Chronic glucocorticoid excess, whatever its cause, leads to the constellation of symptoms and physical features known as Cushing syndrome. It is most commonly iatrogenic, resulting from chronic glucocorticoid therapy. Spontaneous Cushing syndrome is caused by abnormalities of the pituitary or adrenal gland or may occur as a consequence of ACTH or CRH secretion by nonpituitary tumors (ectopic ACTH syndrome; ectopic CRH syndrome) (Figure 9–10). Cushing disease is defined as the specific type of Cushing syndrome due to excessive pituitary ACTH secretion from a pituitary tumor. This section reviews the various types of endogenous Cushing syndrome and discuss their diagnosis and therapy (see also Chapter 4).
Hypothalamic-pituitary axis in Cushing syndrome of different causes. These panels illustrate hormone secretion in the normal state (upper left), and four types of cortisol excess: Pituitary ACTH-dependent (with an ACTH-secreting pituitary tumor) (upper right), adrenal tumor (lower left), ectopic ACTH syndrome due to an ACTH-secreting lung cancer (lower middle), and ectopic CRH syndrome due to a CRH-secreting lung tumor. In contrast to normal secretion and hormone levels, decreased hormonal secretion is indicated by a dotted line and increased secretion by a dark solid line.
Classification and Incidence
Cushing syndrome is classified as either ACTH dependent or ACTH independent (Table 9–11). The ACTH-dependent types of Cushing syndrome—ectopic ACTH syndrome and Cushing disease—are characterized by chronic ACTH hypersecretion, which results in hyperplasia of the adrenal zonae fasciculata and reticularis and, therefore, increased secretion of cortisol, androgens, and DOC.
TABLE 9–11Cushing syndrome: differential diagnosis. |Favorite Table|Download (.pdf) TABLE 9–11 Cushing syndrome: differential diagnosis.
Pituitary adenoma (Cushing disease)
Nonpituitary neoplasm (ectopic ACTH)
Iatrogenic (glucocorticoid, megestrol acetate)
Unilateral adrenal neoplasm/adenoma
Bilateral adrenal hyperplasia/neoplasm
Bilateral macronodular adrenal hyperplasia
McCune Albright syndrome
Primary pigmented nodular adrenal disease
Isolated micronodular adrenocortical disease
ACTH-independent Cushing syndrome may be caused by a primary adrenal neoplasm (adenoma or carcinoma) or bilateral nodular adrenal hyperplasia. In these cases, the cortisol excess suppresses pituitary ACTH secretion.
Traditionally this has been the most frequent type of Cushing syndrome and most studies attribute 80% of reported cases to Cushing disease. It is much more common in women than in men (female-male ratio of about 5:1) and the age at diagnosis is usually 20 to 40 years but may range from childhood to 70 years.
B. Ectopic ACTH hypersecretion
This disorder accounts for approximately 10% of patients with ACTH-dependent Cushing syndrome. The production of ACTH from a tumor of nonpituitary origin may result in severe hypercortisolism, but many of these patients lack the classic features of glucocorticoid excess. This presumably reflects the acuteness of the clinical course in the ectopic ACTH syndrome. The clinical presentation of ectopic ACTH secretion is most frequently seen in patients with tumors of a thoracic origin. Bronchial carcinoid, small cell and non-small cell lung carcinoma are responsible for over 50% of cases of this syndrome. The prognosis in patients with the ectopic ACTH syndrome is generally poor and largely a function of the primary tumor. Individuals with ectopic ACTH syndrome from small cell lung carcinoma have a mean survival of less than 12 months. The ectopic ACTH syndrome may also present in a fashion identical to classic Cushing disease and pose a challenging diagnostic dilemma. A wide variety of tumors has been reported to produce ectopic ACTH and may be radiologically inapparent at the time of the presentation. The ectopic ACTH syndrome is more common in men, and the peak age incidence is 40 to 60 years.
C. Primary adrenal tumors
Primary adrenal tumors are increasingly being recognized as a common cause of Cushing syndrome. Most of these patients have benign adrenocortical adenomas. Adrenocortical carcinomas are uncommon, with an incidence of approximately 2 per million per year. Adrenal carcinomas are more common in women. Autonomous cortisol secretion without the classic features of Cushing syndrome occurs in up to 20% to 25% of patients with adrenal incidentalomas (see later).
D. Childhood Cushing syndrome
Childhood Cushing disease is rare, but is more common in the adolescent population than in younger children. Most pediatric cases occur in patients over 10 years of age with an equal distribution between the sexes. Cushing disease remains the most common cause of Cushing syndrome accounting for more than 80% of cases. Primary adrenal disease accounts for an additional 10% to 15% of all pediatric cases. A hallmark of childhood Cushing syndrome is significant weight gain without accompanying linear growth.
A. Anterior pituitary gland
Pituitary adenomas—Pituitary adenomas are present in over 90% of patients with Cushing disease. These tumors are typically smaller than those secreting GH or PRL; 80% to 90% are less than 10 mm in diameter. A small group of patients have larger tumors (>10 mm); these macroadenomas are frequently invasive, leading to extension outside the sella turcica. Malignant pituitary tumors occur very rarely.
