Chapter 20 Cushing’s Disease
Pathophysiology
Cushing’s syndrome, the syndrome produced by chronic exposure to excess glucocorticoids, has several etiologies (Table 20-1). The most common cause of Cushing’s syndrome is iatrogenic—that is, prescribed glucocorticoids for patients with chronic obstructive pulmonary disease, autoimmune disorders, and transplant patients requiring chronic immunosuppression, among others. Excluding iatrogenic causes, the most common cause of Cushing’s syndrome is an ACTH-secreting pituitary adenoma, defined as CD, which affects 60% to 80% of patients with spontaneous (noniatrogenic) Cushing’s syndrome (Table 20-1).1 The other common causes of Cushing’s syndrome, which must be distinguished from CD, are adrenal tumors and adrenal cortical hyperplasia, and ectopic ACTH secretion from a nonpituitary tumor, most commonly small-cell–lung cancer or bronchial carcinoid. Secretion of ACTH by lung carcinoma is not rare, but the ACTH is usually inactive, termed “big ACTH.”2 A rare cause of Cushing’s syndrome is ectopic secretion of corticotropin-releasing hormone causing corticotroph hyperplasia.
| ACTH-Dependent | 85% |
| Cushing’s disease | 80–85% |
| Ectopic ACTH-secreting tumor | 15–20% |
| Ectopic CRH-secreting tumor | Rare (<1%) |
| ACTH-Independent | 15% |
| Adrenal adenoma | 7% |
| Adrenocortical carcinoma | 7% |
| Bilateral micronodular adrenocortical hyperplasia | Rare (1%) |
| Bilateral macronodular adrenocortical hyperplasia | Rare (<1%) |
Pathology
The typical pituitary adenoma causing CD is a microadenoma (<1 cm greatest diameter) that stains for ACTH by immunohistochemistry. Larger adenomas are occasionally seen and may even present with apoplexy. These tumors are monoclonal.3 They disrupt the normal acinar pattern of the gland most clearly seen when stained for reticulin. They are typically basophilic by hematoxylin and eosin staining, but this terminology is no longer used, as immunohistochemistry for ACTH is more specific. Occasionally Cushing’s syndrome is attributed to corticotroph hyperplasia. When no definite tumor is identified at surgery and partial or total hypophysectomy is performed, the specimen must be meticulously and thoroughly examined with serial slices at closely spaced intervals, because tumors as small as 1 mm diameter, or less, may cause endocrinopathy from excess ACTH secretion. Corticotroph hyperplasia, which is usually a diagnosis of exclusion (i.e., only after no tumor can be found in the specimen from pituitary surgery), should be considered only after a careful search of the gland has ruled out a discrete adenoma. In our experience, hyperplasia is exceedingly rare (only two suspected, but unproven, cases from over 1200 operations for CD). A unique cytoplasmic staining pattern, known as Crooke’s hyaline change, occurs in corticotrophs of the normal pituitary—cells from which ACTH production has been shut down by chronic exposure to hypercortisolemia. The “hyaline” is comprised of intracytoplasmic microfilaments, which do not stain for ACTH. Crooke’s changes may also be found in the cells of the adenoma itself.
Mechanism of Hypercortisolemia in ACTH-Secreting Pituitary Adenomas
The basic endocrine disorder of the adenomas causing CD is that the sensitive negative feedback of cortisol on the production and release of ACTH is impaired (Fig. 20-1). However, ACTH-secreting pituitary adenomas are well-differentiated tumors derived from pituitary corticotrophs; thus, they typically retain negative feedback to glucocorticoids, it is just set at a higher threshold for suppression, as inhibition of ACTH release is retained in response to high doses of glucocorticoid. These well-differentiated tumor cells also retain their expression of CRH receptors and the cellular machinery necessary to respond to CRH. It is these features that underlie the typical diagnostic responses with provocative endocrine tests used for the differential diagnosis of Cushing’s syndrome (see below). Excessive production of ACTH leads to hyperplasia and overproduction of cortisol by the adrenal cortex, loss of normal diurnal plasma cortisol rhythm, and sustained hypercortisolemia. It is the excessive cortisol, rather than ACTH per se that causes the clinical manifestations of CD.
