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Hypercalcemia

Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Calcium levels are regulated and affected by factors such as dietary intake and pH, and the levels of parathyroid hormone (PTH), vitamin D, and albumin. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Generally, neuropsychiatric (confusion, altered mental status), GI (vomiting, abdominal pain ), musculoskeletal ( bone pain , weakness), and renal (polyuria, polydipsia) manifestations are seen. Confirmation of hypercalcemia is required. Correction of the value is based on the albumin levels or after determining the ionized calcium levels (the metabolically active form), which is followed by determining PTH levels. Subsequent laboratory tests and imaging studies are ordered based on history and presentation. Correction of hypercalcemia depends on its severity. Calcium levels > 14 mg/dL are treated using IV isotonic saline hydration, calcitonin, and bisphosphonates . Hemodialysis is considered in rare cases. Treatment of the underlying cause is recommended.

Last updated: April 7, 2024 641 views

Increased bone resorption:

  • Hyperparathyroidism:
    • ↑ PTH → bone resorption from osteoclast activation (also with ↑ intestinal calcium absorption)
    • Primary (frequently from parathyroid adenoma) → most common cause
    • Secondary and tertiary (frequently from CKD )
  • Thyrotoxicosis : Thyroid hormone mediates bone resorption.
  • Malignancy increases bone resorption by:
    • Secretion of PTH-related protein (PTHrP) from solid tumors
    • Metastasis: ↑ osteoclastic activity → ↑ bone resorption
    • ↑ Osteoclast-activating factors, such as interleukin-6 and lymphotoxin (in multiple myeloma )
    • Production of calcitriol from macrophages (in lymphoma)
  • Others:
    • Immobilization
    • Paget disease of the bone
    • Estrogen or antiestrogen (tamoxifen) in patients with breast cancer
    • Hypervitaminosis A: dose-dependent increase in bone resorption

Increased calcium absorption:

  • Milk-alkali syndrome:
    • Consumption of large amounts of calcium carbonate
    • Presents with hypercalcemia, metabolic alkalosis, and acute kidney injury
  • Vitamin D toxicity:
    • Often due to ingestion of calcitriol to treat hypoparathyroidism or hypocalcemia
    • May result from over-the-counter supplements

Others:

  • Adrenal insufficiency : ↑ bone resorption, ↑ renal calcium reabsorption
  • Pheochromocytoma : from PTHrP or as part of MEN syndrome
  • Lithium: reduces renal calcium excretion and alters the PTH secretion set point (PTH may be normal or elevated in lithium-induced hypercalcemia.)
  • Thiazide diuretics : ↓ renal calcium excretion
  • Chronic granulomatous disease ( sarcoidosis , TB ): ectopic vitamin D production
  • Familial hypocalciuric hypercalcemia (FHH): mutation in the calcium-sensing receptor gene
  • Vitamin A and vitamin A derivatives (e.g., isotretinoin ) directly stimulate bone resorption.

 

Mnemonic for Hypercalcemia  

CHIMPANZEES

  • C – Calcium supplementation
  • H – Hydrochlorothiazide
  • I – Iatrogenic, immobilization
  • M – Multiple myeloma, milk-alkali syndrome, medication (e.g Lithium)
  • P – Parathyroid hyperplasia or adenoma
  • A – Alcohol
  • N – Neoplasm (e.g breast cancer, lung cancer)
  • Z – Zollinger Ellison syndrome
  • E – Excessive vitamin D
  • E – Excessive vitamin A
  • S – Sarcoidosis
 جملة تذكرية

  • Usually asymptomatic (especially when total albumin-corrected calcium < 12 mg/dL)
  • Bone pain, arthralgias, myalgias, fractures
  • GI: anorexia, nausea, vomiting, constipation, abdominal pain
  • Neurologic: confusion, lethargy, hyporeflexia, altered mental status, coma (especially if > 14 mg/dL)
  • Cardiovascular: hypertension , bradycardia, ECG changes (1st-degree heart block, shortened QT interval, J waves, T wave inversions)
  • Renal: polyuria or nocturia, polydipsia
  • Musculoskeletal: weakness, bone pain
  • Chronic presentation:
    • Osteoporosis with bone pain
    • Nephrocalcinosis
    • Pancreatitis
    • Hypertension

Management of hypercalcemia
Severe
(calcium >14 mg/dL)
or symptomatic

Rapidly lower calcium levels.

  • Start IV fluid therapy with 0.9% NaCl.
  • Consider adding diuretics if there is volume overload (Avoid loop diuretics unless volume overload (heart failure) exists)
  • Consider calcitonin for rapid-onset, short-term control of hypercalcemia (faster than bisphosphonates)
  • Bisphosphonates for slow-onset, long-term control of hypercalcemia (suppress bone resorption)

Consider targeted therapy based on suspected etiology:

  • Surgery in case of parathyroid adenoma
  • corticosteroids in case of sarcoidosis
Moderate
(calcium 12-14 mg/dL)
  • Usually no immediate treatment required unless symptomatic
  • Treatment is similar to that for severe hypercalcemia
Asymptomatic or mild
(calcium <12 mg/dL)
  • No immediate treatment required
  • Avoid thiazide diuretics, lithium, volume depletion & prolonged bed rest