Epidemiology

Hypercalcemia is defined as a total serum calcium level greater than 10.5 mg/dL and is often divided into categories to describe the severity of symptoms as mild (10.5 to 11.9 mg/dL), moderate (12 to 13.9 mg/dL), and severe (>14 mg/dL).

The prevalence of hypercalcemia is approximately 0.5% to 3% in hospitalized adults.³ Hyperparathyroidism is the most common cause of hypercalcemia, and the incidence of primary hyperparathyroidism is approximately 21 cases per 100,000 person-years.⁴

The paraneoplastic syndrome hypercalcemia of malignancy is the second most common cause of hypercalcemia and occurs in approximately 10% to 30% of patients with cancer. Multiple myeloma and lung, breast, and prostate malignancies are most often associated with this disorder. It is typically seen in the end stages of disease and indicates a poor prognosis.⁵

Pathophysiology

Under normal conditions, excess calcium is excreted together with sodium in the proximal tubules of the kidneys. With hypercalcemia, dehydration caused by vomiting, poor oral intake, and osmotic diuresis results in reabsorption of sodium instead of excretion. This concurrent calcium reabsorption exacerbates the underlying hypercalcemia. PTH regulates the renal excretion of calcium. The excess production of PTH in primary hyperparathyroidism results in inappropriate calcium reabsorption. Causes of primary hyperparathyroidism include solitary adenomas (most common), ectopic adenomas in the mediastinum, diffuse hyperplasia of one or more parathyroid glands, and parathyroid carcinoma.⁶ These parathyroid abnormalities may be independent or a component of the multiple endocrine neoplasia syndromes (MEN 1 or 2a).

Bone acts as a pool of calcium that is regulated by the balance between osteoblast and osteoclast activity. Calcium is released from bone by relative overactivation of osteoclasts and is enhanced by PTH. Prolonged hyperparathyroidism results in osteopenia.

The small intestines are the location of calcium absorption from the diet. Absorption is facilitated by vitamin D. Inactive forms of vitamin D₃ are synthesized in the skin in response to exposure to sunlight; vitamin D₂ is ingested from a normal diet. Vitamins D₂ and D₃ are subsequently converted into the active form 1,25-dihydroxyvitamin D (calcitriol) by enzymatic hydroxylation first in the liver and then in the kidney. Calcitriol acts on villi of the small intestines to augment absorption of calcium and phosphorus. Calcitriol also acts on bone to increase osteoclast activity. Excessive ingestion of vitamin D supplements is a rare cause of hypercalcemia. A serum 25-hydroxyvitamin D concentration greater than 125 nmol/L (50 ng/mL) is considered to be excessive, and greater than 500 nmol/L (200 ng/mL) is potentially toxic.

In the paraneoplastic syndrome hypercalcemia of malignancy, the majority of cases of hypercalcemia arise from tumor secretion of parathyroid hormone–related protein (PTHrP), a PTH homologue that acts on tissues like PTH does. Osteolytic bone metastases and ectopic tumor production of calcitriol and PTH cause the remaining cases of hypercalcemia of malignancy.⁵

Milk-alkali syndrome is the third most common cause of hypercalcemia severe enough to result in hospitalization.⁷ The clinical definition of milk-alkali syndrome is hypercalcemia, alkalosis, and renal failure in a patient ingesting excessive amounts of calcium and an alkali. Diagnosis is based on the patient history when other causes of hypercalcemia are excluded. Over-the-counter calcium carbonate supplements are commonly used for dyspepsia and prevention of osteoporosis and are currently the most frequent cause of milk-alkali syndrome. Historically, ingestion of milk and sodium bicarbonate for the treatment of peptic ulcer disease was the most common cause of milk-alkali syndrome, but this medication regimen went out of favor with the availability of H₂ receptor antagonists and proton pump inhibitors. Serum PTH is low in these patients, indicative of no concurrent hyperparathyroidism.

Several medications rarely cause hypercalcemia. Thiazide diuretics, lithium, and the vitamin A derivatives all-trans-retinoic acid and cis-retinoic acid have been implicated. Some systemic illnesses also have the potential to cause hypercalcemia, including the granulomatous diseases sarcoidosis, leprosy, coccidiomycosis, histoplasmosis, and tuberculosis. The mechanism of hypercalcemia in these conditions is thought to be production of calcitriol by macrophages within granulomas.⁸ Additionally, rare inherited disorders such as familial hypocalciuric hypercalcemia cause hypercalcemia.⁹

Presenting Signs and Symptoms

Patients often become symptomatic from hypercalcemia at levels near 12 mg/dL, and nearly all patients with levels higher than 14 mg/dL will be symptomatic. Hypercalcemia affects a broad array of organ systems (Box 166.1).