Microadenomas are located within the anterior pituitary; they are not encapsulated but surrounded by a rim of compressed normal anterior pituitary cells. With routine histologic stains, these tumors are composed of compact sheets of well-granulated basophilic cells in a sinusoidal arrangement. ACTH, β-lipotropin, and β-endorphin have been demonstrated in these tumor cells by immunocytochemical methods. Larger tumors may appear chromophobic on routine histologic study; however, they also contain ACTH and its related peptides. These ACTH-secreting adenomas typically show Crooke changes (a zone of perinuclear hyalinization that is the result of chronic exposure of corticotroph cells to hypercortisolism). Electron microscopy demonstrates secretory granules that vary in size from 200 to 700 nm. The number of granules varies in individual cells; they may be dispersed throughout the cytoplasm or concentrated along the cell membrane. A typical feature of these adenomas is the presence of bundles of perinuclear microfilaments (average 7 nm in diameter) surrounding the nucleus; these are responsible for Crooke hyaline changes visible on light microscopy.
Hyperplasia—Diffuse hyperplasia of corticotroph cells has been reported rarely in patients with Cushing disease.
Other conditions—In patients with adrenal tumors or ectopic ACTH syndrome, the pituitary corticotrophs show prominent Crooke hyaline changes and perinuclear microfilaments. The ACTH content of corticotroph cells is reduced consistent with their suppression by excessive cortisol secretion present in these conditions.
B. Adrenocortical hyperplasia
Chronic ACTH hypersecretion, usually due to Cushing disease, can lead to bilateral enlargement and hyperplasia of the adrenal cortex. Combined adrenal weight (normal, 8-10 g) is modestly increased, ranging from 12 to 24 g. On histologic study, there is equal hyperplasia of the compact cells of the zona reticularis and the clear cells of the zona fasciculata; consequently, the width of the cortex is increased. Electron microscopy reveals normal ultrastructural features. When ACTH levels are very high as in the ectopic ACTH syndrome, the adrenals are frequently larger, with combined weights up to or more than 50 g. The characteristic microscopic feature is marked hyperplasia of the zona reticularis; columns of compact reticularis cells expand throughout the zona fasciculata and into the zona glomerulosa. The zona fasciculata clear cells are markedly reduced.
C. Nodular adrenal disease
Adrenal nodules that hypersecrete cortisol can be unilateral or bilateral, and their pathology varies depending on the etiology.
Unilateral cortisol-secreting adrenal adenomas—These adenomas are encapsulated, usually weigh 10 to 70 g, and range in size from 1 to 6 cm. Microscopically, clear cells of the zona fasciculata type predominate, although cells typical of the zona reticularis are also seen. The uninvolved adrenal cortex contiguous to the tumor and that of the contralateral gland are atrophic in the presence of functioning adrenal adenomas and carcinomas (see later). The cortex is markedly thinned, whereas the capsule is thickened. Histologically, the zona reticularis is virtually absent; the remaining cortex is composed of clear fasciculata cells. The architecture of the zona glomerulosa is normal.
Adrenal carcinomas—Adrenal carcinomas are usually greater than 4 cm when diagnosed and often weigh more than 100 g, occasionally exceeding 1 kg. They may be palpable as abdominal masses. Grossly, they are encapsulated and highly vascular; necrosis, hemorrhage, and cystic degeneration are common, and areas of calcification may be present. The histologic appearance of these carcinomas varies considerably; they may appear to be benign or may exhibit considerable pleomorphism. Vascular or capsular invasion is predictive of malignant behavior, as is local extension. These carcinomas invade local structures (kidney, liver, and retroperitoneum) and metastasize hematogenously to liver and lung. As in unilateral glucocorticoid-secreting adenomas, the surrounding adrenal cortex is atrophic.
Bilateral nodular adrenal hyperplasia—This can be due to ACTH stimulation (ACTH-dependent) or from several unique ACTH-independent pathophysiologic disorders. Longstanding ACTH hypersecretion—either pituitary or nonpituitary—may result in nodular enlargement of the adrenal gland. The cortex between the nodules is not atrophic as there is ACTH stimulation to the entire gland. These focal nodules are often mistaken for adrenal neoplasms and may lead to unnecessary as well as unsuccessful unilateral adrenal surgery. In occasional cases these nodules may, over a period of time, even become autonomous or semiautonomous. Removal of the ACTH-secreting neoplasm results in regression of the adrenal nodules as well as resolution of hypercortisolism unless the nodules have already developed significant autonomy.
ACTH-independent bilateral nodular adrenal hyperplasia can be divided based on nodular size, diameter less than 1 cm (micronodular) or more than 1 cm (macronodular). Primary pigmented nodular adrenocortical disease (PPNAD) is a micronodular condition that has small to normal sized adrenal glands with multiple black and brown nodules with intranodular cortical atrophy. The pathology of nodules in bilateral macronodular adrenal hyperplasia (BMAH) is similar to unilateral disease, but the internodular cortex can be hyperplastic (commonly) or can be atrophic.
