Version July 2025
ALGORITHM —
IMMEDIATE ACTION —
The degree of hypercalcemia, along with the rate of rise of serum calcium concentration, determines symptoms and urgency of therapy. An acute rise to 12 to 14 mg/dL (3 to 3.5 mmol/L) may cause marked changes in sensorium, which requires more aggressive measures.
Rapidly identify and begin immediate treatment if any of the following are present (see "Treatment of hypercalcemia", section on 'Definitions of severity'):
●Symptoms of hypercalcemia: lethargy, confusion, stupor, coma, muscle weakness regardless of the degree of hypercalcemia.
●Complications of hypercalcemia: acute kidney injury, hypokalemia and other metabolic abnormalities predisposing to delirium and/or cardiac arrhythmias.
●Total calcium concentration >14 mg/dL (3.5 mmol/L) regardless of symptoms.
For patients with new-onset hypercalcemia, measure serum parathyroid hormone (PTH) with concomitant serum calcium (corrected for albumin) or ionized calcium. Treatment should never be delayed for the results of diagnostic testing (or if blood for diagnostic studies cannot be collected). (See "Clinical manifestations of hypercalcemia" and "Diagnostic approach to hypercalcemia".)
INITIAL EVALUATION —
Patients not requiring immediate action require a timely evaluation to identify and treat the underlying cause (table 1).
Review medications and supplements — Review diet and medications (prescription and nonprescription drugs, herbal preparations, calcium and vitamin supplements) to assess for drug-induced hypercalcemia or the milk-alkali syndrome. If possible, any medication or supplement that may be causing hypercalcemia should be discontinued.
Repeat serum calcium — The next step in the evaluation of hypercalcemia is to repeat the measurement (total calcium corrected for albumin or ionized) to confirm that there is a true increase in the serum calcium concentration. (See "Diagnostic approach to hypercalcemia", section on 'Verify elevated calcium'.)
In patients with hypo- or hyperalbuminemia, the measured calcium concentration should be corrected for the abnormality in albumin (calculator 1) (for standard units (calculator 2)). If a laboratory known to measure ionized calcium reliably is available, some experts prefer to measure the serum ionized calcium in this situation.
If available, review previous values for serum calcium. The presence of longstanding, asymptomatic hypercalcemia is more suggestive of primary hyperparathyroidism and also raises the much less common possibility of familial hypocalciuric hypercalcemia (FHH).
Measure PTH — If hypercalcemia is confirmed, measure intact PTH concomitantly with another serum calcium (see "Diagnostic approach to hypercalcemia", section on 'Laboratory evaluation'):
●Elevated PTH – A frankly elevated PTH concentration in the setting of hypercalcemia is likely the result of primary hyperparathyroidism. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Diagnosis'.)
If a patient is taking a thiazide diuretic or lithium, discontinue (if the drug can be stopped without exacerbating the underlying condition) and remeasure calcium and PTH three months later. Persistent hypercalcemia (with elevated or high-normal PTH) after drug withdrawal suggests that the drug has unmasked primary hyperparathyroidism. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Drugs'.)
●Mid- to upper-normal or minimally elevated PTH – Patients with mid- to upper-normal or minimally elevated PTH levels most likely have primary hyperparathyroidism. In the face of hypercalcemia, a normal PTH is not appropriate and is indicative of disease. FHH is possible, although much less common.
To help distinguish between these two possibilities and to inform management of patients with primary hyperparathyroidism, measure:
•Urinary calcium excretion (24-hour urinary calcium or calcium-to-creatinine ratio)
•25-hydroxyvitamin D
Before the diagnosis of FHH can be contemplated, any coexisting vitamin D deficiency must be corrected, as this can lower urinary calcium excretion in patients with primary hyperparathyroidism. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Familial hypocalciuric hypercalcemia' and "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Additional evaluation to determine management'.)
●Low-normal or low PTH – A low or low-normal serum intact PTH level (below 20 pg/mL [20 ng/L]) in the setting of hypercalcemia is most consistent with non-PTH-mediated hypercalcemia (table 1). Hypercalcemia of malignancy is one of the most common causes of non-PTH-mediated hypercalcemia, particularly if the hypercalcemia is of relatively recent onset (table 2). In those cases, PTH levels are not only low but often totally suppressed. It is notable that with the exception of a few cancers, hypercalcemia of malignancy is generally a late manifestation of the disease and not its presenting feature. Vitamin D intoxication is also a relatively common cause of hypercalcemia; supplements may contain vitamin D without the patient's knowledge.
If there is no clinically apparent malignancy:
•Obtain a dietary and supplement history for calcium (including antacids), vitamin D, and vitamin A containing products
•Measure:
-Parathyroid hormone-related protein (PTHrP)
-25-hydroxyvitamin D
-1,25-dihydroxyvitamin D
If PTHrP is elevated and malignancy is not apparent, perform additional work-up to identify malignancy (table 2). An elevated 1,25-dihydroxyvitmain D may also indicate the presence of a malignancy (eg, lymphoma) or, alternatively, chronic granulomatous disease (eg, sarcoidosis). (See "Hypercalcemia of malignancy: Mechanisms" and "Hypercalcemia in granulomatous diseases", section on 'Granulomatous disorders'.)
If PTHrP is low and vitamin D metabolites are low or normal, consider another source for the hypercalcemia (table 1). (See "Diagnostic approach to hypercalcemia".)
REFERENCE RANGE —
The normal range for serum calcium is approximately 8.6 to 10.2 mg/dL (2.15 to 2.54 mmol/L) but can vary depending on the patient population and clinical laboratory. Interpretation of a specific abnormal test result should be based upon the reference range reported with that result. In patients with hypo- or hyperalbuminemia, the measured calcium concentration should be corrected for the abnormality in albumin (calculator 1) (for standard units (calculator 2)).
CITATIONS —
The supporting references for this content are accessible in the linked topics.
