usually divided into the adrenocorticotrophin (ACTH)-dependent and ACTH-independent groups (Table 28.1). The ACTH-dependent group accounts for 80–85% of all cases of endo­genous hypercortisolism, and within this group, 80 and 20% can be attributed to pituitary (Cush­ing’s disease) and ectopic sources of ACTH respectively [13, 14]. Small-cell bronchogenic carcinoma followed by bronchial or thymic car­cinoids, and other neuroendocrine tumors such as pheochromocytoma, pancreatic neuroendo­crine tumors, and gastrointestinal carcinoids are common causesof ectopic ACTH syndromes. Patients suffering from small-cell carcinoma of lung frequently manifest diagnostic para­neoplastic wasting syndrome while, for other ectopic sources of ACTH, the clinical presenta­tion would be difficult to distinguish from Cush­ing’s disease. ACTH-independent Cushing’s syndrome is most commonly due to a unilateral functional adrenal adenoma, accounting for approximately 60% of cases while adrenal carci­noma accounts for the remaining cases. Bilateral adrenal masses such as ACTH-independent macronodular adrenal hyperplasia (AIMAH) and primary pigmented nodular adrenal disease (PPNAD) are, albeit rarely, ACTH-independent causes of Cushing’s syndrome.

Cushing’s syndrome. However, some of these clinical features are neither specific nor fre­quently apparent at presentation. Diagnosis is challenging and depends on a high index of suspicion. In addition, patients with other meta­bolic syndromes frequently share various simi­lar, if not identical, clinical features [11]. Signs of protein wasting including the presence of thin skin in the young, easy bruising, and proximal muscle weakness could more reliably distinguish Cushing’s from metabolic syndrome [11]. In contrast, obesity and decreased linear growth are more common in children with Cushing’s syndrome[15, 16]. Patients typically havetruncal obesity with ‘‘moon face’’ (Fig. 28.2) and fullness of the supraclavicular fat pads (‘‘buffalo hump’’). There are also some differences in presentation between men and women. Purplish abdominal cutaneous striae, muscle atrophy, osteoporosis, and kidney stones more common in male patients [17]. Although gonadal or sexual dysfunction is common in both sexes, oligomenorrhea is a com­mon presentation in premenopausal women and may occur before other manifestations. Renal stones are present in about 50% of patients [18]. More than 70% of patients can present with psy­chiatric symptoms ranging from anxiety to frank

detected adrenal mass should be evaluated for potential subclinical hypercortisolism. In addi­tion, high-risk patient groups such as those with poorly controlled diabetes and/or hypertension with overlapping clinical features should be subjected to routine biochemical screening. However, no single biochemical test is perfect for screening and several tests are usually neces­sary [8]. The currently accepted screening tests include 24 h urinary free cortisol, overnight/ low-dose dexamethasone-suppression test and assessment of late-night salivary cortisol [7].

If ACTH-dependent Cushing’s syndrome is sus­pected based on ACTH measurement but the source of ACTH is nondiagnostic based on the high-dose dexamethasone-suppression and CRH stimulation tests, the next investigation of choice is the pituitary MRI. If both the clinical presentation and the dynamic biochemical stu­dies are compatible with ACTH-dependent Cushing’s syndrome, an isolated lesion of 6 mm or more on pituitary MRI is almost diag­nostic of Cushing’s disease. However, up to 40% of patients with proven Cushing’s disease have normal pituitary MRI scans and up to 10% of the normal population has a pituitary inciden­taloma (usually 5 mm or less). In these patients, bilateral selective inferior petrosal sinus venous sampling to compare the gradient of ACTH with the periphery is the most reliable means of dis­criminating between pituitary and nonpituitary sources of ACTH. However, venous sampling is a highly operator-dependent, technically demanding, skilled, and invasive technique. A greater than 50% increase in central corticotro­phin level compared with basal or a central-to­peripheral ratio of more than 2–3:1 is consistent with Cushing’s disease when stimulated by CRH with a reported sensitivity and specificity of 94% and 95–100%, respectively [39–43]. In one study, 2 of 179 patients noted to have responses consistent with Cushing’s disease were ulti­mately confirmed to have ectopic ACTH syn­drome [44]. However, venous sampling has only 70% accuracy in lateralizing the source of ACTH within the pituitary gland in adults although the accuracy is much greater for children [8, 10, 45]. Direct sampling from the cavernous sinuses does not improve the accuracy. On the other hand, sampling from the internal jugular veins has been proposed as a simplified procedure but is associated with a lower sensitivity and specificity [46].

remission or persistent disease in the postopera­tive period. Larger, invasive, and moreaggressive tumors are associated with worse outcome [59, 62] whereas centers performing a large number of pituitary operations have improved outcomes and minimal morbidity. If there is clear persis­tent disease postoperatively, immediate reopera­tion has been advocated [64, 65]. Despite a clinical and biochemical remission as evident by secondary adrenal insufficiency, there is still a recurrence rate of 5–25% during follow-up [63]. Glucocorticoids replacement is required for patients with secondary adrenal insufficiency postoperatively until the hypothalamo–pituitar­y–adrenal axis recovers full activity usually 6–18 months after surgery. There can be deficiencies of other pituitary hormones (hypopituitarism) in up to 50% over a long follow-up period.

surgery, bilateral laparoscopic adrenalectomy