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Hypercalcemia


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Author: Meghan Sebasky

 

Incidence:

Found in ~15% of hospitalized adult patients (often incidentally)

Pathophysiology:

  • 1% of total body Ca circulates in the body and is exchangeable with extracellular fluid; the rest resides in bone
    • ~50% of extracellular calcium is ionized - physiologically active
    • ~40% bound to protein (mostly albumin) - affected by protein levels
      • Correction of total serum Ca for hypoalbuminemia:  Add 0.8 mg/dL to measured serum Ca for every 1 g/dL decrease in albumin (with normal albumin value of 4 mg/dL)
    • Remainder complexed with anions to form calcium salts

Etiology:

  • Entry of Ca into the circulation exceeds excretion in urine/deposition into bone
    • Accelerated bone resorption, increased gastrointestinal absorption, decreased renal excretion (or combination of these factors)
  • #1 cause - primary hyperparathyroidism (usually due to parathyroid adenoma)
    • Activated osteoclasts resorb bone + increased intestinal absorption of Ca
  • #2 cause - malignancy (this is the most common cause in hospitalized patients)
    • Bone metastases cause local osteolysis; multiple myeloma causes release of osteoclast activating factors; solid tumors secrete PTHrp; lymphoma causes PTH-independent extrarenal production of calcitriol
  • Less common causes
    • Increased bone resorption - thyrotoxicosis, immobilization (several weeks), Paget disease, vitamin A intoxication
    • Increased calcium absorption in intestine - increased calcium ingestion, milk-alkali syndrome, increased endogenous production of 1,25(OH)2D (granulomatous disease, vitamin D excess)
    • Misc: Lithium, thiazide diuretics, tamoxifen, adrenal insufficiency, theophylline toxicity, familial hypocalciuric hypercalcemia (FHH)

Presentation:

  • Symptoms depend on degree and acuity of increase in Ca level
  • Mild hypercalcemia (up to 11-11.5 mg/dL)
    • Symptoms, if present at all, are nonspecific (fatigue, constipation, depression)
  • Moderate/severe hypercalcemia (>12-14 mg/dL)
    • Chronic elevation may be well tolerated
      • Patient may still develop nephrolithiasis (from chronic hypercalciuria) and type 1 renal tubular acidosis
    • Acute rise can cause marked symptoms
      • Polyuria (decreased concentrating ability of distal tubule), polydipsia, dehydration, acute renal insufficiency, anorexia, nausea, muscle weakness, bone pain, altered mental status
    • EKG may show shortened QT interval, AV block, bradycardia
  • Neuropsychiatric disorders most common in patients with primary hyperparathyroidism (anxiety, depression, cognitive dysfunction)
  • No characteristic physical exam findings

Diagnosis:

First, confirm elevated calcium level.

  • Recheck value.  Correct for albumin vs. check ionized Ca.

Second, check PTH.

  • Elevated or high normal PTH indicates PTH-mediated cause - primary hyperparathyroidism (and very rarely FHH)
    • PTH at the upper end of normal range is inappropriate as the PTH should be suppressed in patients with high serum Ca
  • Low serum PTH indicates non-PTH mediated cause - continue workup

If PTH is low, then check:

  • Parathyroid hormone-related peptide (PTHrp)
  • Vitamin D (1,25-dihydroxyvitamin D and 25-hydroxyvitamin D)
    • Elevated 25(OH)D suggests vitamin D intoxication
    • Elevated 1,25(OH)2D suggests granulomatous disease/lymphoma

If PTHrp and Vitamin D levels are normal, then check:

  • Serum and urine protein electrophoresis, TSH, Vitamin A

Other clues:

  • Mild elevation in PTH can also be due to familial hypocalciuric hypercalcemia (low urine Ca level confirms)
  • Thiazide diuretics enhance Ca resorption in distal tubule - low urine Ca
  • Low or low-normal serum phosphorous - hyperparathyroidism and humoral hypercalcemia of malignancy
    • PTH inhibits proximal tubule phosphate reabsorption
  • Calcium > 13 mg/dL usually due to malignancy; <11 mg/dL or high normal typical of hyperparathyroidism

Treatment:

  • Indicated if Ca > 14 or Ca > 12 in symptomatic patient (if asymptomatic then only hydration necessary for Ca of 12)
  • Hydration, usually aggressive, is mainstay of treatment
    • Normal saline at 200-300 cc/hour if severe/symptomatic
  • Consider furosemide 20-100 mg IV after volume replete
    • Mainly to avoid volume overload (does not reduce Ca quickly)
  • Bisphosphonates indicated in malignancy-associated hypercalcemia
    • Pamidronate or zoledronic acid (peak effect takes 48-72 hours)
  • Calcitonin useful if rapid lowering not accomplished with hydration
    • Rapid onset but short duration, patients can develop tolerance (tachyphylaxis within 48-72 hours).
  • Glucocorticoids are first line after hydration in hematologic malignancies or vitamin D intoxication (suppress 1,25(OH)2D)
  • Hemodialysis can be used for resistant, life-threatening hypercalcemia
  • And, of course, treat the underlying condition
    • Consider parathyroidectomy in patients with primary hyperparathyroidism who meet criteria set forth by National Institutes of Health (age <50, T score < -2.5, Creat clearance < 60, calcium > 1mg/dl above normal).

References:

  • Carroll Mary F and Schad David S.  A Practical Approach to Hypercalcemia.  Am Fam Physician 2003; 67:1959-66.  (Contains a great diagnostic algorithm)
  • French Sarah, Subauste Jose, Geraci Stephen.  Calcium Abnormalities in Hospitalized Patients.  Southern Medical Journal 2012; 105(4):231-7.
  • Khosia, Sundeep.  Hypercalcemia and Hypocalcemia.  In: Longo, Dan L et al, eds.  Harrison’s Principles of Internal Medicine – 18th ed. New York, NY: McGraw-Hill; 2012:360.