Pathogenesis and Genetics
TABLE 9–12Genetic causes of adrenal dependent cushing syndrome. |Favorite Table|Download (.pdf) TABLE 9–12 Genetic causes of adrenal dependent cushing syndrome.
|Condition/Gene/Chromosome ||Related Conditions ||Nodular Disease |
|McCune Albright syndrome/GNAS1/20q13.3 ||Fibrous dysplasia of bone, café-au-lait skin pigmentation, precocious puberty ||Unilateral or bilateral, micro- or macronodularity |
|Primary pigmented nodular adrenal disease/PRKAR1A/17q22-24 ||Carney Complex (myxomas, testicular tumors, thyroid nodules, growth hormone producing pituitary adenomas ||Bilateral, micronodular |
|Cortisol producing adenomas/PRKACA/19p13.1 ||No associated syndrome ||Unilateral, usually macronodular |
|Familial adenomatous polyposis/APC/5q22.2 ||Multiple colon polyps and colon cancer ||Unilateral or bilateral, macronodular |
|Multiple endocrine neoplasia type 1/MENIN/11q13 ||Primary hyperparathyroidism, pancreatic endocrine tumors, pituitary adenomas ||Unilateral or bilateral, macronodular |
|Hereditary leiomyomatosis and renal cell cancer syndrome/fumarate hydratase/1q42.1 ||Hereditary leiomyomatosis, renal cell cancer, uterine fibroids ||Bilateral, macromodular |
|Hereditary bilateral adrenal adenomas/ARMC5/16q11.2 ||Hereditary adrenal adenomas, often cortisol-producing (may be subclinical cortisol excess) ||Bilateral, macronodular |
The causes, natural history, and genetics of Cushing disease are reviewed in Chapter 4. Current evidence is consistent with the view that spontaneously arising corticotroph-cell pituitary adenomas are the primary cause and that the consequent ACTH hypersecretion and hypercortisolism lead to the characteristic endocrine abnormalities and hypothalamic dysfunction. This is supported by evidence showing that selective removal of these adenomas by pituitary microsurgery reverses the abnormalities and is followed by return of the HPA axis to normal. In addition, molecular studies have shown that nearly all corticotroph adenomas are monoclonal.
Although these primary pituitary adenomas are responsible for the great majority of cases, a few patients have been described in whom pituitary disease has been limited to corticotroph-cell hyperplasia; these may be secondary to excessive CRH secretion by rare, benign hypothalamic gangliocytoma.
B. Ectopic ACTH syndrome and ectopic CRH syndrome
Ectopic ACTH syndrome arises when nonpituitary tumors synthesize and secrete biologically active ACTH. The related peptides a-lipotropin and β-endorphin are also synthesized and secreted, as are inactive ACTH fragments. Production of CRH has also been demonstrated in ectopic tumors secreting ACTH, but whether CRH plays a role in pathogenesis is unclear. A few cases in which nonpituitary tumors produced only CRH have been reported.
Ectopic ACTH syndrome occurs predominantly in selected tumor types (Figure 9–11); carcinoid tumors of lung, non-small cell, and small cell carcinoma of the lung account for most of the cases. Other tumors causing the syndrome are of neuroendocrine origin from cells in the thymus, gut, ovary, pancreatic islet, or thyroid (ie, C-cells). Multiple other tumor types have also been reported to cause the ectopic ACTH syndrome, but are very rare causes for it (see Chapter 21).
Prevalence of the most common tumors causing ectopic ACTH secretion. (K, carcinoma; NET, neuroendocrine tumor; SCLC, small cell lung carcinoma). (Reproduced with permission from Isidori AM, Lenzi A. Ectopic ACTH syndrome. Arq Bras Endocrinol Metabol. 2007 Nov;51(8):1217-1225.)
C. Nodular adrenal disease
Recent discoveries have allowed a better understanding of the genetics responsible for nodular adrenal disease.
Unilateral cortisol-secreting adrenal adenomas—In 2013, four separate groups from around the world reported a mutation in the gene for the protein kinase A catalytic subunit, PRKACA. Together, these groups investigated more than 200 cortisol-secreting adrenal adenomas. They found mutations in the gene for PRKACA leading to constitutive activation of protein kinase A in more than 40% of the adenomas. The mutations were largely (95%) found in a single hotspot. These mutations were not found to surrounding normal adrenal tissue, in non-functional adenomas, adrenal cortical carcinomas, or in adrenal nodules with subtle cortisol hypersecretion (subclinical Cushing syndrome).
Bilateral micronodular adrenal hyperplasia—Primary pigmented nodular adrenocortical disease is an uncommon familial cause of adrenal-dependent Cushing syndrome. It is associated with myxomas (cardiac, cutaneous, and mammary), spotty skin pigmentation, endocrine overactivity, sexual precocity, acromegaly, and schwannomas—referred to as the Carney complex. Germline inactivating mutations in the regulatory subunit of protein kinase A have been shown to cause constitutive activation of a pathway critical for cortisol production.
Bilateral macronodular adrenal hyperplasia (BMAH)—Multiple distinct entities exist that can result in BMAH. These adrenal nodules may be under the control of abnormal or ectopic hormone receptors. Aberrant regulation of cortisol production and adrenal growth has been shown in some of these patients to be mediated by the abnormal adrenal expression of receptors for a variety of hormones. The best characterized appears to be the expression of glucose-dependent insulinotropic polypeptide (GIP), whose adrenal expression has resulted in the modulation of cortisol production after physiologic postprandial fluctuation of endogenous levels of GIP, causing a state of food-dependent Cushing syndrome. Other abnormal hormone receptors that have been described in association with endogenous hypercortisolism with this phenomenon include vasopressin, beta-adrenergic agonists, human chorionic gonadotropin-LH, serotonin, angiotensin II, and leptin (see also Chapter 21). The identification of an ectopically expressed adrenal receptor raises the possibility of new pharmacologic approaches for control of hypercortisolism by suppressing the endogenous ligands or by blocking the abnormally expressed receptor with specific antagonists.
