Approach
Generally, evaluation of hypercalcemia begins subsequent to an incidental report from blood analysis and is followed by consideration of possible etiologies.[10]
Clinical presentation
Important points to cover in the history include:
Bone pain: may suggest metastases in long bones
Renal stones: typical in hyperparathryoidism
Lethargy, easy fatigue
Confusion
Depression, irritability
Constipation: classic gastrointestinal symptoms may also be present (nausea, vomiting, abdominal pain, peptic ulcer disease, pancreatitis)
Polyuria, polydipsia
Weight loss: would identify malignancy as more likely than hyperparathyroidism
Timing of symptoms: chronic symptoms are more consistent with hyperparathyroidism, whereas recent onset of symptoms suggests malignancy
Drugs, including supplements and non-prescription drugs
Family history: hypocalciuric hypercalcemia.
"Bones, stones, groans and moans" is a useful aide-memoire for some common symptoms of hypercalcemia (bone pain, renal stones, abdominal pain, and psychiatric symptoms).[21]
Examination is usually not helpful in confirming the diagnosis.
Investigations
The most common causes of hypercalcemia are primary hyperparathyroidism and malignancy, together accounting for 90% of cases.[2][10]
They can be distinguished by ordering a serum parathyroid hormone (PTH) level and a simultaneous repeat calcium test.
Total serum calcium is usually satisfactory but if there is an elevated or markedly depressed plasma protein concentration, the physiologically important fraction is ionized calcium. Normal serum or plasma total calcium should be 8.5 to 10.5 mg/dL; ionized calcium should be 4.6 to 5.1 mg/dL.[3]
PTH is elevated in primary hyperparathyroidism, despite elevated calcium indicating a disconnect between the regulating hormone and the ion. In malignancy, calcium is elevated either due to humoral abnormality with a PTH-related protein, or bone destruction in metastases.[14] In cases of malignancy, the PTH might be very low or barely detectable, since the elevated calcium should inhibit PTH secretion.[22]
Step by step
Incidental hypercalcemia
A history should be taken and calcium and PTH drawn simultaneously. If both are elevated, the cause is primary hyperparathyroidism. If PTH is normal to low in the face of hypercalcemia, the most likely cause is malignancy.
Symptomatic metabolic bone disease
Bone imaging (including skeletal survey and x-rays of painful areas)
PTH measurement should be drawn simultaneously with calcium
Bone densitometry.
Coma
Investigations include calcium and electrolytes, glucose, blood urea nitrogen, hematocrit, and an ECG. Calcium levels should be >13 mg/dL to explain coma. Hypercalcemia may be a part of dehydration and not the direct or immediate cause of the diminished consciousness.
Primary hyperparathyroidism, if suspected, can be differentiated from familial hypocalciuric hypercalcemia by measuring 24-hour urinary calcium excretion.[9]
Further tests to consider are: vitamin D levels for vitamin D intoxication; creatinine levels and kidney ultrasound for chronic renal failure and secondary hyperparathyroidism; and chest x-ray for sarcoidosis (if there are pulmonary symptoms, for example cough and dyspnea).
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