Incidence and Etiology of Hypercalcemic Crisis

The incidence of hypercalcemic crisis has never been determined. Bondeson and colleagues11 reported a 10% incidence of hypercalcemic crisis as a complication in 514 cases of PHPT presenting between 1961 and 1988. Hypercalcemic crisis secondary to PHPT is commonly caused by a large parathyroid mass but may also be caused by carcinoma or hyperplasia.2,4 Bondeson and colleagues,11 however, reported that the distribution of parathyroid pathology (adenoma, hyperplasia, and carcinoma) causing hypercalcemic crisis was the same as that of PHPT not complicated by hypercalcemic crisis. Parathyroid carcinoma is usually associated with much higher parathyroid hormone (PTH) and calcium levels than nonmalignant PHPT, and the incidence of hypercalcemic crisis complicating it may be as high as 14%.12 Maselly and coworkers13 reported that 10 of 325 consecutive PHPT patients went on to develop hypercalcemic crisis and that 9 of the 10 patients had a single adenoma. The risk of developing hypercalcemic crisis in untreated PHPT is low. Only 1 of a group of 47 patients observed over a 5-year interval developed hypercalcemic crisis,14 and only 1 of 142 patients, or 0.7%, of the patients in a prospective series at the Mayo Clinic observed for 10 years developed hypercalcemic crisis related to PHPT.15 Fitzpatrick5 reported that age at the time of clinical presentation of hypercalcemic crisis is the same as or lightly lower than the average age of PHPT patients at the time of presentation.4,16,17 Other authors have reported a wide age distribution but that most cases develop in the sixth decade of life.2,4 The male/female ratio (1.0:1.1) was found to be similar to the distribution of parathyroid carcinoma1820 but markedly different from the gender ratios in series of PHPT.16,17

The principal causes of hypercalcemia in inpatient and outpatient settings differ.9 The two most common causes of hypercalcemia, malignancy and PHPT, are also the most common causes of hypercalcemic crisis in hospitalized and ambulatory patients, respectively, accounting for more than 90% of patients (Table 62-1). However, there are many other causes of hypercalcemic crisis. In granulomatous diseases, macrophages activated by the granuloma can metabolize 25-hydroxyvitamin D (25-OH vitamin D, calci-diol) to the more active 1,25-dihydroxyvitamin D3 (l,25(OH)2 vitamin D, calcitriol) and produce endogenous hypervita-minosis D, and on rare occasions the resultant increase in intestinal calcium absorption leads to hypercalcemic crisis.9 Less commonly, some lymphomas have been associated with excess endogenous l,25(OH)2 vitamin D production and sometimes cause hypercalcemic crisis.21 The mechanism of the hypercalcemia in hyperthyroidism is a direct stimulatory effect of thyroxine on osteoclastic bone resorption,3 and hypercalcemia caused by this mechanism may occur when young patients with hyperthyroidism are immobilized. Hypercalcemia may mask the usual hypermetabolic signs of thyrotoxicosis and make the hyperthyroidism more difficult to diagnose.

The most common cause of hypercalcemia in inpatient settings is malignancy.22 There are three separate syndromes in which malignant tumors can result in life-threatening hypercalcemic crisis: a syndrome of humoral hypercalcemia caused by endocrine and paracrine mediators, a syndrome of

TABLE 62-1. Differential Diagnosis of Hypercalcemia

Hyperparathyroidism

Primary (sporadic, familial)

Secondary

Tertiary

Malignancy

Humoral hypercalcemia of malignancy

Parathyroid hormone-related protein

Other mediators

Metastases to bone

Hematologic malignancies

Myeloma

Lymphoma

Familial hypocalciuric hypercalcemia Hyperthyroidism Hypervitaminosis D Hypervitaminosis A Pheochromocytoma Granulomatous disease

Immobilization (with or without Paget's disease of bone)

Medications

Thiazides

Estrogens, antiestrogens Lithium

Milk-alkali syndrome hypercalcemia associated with localized osteolytic disease, and a syndrome of hypercalcemia associated with multiple myeloma and related hematologic malignancies. Humoral hypercalcemia of malignancy (HHM) results from elaboration of a bone-resorbing substance by the tumor, most often PTH-related polypeptide (PTHrP). This 146-amino acid polypeptide is homologous to PTH in 8 of its first 13 aminoterminal residues, and it binds to the PTH receptor and produces the same hypercalcemic effects as PTH on end-organs: bone, gut, and kidney.9 Because PTHrP is secreted by solid malignancies in a manner that is not subject to the feedback regulation by serum calcium that occurs with PHPT, PTHrP secretion may cause an unrelenting hypercalcemic state. Humoral mediators of hypercalcemia in malignancy lead to increases in bone resorption by increasing osteolytic activity, and they probably also lead to complex disturbances in calcium homeostasis in the kidney and gut. Solid tumors of the lung, head, neck, kidney, pancreas, and ovary are often associated with humorally mediated hypercalcemia and produce factors, including PTHrP, that are potent activators of osteoclastic bone resorption and cause hypercalcemia in vivo.9 Hematologic malignancies, most notably multiple myeloma, secrete a number of cytokines, which act locally in the bone marrow to stimulate osteoclastic bone resorption.3

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