Hypocalcemia pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Overview

Hypocalcemia may develop in disorders associated with insufficient parathyroid hormone or vitamin D production or resistance to hormonal activities. Perturbations of calcium homeostasis can be caused by environmental factors or occur as a result of genetic mutations in the calcium-sensing receptor (as in type 1 autosomal dominant hypocalcemia), Gs α subunit (as in type 1A and 1B pseudohypoparathyroidism), vitamin D hydroxylase (as in type 1 vitamin D-dependent rickets , and calcitriol receptor (as in type 2 vitamin D-dependent rickets).

Pathophysiology

Physiology

The normal physiology of Hypocalcemia can be understood as follows:[1][2]

  • The normal concentrations of calcium in the body is maintained within the narrow range and that is required for the minimal activity of the many extra- and intracellular processes calcium regulates. 
  • Calcium transport within the blood is mainly bound to plasma proteins like albumin (45%), phosphate and citrate(15%) and ionized state(40%).
  • Only the ionized form of calcium is active but most laboratories show report of total serum calcium concentrations.
  • The normal concentration of calcium ranges between 8.5 and 10.5 mg/dL.
  • The normal range of ionized calcium in the plasma is 4.65 to 5.25 mg/dL.

Pathogenesis

It is understood that Hypocalcemia is the result caused by the following

Hypoalbuminemia

  • When there is a fluctuation in the protein concentrations especially the one protein which is albumin,total calcium levels in the blood may change.[3][4]
  • Whereas the levels of ionized calcium(free form) remains mostly constant, because it is hormonally regulated.
  • So that the total serum calcium levels may not accurately reflect the physiologically important ionized calcium concentration.

Hormone regulation 

  • Parathyroid hormone (PTH) and vitamin D play a important role in regulating serum calcium.[5]
  • Calcium by itself controls to regulate its own serum levels via a calcium-sensing receptor (CaSR) in the parathyroid gland to inhibit parathyroid hormone (PTH) secretion and on a CaSR in the loop of Henle of the kidney to stimulate renal calcium excretion.[6][7][8][9]
  • Whenever the body serum ionized calcium goes down even in small amounts PTH (parathyroid hormone) is secreted instantaneously.And this occurs in 3 ways[10][11][12][13]
    • 1)PTH (parathyroid hormone) stimulation of calcium reabsorption in the distal tubule of the kidney results in decreased urinary calcium excretion by the kidney.[14]
    • 2)PTH (parathyroid hormone) increases renal production of 1,25-dihydroxyvitamin D which is also called as calcitriol which in turn increases the intestinal calcium absorption.[15]
    • 3)PTH (parathyroid hormone) increases bone resorption which in turn increases the serum calcium levels.[16]
  • When PTH secretion is insufficient Hypokalemia may occur as the sequel, which is classically seen in hypoparathyroidism.

Acid-base disturbances

Alkalosis

  • In alkalosis, hydrogen ions dissociate from the negatively charged albumin, which allows for increased calcium binding and leads to a decreased concentration of free calcium.
  • For an increase in pH of 0.1 unit, there is an approximately 0.05 mmol/L (0.1 mEq/L) fall in the serum level of ionized calcium.

Respiratory Alkalosis

Globulin Binding

Calcium binding to globulin is relatively small (1.0 g of globulin binds 0.2–0.3 mg of calcium) and generally does not influence the total serum calcium concentration.[17]

Genetics

The development of hypocalcemia is the result of genetic mutations such as

  • Mutations in the transcription factor glial-cell missing B (GCMB).
  • Mutations in the calcium-sensing receptor, results in Autosomal dominant hypocalcemia (ADH).which is of 2 types[18]
    • Type 1: Autosomal dominant hypocalcemia (ADH) 1 is due to activating mutation in the CaSR.
    • Type 2: Autosomal dominant hypocalcemia (ADH) 2 is due to activating mutation in the guanine nucleotide binding protein, alpha 11 gene(GNA11).[19][20]

