No specific physical examination findings indicate hypercalcemia. However, patients can present with a wide spectrum of symptoms. Depending on the acuity and severity, patients can either be asymptomatic or can have involvement of multiple organ systems such as gastrointestinal tract (GI), musculoskeletal system, cardiovascular system (CVS), renal involvement, and central nervous system (CNS)or psychiatric disturbances.

The renal manifestations can vary from polyuria, polydipsia, nephrogenic diabetes insipidus, renal insufficiency, distal renal tubular acidosis (RTA) secondary to nephrolithiasis. If left untreated, hypercalcemia and hypercalciuria can lead to tubular atrophy, interstitial fibrosis, and calcification and cause nephrocalcinosis. GI symptoms can vary from anorexia, nausea, and constipation. Excessive calcium deposition in the pancreatic duct can cause pancreatitis. Hypercalcemia also enhances secretion of gastrin levels, which can contribute to peptic ulcer disease. Musculoskeletal symptoms can manifest as muscle weakness and bone pain. CVS manifestations are subtle and include short QTc interval and, rarely, arrhythmias. Excess calcium can deposit in the heart valves and the coronaries and increase cardiovascular morbidity. CNS symptoms depend on the levels. Mild cases are asymptomatic. Severe hypercalcemia can cause lethargy, confusion, and coma, which is commonly seen in the elderly population. Common psychiatric disturbances include anxiety, depression, or cognitive disturbances.

The initial evaluation of hypercalcemia mandates a thorough history and physical, as it can prompt the clinician to the underlying cause and pathology. Prior laboratory data is significant and can give clues about the baseline calcium levels and duration of hypercalcemia. Medication history (prescription, OTC, supplements), dietary history, family history, and any evidence of prior granulomatous disease need to be reviewed systematically. Initial labs to be checked include PTH levels, as this can differentiate between PTH related hypercalcemia and non-PTH related hypercalcemia. Hypercalcemia secondary to PTH is seen in primary hyperparathyroidism and familial hyperparathyroid syndromes, whereas non-PTH related hypercalcemia is seen in malignancies, granulomatous diseases, and vitamin D intoxication. Familial hypocalciuric hypercalcemia (FHH) should be suspected in patients with minimally elevated PTH levels and low urinary calcium excretion on 24-hour urinary calcium. Low-normal or low levels of PTH (less than 20 pg/mL) should raise the suspicion of non-PTH-related causes and PTHrP, and vitamin D metabolites such as 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels should be checked. If PTHrP is elevated, it signifies HHM. Vitamin D intoxication causes elevated 25-hydroxy vitamin D levels. Lymphoma and granulomatous diseases are suspected when 1,25-dihydroxy vitamin D levels are elevated. Serum electrophoresis (SPEP), urine electrophoresis (UPEP) with immunofixation, and serum-free light chains are to be checked to rule out multiple myeloma if the vitamin D levels are in normal range. In patients with malignancy-induced hypercalcemia, PTH levels also should be checked, as there is a higher incidence of coexisting PHPT. Very rarely, band keratopathy can be seen via slit lamp examination, which signifies calcium phosphate deposits in the cornea.

Treatment should be tailored to lower the serum calcium levels to treat the patient’s symptoms and target the underlying cause. Serum phosphorus levels need to be monitored and replaced, as hypophosphatemia is usually associated with hypercalcemia and increases the difficulty in treating hypercalcemia. If the patient is not symptomatic, mild and moderate hypercalcemia does not require immediate therapy and management of the underlying cause is required. Patients should be educated about diet, medications, and avoiding dehydration and physical inactivity. Symptomatic patients with severe hypercalcemia need emergent treatment. Initial treatment includes intravenous (IV) normal saline (NS) along with calcitonin and bisphosphonates. NS acts immediately, and its effect lasts until the fluids are discontinued. Calcitonin acts within 4 to 6 hours and lasts for about 2 days, whereas bisphosphonates exhibit their action in 2 to 3 days and their effect lasts for 2 to 4 weeks. This approach is tailored to lower the serum calcium levels and maintain them.[7][8][9][8]

IV hydration with NS at the rate of 200 to 300 mL/hr is given to maintain adequate urine output of more than 100 mL/hr, thus restoring intravascular volume and increasing urinary calcium excretion. IV hydration is to be given cautiously to patients with heart or renal failure. Loop diuretics, which help in promoting urinary calcium excretion by inhibiting reabsorption of calcium at the Loop of Henle, are given only after adequate IV resuscitation. Calcitonin (4 international units/kg) should be administered along with NS infusion to help prevent bone resorption and increase urinary calcium excretion. It is a very fast acting medication, but its effect is limited. Bisphosphonates, such as zoledronic acid (ZA) (4mg IV over 15 minutes) or pamidronate (60 to 90 mg IV over 2 hours), are also given. ZA is preferred in hypercalcemia secondary to malignancy as it is more potent and can be given over a shorter course of time. Bisphosphonates are also given in patients with bone metastasis to prevent any skeletal complications. The main side effects include osteonecrosis of the jaw and nephrotoxicity.

Denosumab acts by inhibiting the RANKL, and it should be considered when there is no response to zoledronic acid. Glucocorticoids are considered in patients with increased 1,25-dihydroxy vitamin D production, such as lymphomas or granulomatous diseases, as they decrease vitamin D production as well as calcium absorption from the intestines. Calcimimetics, such as Cinacalcet, is preferred in hemodialysis patients and hypercalcemia secondary to parathyroid cancer. If these strategies fail, then hemodialysis is done to treat the hypercalcemia. It is also considered in patients with severe heart or renal failure who cannot tolerate adequate IV hydration.

• Adrenal insufficiency

• Berylliosis

• Coccidioidomycosis

• Crohn’s disease

• Hyperkalemia

• Hypermagnesemia

• Hypernatremia

• Hyperparathyroidism

• Hyperphosphatemia

• Hyperthyroidism

Malignancy-associated hypercalcemia is ideally treated by an interprofessional team that consists of an oncologist, internist, endocrinologist, and a surgeon. It is also important to involve a pain specialist because many patients also have varying degrees of pain. More than 90% of the cases of hypercalcemia are due to primary hyperparathyroidism and malignancy-induced hypercalcemia. Malignancy remains the most common cause of hypercalcemia in hospitalized patients. While most cases are managed as outpatients, severe hypercalcemia requires in-patient treatment. The outcome depends on the stage of the primary malignancy and severity of hypercalcemia. Patients with uncontrolled malignancy and severe hypercalcemia have a poor prognosis.