• Clinical science

Hypercalcemia

Summary

Hypercalcemia is a condition of high calcium levels (total Ca2+> 10.5 mg/dL or ionized Ca2+> 5.25 mg/dL) in the blood serum. For information regarding the physiology and homeostasis of calcium, please see the hypocalcemia article. The most common causes of hypercalcemia are primary hyperparathyroidism and malignancy with paraneoplastic production of parathyroid hormone-related protein (PTHrP). Symptoms of hypercalcemia include nephrolithiasis, bone pain, abdominal pain, and polyuria. Management depends on the severity of calcium imbalance. Mild and asymptomatic moderate hypercalcemia is treated with oral rehydration and low calcium intake, while symptomatic moderate cases and severe cases require IV rehydration and calcitonin administration. Hypercalcemic crisis is a life-threatening complication that manifests with dehydration, oliguria, and altered consciousness and requires immediate forced diuresis.

Definition

Hypercalcemia = total serum calcium concentration > 10.5 mg/dL (> 2.62 mmol/L), or ionized (free) calcium concentration > 5.25 mg/dL (> 1.31 mmol/L) [1]

Etiology

Types of hypercalcemia Etiology Pathophysiology
PTH-mediated Primary hyperparathyroidism
Secondary hyperparathyroidism
Tertiary hyperparathyroidism
Familial hypocalciuric hypercalcemia (FFH)
  • See FHH in subtypes and variants section below.
Non-PTH-mediated Hypercalcemia of malignancy
Granulomatous disorders (e.g., sarcoidosis)
Other Medications
Hyperthyroidism
Long periods of immobilization
  • Lack of weight-bearing activities → osteoclast activation → bone demineralization → hypercalcemia
Milk-alkali syndrome
Paget disease of the bone
Adrenal insufficiency

Primary hyperparathyroidism and hypercalcemia of malignancy account for > 90% of cases of hypercalcemia. Compared to primary hyperparathyroidism, serum calcium is typically higher in hypercalcemia of malignancy (> 13 mg/dL, or > 3.25 mmol/L), and patients, therefore, exhibit more severe symptoms.
References:[3][4]

Clinical features

The clinical presentation is variable and may be asymptomatic.

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:[1]

Subtypes and variants

Familial hypocalciuric hypercalcemia (FHH) [6]

  • Etiology: autosomal dominant inactivating mutation in the CaSR genedecreased sensitivity of G-coupled Ca2+-sensing receptors in the kidneys and parathyroid glands ; higher levels of Ca2+ required to suppress PTH higher reabsorption of Ca2+ in the kidney hypocalciuria with mild hypercalcemia and normal or increased PTH levels
  • Clinical features
  • Diagnosis
    • Hypercalcemia and inappropriately normal or increased PTH
    • Hypocalciuria
  • Therapy: no treatment necessary

Diagnostics

Approach [7]

  1. Evaluate calcium imbalance
  2. Differentiate between low PTH and high PTH: to determine the underlying cause of hypercalcemia
  3. Further tests
    • ECG
    • Further evaluation of bone disorders: See laboratory evaluation of bone diseases.

The corrected calcium concentration calculated using serum albumin may not be accurate when major pH changes have taken place in the body (e.g., following surgery). In these cases, it is better to measure ionized calcium directly.

PTH levels in hypercalcemia

PTH level Conditions Laboratory findings
Low PTH Hypercalcemia of malignancy
Vitamin D intoxication

Sarcoidosis or other granulomatous disease, lymphoma

Milk-alkali syndrome
High to normal PTH Primary hyperparathyroidism
Familial hypocalciuric hypercalcemia (FHH)

Treatment

Thiazide diuretics enhance Tubular calcium resorption → Discontinue them in hypercalcemia. Loop diuretics Lose calcium → Administer them in hypercalcemia.

References:[10][1][9]