Hypercalcemia from any cause can result in fatigue, depression, mental confusion, anorexia, nausea, constipation, renal tubular defects, polyuria, a short QT interval, and arrhythmias. CNS and GI symptoms can occur at levels of serum calcium >2.9 mmol/L (>11.5 mg/dL), and nephrocalcinosis and impairment of renal function occur when serum calcium is >3.2 mmol/L (>13 mg/dL). Severe hypercalcemia, usually defined as >3.7 mmol/L (>15 mg/dL), can be a medical emergency, leading to coma and cardiac arrest.
The regulation of the calcium homeostasis is depicted in Fig. 176-1. The causes of hypercalcemia are listed in Table 176-1. Hyperparathyroidism and malignancy account for >90% of cases.
Feedback mechanisms maintaining extracellular calcium concentrations within a narrow, physiologic range (8.9–10.1 mg/dL [2.2–2.5 mM]). A decrease in extracellular fluid (ECF) calcium (Ca2+) triggers an increase in parathyroid hormone (PTH) secretion (1) via the calcium sensor receptor on parathyroid cells. PTH, in turn, results in increased tubular reabsorption of calcium by the kidney (2) and resorption of calcium from bone (2) and also stimulates renal 1,25(OH)2D production (3). 1,25(OH)2D, in turn, acts principally on the intestine to increase calcium absorption (4). Collectively, these homeostatic mechanisms serve to restore serum calcium levels to normal.
TABLE 176-1CLASSIFICATION OF CAUSES OF HYPERCALCEMIA ||Download (.pdf) TABLE 176-1CLASSIFICATION OF CAUSES OF HYPERCALCEMIA
Solitary adenomas or rarely carcinoma
Multiple endocrine neoplasia
Familial hypocalciuric hypercalcemia
Solid tumor with humoral mediation of hypercalcemia (lung, kidney, squamous cell carcinoma)
Solid tumor with metastases (breast)
Hematologic malignancies (multiple myeloma, lymphoma, leukemia)
Vitamin D intoxication
↑ 1,25(OH)2D; sarcoidosis and other granulomatous diseases
↑ 1,25(OH)2D; impaired 1,25(OH)2D metabolism due to 24-hydroxylase deficiency
Associated with high bone turnover
Vitamin A intoxication
Associated with renal failure
Severe secondary or tertiary hyperparathyroidism
Primary hyperparathyroidism is a generalized disorder of bone metabolism due to increased secretion of parathyroid hormone (PTH) by an adenoma (80%) or rarely a carcinoma in a single gland, or by parathyroid hyperplasia (15%). Familial hyperparathyroidism may be part of multiple endocrine neoplasia type 1 (MEN 1), which also includes pituitary and pancreatic islet tumors, or of MEN 2A, in which hyperparathyroidism occurs with pheochromocytoma and medullary carcinoma of the thyroid.
Hypercalcemia associated with malignancy is often severe and difficult to manage. Mechanisms for this include excess production and release of PTH-related protein (PTHrP) in lung, kidney, and squamous cell carcinoma (humoral hypercalcemia of malignancy); local bone destruction in myeloma and breast carcinoma; activation of lymphocytes leading to release of cytokines in myeloma and lymphoma; or an increased synthesis of 1,25(OH)2D in lymphoma.
Several other conditions have been associated with hypercalcemia. These include sarcoidosis and other granulomatous diseases, which lead to increased synthesis of 1,25(OH)2D; vitamin D intoxication from chronic ingestion of large vitamin doses (50–100 × physiologic requirements); lithium therapy, which results in hyperfunctioning of the parathyroid glands; and familial hypocalciuric hypercalcemia (FHH) due autosomal dominant inheritance of an inactivating mutation in the calcium-sensing receptor, which results in inappropriately normal or even high secretion of PTH, despite hypercalcemia and enhanced renal calcium resorption. Severe secondary hyperparathyroidism associated with end-stage renal disease may progress to tertiary hyperthyroidism, in which PTH hypersecretion becomes autonomous, causes hypercalcemia, and is no longer responsive to medical therapy.
Most pts with mild to moderate hyperparathyroidism are asymptomatic, even when the disease involves the kidneys and the skeletal system. Pts frequently have hypercalciuria and polyuria, and calcium can be deposited in the renal parenchyma (nephrocalcinosis) or form calcium oxalate stones. The characteristic skeletal lesion is osteopenia or osteoporosis; rarely, the more severe disorder osteitis fibrosa cystica occurs as a manifestation of long-standing, more severe hyperparathyroidism. Increased bone resorption primarily involves cortical rather than trabecular bone. Hypercalcemia may be intermittent or sustained, and serum phosphate is usually low but may be normal.
