The causes of hypercalcemia can be understood and classified based on derangements in the normal feedback mechanisms that regulate serum calcium (Table 65-1). Excess PTH production, which is not appropriately suppressed by increased serum calcium concentrations, occurs in primary neoplastic disorders of the parathyroid glands (parathyroid adenomas; hyperplasia; or, rarely, carcinoma) that are associated with increased parathyroid cell mass and impaired feedback inhibition by calcium. Inappropriate PTH secretion for the ambient level of serum calcium also occurs with heterozygous inactivating calcium sensor receptor (CaSR) or G protein mutations, which impair extracellular calcium sensing by the parathyroid glands and the kidneys, resulting in familial hypocalciuric hypercalcemia (FHH). Although PTH secretion by tumors is extremely rare, many solid tumors produce PTH-related peptide (PTHrP), which shares homology with PTH in the first 13 amino acids and binds the PTH receptor, thus mimicking effects of PTH on bone and the kidney. In PTHrP-mediated hypercalcemia of malignancy, PTH levels are suppressed by the high serum calcium levels. Hypercalcemia associated with granulomatous disease (e.g., sarcoidosis) or lymphomas is caused by enhanced conversion of 25(OH)D to the potent 1,25(OH)2D. In these disorders, 1,25(OH)2D enhances intestinal calcium absorption, resulting in hypercalcemia and suppressed PTH. Disorders that directly increase calcium mobilization from bone, such as hyperthyroidism or osteolytic metastases, also lead to hypercalcemia with suppressed PTH secretion as does exogenous calcium overload, as in milk-alkali syndrome, or total parenteral nutrition with excessive calcium supplementation.
TABLE 65-1Causes of Hypercalcemia ||Download (.pdf) TABLE 65-1Causes of Hypercalcemia
|Excessive PTH production |
| Primary hyperparathyroidism (adenoma, hyperplasia, rarely carcinoma) |
| Tertiary hyperparathyroidism (long-term stimulation of PTH secretion in renal insufficiency) |
| Ectopic PTH secretion (very rare) |
| Inactivating mutations in the CaSR or in G proteins (FHH) |
| Alterations in CaSR function (lithium therapy) |
|Hypercalcemia of malignancy |
| Overproduction of PTHrP (many solid tumors) |
| Lytic skeletal metastases (breast, myeloma) |
|Excessive 1,25(OH)2D production |
| Granulomatous diseases (sarcoidosis, tuberculosis, silicosis) |
| Lymphomas |
| Vitamin D intoxication |
|Primary increase in bone resorption |
| Hyperthyroidism |
| Immobilization |
|Excessive calcium intake |
| Milk-alkali syndrome |
| Total parenteral nutrition |
|Other causes |
| Endocrine disorders (adrenal insufficiency, pheochromocytoma, VIPoma) |
| Medications (thiazides, vitamin A, antiestrogens) |
Mild hypercalcemia (up to 11–11.5 mg/dL) is usually asymptomatic and recognized only on routine calcium measurements. Some patients may complain of vague neuropsychiatric symptoms, including trouble concentrating, personality changes, or depression. Other presenting symptoms may include peptic ulcer disease or nephrolithiasis, and fracture risk may be increased. More severe hypercalcemia (>12–13 mg/dL), particularly if it develops acutely, may result in lethargy, stupor, or coma, as well as gastrointestinal symptoms (nausea, anorexia, constipation, or pancreatitis). Hypercalcemia decreases renal concentrating ability, which may cause polyuria and polydipsia. With long-standing hyperparathyroidism, patients may present with bone pain or pathologic fractures. Finally, hypercalcemia can result in significant electrocardiographic changes, including bradycardia, AV block, and short QT interval; changes in serum calcium can be monitored by following the QT interval.
The first step in the diagnostic evaluation of hyper- or hypocalcemia is to ensure that the alteration in serum calcium levels is not due to abnormal albumin concentrations. About 50% of total calcium is ionized, and the rest is bound principally to albumin. Although direct measurements of ionized calcium are possible, they are easily influenced by collection methods and other artifacts; thus, it is generally preferable to measure total calcium and albumin to “correct” the serum calcium. When serum albumin concentrations are reduced, a corrected calcium concentration is calculated by adding 0.2 mM (0.8 mg/dL) to the total calcium level for every decrement in serum albumin of 1.0 g/dL below the reference value of 4.1 g/dL for albumin, and, conversely, for elevations in serum albumin.
