Hypercalcemia

Corrected Ca2+ = Measured Ca2++ 0.8 (4 – Albumin)

Signs & Symptoms

  • Typically seen when Calcium levels are > 12.0 mg/dL
  • Stones, bones, groans, psychiatric overtones
    • Nephrolithiasis
    • Bone pain
    • Abdominal pain
    • Psychosis/altered mental status
  • Increased urination and thirst
  • EKG: Shortened QT interval (1)

Hormonal Control

Calcitonin: Decreases serum Ca2+ and PO43-

  • Synthesized by thyroid parafollicular cells (“C-cells”)
  • Activates osteoblasts -> moves Ca2+ from blood to the bone

Parathyroid Hormone: Increases serum Ca2+ and lowers serum PO43-

  • Synthesized by parathyroid chief cells
  • Activates osteoclasts -> moves Ca2+ from bone to the blood
  • Increases renal reabsorption of Ca2+
  • Decreases renal reabsorption of PO43-
  • Activates 1-α-hydroxylase (increases levels of 1,25-(OH)-Vitamin D)

Vitamin D: Increases serum Ca2+ and serum PO43-

  • Absorbed through diet or via sunlight exposure
    • Converted to 25-(OH)-Vitamin D (Calcidiol) by liver
      • Converted to 1,25-(OH)-Vitamin D (Calcitriol) by kidneys
  • Increases GI absorption of Ca2+
  • Activates osteoclasts -> moves Ca2+ and PO43- from bone to the blood

Approach

*: If PTH is normal, this is inappropriate – in hypercalcemia, the PTH should be low because of calcium-mediated feedback inhibition of the parathyroid gland.
**: Granulomas contain the enzyme 1-α-hydroxylase, which converts 25-(OH)-Vitamin D to 1,25-(OH)-Vitamin D, which in turn leads to increased calcium levels

Management

  1. Treat Underlying Condition (i.e. parathyroidectomy, immunosuppression, stop thiazides, etc.)
    • Parathyroidectomy indications in hyperparathyroidism
      • Age < 50
      • Calcium level > 1 mg/dL above UNL
      • Creatinine clearance < 60 mL/min
      • Urinary calcium > 400 mg/day
      • Nephrolithiasis
      • Osteoporosis
  2. IV Fluids
    • Hypercalcemia causes decreased reabsorption of Na+ in the kidneys, therefore producing a natriuresis leading to volume depletion
    • Normal Saline preferred instead of Lactated Ringer’s because of calcium component of Lactated Ringer’s
    • 200-300 mL/hr, with a goal urine output of 100-150 mL/hr (2)
  3. Bisphosphonates (Effect in few days)
    • Inactivates osteoclasts, leading to reduction of bone resorption
    • Pamidronate
    • Zoledronic acid (preferred, more potent)
  4. Calcitonin (Effect in ~4 hours) (3)
    • Activates osteoblasts, increasing bone resorption
    • Dosing: 4-8 IU/kg q6-12 hours (tailored to response)
    • Calcium should drop ~ 2 mg/dl
    • Indicated if severe hypercalcemia (>14 mg/dL)
  5. Denosumab
    • RANKL-inhibitor, decreasing osteoclastic activity, leading to reduction of bone resorption
    • Indicated if hypercalcemia is refractory to bisphosphonates or if bisphosphonates are contraindicated due to renal impairment (4)
  6. Calcimimetics
    • Cinacalcet
    • Increases sensitivity of the calcium-sensing receptor, decreasing PTH secretion
    • Indicated in hypercalcemia secondary to parathyroid carcinoma (5)
    • Also hold promise in the treatment of FHH
  7. Dialysis
    • Indicated if severe hypercalcemia, life-threatening findings (neurologic changes or EKG changes), refractory, or associated with renal failure or heart failure (in which patients may not tolerate large amount of fluid administration) (6)

References

  1. Kelwade, J., Modi, K., Kumar, N., & Parekh, H. (2016). Hypercalcemia and electrocardiogram changes. Retrieved February 17, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5105587/
  2. Holliman, K. (2012, May 15). Too much of a good thing. Retrieved February 19, 2021, from https://acphospitalist.org/archives/2012/05/hypercalcemia.htm
  3. Mirrakhimov, A. E. (2015, November). Hypercalcemia of Malignancy: An update ON pathogenesis and management. North American journal of medical sciences. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683803/. 
  4. Thosani, S., & Hu, M. (2015). Denosumab: A new agent in the management of hypercalcemia of malignancy. Retrieved February 19, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976858/
  5. Loh, H., & Mohd Noor, N. (2014). The use of hemodialysis in refractory hypercalcemia secondary to parathyroid carcinoma. Retrieved February 19, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4010034/
  6. Basok, A., Rogachev, B., Haviv, Y., & Vorobiov, M. (2018, May 31). Treatment of extreme hypercalcaemia: The role of haemodialysis. Retrieved February 19, 2021, from https://casereports.bmj.com/content/2018/bcr-2017-223772

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