Diagnosis

measure ionized calcium OR calculate corrected calcium using total calcium and serum albumin.

• Begin treatment immediately for patients with severe hypercalcemia or symptomatic patients while pursuing further diagnostic workup.

• Perform volume status assessment.

• Obtain ECG

• Identify concurrent electrolyte abnormalities.

• Measure serum intact PTH: initial study to determine the etiology of hypercalcemia and to differentiate PTH-mediated hypercalcemia from non-PTH-mediated hypercalcemia

• Order other routine tests as guided by clinician suspicion : e.g. alkaline phosphatase, TSH

Consider these based on the results of initial investigations.

• Normal or ↑ PTH: urine calcium excretion

• ↓ PTH: PTHrP and vitamin D levels

Consider these based on combined results of the initial and intermediate investigations (see “Other investigations to consider” for details).

• ↑ PTHrP or ↑ 1,25-dihydroxyvitamin D: investigations for tumors, lymphoma, or granulomatous diseases

• Normal or ↓ PTHrP, and normal or ↓ vitamin D levels: investigations for multiple myeloma, thyrotoxicosis, Paget disease, vitamin A toxicity, or adrenal insufficiency

• ↓ Urine calcium excretion: investigations for FHH (e.g., genetic testing, see FHH)

• Adjunctive studies: consider on an individual basis (e.g., bone densitometry or detailed laboratory evaluation of bone disease)

• Serum calcium

  • Total calcium

  • Ionized calcium

  • Corrected calcium (mg/dL) = measured total Ca2+ (mg/dL) + [0.8 x (4.0 - albumin concentration in g/dL)]

• Other laboratory studies

  • Albumin

  • Phosphate: typically low in primary hyperparathyroidism and PTHrP-mediated hypercalcemia [8]

  • BMP

  • Alkaline phosphatase

  • ABG/VBG

  • CBC

• ECG findings may include:

  • QT interval shortening and in severe hypercalcemia J wave

  • Bradycardia

  • Arrhythmias

• Serum intact PTH

  • Normal or ↑ PTH: PTH-mediated hypercalcemia

  • ↓ PTH: non-PTH-mediated hypercalcemia

• PTHrP

  • A protein produced by malignant cells that has the same function as parathyroid hormone.

  • Production of PTHrP is the most common cause of hypercalcemia of malignancy.

  • ↑ PTHrP: solid malignancy or neuroendocrine tumors

  • Normal or ↓ PTHrP: Consider other causes of non-PTH-mediated hypercalcemia (see “Etiology of hypercalcemia”).

• Vitamin D levels

  • ↑ 1,25-dihydroxyvitamin D: lymphoma, granulomatous disease, or calcitriol ingestion

  • ↑ 25-hydroxyvitamin D: vitamin D intoxication (i.e., due to ingestion of ergocalciferol, cholecalciferol, or calcidiol)

• Assessment of urinary calcium excretion [2][8][15][16]

  • Studies

    • 24-hour urinary excretion of calcium

    • AND/OR urine Ca/Cr clearance ratio (an index of renal calcium excretion; determined by measuring the concentrations of calcium and creatinine in the serum and in a 24-hour urine collection sample) [17]

  • Interpretation [8][16]

    • Normal or ↑ urine calcium (urine Ca/Cr clearance ratio > 0.02 or 24-hour urine calcium > 200 mg): primary hyperparathyroidism [15]

    • ↓ Urine calcium (urine Ca/Cr clearance ratio < 0.02 or 24-hour urine calcium < 200 mg): FHH or primary hyperparathyroidism; consider genetic testing for FHH

• Laboratory studies

  • TSH, T4, T3: assess for thyrotoxicosis

  • Cortisol and ACTH stimulation test: assess for adrenal insufficiency

  • Vitamin A levels: assess for vitamin A toxicity

  • Serum protein electrophoresis and urine Bence Jones protein: assess for multiple myeloma

  • Detailed laboratory evaluation of bone disease: further evaluation of bone disorders

  • Genetic testing: See FHH.

• Imaging

  • CT chest, abdomen, pelvis: assess for tumors, lymphoma, or granulomatous diseases

  • Skeletal survey: assess for lytic bone lesions and Paget disease

  • Bone densitometry: further evaluation of patients with primary hyperparathyroidism