hypercalcemia

Introduction

Elevation of serum/plasma Ca+2, clinically significant when ionized Ca+2 is increased. Albumin binds 45% of serum Ca+2, thus a normal calcium in the face of hypoalbuminemia may result in clinically significant hypercalcemia.

Etiology

• common causes of hypercalcemia:
  • primary hyperparathyroidism
    • most cases of hypercalcemia in ambulatory patients
    • 85% are due to adenoma of a single gland
    • 15% due to hyperplasia of all 4 glands
    • 1% due to parathyroid carcinoma
  • hypercalcemia of malignancy
    • responsible for most hypercalcemia found in hospitalized patients
    • see pathology
• uncommon causes of hypercalcemia
  • granulomatous disease
    • sarcoidosis
    • Wegener's granulomatosis
    • pulmonary mycosis
    • Mycobacterium tuberculosis or Mycobacterium leprae
  • hyperthyroidism (thyrotoxicosis)
  • prolonged immobilization
  • familial hypocalciuric hypercalcemia
  • renal failure
  • adrenal insufficiency
  • elevated plasma protein concentration
• pharmacologic causes:
  • antacids with absorbable alkali (milk-alkali syndrome)
  • thiazides (not PTH-mediated)
  • vitamin D, vitamin A
  • lithium carbonate (PTH-mediated)
  • estrogens & antiestrogens
  • androgens
  • vitamin D & calcium supplementation in postmenopausal women
  • total parenteral nutrition

Epidemiology

• primary hyperparathyroidism
  • common, especially in elderly women
  • annual incidence of 2/1000

Pathology

• hypercalcemia of malignancy occurs largely via 2 mechanisms:
  • local osteolytic hypercalcemia
    • cytokines produced by tumor cells act locally to stimulate bone resorption
    • extensive bone involvement of tumor, especially in breast carcinoma, multiple myeloma & lymphoma
  • humoral hypercalcemia of malignancy
    • PTH-related peptide or other related peptides secreted by tumor cells act systemically to stimulate bone resorption &/or inhibit Ca+2 excretion
      • squamous cell carcinoma of the lung, head & neck cancer, esophageal cancer, kidney cancer, bladder cancer, & ovarian cancer are most frequently implicated
    • in B-cell lymphoma, increased 1-alpha hydroxylase activity can result in increased calcitriol
• granulomatous disease
  • in the setting of renal failure, macrophage 25-hydroxyvitamin D-1 alpha hydroxylase activity can result in increased calcitriol

Clinical manifestations

• most patients with primary hyperparathyroidism have asymptomatic hypercalcemia found incidentally
• GU: polyuria, polydypsia, nocturia, dehydration, nephrolithiasis, nephrocalcinosis, acute renal failure
• GI: nausea/vomiting, anorexia, constipation, abdominal pain, pancreatitis
• neurologic: muscle weakness, fatigue, confusion, psychosis, delirium, stupor, coma
• cardiac: hypertension, increased susceptibility to digitalis toxicity
• skeletal changes: bone pain, fractures, osteoporosis
• clinical manifestations of hypercalcemia tend to occur when serum Ca+2 rises above 12 mg/dL
  • may include mental status changes & coma > 14 mg/dL
• ectopic soft tissue calcification occurs when the Ca+2 rises above 13 mg/dL

* Mnemonic: bones, stones, groans, thrones, psychiatric overtones

Laboratory

• calcium in 24 hour urine excretion generally > 4 mg/kg
  • collect with urine creatinine, calculate calcium/creatinine in urine
  • high with hyperparathyroidism
  • high with sarcoidosis
  • low with familial hypocalciuric hypercalcemia, vitamin D toxicity, thiazide diuretics
  • unnecessary if immobilization suspected causes
• serum ionized Ca+2
• serum Ca+2: high*
  • serum Ca+2 > 12 mg/dL = hypercalcemia of malignancy or milk-alkali syndrome
• serum phosphate
  • low with primary hyperparathyroidism
  • normal or low with humoral hypercalcemia of malignancy, local osteolysis
  • high with multiple myeloma, granulomatous disease (sarcoidosis, tuberculosis B-cell lymphoma), milk alkali syndrome
• serum parathyroid hormone (PTH)*
  • increased or inappropriately normal with primary hyperparathyroidism
  • decreased with hypercalcemia of malignancy or local osteolysis, typically < 10-15 pg/mL
• serum parathyroid-related peptide
  • elevated with humoral hypercalcemia of malignancy
• bone alkaline phosphatase in serum if immobilization suspected cause
• 25-OH vitamin D in serum
  • suspected vitamin D toxicity
  • 1,25-dihydroxyvitamin D in serum if granulomatous disease suspected
• other serum chemistries: serum chloride & serum albumin
• complete blood count (CBC)
• serum protein electrophoresis if proteinuria +/- anemia
• see ARUP consult

* simultaneous measurement of serum calcium & serum PTH facilitates classification as PTH-related or non-PTH-related hypercalcemia, thus serum PTH takes priority over serum ionized Ca+2

Diagnostic procedures

• electrocardiogram:
  • shortened QT interval
  • AV block (rare)

Management

(see hypercalcemia of malignancy)

• hydration with normal saline
  • 1st line therapy for acute hypercalcemia (symptomatic or serum calcium > 14 mg/dL)
  • follow with furosemide diuresis if renal failure, heart failure or hypervolemia, otherwise avoid loop diuretics
  • avoid thiazide diuretics which impair Ca+2 excretion
• glucocorticoids for (1,25 (OH)2 vit D-mediated hypercalcemia
  • multiple myeloma, B-cell lymphoma, sarcoidosis
• IV bisphosphonate (pamidronate, etidronate, zoledronate) for longer-term control
• calcitonin causes a rapid but short-lived drop in serum Ca+2 & serum phosphate by promoting incorporation into bone
• plicamycin (mithramycin)
  • reserved for volume-repleted patients who have failed pamidronate & calcitonin
• oral phosphate
• gallium nitrate

More general terms

• electrolyte disorder
• sign/symptom
• disorder of calcium metabolism

More specific terms

• familial hypocalciuric hypercalcemia
• hypercalcemia of malignancy

Additional terms

• calcium (Ca+2) in serum/plasma
• hyperparathyroidism
• milk-alkali syndrome (Burnett syndrome)

Patient information

hypercalcemia patient information