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 PO₄^3-

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

Parathyroid Hormone: Increases serum Ca²⁺ and lowers serum PO₄^3-

• Synthesized by parathyroid chief cells
• Activates osteoclasts -> moves Ca²⁺ from bone to the blood
• Increases renal reabsorption of Ca²⁺
• Decreases renal reabsorption of PO₄^3-
• Activates 1-α-hydroxylase (increases levels of 1,25-(OH)-Vitamin D)

Vitamin D: Increases serum Ca²⁺ and serum PO₄^3-

• 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 PO₄^3- from bone to the blood

Approach

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