Another recent discovery that has furthered our knowledge of adrenal tumor genetics is that of the role of the armadillo-repeat containing 5 (ARMC5) gene. ARMC5 is a putative tumor suppressor gene located on chromosome 16p11.2. An investigation of apparently sporadic cases of BMAH showed mutations in both alleles of ARMC5, one germline and one somatic. The inactivating mutations in ARMC5 appear to decrease steroidogenesis in vitro and may explain why very large nodules are required to produce cortisol excess. Several studies have looked at relatives of patients with BMAH and found germline mutations in over half of the studied relatives. In these individuals without any symptoms of Cushing syndrome, adrenal nodular hyperplasia was frequently discovered. It has also been reported that ACTH may be produced in the adrenal glands of patients with BMAH. This intraadrenal ACTH production may be the reason why there is internodular hyperplasia in many patients with BMAH.
McCune-Albright syndrome (characterized by fibrous dysplasia of bone, café-au-lait skin pigmentation, precocious puberty, and endocrine hormone excess) is caused by activating mutations of Gsα that lead to constitutive steroidogenesis in adrenal nodules carrying the mutation.
Additionally, BMAH has been found to be associated with several other genetic syndromes including multiple endocrine neoplasia type 1, familial adenomatous polyposis, and hereditary leiomyomatosis and renal cell cancer syndrome.
The diagnosis of Cushing syndrome. (Reproduced with permission from Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008 May;93(5):1526-1540.)
In Cushing disease, ACTH hypersecretion is random and episodic and causes cortisol hypersecretion in the absence of the normal circadian rhythm. Feedback inhibition of ACTH (secreted from the pituitary adenoma) by physiologic levels of glucocorticoids is suppressed; thus, ACTH hypersecretion persists despite elevated cortisol secretion and results in chronic glucocorticoid excess. The episodic secretion of ACTH and cortisol results in variable plasma levels that may at times be within the normal range. However, demonstration of elevated late-night serum or salivary cortisol levels, lack of suppression of cortisol after dexamethasone, or elevation of urine free cortisol confirms cortisol hypersecretion (see sections on Laboratory Evaluation and Diagnosis of Cushing Syndrome). The overall increase in glucocorticoid secretion causes the clinical manifestations of Cushing syndrome. ACTH and a-lipotropin secretion are not usually elevated sufficiently to cause hyperpigmentation.
Abnormalities of ACTH secretion—Despite ACTH hypersecretion, stress responsiveness is absent; stimuli such as hypoglycemia or surgery fail to further elevate ACTH and cortisol secretion. This is probably due to suppression of hypothalamic function and CRH secretion by hypercortisolism, resulting in loss of hypothalamic control of ACTH secretion (see Chapter 4).
Effect of cortisol excess—Cortisol excess not only inhibits normal pituitary and hypothalamic function, affecting ACTH, TSH, GH, and gonadotropin release, but also results in all the systemic effects of glucocorticoid excess described in previous sections and in the section on Clinical Features later.
Androgen excess—Secretion of adrenal androgens is also increased in Cushing disease, and the degree of androgen excess parallels that of ACTH and cortisol. Thus, plasma levels of DHEA, DHEA sulfate, and androstenedione may be moderately elevated in Cushing disease; the peripheral conversion of these hormones to testosterone and dihydrotestosterone leads to androgen excess. In women, this causes hirsutism, acne, and amenorrhea. In men with Cushing disease, cortisol suppression of LH secretion decreases testosterone secretion by the testis, resulting in decreased libido and impotence. The increased adrenal androgen secretion is insufficient to compensate for the decreased gonadal testosterone production.
Hypersecretion of ACTH and cortisol is usually greater in patients with ectopic ACTH syndrome than in those with Cushing disease. ACTH and cortisol hypersecretion is randomly episodic, and the levels are often greatly elevated. Usually, ACTH secretion by ectopic tumors is not subject to negative feedback control; that is, secretion of ACTH and cortisol is nonsuppressible with pharmacologic doses of glucocorticoids (see section on Diagnosis later).
Plasma levels, secretion rates, and urinary excretion of cortisol, the adrenal androgens, and DOC are often markedly elevated; despite this, the typical features of Cushing syndrome maybe absent, presumably because of rapid onset of hypercortisolism, anorexia, and other manifestations of the associated malignant disease. Features of mineralocorticoid excess (hypertension and hypokalemia) are frequently present and have been attributed to increased secretion of DOC and the mineralocorticoid effects of cortisol. With ectopic CRH secretion, pituitary corticotroph hyperplasia and ACTH hypersecretion are observed along with resistance to negative feedback by cortisol.
Autonomous secretion—Primary adrenal tumors, both adenomas and carcinomas, autonomously hypersecrete cortisol. Circulating plasma ACTH levels are suppressed, resulting in cortical atrophy of the uninvolved adrenal. Secretion is randomly episodic, and these tumors are typically unresponsive to manipulation of the hypothalamic-pituitary axis with pharmacologic agents such as dexamethasone and metyrapone.