Neurologic symptoms progress with increasing serum levels of calcium and range from mild cognitive impairment and depression to drowsiness, altered mental status, delirium, and obtundation.

Gastrointestinal symptoms include anorexia, constipation, nausea, vomiting, and paralytic ileus. Pancreatitis secondary to hypercalcemia is a well-described clinical phenomenon, but the exact mechanism of the development of this condition is still unclear. There is also an association between hypercalcemia and the development of peptic ulcer disease, in addition to a link between milk-alkali syndrome and antacid use in the treatment of this condition.

A common renal manifestation of hypercalcemia is osmotic diuresis manifested as polyuria and excessive thirst. Nephrolithiasis and nephrocalcinosis are hallmarks of hypercalcemia. In patients with primary hyperparathyroidism, up to 20% have a history of symptomatic nephrolithiasis. Case series of patients with kidney stones have demonstrated a 2% to 8% incidence of primary hyperparathyroidism.¹⁰ It is thought that excessive calciuria combined with dehydration and decreased urine output leads to stone formation.

Cardiac manifestations of hypercalcemia are generally manifested as asymptomatic electrocardiographic (ECG) changes. Shortening of the QT interval (QTc <0.4 msec) is common, and ST elevations that may mimic acute myocardial infarction have been reported^11,12 (Fig. 166.2). Symptomatic cardiac manifestations are rare and generally limited to bradydysrhythmias.

Fig. 166.2 Electrocardiographic manifestations of hypercalcemia.

Note the shortened QT interval, T-wave inversions, and ST-segment elevation.

(Courtesy Loren K. Rood, MD, Indiana University School of Medicine, Indianapolis.)

Musculoskeletal symptoms of hypercalcemia include muscle weakness, bone pain, and osteopenia.

Differential Diagnosis and Medical Decision Making

The serum calcium level is generally reported when a basic or comprehensive metabolic panel is ordered. Special consideration of hypercalcemia should be included in the evaluation of vague chief complaints such as fatigue, weakness, nausea and vomiting, abdominal pain, and altered mental status.

Discovery of significant hypercalcemia on laboratory testing should prompt a directed history for idiopathic causes of hypercalcemia, including ingestion of calcium or vitamin D supplements and use of thiazide diuretics or lithium. Evaluation for hyperparathyroidism, granulomatous diseases, and neoplasms should follow if a cause is not discovered on the history.

Treatment

Initial therapy for hypercalcemia includes correction of dehydration and facilitation of renal excretion of calcium through volume reexpansion with normal saline at a rate of 200 to 500 mL/hr. Patients with severe hypercalcemia may require several liters of fluid resuscitation. For example, in a case series of patients with severe hyperparathyroid crisis requiring parathyroidectomy, a mean of 16 ± 6 L of isotonic fluid was administered over a period of several days before surgery.⁶

Loop diuretics may be used to facilitate forced calcium excretion in urine. Evidence for the effectiveness of loop diuretics is poor, and they should be used only after normovolemia has been achieved.

An additional therapy that has been studied most extensively in patients with hypercalcemia of malignancy is the use of bisphosphonates. These medications act on osteoclasts and limit release of calcium from bone. Their maximum calcium-lowering effects do not occur until several days after administration and can last for several weeks to months.^13–15 Side effects of the bisphosphonates include hypophosphatemia, hypomagnesemia, osteonecrosis of the jaw, and postadministration acute phase reactions (fever, arthralgias, fatigue, malaise, myalgias). Table 166.1 summarizes the dosing regimens for available bisphosphonates.

Table 166.1 Bisphosphonates Available in the United States for the Treatment of Hypercalcemia of Malignancy

A treatment of hypercalcemia that is immediately effective in lowering serum calcium is calcitonin. Calcitonin inhibits urinary reabsorption of calcium and osteoclast maturation. The most commonly available form of this medication is salmon calcitonin administered at 4 to 8 U/kg subcutaneously every 8 to 12 hours. Lowering of the serum calcium level can occur as quickly as 2 hours after administration, but the effects are generally modest (lowering calcium by up to 3.8 mg/dL)¹⁶ and short-lived. Tachyphylaxis to this treatment occurs within 2 days. Side effects of salmon calcitonin include flushing, nausea, vomiting, and abdominal cramps.

