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The clinical recognition of Cushing's syndrome and its biochemical confirmation is a challenging problem. The best diagnostic approach to patients with suspected Cushing's syndrome is still evolving. The traditional diagnostic approach of urine free cortisol and low-dose dexamethasone suppression testing may be inadequate when the degree of hypercortisolism is mild. Late-night salivary cortisol determinations may evolve as the simplest means of screening patients for suspected hypercortisolism. Repeated measurements of cortisol secretion (urine free cortisol or late-night salivary cortisol) over an extended period of time may be necessary to provide diagnostic certainty. The dexamethasone-CRH test is a reasonable approach in patients with equivocal data. The introduction of reliable, sensitive, and specific plasma ACTH measurements, the use of IPSS for ACTH with CRH stimulation, and the improved techniques of pituitary and adrenal imaging have made the differential diagnosis of Cushing's syndrome relatively straightforward (see Fig. 2). Clinicians who have never missed the diagnosis of Cushing's syndrome or have never been fooled by attempting to establish its cause should refer their patients with suspected hypercortisolism to someone who has.

The best diagnostic approach to patients with suspected Cushing's disease continues to evolve. The introduction of transsphenoidal pituitary surgery as the treatment of choice for Cushing's disease as well as the absence of any pituitary imaging abnormalities in many patients with Cushing's disease has made accurate diagnosis and differential diagnosis essential. In the authors' opinion, two or three late night (11 PM) salivary cortisol determinations and the measurement of 24-hour UFC are the best and simplest means to evaluate patients with suspected hypercortisolism. L-DST can no longer be recommended to exclude the diagnosis of Cushing's disease, particularly if the hypercortisolism is mild. The combination of L-DST and CRH stimulation is a new and apparently sensitive means to establish the presence or absence of pathologic hypercortisolism in equivocal cases. In the absence of an overt pituitary tumor on MR imaging, inferior petrosal sinus sampling with CRH stimulation should be performed to secure the diagnosis of Cushing's disease as well as identify the probable location of the corticotroph adenoma.

Renal phosphate wasting related to a tumor (oncogenous osteomalacia) is a rare disorder usually associated with benign mesenchymal tumors. In this article, the authors describe a man with renal phosphate wasting and the syndrome of inappropriate antidiuretic hormone associated with small cell carcinoma. Chemotherapy markedly reduced tumor burden and was associated with normalization of renal phosphate handling and serum sodium. With recurrence, renal phosphate wasting and the syndrome of inappropriate antidiuretic hormone developed again, with the additional complication of hypercortisolism secondary to ectopic corticotropin production. The authors report the rare occurrence of renal phosphate wasting with small cell carcinoma (5 previously reported cases) and the unique co-existence of this paraneoplastic syndrome with the syndrome of inappropriate antidiuretic hormone and ectopic corticotropin production.

In summary, the technological advances in the past decade have greatly improved the biochemical and radiological diagnosis of Cushing's syndrome. Figure 13 illustrates an algorithm for the differential diagnosis of Cushing's syndrome that focuses on the importance of ACTH-IRMA and provides two potential diagnostic approaches for the evaluation of ACTH-dependent hypercortisolism. The first approach directly proceeds to IPSS as the most rapid and possibly most cost effective method to establish an accurate diagnosis. A more traditional approach employs high dose dexamethasone suppression testing followed by MR studies of the pituitary. If the biochemical or radiological studies are the least bit equivocal, IPSS should be performed before definitive therapy is recommended.

Hypercalcemia associated with the extrarenal production of 1,25-dihydroxyvitamin D (1,25(OH)2D) has been reported in several disorders, most notably granulomatous diseases such as sarcoidosis. The authors describe a woman with hypercalcemia, renal insufficiency, microscopic hematuria, and anemia. The circulating 1,25(OH)2D level was higher than appropriate for the ambient conditions (renal insufficiency, suppressed intact parathyroid hormone, and hypercalcemia). A kidney biopsy was consistent with Wegener's granulomatosis, and treatment with prednisone and cyclophosphamide was associated with normalization of serum calcium levels, improved renal function, a marked decrease in serum 1,25(OH)2D levels, and increased serum intact parathyroid hormone levels. These findings are consistent with the unregulated production of 1,25(OH)2D by inflammatory cells associated with Wegener's granulomatosis.

Cushing's disease is a form of Cushing's syndrome, persistent inappropriate hypercortisolism, that results from pituitary ACTH hypersecretion. It currently accounts for 70 per cent of adult cases of Cushing's syndrome and affects mainly women of childbearing age. The pathology, cause, and clinical and laboratory features of the disease are discussed. The initial step in diagnosis is documentation of endogenous hypercortisolism, which is followed by identification of the cause. Selective transsphenoidal resection of ACTH-producing pituitary adenomas is the initial treatment of choice. The roles of radiotherapy and medical therapy are discussed.