References

  1. ↑ Fong J, Khan A (February 2012). "Hypocalcemia: updates in diagnosis and management for primary care". Can Fam Physician. 58 (2): 158–62. PMC 3279267. PMID 22439169.
  2. ↑ Carroll R, Matfin G (February 2010). "Endocrine and metabolic emergencies: hypocalcaemia". Ther Adv Endocrinol Metab. 1 (1): 29–33. doi:10.1177/2042018810366494. PMC 3474611. PMID 23148147.
  3. ↑ Fong J, Khan A (February 2012). "Hypocalcemia: updates in diagnosis and management for primary care". Can Fam Physician. 58 (2): 158–62. PMC 3279267. PMID 22439169.
  4. ↑ Carroll R, Matfin G (February 2010). "Endocrine and metabolic emergencies: hypocalcaemia". Ther Adv Endocrinol Metab. 1 (1): 29–33. doi:10.1177/2042018810366494. PMC 3474611. PMID 23148147.
  5. ↑ Riccardi D, Brown EM (March 2010). "Physiology and pathophysiology of the calcium-sensing receptor in the kidney". Am. J. Physiol. Renal Physiol. 298 (3): F485–99. doi:10.1152/ajprenal.00608.2009. PMC 2838589. PMID 19923405.
  6. ↑ Goodman WG (January 2004). "Calcium-sensing receptors". Semin. Nephrol. 24 (1): 17–24. PMID 14730506.
  7. ↑ Quarles LD (July 2003). "Extracellular calcium-sensing receptors in the parathyroid gland, kidney, and other tissues". Curr. Opin. Nephrol. Hypertens. 12 (4): 349–55. doi:10.1097/01.mnh.0000079682.89474.80. PMID 12815330.
  8. ↑ Toka HR, Pollak MR (September 2014). "The role of the calcium-sensing receptor in disorders of abnormal calcium handling and cardiovascular disease". Curr. Opin. Nephrol. Hypertens. 23 (5): 494–501. doi:10.1097/MNH.0000000000000042. PMID 24992569.
  9. ↑ Egbuna OI, Brown EM (March 2008). "Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations". Best Pract Res Clin Rheumatol. 22 (1): 129–48. doi:10.1016/j.berh.2007.11.006. PMC 2364635. PMID 18328986.
  10. ↑ Blaine J, Chonchol M, Levi M (July 2015). "Renal control of calcium, phosphate, and magnesium homeostasis". Clin J Am Soc Nephrol. 10 (7): 1257–72. doi:10.2215/CJN.09750913. PMC 4491294. PMID 25287933.
  11. ↑ Akerström G, Hellman P, Hessman O, Segersten U, Westin G (April 2005). "Parathyroid glands in calcium regulation and human disease". Ann. N. Y. Acad. Sci. 1040: 53–8. doi:10.1196/annals.1327.005. PMID 15891005.
  12. ↑ Carroll R, Matfin G (February 2010). "Endocrine and metabolic emergencies: hypocalcaemia". Ther Adv Endocrinol Metab. 1 (1): 29–33. doi:10.1177/2042018810366494. PMC 3474611. PMID 23148147.
  13. ↑ Carrillo-López N, Fernández-Martín JL, Cannata-Andía JB (2009). "[The role of calcium, calcitriol and their receptors in parathyroid regulation]". Nefrologia (in Spanish; Castilian). 29 (2): 103–8. doi:10.3265/Nefrologia.2009.29.2.5154.en.full. PMID 19396314.
  14. ↑ Wu X, Sonnenberg H (November 1995). "Effect of renal perfusion pressure on excretion of calcium, magnesium, and phosphate in the rat". Clin. Exp. Hypertens. 17 (8): 1269–85. PMID 8563701.
  15. ↑ Mortensen L, Hyldstrup L, Charles P (January 1997). "Effect of vitamin D treatment in hypoparathyroid patients: a study on calcium, phosphate and magnesium homeostasis". Eur. J. Endocrinol. 136 (1): 52–60. PMID 9037127.
  16. ↑ Poole, K; Reeve, J (2005). "Parathyroid hormone — a bone anabolic and catabolic agent". Current Opinion in Pharmacology. 5 (6): 612–617. doi:10.1016/j.coph.2005.07.004. ISSN 1471-4892.
  17. ↑ Taal, Maarten (2012). Brenner & Rector's the kidney. Philadelphia, PA: Elsevier/Saunders. ISBN 978-1416061939.
  18. ↑ Baron J, Winer KK, Yanovski JA, Cunningham AW, Laue L, Zimmerman D, Cutler GB (May 1996). "Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism". Hum. Mol. Genet. 5 (5): 601–6. PMID 8733126.
  19. ↑ Li D, Opas EE, Tuluc F, Metzger DL, Hou C, Hakonarson H, Levine MA (September 2014). "Autosomal dominant hypoparathyroidism caused by germline mutation in GNA11: phenotypic and molecular characterization". J. Clin. Endocrinol. Metab. 99 (9): E1774–83. doi:10.1210/jc.2014-1029. PMC 4154081. PMID 24823460.
  20. ↑ Nesbit MA, Hannan FM, Howles SA, Babinsky VN, Head RA, Cranston T, Rust N, Hobbs MR, Heath H, Thakker RV (June 2013). "Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia". N. Engl. J. Med. 368 (26): 2476–2486. doi:10.1056/NEJMoa1300253. PMC 3773604. PMID 23802516.

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