10. Hypercalcemia

Definition: serum [Ca2+] >10.1mg/dL, ionized >1.36 mmol/L.

Etiology/Risk Factors

  • Almost always due to a combination of increased bone resorption/increased GI absorption and decreased renal excretion. 
    • 90% due to hyperparathyroidism or malignancy. If mild, more likely primary hyperparathyroidism; if moderate to severe, more likely malignancy-related.
    • 10% due mostly to granulomatous disease, as well as some rare causes. 
  • Differential diagnosis:
    • Calcium excess.
    • Hyperparathyroidism (primary and tertiary).
    • Immobilization/Inherited (familial hypocalciuric hypercalcemia).
    • Meds (thiazide, lithium, vitamin D, vitamin A).
    • Paget’s disease.
    • Adrenal insufficiency/Addison’s disease.
    • Neoplasm (metastases, PTHrP producing, calcitriol producing, or osteolytic/blastic activity. Commonly, breast, lung, myeloma, lymphoma).
    • Zollinger-Ellison syndrome.
    • Endocrine (hyperthyroidism causing excess bone resorption).
    • Sarcoid and other granulomatous diseases (TB, histoplasmosis, berylliosis, Hodgkin’s).

Evaluation

1. Check PTH level: 

  • If high, this is suggestive of primary hyperparathyroidism. If minimally elevated or normal (inappropriate for calcium level), check 24-hour urine calcium excretion.
    • HIGH: >250 mg (men) or >200 mg (women), suggestive of primary hyperparathyroidism.
    • LOW: milk alkali syndrome (rarely), familial hypocalciuric hypercalcemia.
  • Low PTH (appropriately suppressed):
    • Look for offending medications (vitamin D, calcium supplements).
    • Consider granulomatous disease, endocrinopathies (thyroid or adrenal insufficiency), or malignancy; see step 2.

2. If PTH level is low, consider the following additional workup: 

  • Labs:
    • Serum: 
      • Albumin, alkaline phosphatase.
      • 25-OH and 1,25-OH vitamin D (1,25-OH is elevated in granulomatous disease).
      • PTHrP.
      • SPEP with immunofixation.
      • Consider AM cortisol, TSH, insulin-like growth factor.
    • Urine: 
      • Urine calcium and creatinine (ideally, 24 hour collection).
      • UPEP with immunofixation.
  • Imaging:
    • CXR (for sarcoid, TB, fungal infections).
    • Bone scan (for malignancy).
    • Bone survey (for multiple myeloma).
    • CT scan (for primary tumor).
  • If workup is negative, consider immobility, though this is a diagnosis of exclusion.

Management

  • Evaluate for symptoms: “stones, bones, abdominal groans, with psychiatric overtones.”
    • Renal: polyuria, nephrolithiasis, chronic kidney disease (nephrocalcinosis), AKI (calcium-induced vasoconstriction and hypovolemia).
    • GI: anorexia, nausea, vomiting, constipation; can rarely lead to pancreatitis.
    • Neuro: weakness, fatigue, confusion, stupor, coma.
    • Musculoskeletal: bone pain.
    • Cardiac: shortened QT, hypertension.
  • Treatment:
    • Hypercalcemia causes loop diuretic-like effect and partial nephrogenic DI which can lead to volume depletion. 
      • Volume resuscitation with normal saline: at least 3-4 L in first 24 hours.
      • In contrast to classic teaching, recent studies show no clear benefit of loop diuretics in addition to fluids. Can consider IV diuresis after volume repletion in patients where volume overload is a concern.
    • Bisphosphonates block osteoclastic bone resorption and have been shown to decrease skeletal morbidity but not mortality in metastatic malignancy.
      • Pamidronate: 90 mg IV over 4 hours (for Ca >13.5).
      • Zoledronic acid: 4 mg IV over 15 min-30 min (adjusting for GFR), along with crystalloid. Better studied in malignancy.
      • Both agents work over 72 hrs. Side effects include ↓ magnesium/phosphorus and low-grade fever. Be sure to check electrolytes frequently and replete Mg and Phos as needed after administration.
    • Calcitonin (salmon): more rapid onset but weak/transient effect (1-3 mg/dL) that wanes after 2-3 days due to tachyphylaxis. Be wary of cramps and flushing.
      • 4-8 SQ/IM q 12 hours x 1 to 3 days.
    • Glucocorticoids decrease GI absorption and prevent 1,25-OH vitamin D formation in granulomatous disease; may be anti-neoplastic (myeloma, lymphoma).

Key Points

  • 90% of hypercalcemia is due to hyperparathyroidism or malignancy. 
  • Evaluation is based on determining whether hypercalcemia is PTH-mediated.
  • Primary initial treatment of hypercalcemia is aggressive fluid resuscitation.
  • Presence of hypercalcemia is a very poor prognostic indicator in non-parathyroid malignancy (hypercalcemia of malignancy—30 day mortality >50% with median survival 4-6 weeks).

 

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LeGrand SB, Leskuski D, Zama I. Narrative Review: Furosemide for Hypercalcemia: An Unproven yet Common Practice.Susan B. LeGrand, Ann Intern Med August 19, 2008 149:259-263

Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 2001;19:558-567