Hypercalcemia

ALSO KNOWN AS: High levels of calcium in the blood

RELATED CONDITIONS: Primary hyperparathyroidism, hyperthyroidism

DEFINITION: Hypercalcemia is a condition in which the calcium level in the blood is above normal limits (total serum calcium greater than 10.5 milligrams/deciliter (mg/dl) in adults). Serum-ionized calcium and intracellular calcium concentrations play a major role in many biological activities, including bone formation, hormone secretion, neurotransmitter release, muscle contraction, and enzyme activities. Parathyroid hormone (PTH) and calcitonin are primary regulators. Parathyroid hormone stimulates the bones to release calcium into the blood, while the thyroid gland produces calcitonin, a hormone that slows calcium release. A condition of hypercalcemia reflects a significant disturbance in this delicate balance.

Risk factors: Two fundamental genetic abnormalities—the overactivity of oncogenes and the loss of function of tumor-suppressor genes—are associated with parathyroid gland tumors.

Etiology and the disease process: Causes of hypercalcemia can include the following:

• Primary hyperparathyroidism (excessive secretion of PTH)
• Malignancy (with and without bony metastasis)
• Cancers that produce blood dyscrasias: lymphoma, multiple myeloma, leukemia
• Multiple endocrine neoplasias (MEN): hormone-producing tumors
• Granulomatous diseases: sarcoidosis, tuberculosis
• Hyperthyroidism
• Vitamin D and vitamin A excess
• Medications: lithium therapy, thiazide diuretics
• Milk-alkali syndrome
• Severe, generalized immobilization
• Other conditions: Addison disease, peptic ulcer disease, hypophosphatasia, familial hypercalcemia

Primary hyperparathyroidism and malignancy account for nearly 90 percent of all cases of hypercalcemia.

Incidence: The annual incidence of hypercalcemia is estimated to be 0.2 percent in patients over sixty, with an estimated prevalence of 1 to 2 percent of the general population. It is estimated to affect 10 to 20 percent of people with cancer, called cancer-related hypercalcemia or hypercalcemia of malignancy. Cancer-related hypercalcemia and hypercalcemia due to hyperparathyroidism comprise around 90 percent of cases. The condition may manifest subtly and have a benign course for many years or a lifetime. It is more common in women than men by a ratio of 3:1.

Symptoms: In mild hypercalcemia, many patients do not exhibit symptoms. Patients with moderate hypercalcemia can complain of a constellation of symptoms involving the skeletal system (bones and muscles), the gastrointestinal tract, the kidneys, and the central nervous system. Severe symptoms (these associated with calcium levels of 13 to 15 mg/dl) include the following:

• Nausea and vomiting
• Anorexia
• Polydipsia (excessive thirst)
• Polyuria (frequent urination)
• Recurrent nephrolithiasis (formation of kidney stones)
• Profound muscle weakness (fatigue)
• Severe abdominal pain (constipation, peptic ulcer disease, pancreatitis)
• Muscle and joint aches
• Lethargy/fatigue
• Delirium (mental confusion) and psychosis
• Coma
• Cardiac arrhythmias (irregular heartbeat leading to cardiac arrest)

Screening and diagnosis: The current consensus is that simple medical surveillance is appropriate for patients over fifty years of age when bone and renal statuses are satisfactory. The immunoassay for parathyroid hormone (PTH) is especially useful, reliable, and accurate in distinguishing major causes.

Diagnostic tests to confirm a diagnosis of hypercalcemia include PTH immunoassays (checking circulating levels of parathyroid hormone), serum calcium and creatinine tests, a twenty-four-hour urinary calcium test, and creatinine clearance tests. Selective imaging may employ the evaluation of bone density (X-ray, computed tomography, dual-energy X-ray absorptiometry, or DEXA scans). Magnetic resonance imaging (MRI) usually demonstrates the identification of soft-tissue masses.

Treatment and therapy: In cases of severe hypercalcemia, individuals may need to be hospitalized to reduce calcium to a safe level. Treatment protocols include the following:

• Intravenous fluids
• Loop diuretic medications (furosemide-lasix) to flush excess calcium from the body and keep the kidneys functioning
• Intravenous bisphosphonates (drugs that inhibit bone breakdown). Denosumab (Prolia, Xgeva) may be used in patients with cancer who respond poorly to bisphosphonates
• Calcitonin (Miacalcin), a hormone produced by the thyroid gland to reduce bone resorption and slow bone loss
• Calcimimetics like Cinacalcet (Sensipar) help control overactive parathyroid glands.
• Glucocorticoids to help counter the effects of vitamin D toxicity by inhibiting vitamin D conversion to calcitriol
• Mobilization to prevent bone resorption
• Hemodialysis (filtering of the blood to remove excess calcium)
• Surgery such as parathyroidectomy for primary hyperparathyroidism

The critical management question is whether the disease should be treated surgically. A 30 percent reduction in creatinine clearance, a twenty-four-hour urinary calcium greater than 400 mg, and an elevated serum calcium level are persuasive factors. Traditionally, surgery (for hyperparathyroidism) has involved an extensive cervical incision and general anesthesia. A radioisotope scan is performed preoperatively in radio-guided parathyroidectomy to locate the abnormal parathyroid gland. The operation is performed in less than an hour through a one-inch incision. All surgery poses some risks. A small percentage of people undergoing this intervention can experience damage to the nerves controlling the vocal cords, and some develop a chronically low calcium level, requiring lifelong supplements of calcium and vitamin D.

Prognosis, prevention, and outcomes: Calcium metabolism is carefully and strictly regulated within a narrow range (8.5 to 10.2 mg/dl). Too much calcium, for whatever reason, can interfere with essential life processes. Conservative care is indicated for mild to moderate electrolyte disturbances, but surgery is a viable treatment option and should be considered in conditions related to hyperparathyroidism and malignancy.

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