Adrenal adenomas—Adrenal adenomas causing Cushing syndrome typically present solely with clinical manifestations of glucocorticoid excess, because they usually secrete only cortisol. Thus, the presence of androgen or mineralocorticoid excess should suggest that the tumor is an adrenocortical carcinoma.
Adrenal carcinomas—Adrenal carcinomas frequently hypersecrete multiple adrenocortical steroids and their precursors. Cortisol and androgens are the steroids most frequently secreted in excess; 11-deoxycortisol is often elevated, and there may be increased secretion of DOC, aldosterone, or estrogens. Plasma cortisol and urine free cortisol are often markedly increased; androgen excess is usually even greater than that of cortisol. Thus, high levels of plasma DHEA, DHEA sulfate, and of testosterone typically accompany the cortisol excess. Clinical manifestations of hypercortisolism are usually severe and rapidly progressive in these patients. In women, features of androgen excess are prominent; virilism may occasionally occur. Hypertension and hypokalemia are frequent and most commonly result from the mineralocorticoid effects of cortisol; less frequently, DOC and aldosterone hypersecretion also contribute.
TABLE 9–13Clinical features of Cushing syndrome (% prevalence). |Favorite Table|Download (.pdf) TABLE 9–13 Clinical features of Cushing syndrome (% prevalence).
Menstrual disorders 70%
Impotence, decreased libido 85%
Glucose intolerance 75%
Kidney stones 15%
Obesity—Obesity is the most common manifestation, and weight gain is usually the initial symptom. It is classically central, affecting mainly the face, neck, trunk, and abdomen, with relative sparing of the extremities. Generalized obesity with central accentuation is equally common, particularly in children.
Accumulation of fat in the face leads to the typical facial rounding, moon facies, which is present in 75% of cases and is accompanied by facial plethora in most patients. Fat accumulation around the neck is prominent in the supraclavicular and dorsocervical fat pads.
Obesity is absent in a handful of patients who do not gain weight; however, they usually have central redistribution of fat and a typical facial appearance.
Skin changes—Skin changes are frequent, and their presence should arouse a suspicion of cortisol excess. Atrophy of the epidermis and its underlying connective tissue leads to thinning (a transparent appearance of the skin) and facial plethora. Easy bruisability following minimal trauma is present in about 40%. Striae occur in 50% but are very unusual in patients over 40 years of age. These are typically red to purple, depressed below the skin surface secondary to loss of underlying connective tissue, and wider (not infrequently >1-2 cm) than the pinkish-white striae that may occur with pregnancy or rapid weight gain. These striae are most commonly abdominal but may also occur over the breasts, hips, buttocks, thighs, and axillae.
Acne presenting as pustular or papular lesions may result from glucocorticoid excess or hyperandrogenism.
Minor wounds and abrasions may heal slowly, and surgical incisions sometimes undergo dehiscence.
Mucocutaneous fungal infections are frequent, including tinea versicolor, involvement of the nails (onychomycosis), and oral candidiasis.
Hyperpigmentation of the skin is rare in Cushing disease or adrenal tumors but is common in ectopic ACTH syndrome.
Hirsutism—Hirsutism is present in about 80% of female patients owing to hypersecretion of adrenal androgens. Facial hirsutism is most common, but increased hair growth may also occur over the abdomen, breasts, chest, and upper thighs. Acne and seborrhea usually accompany hirsutism. Virilism is unusual except in cases of adrenal carcinoma, in which it occurs in about 20% of patients.
Hypertension—Hypertension is a classic feature of spontaneous Cushing syndrome; it is present in about 75% of cases, and the diastolic blood pressure is greater than 100 mm Hg in over 50%. Hypertension and its complications contribute greatly to the morbidity and mortality rates in spontaneous Cushing syndrome.
Gonadal dysfunction—This is very common as a result of elevated androgens (in females) and cortisol (in males and to a lesser extent in females). Amenorrhea occurs in 75% of premenopausal women and is usually accompanied by infertility. Decreased libido is frequent in males, and some have decreased body hair and soft testes.
Central nervous system and psychologic disturbances—Psychologic disturbances occur in the majority of patients. Mild symptoms consist of emotional lability and increased irritability. Anxiety, depression, poor concentration, and poor memory may also be present. Euphoria is frequent, and occasionally patients manifest overtly manic behavior. Sleep disorders are present in most patients, with either insomnia or early morning awakening.
Severe psychologic disorders occur in a few patients and include severe depression, psychosis with delusions or hallucinations, and paranoia. Some patients have committed suicide. Loss of brain volume that is at least partially reversible following correction of hypercortisolism has been observed in several reports.
Muscle weakness—This occurs in about 60% of cases; it is more often proximal and is usually most prominent in the lower extremities. Hypercortisolism is associated with both low fat-free muscle mass and low total body protein.
Osteoporosis—Owing to the profound effects of glucocorticoids on the skeleton, patients with Cushing syndrome frequently have evidence of significant osteopenia and osteoporosis. Patients may present with multiple fragility fractures—typically of the feet, ribs, or vertebrae. Back pain may be the initial complaint. Compression fractures of the spine are demonstrated radiographically in 15% to 20% of patients. In fact, unexplained osteopenia in any young or middle-aged adult should always prompt an evaluation for Cushing syndrome, even in the absence of any other signs or symptoms of cortisol excess. Although avascular necrosis of bone has been associated with exogenous glucocorticoid administration, the problem is rarely observed in patients with endogenous hypercortisolism.
