Endogenous Cushing’s syndrome is due to one of three causes: overproduction of glucocorticoid by a primary adrenal neoplasm, excessive production of adrenocorticotropic hormone (ACTH) by a pituitary adenoma, or a paraneoplastic syndrome in which either ACTH or corticotropin-releasing hormone (CRH) are produced ectopically by the tumor. A number of tumors are capable of producing ACTH, its prohormone “big ACTH,” or proopiomelanocortin (POMC) (Table 36.4). The POMC gene is located at p23 on the short arm of chromosome 2 near N-myc oncogene at p24. Normally the expression of the POMC gene is influenced by glucocorticoids, which suppress transcription, and CRH, which stimulates transcription through cyclic adenosine monophosphate. The activation of alternative steroid-insensitive promoters may result in ectopic ACTH production that is insensitive to glucocorticoid suppression. Pituitary cells and some tumors produce the normal 1,200base mRNA transcript; however, some nonpituitary tissues produce either a larger or smaller POMC mRNA transcript. Alternative posttranscription processing of POMC gives rise to a large number of biologically active peptides in addition to ACTH. These include pro-ACTH and a number of different peptides containing melanocyte-stimulating hormone (MSH) (α-MSH, ACTH, pro-ACTH, β-MSH, τ-lipotropin, β-lipotropin, τ-MSH, N-POMC, and pro-τ-MSH), all of which can lead to generalized hyperpigmentation (10, 11). Radioimmunoassays differ in their abilities to detect aberrant ACTH. The immunoradiometric assay for ACTH is able to distinguish between ACTH and its larger precursors, pro-ACTH, and POMC (12).

Malignancies are frequently associated with disorders of calcium metabolism, including hypercalciuria and hypercalcemia, and are the most common cause of hypercalcemia in hospitalized patients. After primary hyperparathyroidism, they are the second most common cause overall. Malignancies produce hypercalcemia by one of three mechanisms. Neoplasms may secrete parathyroid hormone-related protein (PTHrP), which, although distinct from PTH, has sufficient amino-terminal homology with PTH to mimic its effects on PTH receptors. This is the most common mechanism subserving malignancy-associated hypercalcemia, accounting for 80% of all cases (16). PTHrP is produced most commonly by squamous cell cancers (head, neck, lung, and esophagus), renal cell carcinoma, and breast cancer. Metastases with extensive localized bone destruction constitute the second most common mechanism of tumor-related hypercalcemia. Finally, hematologic neoplasms (e.g., multiple myeloma and lymphoma) cause hypercalcemia by releasing osteoclast-activating cytokines, and occasionally (in lymphomas), 1,25-dihydroxyvitamin D. Patients with malignancy may also have hypercalcemia from a cause unrelated to their cancer. In particular, hypercalcemia from primary hyperparathyroidism is a common disorder in the general population.

Most cancer-related hypercalcemia complicates an advanced malignancy that is already diagnosed and associated with a poor prognosis. Rarely, the tumor is occult and requires an extensive workup to unmask it. The features of advanced cancer typically dominate the presentation, with weight loss, anorexia, fatigue, and pain from bone metastases. Hypercalcemia is more acute and severe (often >14 mg/dL) than is typical for primary hyperparathyroidism and is more likely to cause nausea, vomiting, dehydration, and changes in mentation (hypercalcemic crisis). When possible, treatment is directed toward the primary tumor. Hypercalcemic crisis is treated medically (Table 36.5). Patients with severe hypercalcemia are typically dehydrated, with resultant diminished urine output. This further exacerbates the hypercalcemia by reducing the ability of the kidneys to eliminate calcium in the urine. Therefore, the first step in treating hypercalcemia is vigorous hydration to reestablish urine output and calciuresis. After adequate rehydration, loop diuretics such as furosemide can be used to further promote a calciuric diuresis. This therapy has the advantage of working rapidly (over hours) but is limited by incomplete calcium-lowering effects and the need for intravenous fluids. Calcitonin injections are often used concomitantly with hydration because of their rapid action, although their efficacy is somewhat limited by modest calcium-lowering effects and by tachyphylaxis. Intravenous infusion of a bisphosphonate, either pamidronate or zoledronate, is the most consistently effective treatment of cancer-related hypercalcemia, although the infusion has a delay of 1 to 2 days in the onset of action. A single infusion will normalize calcium levels in most patients with a persistent duration of action lasting a few weeks to several months. Increased bone resorption by PTHrP-activated osteoclasts is the mechanism subserving most cancer-related hypercalcemia, and intravenous bisphosphonates effectively block this pathway. Therefore, the usual therapy in hypercalcemic crisis is to begin rapid onset, partially effective therapy with hydration and calcitonin, while giving an infusion of a bisphosphonate that will have potent calcium-lowering effects in a day or two. Other therapies are used in selected cases of hypercalcemia. For example, glucocorticoids are useful calcium-lowering agents in hematologic malignancies and in hypercalcemia mediated by vitamin D intoxication. Many other therapies, commonly used in the past, have been supplanted by the safety and potency of bisphosphonates. These include intravenous and oral phosphates, gallium nitrate, plicamycin, and indomethacin.

Hypocalcemia is an uncommon paraneoplastic syndrome occurring primarily in patients with bony metastases. It occurs most commonly in association with osteoblastic metastases of the breast, prostate, and lung; its incidence is approximately 16% (17). Tetany is a rare complication of tumor-associated hypocalcemia. The etiology of the
hypocalcemia is not understood. Ectopic calcitonin secretion from the underlying tumor has been rarely implicated. Acute hypocalcemia is treated by i.v. calcium gluconate or calcium chloride (Table 36.6). Vitamin D and calcium supplements are the therapeutic mainstays of all forms of chronic hypocalcemia.