A detailed history may provide important clues regarding the etiology of the hypercalcemia (Table 65-1). Chronic hypercalcemia is most commonly caused by primary hyperparathyroidism, as opposed to the second most common etiology of hypercalcemia, an underlying malignancy. The history should include medication use, previous neck surgery, and systemic symptoms suggestive of sarcoidosis or lymphoma.
Once true hypercalcemia is established, the second most important laboratory test in the diagnostic evaluation is a PTH level using a two-site assay for the intact hormone. Increases in PTH are often accompanied by hypophosphatemia. In addition, serum creatinine should be measured to assess renal function; hypercalcemia may impair renal function, and renal clearance of PTH may be altered depending on the fragments detected by the assay. If the PTH level is increased (or “inappropriately normal”) in the setting of elevated calcium and low phosphorus, the diagnosis is almost always primary hyperparathyroidism. Because individuals with FHH may also present with mildly elevated PTH levels and hypercalcemia, this diagnosis should be considered and excluded because parathyroid surgery is ineffective in this condition. A calcium/creatinine clearance ratio (calculated as urine calcium/serum calcium divided by urine creatinine/serum creatinine) of <0.01 is suggestive of FHH, particularly when there is a family history of mild, asymptomatic hypercalcemia. In addition, sequence analysis of the CaSR gene is now commonly performed for the definitive diagnosis of FHH, although in some families, FHH may be caused by mutations in G proteins that mediate signaling by the CaSR. Ectopic PTH secretion is extremely rare.
A suppressed PTH level in the face of hypercalcemia is consistent with non-parathyroid-mediated hypercalcemia, most often due to underlying malignancy. Although a tumor that causes hypercalcemia is generally overt, a PTHrP level may be needed to establish the diagnosis of hypercalcemia of malignancy. Serum 1,25(OH)2D levels are increased in granulomatous disorders, and clinical evaluation in combination with laboratory testing will generally provide a diagnosis for the various disorders listed in Table 65-1.
Mild, asymptomatic hypercalcemia does not require immediate therapy, and management should be dictated by the underlying diagnosis. By contrast, significant, symptomatic hypercalcemia usually requires therapeutic intervention independent of the etiology of hypercalcemia. Initial therapy of significant hypercalcemia begins with volume expansion because hypercalcemia invariably leads to dehydration; 4–6 L of intravenous saline may be required over the first 24 h, keeping in mind that underlying comorbidities (e.g., congestive heart failure) may require the use of loop diuretics to enhance sodium and calcium excretion. However, loop diuretics should not be initiated until the volume status has been restored to normal. If there is increased calcium mobilization from bone (as in malignancy or severe hyperparathyroidism), drugs that inhibit bone resorption should be considered. Zoledronic acid (e.g., 4 mg intravenously over ∼30 min), pamidronate (e.g., 60–90 mg intravenously over 2–4 h), and ibandronate (2 mg intravenously over 2 h) are bisphosphonates that are commonly used for the treatment of hypercalcemia of malignancy in adults. Onset of action is within 1–3 days, with normalization of serum calcium levels occurring in 60–90% of patients. Bisphosphonate infusions may need to be repeated if hypercalcemia relapses. An alternative to the bisphosphonates is gallium nitrate (200 mg/m2 intravenously daily for 5 days), which is also effective, but has potential nephrotoxicity. In rare instances, dialysis may be necessary. Finally, although intravenous phosphate chelates calcium and decreases serum calcium levels, this therapy can be toxic because calcium-phosphate complexes may deposit in tissues and cause extensive organ damage.
In patients with 1,25(OH)2D-mediated hypercalcemia, glucocorticoids are the preferred therapy, as they decrease 1,25(OH)2D production. Intravenous hydrocortisone (100–300 mg daily) or oral prednisone (40–60 mg daily) for 3–7 days is used most often. Other drugs, such as ketoconazole, chloroquine, and hydroxychloroquine, may also decrease 1,25(OH)2D production and are used occasionally.