Renal calculi—Calculi secondary to glucocorticoid-induced hypercalciuria occur in approximately 15% of patients, and renal colic may occasionally be a presenting complaint.
Thirst and polyuria—Polyuria is rarely due to overt hyperglycemia but is usually caused by glucocorticoid-induced inhibition of vasopressin (antidiuretic hormone or ADH) secretion and the direct enhancement of renal free water clearance by cortisol.
Growth deceleration—In children, nearly all (>95%) show decreasing linear growth. Weight gain accompanying decreasing linear growth in a child should prompt an evaluation for Cushing syndrome.
Routine laboratory examinations are described here. Specific tests to establish the diagnosis of Cushing syndrome are discussed in the section on Diagnosis.
High normal hemoglobin, hematocrit, and red cell counts are usual; polycythemia is rare. The total white count is usually normal; however, both the percentage of lymphocytes and the total lymphocyte count may be subnormal. Eosinophils are also depressed, and a total eosinophil count less than 100/μL is present in most patients. Serum electrolytes, with rare exceptions, are normal in Cushing disease; however, hypokalemic alkalosis occurs when there is marked steroid hypersecretion with the ectopic ACTH syndrome or adrenocortical carcinoma.
Although fasting hyperglycemia occurs in only 10% to 15% of patients, glucose intolerance is a relatively common finding and occurs in 60% of patients. Most patients have secondary hyperinsulinemia and abnormal glucose tolerance tests.
Serum calcium is normal; serum phosphorus is low normal or slightly depressed. Hypercalciuria is present in 40% of cases.
Routine radiographs may reveal cardiomegaly, due to hypertensive or atherosclerotic heart disease, or mediastinal widening, due to central fat accumulation. Vertebral compression fractures, rib fractures, and renal calculi may be present.
D. Electrocardiographic findings
Hypertensive, ischemic, and electrolyte-induced changes may be present on the electrocardiogram.
Features Suggesting a Specific Cause
Cushing disease typifies the classic clinical picture: female predominance, onset generally between ages 20 and 40, and a slow progression over several years. Hyperpigmentation and hypokalemic alkalosis are rare; androgenic manifestations are limited to acne and hirsutism. In general, secretion of cortisol and adrenal androgens is only moderately increased.
B. Ectopic ACTH syndrome (carcinoma)
In contrast, this syndrome occurs predominantly in males, with the highest incidence between ages 40 and 60. The clinical manifestations of hypercortisolism are frequently limited to weakness, hypertension, and glucose intolerance; the primary tumor is usually apparent. Hyperpigmentation, hypokalemia, and alkalosis are common, as are weight loss and anemia. The hypercortisolism is of rapid onset, and steroid hypersecretion is frequently severe, with equally elevated levels of glucocorticoids, androgens, and DOC.
C. Ectopic ACTH syndrome (benign tumor)
A minority of patients with ectopic ACTH syndrome due to more benign tumors, especially bronchial carcinoids, present a more slowly progressive course, with typical features of Cushing syndrome. These patients may be clinically identical to those with pituitary-dependent Cushing disease, and the responsible tumor may not be apparent. Hyperpigmentation, hypokalemic alkalosis, and anemia are variably present. Further confusion may arise, since a number of these patients with occult ectopic tumors may have ACTH and steroid dynamics typical of Cushing disease (see later).
The clinical picture in patients with adrenal adenomas is usually that of glucocorticoid excess alone, and androgenic effects such as hirsutism are absent. Onset is gradual, and hypercortisolism is mild to moderate. Plasma androgens are usually in the low normal or subnormal range.
In general, adrenal carcinomas have a rapid onset of the clinical features of excessive glucocorticoid, androgen, and mineralocorticoid secretion and are rapidly progressive. Marked elevations of both cortisol and androgens are usual; hypokalemia is common, as are abdominal pain, palpable masses, and hepatic and pulmonary metastases.
The clinical suspicion of Cushing syndrome must be confirmed with biochemical studies. Initially, a general assessment of the patient regarding the presence of other illnesses, drugs, alcohol, or psychiatric problems must be done since these factors may confound the evaluation. In the majority of cases, the biochemical diagnosis of Cushing syndrome can be easily performed in the ambulatory setting (see Figure 9–12).
A. Dexamethasone suppression test
The overnight 1-mg dexamethasone suppression test is a valuable screening test in patients with suspected hypercortisolism. This study employs the administration of 1 mg of dexamethasone at bedtime (11:00 pm), with determination of a plasma cortisol early the following morning. Normal subjects should suppress plasma cortisol to less than 1.8 μg/dL (50 nmol/L) following an overnight 1-mg test. Although a level of less than 5 μg/dL has been used in the past, several false-negative studies have been discovered using this test criterion. False-negative results may occur in some patients with mild hypercortisolism and in those with intermittent hypercortisolism. False-positive results with the overnight 1-mg dexamethasone suppression test may be caused by drugs that accelerate dexamethasone metabolism (phenytoin, phenobarbital, rifampin) or by drugs that increase CBG and resultant total cortisol levels (estrogens). False-positive results also occur in patients with renal failure, depression, alcoholism, or in patients undergoing a stressful event or serious illness.