Clinical Manifestations
The typical patient with Cushing’s syndrome has truncal obesity with associated moon facies, enlarged dorsal fat pads (“buffalo hump”), and abdominal fat deposition with associated purple striae or “stretch marks” (Table 20-2). Hirsutism, especially noticeable on the face of women, is a common component, as are thin skin and easy bruisability, especially of the hands and forearms. Along with the outward appearance, mood or psychiatric disturbances are common, especially depression. A reversible form of brain atrophy is frequently displayed on imaging studies4 and may be a clue to the presence of Cushing’s syndrome in pediatric patients. Other signs include hypertension and hyperglycemia, often with frank diabetes mellitus. A hypercoagulable state has been described with Cushing’s syndrome, so prophylaxis for deep venous thrombosis in high-risk situations has been encouraged.5 Patients also may have complications related to immunosuppression, such as fungal or opportunistic infections. Spinal epidural lipomatosis may be symptomatic.6 Osteoporosis is common; related complications include vertebral compression fractures and susceptibility to traumatic long-bone fractures with minor trauma. Pediatric patients with CD stop growing linearly and gain weight, often producing morbid obesity.7 This “crossing of the weight and height curves” is so common in childhood Cushing’s syndrome that many consider it diagnostic of the condition. Affected children often appear cherubic. Symptoms caused by tumor growth and pressure on the optic nerves and chiasm are rare with CD, as the tumors are usually microadenomas.
| Fat Distribution | Skin Manifestations |
| Centripetal obesity | Purple striae |
| Moon facies | Plethora |
| “Buffalo hump” | Hirsutism |
| Supraclavicular fat pads | Acne |
| Epidural lipomatosis | Bruising |
| Musculoskeletal | Metabolic/Circulatory |
| Osteoporosis; fractures | Hypertension |
| Proximal muscle weakness Pituitary Dysfunction Amenorrhea Decreased libido, impotence Hypothyroidism Dwarfism (children) |
Glucose intolerance Hypokalemic alkalosis Mental Changes Irritability Psychosis |
Life expectancy is greatly foreshortened by untreated CD. If left untreated, most patients succumb early to complications of the disease (diabetes, hypertension, myocardial infarction, stroke, or complications associated with immunosuppression).8
Diagnosis
Establishing Hypercortisolism
Urine-free cortisol (UFC) measurements are assayed using a variety of techniques. The normal upper levels vary with the technique used and with the laboratory performing the assay (Fig. 20-2). Hypercortisolism is associated with loss of normal diurnal variation in cortisol secretion, which is demonstrated by obtaining morning (8 to 9 a.m.) and evening (11 to 12 p.m.) plasma cortisol levels (Fig. 20-3). Salivary cortisol levels are also reliably used for this and are well suited for outpatient screening of adult and pediatric patients for hypercortisolism.9 A study of more than 140 patients demonstrated a sensitivity of 93% and a specificity of 100% using this test to determine the presence of Cushing’s syndrome (Fig. 20-4).10 Because of its simplicity, the overnight low-dose (1 mg) dexamethasone suppression test is commonly used to screen patients for hypercortisolism (Fig. 20-5). In persons with a normal hypothalamic-pituitary-adrenal axis, AM cortisol levels are suppressed by the overnight low-dose dexamethasone suppression test (1.0 mg given the night before a morning [7 to 8 a.m.] cortisol measurement). A morning plasma cortisol level greater than 1.8 μg/dl after the bedtime (11 p.m.) administration of 1 mg of dexamethasone detects most patients with Cushing’s syndrome and justifies further diagnostic evaluation.11
(Modified from Loriaux DL, Cutler GB Jr. Diseases of the adrenal glands. In: Kohler PO, ed. Clinical Endocrinology. New York: Wiley; 1986:167-238, with permission.)60
, patient controls 
, pseudo-Cushing patients 
, and patients with Cushing’s syndrome 
. Samples were collected at 12 midnight from inpatients and at bedtime (11 p.m. to 2 a.m.) from outpatients. To convert salivary cortisol nanograms per deciliter to nanomoles per liter, multiply by 0.0276.
