sympathetic ganglion chain, which is also composed of chromaffin tissue.

[edit] Pathophysiology.

Excess production of catecholamines has a variety of physiologic effects. Catecholamines stimulate renal sodium retention by a direct tubular effect, by increased renin secretion, and by reduced intrarenal hydrostatic pressure. Shunting of blood toward the heart, increased cardiac inotropy, and increased peripheral resistance due to vasoconstriction are also consequences of catecholamine excess. Metabolic effects include hyperglycemia, hyperlipidemia, hypokalemia, and increased tissue oxygen consumption. Most of these effects occur due to increased β-receptor–mediated stimulation of adenyl cyclase in cell membranes, which results in increased conversion of ATP to cAMP. Hyperglycemia occurs due to catecholamine-mediated increases in glycogenolysis and gluconeogenesis. Catecholamines also diffusely inhibit gut motility.

[edit] History and Physical Findings.

Most patients have persistently elevated blood pressure with superimposed paroxysms of severe hypertension. Despite the hypertension, patients are usually orthostatic due to volume contraction. A minority of patients are normotensive between paroxysmal hypertensive episodes. Episodes are accompanied by headache, sweating, palpitations, anxiety, tremulousness, and nervousness lasting from 15 to 30 minutes. The symptom triad of headache, palpitations, and diaphoresis in association with hypertension has been found to have a high specificity (93.8%) and sensitivity (90.9%) for the diagnosis in hypertensive patients. Other symptoms of pheochromocytoma may include dizziness, constipation, weight loss, flushing, and psychiatric symptoms. Laboratory findings may include hyperglycemia, hyperlipidemia, and hypokalemia. The presentation may be less typical among the elderly, since cardiomegaly and left ventricular hypertrophy (LVH) were the only features recognized retrospectively among elderly hypertensives found at autopsy to have pheochromocytoma in one series.^[11]

[edit] Diagnosis.

Excess production of epinephrine and/or norepinephrine is best determined by measurement of their excreted metabolites. Normal urinary values for catecholamines are listed in Table 98-3. Care must be taken in determining who to screen for this disorder. Because of its low prevalence among hypertensives, even a highly specific screening test results in a significant number of false-positives. Therefore screening should be performed only in those in whom clinical suspicion is truly high. In particular, it should be reserved for those with uncontrollable hypertension; for those with hypertension and the above-mentioned symptom triad of headache, palpitations, and sweating; or for those with a personal or family history of disorders suggestive of the MEN syndromes.

Table 98-3 Normal Catecholamine Values

The 24-hour urine collection must be performed carefully. Chlorpromazine, the benzodiazepines, α-methyldopa, and the β-blockers should be eliminated 2 weeks before testing. Ethanol, amphetamines, quinidine, theophylline, tetracycline, reserpine, clofibrate, and disulfiram can also interfere with the test results by raising or lowering catecholamine levels. If antihypertensive agents must be continued, diuretics or vasodilators such as hydralazine and minoxidil cause minimal interference. Levels of metanephrines, vanillylmandelic acid (VMA), and catecholamines can be measured. Total or fractionated urinary catecholamines using the high-performance liquid chromatography (HPLC) method may be the most sensitive and specific urinary test, with twofold elevations in over 95% of patients with pheochromocytoma. Urinary free norepinephrine was 100% sensitive and 98% specific for pheochromocytoma in one series. Mildly elevated values of all the catecholamine metabolites are common among hypertensives; only very high values are consistent with a diagnosis of pheochromocytoma. Plasma catecholamine measurements can also be used and may be as reliable as urinary measurements, but can be artificially elevated by stress, volume depletion, activity, anoxia, smoking, and medications; thus they must be performed under idealized conditions at complete bed rest. A clonidine suppression test can also be used when the diagnosis is uncertain and plasma norepinephrine levels are only modestly elevated (500 to 1000 pg/ml). Clonidine, 0.3 mg, is given and plasma norepinephrine levels are measured 3 hours later. Virtually all patients with essential hypertension suppress norepinephrine levels to below 500 pg/ml, whereas patients with pheochromocytoma do not.

Localization of pheochromocytoma after biochemical confirmation may be performed with adrenal CT scan or MRI. CT scan is the most cost-effective initial study, and has >98% sensitivity for detection of adrenal tumors, but a specificity of only 70%.^[11] MRI has comparable sensitivity, but has higher specificity in distinguishing medullary pheochromocytoma from adrenal cortical tumors. The latter may be superior in the detection of small tumors. Extraadrenal pheochromocytomas or very small adrenal tumors are harder to localize and may require¹³¹I metaiodobenzylguanidine (MIBG) scanning. This isotope, although expensive, is specific for catecholamine-producing tissue and has 80% sensitivity and over 95% specificity for localization of malignant pheochromocytomas. Another effective isotope used for imaging, which is reported to be of similar sensitivity, is¹¹¹In-pentetreotide (Octreoscan). Those who are found to have bilateral adrenal tumors should be screened for other manifestations of the MEN syndromes.

[edit] Management.