Glucocorticoids inhibit conversion of 25-hydroxyvitamin D to calcitriol, which causes a decrease in intestinal absorption of calcium and an increase in renal calcium excretion. Efficacy in lowering serum calcium has been demonstrated only in the treatment of certain types of lymphoma that secrete calcitriol, vitamin D intoxication, and the granulomatous diseases.⁸ Additionally, administration of glucocorticoids may delay tachyphylaxis to calcitonin, so they are often used in conjunction with salmon calcitonin. A common regimen for the treatment of hypercalcemia is hydrocortisone, 200 to 300 mg/day intravenously for 3 to 5 days.

An older medication for the treatment of hypercalcemia that has primarily been supplanted by use of the bisphosphonates is gallium nitrate. Gallium nitrate acts to lower serum calcium by inhibition of osteoclast activity. It is also thought to inhibit PTHrP. The typical dose is 200 mg/m²/day of gallium nitrate for 5 days by continuous infusion. The need for several days of continuous infusion is a significant drawback to the use of this medication. Because of risk for nephrotoxicity, gallium nitrate is generally indicated only when bisphosphonates are contraindicated or in refractory cases of hypercalcemia of malignancy when tumors exhibit a high level of PTHrP secretion.

An important step in the treatment of all causes of hypercalcemia is discontinuation of vitamin D and calcium-containing products. In the setting of milk-alkali syndrome, discontinuation of supplements and fluid resuscitation are often the only treatments required. Hemodialysis may be indicated for patients with severe hypercalcemia complicated by renal failure or for cases refractory to other therapies.

Follow-Up, Next Steps in Care, and Patient Education

Hospital admission is indicated for patients with symptomatic hypercalcemia, especially in the setting of altered mental status, dehydration, or acute renal failure. Definitive treatment of any underlying diseases causing hypercalcemia should be undertaken, as clinically appropriate. This may include parathyroidectomy for primary hyperparathyroidism or initiation of therapy for malignancy. Patients should be educated about the proper use of dietary supplements or antacids containing calcium and vitamin D (Table 166.2).

Table 166.2 Recommended Daily Dietary Intake of Vitamins and Minerals by Age and Sex

Epidemiology

Hypocalcemia is defined as a serum calcium level lower than 8.5 mg/dL, although symptoms of hypocalcemia typically do not occur until serum calcium is below 7.0 to 7.5 mg/dL or ionized calcium is below 2.8 mg/dL (0.7 mmol/L).¹⁷ The incidence of hypocalcemia has not been well quantified.

Pathophysiology

The most common cause of hypocalcemia is hypoparathyroidism, which is defined as inadequate release of PTH from the parathyroid glands. Inappropriate release of PTH results in poor calcium absorption from the gastrointestinal tract, excessive excretion of calcium in urine, and sequestration in bone.

The most common cause of hypoparathyroidism is neck surgery, specifically parathyroidectomy, followed by thyroidectomy and then other neck surgeries. Autoimmune destruction of the parathyroid glands also causes hypoparathyroidism. Antiparathyroid antibodies are found in more than 30% of patients with isolated hypoparathyroidism and in more than 40% of patients with hypoparathyroidism accompanied by other autoimmune diseases. Infiltration of the parathyroids as a result of sarcoidosis, Wilson disease, hemochromatosis, or amyloidosis is a rare cause of hypoparathyroidism.

Pseudohypoparathyroidism is defined as a blunted renal response to PTH and is manifested similar to hypoparathyroidism as low serum calcium and elevated phosphorus levels; PTH in this setting is normal or elevated. Several genetic pseudohypoparathyroid syndromes are associated with hypocalcemia, as well as abnormal skeletal development, dysmorphic features, and abnormal development.

Vitamin D deficiency (rickets) is rarely symptomatic in adults unless hypocalcemia develops. The majority of patients with vitamin D deficiency have osteopenia with potential for the development of osteoporosis and pathologic fractures. It is most common in elderly, hospitalized, or institutionalized persons. These patients have impaired skin production of vitamin D in response to sun exposure because of aging, a low amount of sun exposure, or dietary deficiency. Individuals with darker skin that is highly pigmented by melanin are at higher risk than lighter-skinned individuals for vitamin D deficiency secondary to relative underproduction of vitamin D in response to sun exposure. Measurement of 25-hydroxyvitamin D is considered the best measure of body vitamin D stores. Serum levels of 25-hydroxyvitamin D below 30 to 50 nmol/L (<12 to 20 ng/mL) are considered deficient.

Pancreatitis causes hypocalcemia when peripancreatic fat combines with extracellular calcium to form insoluble salts. This processes is called saponification. Other causes of hypocalcemia include sepsis, critical illness, chronic renal failure, and massive transfusion of blood anticoagulated with citrate.

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