Mechanism by which Thiazide Diuretics cause Hypercalcemia.

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Thiazide diuretics:
    • Cause hypercalcemia primarily by enhancing renal calcium reabsorption in the distal convoluted tubule:
      • Which reduces urinary calcium excretion and leads to calcium retention
  • The mechanism involves:
    • Thiazide-induced blockade of the apical NaCl cotransporter in the distal convoluted tubule:
      • This blockade reduces intracellular chloride:
        • Causing chloride to exit through chloride channels:
          • Which hyperpolarizes the cell membrane
        • The resulting hyperpolarization stimulates calcium entry:
          • Through voltage-sensitive, dihydropyridine-sensitive calcium channels on the apical membrane
        • Additionally, thiazides upregulate expression of distal tubule calcium transport molecules including:
          • TRPV5, TRPV6, and calbindin-D9k
  • The presence of parathyroid hormone (PTH):
    • Is necessary for thiazides to reduce urinary calcium excretion:
      • Studies in hypoparathyroid patients show minimal hypocalciuric effect compared to euparathyroid controls:
        • This suggests thiazides may potentiate PTH action on the nephron
  • In patients receiving vitamin D or with hyperparathyroidism:
    • Thiazides can also increase calcium release from bone:
      • Contributing to more pronounced hypercalcemia:
        • This bone effect appears to require either pharmacologic doses of vitamin D or enhanced bone resorption states
  • Importantly, many patients with thiazide-associated hypercalcemia have underlying primary hyperparathyroidism:
    • That becomes unmasked:
      • Approximately 24% are ultimately diagnosed with primary hyperparathyroidism:
        • 71% continue to have hypercalcemia after thiazide discontinuation
      • The hypercalcemia is typically mild and PTH-independent in those without underlying parathyroid disease
  • References
    Hypercalcemia: A Review. Walker MD, Shane E. JAMA. 2022;328(16):1624-1636. doi:10.1001/jama.2022.18331.
    Drug-Related Hypercalcemia. Lecoq AL, Livrozet M, Blanchard A, Kamenický P. Endocrinology and Metabolism Clinics of North America. 2021;50(4):743-752. doi:10.1016/j.ecl.2021.08.001.
    Mechanism of Calcium Transport Stimulated by Chlorothiazide in Mouse Distal Convoluted Tubule Cells. Gesek FA, Friedman PA. The Journal of Clinical Investigation. 1992;90(2):429-38. doi:10.1172/JCI115878.
    The Role of Calbindin-D28k on Renal Calcium and Magnesium Handling During Treatment With Loop and Thiazide Diuretics. Lee CT, Ng HY, Lee YT, Lai LW, Lien YH. American Journal of Physiology. Renal Physiology. 2016;310(3):F230-6. doi:10.1152/ajprenal.00057.2015.
    Changes in Serum and Urinary Calcium During Treatment With Hydrochlorothiazide: Studies on Mechanisms. Brickman AS, Massry SG, Coburn JW. The Journal of Clinical Investigation. 1972;51(4):945-54. doi:10.1172/JCI106889.
    The Interactions of Thiazide Diuretics With Parathyroid Hormone and Vitamin D. Studies in Patients With Hypoparathyroidism. Parfitt AM. The Journal of Clinical Investigation. 1972;51(7):1879-88. doi:10.1172/JCI106990.
    Thiazide-Associated Hypercalcemia: Incidence and Association With Primary Hyperparathyroidism Over Two Decades. Griebeler ML, Kearns AE, Ryu E, et al. The Journal of Clinical Endocrinology and Metabolism. 2016;101(3):1166-73. doi:10.1210/jc.2015-3964.
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Published by Rodrigo Arrangoiz MS, MD, FACS, FSSO

My name is Rodrigo Arrangoiz I am a breast surgeon/ thyroid surgeon / parathyroid surgeon / head and neck surgeon / surgical oncologist that works at Center for Advanced Surgical Oncology in Miami, Florida. I was trained as a surgeon at Michigan State University from (2005 to 2010) where I was a chief resident in 2010. My surgical oncology and head and neck training was performed at the Fox Chase Cancer Center in Philadelphia from 2010 to 2012. At the same time I underwent a masters in science (Clinical research for health professionals) at the University of Drexel. Through the International Federation of Head and Neck Societies / Memorial Sloan Kettering Cancer Center I performed a two year head and neck surgery and oncology / endocrine fellowship that ended in 2016. Mi nombre es Rodrigo Arrangoiz, soy cirujano oncólogo / cirujano de tumores de cabeza y cuello / cirujano endocrino que trabaja Center for Advanced Surgical Oncology en Miami, Florida. Fui entrenado como cirujano en Michigan State University (2005 a 2010 ) donde fui jefe de residentes en 2010. Mi formación en oncología quirúrgica y e n tumores de cabeza y cuello se realizó en el Fox Chase Cancer Center en Filadelfia de 2010 a 2012. Al mismo tiempo, me sometí a una maestría en ciencias (investigación clínica para profesionales de la salud) en la Universidad de Drexel. A través de la Federación Internacional de Sociedades de Cabeza y Cuello / Memorial Sloan Kettering Cancer Center realicé una sub especialidad en cirugía de cabeza y cuello / cirugia endocrina de dos años que terminó en 2016.

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