Today, we discussed the case of a middle-aged woman with no significant medical history who presented to PCP with a month of nausea, vomiting, weakness, and 30 pound weight loss, found to have severe hypercalcemia likely secondary to a granulomatous disease.  Final diagnosis pending biopsy results.

Clinical Pearls

  • The first step in working up hypercalcemia is correcting for albumin.  Keep in mind that patients with hypoalbuminemia may have a falsely low serum calcium level.  Conversely, patients with multiple myeloma who have a high paraprotein serum concentration may have a falsely elevated total serum calcium level.  When in doubt, check an ionized serum calcium to confirm true hypercalcemia.
  • Think of hypercalcemia in two broad categories of PTH dependent disorders and PTH independent disorders (see below).
  • 25-OH vitamin D has a long half life and is the best laboratory test to determine adequate nutritional intake of vitamin D.  In contrast, 1,25OH vitamin D has a short half life.

Calcium homeostasis:

  • Remember that bone is the largest reservoir of calcium in the body.

calcium homeostasis

Source: this NEJM case

Work up of hypercalcemia

  • Remember to confirm true hypercalcemia by correcting for albumin and/or measuring ionized calcium for people with conditions such as multiple myeloma who may have a falsely elevated total serum calcium due to increased paraprotein binding.
  • Check out this super awesome previous post on hypercalcemia on our blog for more details.  Here is the simplified diagnostic algorithm we went over today:

Hypercalcemia algorithm


  • Ca <12
    • No treatment if asymptomatic
    • Avoid exacerbating factors
  • Ca 12-14
    • If chronic/asymptomatic ⇒ same treatment as Ca <12
    • If acute/symptomatic ⇒ same treatment as Ca 14-18
  • Ca 14-18
    • IVF – LOTS!
    • Lasix only if the patient has concurrent renal/heart failure
    • Calcitonin
    • Bisphosphobates
      • Zoledronic acid >> pamidronate for patients with malignancy
      • Do not use in patients with Cr >4.5
    • Denosumab (RANKL) if refractory to zoledronic acid or in patients with severe renal impairment
  • Ca >18
    • Same treatment as Ca 14-18 PLUS
    • Hemodialysis

Treatment options: (table adapted from UpToDate)


Treatment of hypercalcemia

* Only used in patients with renal insufficiency or heart failure, judicious use of loop diuretics may be required to prevent fluid overload during saline hydration.

Vitamin D metabolism

  • Remember the following simplified pathway of vitamin D metabolism

Vitamin D

Source: Hepatitis B Foundation

  • 25-OH vitamin D has a long half-life and the best laboratory test to perform to determine adequacy of nutritional intake
  • In work up of hypercalcemia, it is also important to check 1,25-dihydroxyvitamin D levels.  Why?
    • Remember that 1-alpha hydroxylase is an enzyme in the kidney that converts 25-OH vitamin D into its metabolically active form ⇒ 1,25-dihydroxyvitamin D
    • It turns out that in certain granulomatous diseases and lymphoma, activated monocytes in affected tissues start to express 1-alpha hydroxylase as well, resulting in overproduction of 1,25-dihydroxyvitamin D.
    • So, in work up of hypercalcemia that is PTH-independent, if you notice elevated 1,25-dihydroxyvitamin D with normal 25-OH vitamin D levels, suspect granulomatous disease or lymphoma causing exogenous 1,25-dihydroxyvitamin D  production.

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