Inpatient / Nephrology

Hypercalcemia

If You Remember Nothing Else

Hypercalcemia is most commonly found incidentally in the outpatient setting, but when diagnosed inpatient, especially when severe, it needs to be taken seriously. The most common cause of hypercalcemia in the inpatient setting is malignancy.

After correcting for albumin (or getting an iCal), if hypercalcemia is severe (>14 or >12 with symptoms), patients need to be aggressively resuscitated (within reason to avoid overload) with normal saline to protect the kidneys, and with calcitonin as a bridge to other mainstay calcium-lowering agents such as bisphosphonates which take 2-4 days to work.
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Clinical Pearls

• Calcium is part of the BMP; historically a "Chem 7" panel didn't have it, but now we have many more incidental findings of hyper and hypocalcemia mostly found in the outpatient setting
• Only 1% of total body calcium is outside your bones and teeth. Of the ~0.1% (~350mg) that circulates in plasma, 40% is bound to protein (albumin), 10% complexed with anions, 50% is "free" ionized calcium (iCal). Only iCal is physiologically active.
• We think of "normal" calcium levels as ~10 because the total is reported as mg/dL, This equates to 2.5 when reported as mmol/L. As above, Ionized calcium is 50% of the total, and is reported as mmol/L, This is why "normal" iCal is ~1.25 mmol/L
• Hydrogen ions compete with calcium for protein-binding sites. Acidosis decreases calcium binding and increases the proportion of total calcium that is ionized.In general, every 0.1 decrease in pH leads to an increase of 0.05 mmol/L of iCal
• Why don't we always report iCal in a BMP? Measurement of iCal requires more complex preservation of the blood sample (maintaining a certain pH, temperature, etc). However, it's easy to measure immediately at the point of care (think VBG in the ICU).
• The most common outpatient presentation is primary hyperparathyroidism from adenoma; the most common inpatient presentation is PTHrP positive ectopic production from cancer
• Hypercalcemia is formally diagnosed by elevated calcium levels in two samples at least 1 week apart over a 3 month time span
• Primary Hyperparathyroidism will usually show high calcium and an inappropriately normal PTH vs high PTH
• Phosphorus is a surrogate for PTH level - will usually be low if the hypercalcemia is PTH mediated
• Calcium is a diuretic, patients often present volume depleted which is why volume resuscitation is so important to avoid renal injury which limits the options for treatment
• Calcitonin quickly lowers calcium levels, however calciphylaxis occurs within 2-3 days; Bisphosphonates are actually more potent than calcitonin, they just take time to work (usually 3-4 days)
• Hypercalcemia is present in 20-30% of patients with cancer, and is associated with a poorer prognosis secondary to advanced disease and metastases; to be the cause of severe hypercalcemia, bony mets need to be widespread - median survival is ~2 months with 50% mortality within 30 days of diagnosis
• If driven by PTHrP (>12), the effect of bisphosphonates less potent and lasts for less time (more common relapse within 14 days)
• Vitamin D - 25(OH)D is calcidiol which is the storage form  to assess for insufficiency; 1,25(OH)D (calcitriol) is the active form
• What is considered a vitamin D deficiency? Calcidiol <20 ng/mL is deficient, Calcidiol <12 is severely deficient. Some consider Calcidiol 20-30 to be "insufficient", though the value of supplementation at this level is debated
• Vitamin D2 (ergocalciferol) comes from plant sources; D3 (cholecalciferol) is formed in the skin and comes from animal sources and is more effective at raising levels when supplemented and is thus preferred; the difference is at the level of liver metabolism
• How much vitamin D should we give when supplementing? Calcidiol <12 - load with 50,000 U D3 weekly for 6-8 weeks, then 800-1000 U daily; Calcidiol 12-20 - 1000-2000 U daily. In both caes, repeat the level in 3-4 months and go from there.
• Increased production of calcitriol (active VitD) is the cause of most hypercalcemia in Hodgkin Lymphoma and ~⅓ of cases in non-Hodgkin Lymphoma
• To get hypercalcemia from immobility needs to be over a long period of time, and true immobility from paralysis or severe illness
• Calcitonin blocks the activity of osteoclasts and decreases the reabsorption of calcium in the kidneys (opposite of PTH activity); Tachyphylaxis is likely related to the downregulation of calcitonin receptors on osteoclasts
• Loop diuretics lower calcium levels, but should only be given if evidence of overload with HF, CKD
• Bisphosphonates work by leading to apoptosis of osteoclasts
• Zoledronate is better than pamidronate for lowering calcium levels in cancer patients, but is also more likely to cause AKI/ATN so should be avoided if there is a concern for myeloma and should be used with caution in CKD
• The risk of osteonecrosis of jaw (ONJ) and femur fracture with bisphosphonate use is rare and usually in patients who require high-dose, long-term IV therapy. The true incidence of ONJ is unknown. In general, it is very rare with PO use; incidence < 1 per 100,00 person-years. In IV use, it's likely much higher (~0.1%-1% after 1 year, ~10% after 4 years) and highest in zoledronic acid and pamidronate.
• ONJ is thought to be related to the prolonged suppression of osteoclasts, leading to less bone turnover which leads to abnormally dense bone that is more susceptible to avascular necrosis

Trials and Literature

• Zoledronic Acid is superior to pomidronate in hypercalcemia of malignancy in a pooled RCT - complete response was 88% vs 60%, and durection of effect was 32-42 days vs 18 days (JCO 2001)
• Review on Hypercalcemia associated with cancer (NEJM 2005)
• Review on Diagnosis and Management of hypercalcemia (BMJ 2015)
• Review on Indications for surgical managmeent of hyperparathyroidism (JAMA Surg 2017)

Other Resources

• The Curbsiders - #281 Hypercalemia and #358 Oncologic Emergencies
• Clinical Problem Solvers - Hypercalcemia Dx Schema

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