Differential Diagnosis of Hypercortisolism
Once excess cortisol production has been established, plasma ACTH levels are measured to distinguish between an ACTH-dependent and ACTH-independent etiology (Fig. 20-6; see also Fig. 20-1). With CD or ectopic ACTH secretion, the ACTH levels will be normal or elevated relative to the degree of glucocorticoid secretion. For this reason, these two entities are categorized as “ACTH-dependent” Cushing’s syndrome (see Table 20-1), in contrast to adrenal disease, in which plasma ACTH is low (<5 pg/ml) or undetectable (“ACTH-independent” Cushing’s syndrome, as the adrenal cortical cortisol secretion is autonomous).
(From Besser GM, Edwards CRW. Cushing’s syndrome. Clin Endocrinol Metab. 1972;1:451-490, with permission.)64
At one time, the presence of Cushing’s syndrome and then differentiating CD from adrenal disease or ectopic ACTH secretion were examined with the 6-day dexamethasone suppression test, as described by Liddle.12,13 The first 2 days of the test were used for measurement of basal cortisol secretion. In most patients with CD, cortisol secretion, an indirect measure of ACTH secretion by the pituitary gland or the tumor, is not suppressed during the 2 days of low-dose dexamethasone (0.5 mg every 6 hours for 48 hours), but 24-hour urinary cortisol secretion is suppressed to less than 10% of baseline values by 2 days of high-dose dexamethasone (2 mg every 6 hours for 48 hours). In contrast, high-dose dexamethasone fails to suppress cortisol secretion in most cases of ectopic ACTH secretion. Because of the difficulty in successfully completing this test today, it is now rarely used, but has been replaced with the high-dose overnight dexamethasone suppression test. For this test, 8 mg of dexamethasone is administered orally at 11 p.m. and a morning (7 to 8 a.m.) plasma cortisol measurement is obtained;14 for greatest diagnostic accuracy, suppression of morning serum cortisol of greater than 68% is required to assign a diagnosis of CD (Fig. 20-7).14,15
Another test available today to distinguish ectopic ACTH secretion from an ACTH-secreting pituitary tumor is the CRH stimulation test.16–18 Since they are well-differentiated tumors derived from pituitary corticotrophs, most ACTH-secreting pituitary adenomas retain receptors for, and response to, CRH, whereas most ectopic tumors, tumors that are not derived from pituitary tissue, do not express receptors for CRH and do not respond to it (Fig. 20-8). The sensitivity and specificity of the test are optimal using ≥35% for the maximum ACTH response from the 15- or 30-minute samples to indicate CD (see Fig. 20-8B).18
, six patients with Cushing’s syndrome due to ectopic ACTH secretion 
, and 10 human controls 
. (Modified from Chrousos GP, Schulte HM, Oldfield EH, Gold PW, Cutler GB Jr, Loriaux DL. The corticotropin-releasing factor stimulation test. An aid in the evaluation of patients with Cushing’s syndrome. N Engl J Med. 1984;310:622-626.)B, Responses of plasma ACTH and cortisol to intravenous administration of ovine CRH in patients with CD and ectopic ACTH secretion. ACTH responses are expressed as the percent change in mean ACTH concentration 15 and 30 min after CRH from the basal value 1 and 5 min before the injection. Dashed line indicates a response of 35%. Cortisol responses are expressed as the percent change in mean cortisol concentration 30 and 45 min after CRH from the basal value 1 and 5 min before the injection. Dashed line indicates a response of 20%.The test with the greatest diagnostic accuracy for the differential diagnosis of CD versus ectopic ACTH syndrome is bilateral simultaneous inferior petrosal sinus sampling performed with and without intravenous CRH administration.19 The test is performed by placement of catheters with their tips in the inferior petrosal sinuses and in a peripheral vein (Fig. 20-9A), and then obtaining serial, simultaneous samples for central and peripheral plasma ACTH concentrations at 2 and 0 minutes before and at 3, 5, and 10 minutes after intravenous CRH administration (1 