Another study used in the diagnosis of Cushing syndrome is the determination of urine free cortisol measured by HPLC or LC/MS/MS in a 24-hour urine collection. These methods are highly accurate and specific for the measurement of cortisol. Commonly used drugs and medications do not interfere; however, carbamazepine and fenofibrate can cause falsely elevated results with HPLC since they elute with cortisol. Urinary free cortisol is usually less than 50 μg/24 h (<135 nmol/24 h) when measured by HPLC or LC/MS/MS. The major liability of urine free cortisol is its poor sensitivity for detecting patients with mild to moderate hypercortisolism (sensitivity <75%). Consequently, this modality should not be used alone to exclude Cushing syndrome.
C. Late-night serum and salivary cortisol
The absence of diurnal cortisol rhythm is a hallmark of Cushing syndrome. Normally, cortisol is secreted episodically with a diurnal rhythm paralleling the secretion of ACTH. Levels are usually highest early in the morning and decrease gradually throughout the day, reaching the nadir in the late evening between 11:00 pm and midnight. Several studies have demonstrated that an elevated midnight plasma cortisol level (>5.2-7.0 μg/dL [140-190 nmo1/L]) is highly accurate in differentiating patients with Cushing syndrome from normal subjects and from patients with pseudo-Cushing conditions such as depression or alcoholism.
Because obtaining such plasma cortisol measurements is impractical on an ambulatory basis, the measurement of salivary cortisol provides a simple and more convenient means of probing nighttime cortisol secretion. Saliva can easily be sampled at home by the patient using a variety of techniques. Reference ranges for late-night salivary cortisol concentrations are dependent on the assay employed; however, using a radioimmunoassay, normal subjects should have values less than 0.15 μg/dL (4 nmol/L).
It has become increasingly appreciated that many common physiologic situations and medical disorders can also cause sustained or intermittent hypercortisolism and may mimic—clinically and biochemically—the neoplastic causes of Cushing syndrome with which we are so familiar (pituitary/nonpituitary ACTH-secreting tumors and adrenal neoplasia). These disorders have been characterized as “pseudo-Cushing syndrome.” Of course, the clinical features of Cushing syndrome such as obesity, hypertension, diabetes, myopathy, osteoporosis, and neuropsychiatric problems may be evident in some patients with chronic physiologic/non-neoplastic hypercortisolism (eg, depression, chronic alcoholism, and chronic kidney disease) and be indistinguishable from those with pathologic Cushing syndrome.
These conditions may have biochemical features of Cushing syndrome, including elevations of urine free cortisol, disruptions in the normal diurnal pattern of cortisol secretion, and lack of suppression of cortisol after the overnight 1-mg dexamethasone suppression test. Although the history and physical examination may provide specific clues to the appropriate diagnosis, definitive biochemical confirmation may be difficult and may require repeated testing.
The ACTH and cortisol responses to DDAVP have been used to distinguish patients with pathologic/neoplastic Cushing syndrome from those with physiologic/non-neoplastic hypercortisolism. Since corticotroph adenomas harbor vasopressin receptors, patients with Cushing disease have an exaggerated ACTH response to desmopressin (peak response >70 pg/mL [>15.4 pmol/L] or an increase >27 pg/mL [>5.9 pmol/L]), while those with alcohol-induced Cushing syndrome (and other nonneoplastic hypercortisolemic states) have a blunted ACTH response. The cortisol responses have been less valuable in this differentiation.
Another study to distinguish mild Cushing syndrome from pseudo-Cushing conditions is the use of dexamethasone suppression followed by CRH stimulation. This test takes advantage of differential response of patients with Cushing syndrome and pseudo-Cushing syndrome to both dexamethasone and CRH by combining these tests to provide greater accuracy in the diagnosis. This study involves the administration of dexamethasone, 0.5 mg every 6 hours for eight doses, followed immediately by a CRH stimulation test, starting 2 hours after the completion of the low-dose dexamethasone suppression. A plasma cortisol concentration greater than 1.4 μg/dL (38.6 nmol/L) measured 15 minutes after administration of CRH correctly identifies the majority of patients with Cushing syndrome. After administration of high-dose dexamethasone, patients with pseudo-Cushing syndrome do not have a rise in cortisol or ACTH in response to CRH. However, it is now appreciated that some patients with pseudo-Cushing syndrome (eg, anorexia nervosa) may have abnormal dexamethasone-CRH suppression tests.
The differential diagnosis of Cushing syndrome can be difficult and should always be performed in consultation with an endocrinologist. The introduction of several technologic advances, including a specific and sensitive IRMA or ICMA for ACTH, CRH stimulation test, inferior petrosal sinus sampling (IPSS), CT and magnetic resonance imaging (MRI) of the pituitary and adrenal glands have all provided means for an accurate differential diagnosis.