Surgical removal is the treatment of choice in most cases of benign and malignant pheochromocytoma. Medical treatment must begin at least 2 weeks before surgery to avoid intraoperative hypertensive crisis or hypotension after resection. This includes restoration of plasma volume, which is usually profoundly depleted by catecholamine-induced vasoconstriction, and α- andalpha;-and β-blockade. Phenoxybenzamine is the α-blocker of choice, starting at 10 mg twice daily and increasing as tolerated to 0.5 to 1 mg/kg/day until near normotension and control of symptoms are achieved. Prazosin may also be effective preoperatively; however, it does not control intraoperative hypertension well, so phenoxybenzamine must be used intraoperatively. Prazosin is started slowly at 1 mg three times a day to avoid postural hypotension and increased to 2 to 5 mg three times a day. After α-blockade has been achieved, β-blockers can be added if needed to control tachycardia, arrhythmias, or angina. β-Blockers should never be administered before α-blockade because they can precipitate hypertensive crisis due to unopposed α-receptor stimulation. Calcium channel blockers have also been used successfully preoperatively and intraoperatively. During surgery volume expansion with blood or plasma is advocated to keep blood pressure normal.

The same medications are used to manage the symptoms of malignant pheochromocytoma when complete surgical resection is not possible. An additional agent, α-methylparatyrosine, a catecholamine synthesis inhibitor, actually lowers serum catecholamine levels and can also be effective for these patients.¹³¹I-MIBG also shows promise in the treatment of unresectable pheochromocytoma.

[edit] INCIDENTAL ADRENAL MASS

The ability of abdominal CT scan or MRI performed for unrelated reasons to detect adrenal masses of 0.5 cm or smaller has resulted in a diagnostic dilemma. The prevalence of such incidentally discovered masses is 1% to 4% depending on the series. These small adrenal tumors are not new, having been previously reported at autopsy in up to 30% of patients without known endocrinopathy; what is new is our ability to detect them during life.

[edit] Evaluation Criteria

Once these lesions are detected, a limited hormonal evaluation is considered appropriate to rule out occult hypersecretory states. Although most (up to 94%) are nonsecretory, clinically silent hypersecretory pheochromocytomas, aldosteronomas, and cortisol-secreting tumors have been extensively reported, and between 50% to 70% of adrenal carcinomas are secretory; thus, a hormonal evaluation should be performed for all patients.^[12]Table 98-4 indicates the frequency of the various diagnoses to be excluded and the appropriate hormonal evaluations necessary. Identification of hormonal activity indicates the need for surgical removal.

Table 98-4 Recommended Biochemical Screening Tests for All Incidental Adrenal Masses

Adrenal masses found to be nonhypersecretory require an investigation to rule out malignancy. Prior treatment algorithms based on the presumption that malignancies are usually over 3 cm in size have low sensitivity and specificity. In one series of 86 adrenal masses, all eight lesions found to be primary carcinomas of the adrenal were 3 cm or larger, but over 60% of lesions found to be metastatic to the adrenal from other primary sites were 3 cm or smaller.^[12] Those with known primary malignancies and extensive metastatic disease elsewhere do not need further investigation. Those with primary malignancies in other sites without known metastases require biopsy of the adrenal lesion for appropriate staging of their primary tumor. In those patients who have nonhypersecretory lesions without known primary malignancies elsewhere, CT and MRI imaging features may be more accurate than size criteria in distinguishing benign vs. malignant adrenal lesions. Non-contrast CT attenuation characteristics may be helpful, as an attenuation coefficient of <10 Hounsfield units (HU) has been shown to be highly specific (92%) for benign adenomas. However, sensitivity is low (58%), as many benign adenomas have higher values.^[13] MRI T1-and T2-weighted imaging may have similar utility, but at least one study found CT attenuation coefficients to be better discriminators. If contrast CT is performed, delayed images at 1 hour may distinguish between benign lesions (<30 HU) and malignant ones (>30 HU). Chemical shift MRI for lesions with >10 HU on non-contrast CT or >30 HU on contrast CT shows promise in distinguishing those lesions with high fat content (adenomas, myelolipomas) from those with low fat content (hemorrhages, pheochromocytomas, metastases, cysts). Loss of signal with MRI chemical shift imaging indicates high fat content, while no signal loss is seen in lesions with low fat content, indicating the need for biopsy. An algorithm using these imaging criteria to determine the need for biopsy is outlined in Fig. 98-6. This strategy has been shown to correctly characterize over 90% of incidental adrenal masses. Biopsy is recommended for all lesions >3 cm and those <3 cm with suspicious radiologic characteristics. An alternate approach recommended by some experts is performance of¹³¹I-iodomethylnorcholesterol (NP-59) imaging in all patients with nonhypersecretory lesions, regardless of size, with biopsy of those with imaging patterns more characteristic of malignancy (decreased, absent, or distorted radioisotope distribution).^[12] In all cases, hormonal studies must be completed before needle biopsy, since manipulation of an unsuspected pheochromocytoma is quite dangerous.

Figure 98-6 Diagnostic approach to incidental adrenal mass. (From Peppercorn PD, Grossman AB, Reznek RH:Clin Endocrinol 48:379-388, 1998.)

[edit] Monitoring

Those who do not meet the criteria for further investigation should be followed clinically, with yearly history and physical examination. Some experts recommend repeat CT scan or MRI in 3 months, with removal of tumors evidencing growth to >3 cm at 3 months. Small lesions of less than 3 cm that are stable in size for 1 year in asymptomatic patients can be monitored infrequently.

[edit] REFERENCES