Hypercalcemia

Essentials of Diagnosis

• Most common causes: primary hyperparathyroidism and malignancy-associated hypercalcemia

• Hypercalciuria usually precedes hypercalcemia

• Asymptomatic, mild hypercalcemia (≥ 10.5 mg/dL [or 2.6 mmol/L]) is usually due to primary hyperparathyroidism

• Symptomatic, severe hypercalcemia (≥ 14 mg/dL [or 3.5 mmol/L]) is due to hypercalcemia of malignancy

General Considerations

• Important causes of hypercalcemia are listed in Table 21–7

• Primary hyperparathyroidism and malignancy account for 90% of cases

• Primary hyperparathyroidism is the most common cause of hypercalcemia (usually mild) in ambulatory patients

• Chronic hypercalcemia (over 6 months) or some manifestation such as nephrolithiasis also suggests a benign cause

• Tumor production of PTH-related proteins (PTHrP)

  • Most common paraneoplastic endocrine syndrome, accounting for most cases of hypercalcemia in inpatients

  • The neoplasm is clinically apparent in nearly all cases when the hypercalcemia is detected

• Granulomatous diseases, such as sarcoidosis and tuberculosis, cause hypercalcemia via overproduction of active vitamin D₃ (1,25 dihydroxyvitamin D₃)

• Milk-alkali syndrome has had a resurgence due to calcium ingestion for prevention of osteoporosis

• Hypercalcemia causes nephrogenic DI through activation of calcium-sensing receptors in collecting ducts, which reduces ADH-induced water permeability

• Volume depletion further worsens hypercalcemia

History and physical examination

• Should focus on the duration of hypercalcemia and evidence for a neoplasm

Symptoms and Signs

• May affect gastrointestinal, kidney, and neurologic function

• Mild hypercalcemia is often asymptomatic

• Symptoms usually occur if the serum calcium is > 12 mg/dL (or > 3 mmol/L) and tend to be more severe if hypercalcemia develops acutely

• Constipation and polyuria

• Polyuria is absent in hypocalciuric hypercalcemia

• Polyuria from hypercalciuria-induced nephrogenic diabetes insipidus can result in volume depletion and acute kidney injury

• Other abdominal symptoms include

  • Nausea

  • Vomiting

  • Anorexia

  • Peptic ulcer disease

  • Renal colic

  • Hematuria from nephrolithiasis

• Neurologic manifestations may range from mild drowsiness to weakness, depression, lethargy, stupor, and coma in severe cases

• Ventricular ectopy and idioventricular rhythm occur and can be accentuated by digitalis

Laboratory Tests

• The ionized calcium exceeds 1.32 mmol/L

• A high serum chloride concentration and a low serum phosphate concentration in a ratio > 33:1 (or > 102 if SI units are utilized) suggests primary hyperparathyroidism where PTH decreases proximal tubular phosphate reabsorption

• A low serum chloride concentration with a high serum bicarbonate concentration, along with elevated BUN and creatinine, suggests milk-alkali syndrome

• Severe hypercalcemia (> 15 mg/dL [3.75 mmol/L]) generally occurs in malignancy

• More than 300 mg (7.5 mmol) per day of urinary calcium excretion suggests hypercalciuria; < 100 mg (2.5 mmol) per day suggests hypocalciuria

• Hypercalciuric patients (such as those with malignancy or those receiving oral active vitamin D therapy)

  • May easily develop hypercalcemia in case of volume depletion

  • Serum phosphate may or may not be low, depending on the cause.

• Hypocalciuric hypercalcemia occurs in milk-alkali syndrome, thiazide diuretic use, and familial hypocalciuric hypercalcemia

Imaging Studies

• Chest radiograph: to exclude malignancy or granulomatous disease

Diagnostic Procedures

• ECG: shortened QT interval

Medications

• Renal excretion of calcium is promoted through aggressive hydration and forced calciuresis until the primary cause can be identified and treated

• In volume-depleted patients with normal cardiac and kidney function, 0.45% saline or 0.9% saline can be given rapidly (250–500 mL/h)

• Bisphosphonates

  • Treatment of choice for hypercalcemia of malignancy; they are safe, effective, and normalize calcium in more than 70% of patients

  • May require up to 48–72 hours before reaching full therapeutic effect

• Calcitonin may be helpful in the short-term until bisphosphonates reach therapeutic levels

• Denosumab

  • A monoclonal antibody against RANKL

  • Inhibits osteoclasts, reducing bone resorption and serum calcium levels

  • FDA-approved for malignancy-associated hypercalcemia refractory to bisphosphonate therapy

• Cinacalcet

  • Calcimimetic agent

  • Suppresses PTH secretion and decreases serum calcium concentration

  • Has been recommended for use in patients with symptomatic or severe primary hyperparathyroidism who are unable to undergo parathyroidectomy and patients with inoperable parathyroid carcinoma

• Loop diuretics

  • Should generally be avoided due to possible complications, such as nephrolithiasis

  • May be carefully used in the context of preventing or managing volume overload, particularly in patients with heart failure or kidney dysfunction

• Thiazides can worsen hypercalcemia

Therapeutic Procedures

• In emergency cases, dialysis with low calcium dialysate may be needed

• Hypercalcemia in dialysis patients

  • Usually occurs in the presence of hyperphosphatemia

  • Metastatic calcification may occur

  • Malignancy should be considered as a cause of the hypercalcemia

Prognosis

• Depends on the underlying disease

• Poor prognosis in malignancy

Prevention

• Prevent dehydration that can further aggravate hypercalcemia

When to Refer

• Patients may require referral to an oncologist or endocrinologist depending on the underlying cause of hypercalcemia

• Patients with granulomatous diseases (eg, tuberculosis and other chronic infections, granulomatosis with polyangiitis, sarcoidosis) may require consultation with infectious disease specialists, rheumatologists, or pulmonologists

When to Admit

• Patients with symptomatic or severe hypercalcemia require immediate treatment

• Unexplained hypercalcemia with associated conditions, such as acute kidney injury or suspected malignancy, may also require urgent treatment and expedited evaluation