Initially, the differential diagnosis for Cushing syndrome must distinguish between ACTH-dependent Cushing syndrome (pituitary or nonpituitary ACTH-secreting neoplasm) and ACTH-independent hypercortisolism. The best way to distinguish these forms of Cushing syndrome is measurement of plasma ACTH by IRMA or ICMA. The development of this sensitive and specific test has made it possible to reliably identify patients with ACTH-independent Cushing syndrome. The ACTH level is generally less than 10 pg/mL (2.2 pmol/L) and exhibits a blunted response to CRH (peak response <10 pg/mL [2.2 pmol/L]) in patients with cortisol-producing adrenal neoplasms, autonomous bilateral adrenal cortical hyperplasia, and factitious Cushing syndrome (Figure 9–13). Patients with ACTH-secreting neoplasms usually have plasma ACTH levels greater than 20 pg/mL (4.4 pmol/L) and frequently greater than 52 pg/mL (11.5 pmol/L). The major challenge in the differential diagnosis of ACTH-dependent Cushing syndrome is identifying the source of the ACTH-secreting tumor. The vast majority of these patients (90%) have a pituitary tumor, whereas the others harbor a nonpituitary neoplasm. Diagnostic studies needed to differentiate these two entities must yield nearly perfect sensitivity, specificity, and accuracy. Although plasma ACTH levels are usually higher in patients with ectopic ACTH than those with pituitary ACTH-dependent Cushing syndrome, there is considerable overlap between these two entities. Many of the ectopic ACTH-secreting tumors are radiologically occult at the time of presentation and may not become clinically apparent for many years after the initial diagnosis. However, an enhanced ACTH response for CRH administration is more frequently found in pituitary Cushing syndrome compared with ectopic ACTH syndrome.
Plasma ACTH-IRMA (pmol/L or pg/mL) of patients with pituitary-adrenal disorders. Dashed horizontal lines indicate reference range. CD = Cushing disease, EAS = Ectopic ACTH syndrome, ACS = Adrenal ACTH-independent Cushing syndrome, 10 AI = primary adrenal insufficiency, 20 AI = Secondary adrenal insufficiency, Pit = Secondary adrenal insufficiency due to pituitary disease, Steroids = Secondary adrenal insufficiency due to exogenous steroid use.
When ACTH-dependent Cushing syndrome is present, MRI of the pituitary gland with gadolinium enhancement should be performed and will identify an adenoma in at least 50% to 60% of the patients. If the patient has classic clinical laboratory findings of ACTH-dependent hypercortisolemia and an unequivocal pituitary lesion on MRI, the likelihood of Cushing disease is 98% to 99%. However, it must be emphasized that approximately 10% of the population in the age group from 20 to 50 years will have incidental tumors of the pituitary demonstrable by MRI. Therefore, some patients with ectopic ACTH syndrome will have radiographic evidence of a pituitary lesion.
C. High-Dose dexamethasone suppression
Traditionally, the high-dose dexamethasone suppression test has been utilized in the differential diagnosis of Cushing syndrome. However, the diagnostic accuracy of this procedure is only 70% to 80%, which is actually less than the pretest probability of Cushing disease—on average about 90%. As a result, this study is no longer recommended.
D. Inferior petrosal sinus sampling (IPSS)
The most definitive means of accurately distinguishing pituitary from nonpituitary ACTH-dependent Cushing syndrome is the use of bilateral simultaneous IPSS with CRH stimulation, and this procedure is the next step in the evaluation of patients with ACTH-dependent Cushing syndrome when MRI does not reveal a definite adenoma. This study takes advantage of the means by which pituitary hormones reach the systemic circulation. Blood leaves the anterior lobe of the pituitary and drains into the cavernous sinuses, which then empty into the inferior petrosal sinuses and subsequently into the jugular bulb and vein. Simultaneous inferior petrosal sinus and peripheral ACTH measurement before and after CRH stimulation can reliably confirm the presence or absence of an ACTH-secreting pituitary tumor. An inferior petrosal sinus to peripheral (IPS-P) ACTH ratio greater than 2.0 prior to CRH and greater than 3.0 after CRH is consistent with a pituitary ACTH-secreting tumor, and an IPSP ACTH ratio less than 1.8 supports the diagnosis of ectopic ACTH. Anatomical variants can cause false-negative studies; however, simultaneous measurement of PRL can be used to construct a PRL-normalized ACTH ratio that can eliminate false negatives caused by anatomical variants.
Bilateral IPSS with CRH stimulation does require a skilled interventional radiologist. However, in experienced hands, the procedure has yielded a diagnostic accuracy approaching 100% in identifying the source of ACTH-dependent Cushing syndrome.
If the IPSS study is consistent with a nonpituitary ACTH-secreting tumor, a search for an occult ectopic ACTH-secreting tumor is needed. Because the majority of these lesions are in the thorax, high-resolution CT of the chest may be useful; MRI of the chest may have even better sensitivity in finding these lesions, which are usually small bronchial carcinoid tumors. Unfortunately, utilization of a radiolabeled somatostatin analog scan (octreotide acetate scintigraphy) has met with only mixed results in localizing these tumors.
F. Adrenal localizing procedures
CT (Figure 9–14) and MRI are used to define adrenal lesions. Their primary use is to localize adrenal tumors in patients with ACTH-independent Cushing syndrome. Most adenomas exceed 2 cm in diameter and have a low density on CT; carcinomas are usually much larger with irregular borders and have high density and low contrast washout on CT.
Adrenal CT scan in Cushing syndrome. The patient has family history of macronodular adrenal disease with associated Cushing syndrome. Both adrenal glands visualized in this CT have nodular enlargement with the right adrenal gland showing significant macronodular hyperplasia. The adrenal nodules seen here have low CT attenuation, indicative of non-malignant lesions.