Evaluation of hypercalcemia

Hypercalcemia may result in a wide variety of clinical symptoms. Even in minimally symptomatic patients, subtle neurologic dysfunction is often reported, and may range from subtle cognitive impairment or drowsiness to mild depression. Worsening hypercalcemia may result in frank confusion, delirium, or obtundation. Minimally symptomatic patients may also manifest muscle weakness particularly if the hypercalcemia becomes more severe. Constipation may be commonly reported together with anorexia with severe hypercalcemia, prompting nausea, vomiting, and other gastrointestinal symptoms. The hypercalcemia associated with primary hyperparathyroidism has frequently resulted in the development of pancreatitis and peptic ulcer disease; however, the pathophysiologic mechanism of this association remains uncertain. Frequent urination and thirst are not uncommon with moderate hypercalcemia, and result from the increased renal water clearance necessary to excrete the filtered calcium load. Persistent hypercalcemia may result in the development of renolithiasis or nephrocalcinosis. Cardiac manifestations of hypercalcemia include decreased repolarization time associated with shortened QT interval, bradycardia, first-degree atrioventricular block, and other cardiac dysrhythmias. Chronic hypercalcemia eventually may be associated with osteopenia or osteoporosis and subsequent increased fracture risk. Most patients with hypercalcemia will remain asymptomatic or minimally symptomatic unless the serum calcium increases beyond a threshold of approximately 12 mg/dL or in the event the serum calcium undergoes a rapid increase over a short period of time. All patients essentially will become symptomatic when the serum calcium exceeds 14 mg/dL.

Differential diagnosis

The differential diagnosis of hypercalcemia is quite broad. The most common cause of outpatient hypercalcemia remains primary hyperparathyroidism, whereas the most common cause of hypercalcemia in hospitalized patients is malignancy. In most cases, the differential diagnosis of hypercalcemia may be broadly divided into PTH-mediated and non-PTH–mediated hypercalcemia ( Tables 1–3 ).

PTH-mediated hypercalcemia is associated most frequently with primary hyperparathyroidism (see Table 1 ). However, it may be caused by physiologic secondary hyperparathyroidism, defined as hyperparathyroidism caused by a recognized physiologic effect without associated renal insufficiency, or pathologic secondary hyperparathyroidism, with associated chronic renal failure. Tertiary hyperparathyroidism may occur in patients with long-standing renal insufficiency or chronic renal failure.

Physiologic secondary hyperparathyroidism can occur in patients with insufficient calcium intake, decreased intestinal calcium absorption, insufficient vitamin D intake or malabsorption, or renal hypercalciuria, and represents the homeostatic attempt to maintain normal serum calcium levels by any physiologic means. It is important to distinguish physiologic secondary hyperparathyroidism from primary hyperparathyroidism before approaching primary hyperparathyroidism surgically. This distinction is discussed later when considering the diagnosis of primary hyperparathyroidism. It is thought that the hyperparathyroidism associated with both pathologic secondary hyperparathyroidism and tertiary hyperparathyroidism results from subtle ionized hypocalcemia persisting over months to years, resulting in chronic stimulation of the parathyroid glands. Eventually, after long-standing renal insufficiency or failure, parathyroid glands may become autonomous and no longer respond to regulation by serum ionized calcium, and develop tertiary hyperparathyroidism.

Familial hypocalciuric hypercalcemia (FHH) may mimic the serum biochemical appearance of primary hyperparathyroidism and should not be confused with that entity, as this may result in unnecessary parathyroid surgery. FHH represents an autosomal dominant disorder, linked to chromosomes 3q, 13 p, and 19q, and is largely caused by inactivating mutations in the parathyroid cell calcium sensing receptor (CaSR) linked to chromosome 3q. This entity results in mild hypercalcemia associated with high normal or mildly increased intact PTH levels. Patients with FHH have a low 24-hour urinary calcium excretion relative to their hypercalcemia. The best physiologic study to distinguish FHH from primary hyperparathyroidism is the 24-hour urinary calcium to creatinine clearance ratio. The calculation of this ratio requires knowledge of the 24-hour urinary calcium and creatinine, with simultaneously measured serum calcium and creatinine levels. Patients with FHH typically have ratios of less than 0.01, whereas patients with primary hyperparathyroidism have ratios that exceed 0.01.

The second most frequent cause of hypercalcemia is that of malignancy (see Table 2 ). Malignancy-associated hypercalcemia is most commonly caused by humoral hypercalcemia of malignancy (HHM), which occurs as a result of excessive PTHrP secretion by tumors of various types. A wide range of solid tumors have been reported to secrete excessive PTHrP including those of the lung, esophagus, head and neck, kidney, ovary, bladder, breast, and pancreas. Further, thymic carcinoma, islet cell carcinomas, malignant carcinoid tumors, and sclerosing hepatic carcinomas have been reported to also secrete this hormone. PTHrP production in excess has further been associated with adult T-cell leukemia or lymphoma, or B-cell lymphoma.

Ectopic PTH secretion has been documented in single cases of small cell lung cancer, small cell ovarian carcinoma, squamous cell lung carcinoma, ovarian adenocarcinoma, thymoma, papillary thyroid carcinoma, hepatocellular carcinoma, and undifferentiated neuroendocrine tumor. In addition, ectopic 1,25-dihdroxyvitamin D may be produced in excess by B-cell lymphomas, Hodgkin disease, or lymphomatoid granulomatosis.

The hypercalcemia caused by malignancy may occur as a result of extensive lytic bone metastases due to multiple myeloma, lymphomas, breast cancer, or invasive sarcomas. In these cases, where extensive bone destruction is the mechanism, patients are usually late in the course of their malignancy and the underlying diagnosis is generally not in doubt.

Many nonmalignant causes of non-PTH–mediated hypercalcemia are known (see Table 3 ). Certain benign tumors, including those of ovarian dermoid cysts or uterine fibroids, may occasionally secrete PTHrP or other bone resorbing cytokines. Non-PTH–mediated hypercalcemia may be caused by a variety of endocrine disorders including thyrotoxicosis (resulting from increased bone resorption), pheochromocytoma, adrenal insufficiency or crisis, and VIPomas.

Granulomatous diseases will often cause hypercalcemia when malignancy or endocrine disorders are not present, especially when occurring in younger and middle-aged adults, and may occasionally present with hypercalcemia as the presenting finding. Case reports of hypercalcemia caused by overproduction of 1,25-dihydroxyvitamin D have come from patients with sarcoidosis, Wegener granulomatosis, berylliosis, silicone- or paraffin-induced granulomatosis, eosinophilic granuloma, focal or disseminated tuberculosis, and histoplasmosis, as well as coccidiomycosis and cat-scratch disease.

Medications are a well-known cause of hypercalcemia occurring as a consequence of a variety of physiologic mechanisms. Excess vitamin D intake may stimulate intestinal calcium absorption, and thiazide diuretics may directly inhibit renal calcium excretion. Lithium therapy may interfere with the ability of calcium to interact with parathyroid and renal CaSRs, thereby increasing PTH secretion by the parathyroid glands. Vitamin A excess may stimulate bone resorption by as yet undetermined mechanisms, and a variety of other agents, including estrogens, antiestrogens or androgens, aminophylline or theophylline, ganciclovir, recombinant growth hormone in AIDS patients, as well as others may affect other physiologic mechanisms, resulting in hypercalcemia.