μg/kg body weight). IPSS is only used in patients with confirmed hypercortisolism, as the test cannot discriminate between normal subjects and patients with CD. Further, since this is an invasive procedure with rare but serious associated risks,20 it is generally used in patients in whom the results of provocative endocrine testing to distinguish ectopic ACTH secretion from CD are conflicting or equivocal and in instances in which the sella MRI is negative. In this test the levels of ACTH in the primary venous drainage of the pituitary, the inferior petrosal sinuses, are compared to simultaneous ACTH measurements in the peripheral blood. A peak ratio of 2:1 petrosal:peripheral during baseline (before CRH) or 3:1 before or after CRH indicates a pituitary source of the excess ACTH, that is, CD.19 The sensitivity of the test is increased by sampling after administration of CRH, which, because it stimulates a pituitary adenoma to secrete ACTH, enhances the ACTH concentration differential between the central (inferior petrosal sinus) and the peripheral blood (Fig. 20-9B).19 It originally seemed that the procedure had a diagnostic accuracy 100%. However, reports of diagnostic errors, almost all false negative, have appeared, although in our experience the diagnostic accuracy approaches 100%. The accuracy of the test also relies upon successful placement of the catheter tips in the petrosal sinus bilaterally, since a false negative result may arise if the blood from both inferior petrosal sinuses cannot be catheterized successfully. Thus, venography is performed to ensure correct catheter placement and to evaluate the venous anatomy. A hypoplastic or anomalous inferior petrosal sinus in 0.8% of 501 patients was associated with false-negative results in patients with proven CD.21 It was briefly thought that comparison of petrosal sinus ACTH from the right to left sides would accurately indicate the side of the pituitary in which a small pituitary tumor was located, permitting a more focused search for it at surgery, or permitting removal of the half of the pituitary containing an adenoma that was too small to identify despite a thorough search of the gland during surgery.22 However, more experience with the technique for lateralization indicated that the lateralization accuracy is only about 70%, and even less so in pediatric patients,23 compromising its usefulness as a localizing measure during surgery.19
Imaging
Sella magnetic resonance imaging (MRI) is the imaging procedure of choice for detecting and localizing the pituitary adenoma in patients with CD. MRI should be performed with and without contrast, as the adenomas typically have decreased enhancement compared to the normal gland (Fig. 20-10). The resolution of a 1.5-T magnet may reveal tumors as small as 3 mm in diameter. MRI provides other important anatomical information for the surgeon: aeration of the sphenoid, parasellar anatomy, location of the carotid arteries or coexisting aneurysms, extent of supra- or para-sellar extension of an adenoma, and ectopic parasellar tumors. Recently the spoiled gradient recalled acquisition (SPGR) technique, used with 1-mm nonoverlapping slices was shown to be more sensitive than the conventional spin echo approach (sensitivity 80% vs. 49%), a finding also true in pediatric CD.24,25 However, the incidence of false positives was also higher (4% vs. 2%). Since the sensitivity of the conventional MRI techniques (spin echo) for CD is only 50% to 75%,26–29 many patients have a negative MRI. Furthermore, MRI is not always available or possible, as in patients with an MRI incompatible cardiac pacemaker or a morbidly obese patient who cannot be accommodated by the scanner. In these patients, a sella computerized tomography image (CT) with and without contrast may demonstrate a tumor, but CT is less sensitive than MRI. Furthermore, since the specificity of MRI is not 100% (MRI abnormalities consistent with adenomas occur in the pituitary gland in 10% of normal volunteers30
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