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Hypercalcemia

Last updated: April 30, 2021

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Hypercalcemia refers to high serum calcium levels (total Ca > 10.5 mg/dL or ionized Ca2+ > 5.25 mg/dL). The most common causes of hypercalcemia are primary hyperparathyroidism and malignancy involving paraneoplastic production of parathyroid hormone-related protein (PTHrP). Manifestations of hypercalcemia include nephrolithiasis, bone pain, abdominal pain, polyuria, muscle weakness, and neuropsychiatric symptoms. The most important initial diagnostic steps are ruling out factitious hypercalcemia (by measuring ionized calcium or calculating the corrected calcium) and measuring intact PTH levels (to differentiate between PTH-mediated hypercalcemia and non-PTH-mediated hypercalcemia). Management depends on the severity of the calcium imbalance. Mild and asymptomatic moderate hypercalcemia is treated with oral rehydration and low calcium intake, while symptomatic or severe hypercalcemia is a potentially life-threatening medical emergency requiring hospitalization and immediate treatment with IV fluid repletion and medications that inhibit bone resorption (e.g., calcitonin, bisphosphonates). In addition, identification and treatment of the underlying cause of hypercalcemia are essential.

See “Hypocalcemia” for details on calcium physiology and homeostasis.

Hypercalcemia may be due to PTH-mediated or non-PTH-mediated causes. Primary hyperparathyroidism and malignancy are the most common causes, accounting for ∼ 90% of all cases. [2]

Causes of hypercalcemia [2][3]
Types of hypercalcemia Etiology Pathophysiology
PTH-mediated hypercalcemia Primary hyperparathyroidism
Tertiary hyperparathyroidism
Familial hypocalciuric hypercalcemia
  • See “Familial hypocalcuric hypercalcemia” in “Subtypes and variants.”
Non-PTH-mediated hypercalcemia Hypercalcemia of malignancy
Granulomatous disorders (e.g., sarcoidosis)
Medications
Thyrotoxicosis
Long periods of immobilization
  • Lack of weight-bearing activities → osteoclast activation → bone demineralization → hypercalcemia
  • Usually occurs in patients with high bone turnover at baseline [8]
Milk-alkali syndrome
Adrenal insufficiency
  • The exact pathophysiology is unknown; several mechanisms have been proposed. [9]

Severe/symptomatic hypercalcemia usually develops acutely and is typically caused by excessive osteoclast-mediated bone resorption, most commonly in association with malignancy.
In primary hyperparathyroidism, serum calcium is typically lower and rises more slowly than in hypercalcemia of malignancy. Patients are, therefore, less symptomatic.

The clinical presentation is variable and ranges from asymptomatic presentation in mild hypercalcemia to life-threatening clinical features in severe hypercalcemia. See “Classification of hypercalcemia.”

Hypercalcemia can cause pancreatitis. Hypocalcemia in patients with pancreatitis suggests pancreatic necrosis.

The presentation of hypercalcemia includes stones (nephrolithiasis), bones (bone pain, arthralgias), thrones (increased urinary frequency), groans (abdominal pain, nausea, vomiting), and psychiatric overtones (anxiety, depression, fatigue). Note that these are also the findings of vitamin D overdose!

References:[11]

Laboratory values and the presence of symptoms should be used in conjunction to determine the need for treatment. Acutely symptomatic moderate hypercalcemia and severe hypercalcemia are medical emergencies and require hospital admission and immediate initiation of treatment.

Familial hypocalciuric hypercalcemia (FHH) [12]

Approach [1][2][3][8]

Severe or symptomatic hypercalcemia is a medical emergency. Treatment should be initiated immediately, in parallel with diagnostic workup.

Routine investigations [2][8]

The corrected calcium concentration, calculated using serum albumin, may not be accurate in the setting of major acid-base imbalances. In patients with significant alkalemia or acidemia, it is recommended to measure ionized calcium directly.

Investigations to determine underlying etiology

Measurement of serum intact PTH level is the key initial study for confirmed hypercalcemia with no immediately evident etiology.

Other investigations to consider [1][8]

Approach [2][8]

Supportive care

  • Ensure adequate hydration.
  • Reduce dietary intake of calcium.
  • Avoid; potentially aggravating medications (e.g., thiazides; , lithium, vitamin D, calcidiol, calcitriol).
  • Encourage mobility and avoid prolonged bed rest/inactivity. [8]

Fluid therapy and volume status management

Thiazide diuretics enhance Tubular calcium upTake: Discontinue them in hypercalcemia. Loop diuretics Lose calcium: They may be used to treat fluid overload in patients with hypercalcemia.

Standard pharmacotherapy

Pharmacotherapy is aimed at inhibiting bone resorption.

  • Consider calcitonin for rapid-onset, short-term control of hypercalcemia.
    • Reduces serum calcium within 2–6 hours, with maximal effect within 12–24 hours
    • Often limited by tachyphylaxis after 48 hours of use
  • Bisphosphonates for slow-onset, long-term control of hypercalcemia
    • Options
    • Typically lead to normalization of serum calcium within 2–4 days, with effect duration of days to weeks following a single dose
    • The dose may be repeated, if needed, after a minimum of 7 days.
    • Contraindicated in severe CKD (CrCl < 30 mL/min)

Targeted therapies

Alternative therapeutic options

These treatment options may be considered if hypercalcemia is resistant to other measures or the use of bisphosphonates is contraindicated due to severe renal failure.

  • Denosumab [2][8][20]
  • Hemodialysis may additionally be considered in the following circumstances:
    • Aggressive fluid repletion is contraindicated (e.g., patients with fluid overload due to severe heart failure or oliguric AKI).
    • Immediate reduction of calcium levels is necessary due to life-threatening symptomatic hypercalcemia. [21]
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