Primary hyperparathyroidism is confirmed by demonstration of an inappropriately high PTH level for the degree of hypercalcemia. Hypercalciuria helps to distinguish this disorder from FHH, in which PTH levels are usually in the normal range and the urine calcium level is low. Differentiation between primary hyperparathyroidism and FHH is important because the latter does not respond to parathyroid surgery. Levels of PTH are low in hypercalcemia of malignancy (Table 176-2).
TABLE 176-2DIFFERENTIAL DIAGNOSIS OF HYPERCALCEMIA: LABORATORY CRITERIA ||Download (.pdf) TABLE 176-2DIFFERENTIAL DIAGNOSIS OF HYPERCALCEMIA: LABORATORY CRITERIA
| ||Blooda |
| ||Ca ||Pi ||1,25(OH)2D ||iPTH |
|Primary hyperparathyroidism ||↑ ||↓ ||↑↔ ||↑(↔) |
|Malignancy-associated hypercalcemia: || || || || |
|Humoral hypercalcemia ||↑↑ ||↓ ||↓↔ ||↓ |
|Local destruction (osteolytic metastases) ||↑ ||↔ ||↓↔ ||↓ |
Total serum calcium should be corrected when serum albumin is abnormal (addition of 0.2 mM [0.8 mg/dL] to calcium value for every 1.0-g/dL decrement in albumin below 4.1 g/dL, or the converse for an increase in albumin). Alternatively, ionized calcium can be measured. Third-generation PTH assays should be used for PTH measurement, especially in pts with renal impairment.
The type of treatment is based on the severity of the hypercalcemia and the nature of the associated symptoms. Table 176-3 shows general recommendations that apply to therapy of severe hypercalcemia (levels of >3.2 mmol/L [>13 mg/dL]) from any cause.
In pts with severe primary hyperparathyroidism, surgical parathyroidectomy should be performed promptly. Asymptomatic disease may not require surgery; usual surgical indications include age <50, nephrolithiasis, creatinine clearance <60 mL/min, reduction in bone mass (T score <–2.5), or serum calcium >0.25 mmol/L (>1 mg/dL) above the normal range. A minimally invasive approach may be used if preoperative localization via sestamibi scans with single-photon emission computed tomography (SPECT) or neck ultrasound demonstrates a solitary adenoma and intraoperative PTH assays are available. Otherwise, neck exploration is required. Surgery in a center experienced in parathyroid interventions is recommended. Postoperative management requires close monitoring of calcium and phosphorus, as transient hypocalcemia is common. Calcium supplementation is given for symptomatic hypocalcemia.
Hypercalcemia of malignancy is managed by treating the underlying tumor. Adequate hydration and parenteral bisphosphonates can be used to reduce calcium levels. Long-term control of hypercalcemia is difficult unless the underlying cause can be eliminated.
No therapy is recommended for FHH. Secondary hyperparathyroidism should be treated with phosphate restriction, the use of nonabsorbable antacids or sevelamer, and calcitriol. Tertiary hyperparathyroidism requires parathyroidectomy.
TABLE 176-3THERAPIES FOR SEVERE HYPERCALCEMIA ||Download (.pdf) TABLE 176-3THERAPIES FOR SEVERE HYPERCALCEMIA
|Treatment ||Onset of Action ||Duration of Action ||Advantages ||Disadvantages |
|Hydration with saline (≤6 L/d) ||Hours ||During infusion ||Rehydrates; rapid action ||Volume overload; electrolyte disturbance |
|Forced diuresis (furosemide along with aggressive hydration) ||Hours ||During treatment ||Rapid action ||Monitoring required to avoid dehydration |
|Pamidronate 30–90 mg IV over 4 h ||1–2 days ||10–14 days ||High potency; intermediate onset of action ||Fever in 20%, ↓ Ca, ↓ phosphate, ↓ Mg, rarely jaw necrosis |
|Zoledronate 4–8 mg IV over 15 min ||1–2 days ||>3 weeks ||High potency; prolonged action; rapid infusion ||Minor: Fever; rare ↓ Ca, ↓ phosphate, jaw necrosis |
|Calcitonin (2–8 U/kg SC q6-12h) ||Hours ||1–2 days ||Rapid onset ||Limited effect; rapid tachyphylaxis |
|Glucocorticoids (prednisone 10–25 mg PO qid) ||Days ||Days-weeks ||Useful in myeloma, lymphoma, breast CA, sarcoid, vitamin D intox ||Effects limited to certain disorders; glucocorticoid side effects |
|Dialysis ||Hours ||During use–2 days ||Useful in renal failure; immediate effect ||Complex procedure |