Hypercalcemia pathophysiology

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


Normal calcium homeostasis is maintained by parathyroid hormone and vitamin D. Normally, parathyroid hormone increases serum calcium and magnesium concentration, and decreases serum phosphate concentration. Secretion of parathyroid hormone from parathyroid gland is stimulated by low serum calciumParathyroid glands have calcium-sensing receptors responsible for sensing extracellular ionized calciumCalcium and magnesium provides a negative feedbackfor secretion of parathyroid hormone. Hypercalcemia may result due to increase in secretion of parathyroid hormone (PTH), most common cause. Other mechanism of hyperlcacemia include secretion of parathyroid hormone-related protein (PTHrP) by tumor cells, which has similar action as parathyroid hormone, excess intake of calcium or vitamin D, and production of vitamin D by macrophages in granulomatous diseases.


Mineral Homeostasis

Effect of minerals and vitamin D on parathyroid hormone:[1][2]

The effect of parathyroid hormone on mineral metabolism is as follows:

The Sequence of Events in Mineral Homeostasis

Parathyroid hormone
Decreased excretion of magnesium
Increasead conversion of inactive 25-hydroyx vitamin D to the active 1,25-dihydroy xvitamin D
Increase excretion of inorganic phosphate
Decrease excretion of calcium
Increased resorption of bone
Increased serum concentration of magnesium
Increased absorption of calcium from gut
Decreased serum concentration of inorganic phosphate
Prevents precipitation of calcium phosphate in bones
Increased serum concentration of calcium


Mechanism of hypercalcemia in various diseases
Disorder Mechanism of hypercalcemia Clinical features
Hyperparathyroidism Primary hyperparathyroidism Increase in secretion of parathyroid hormone (PTH) from a primary process in parathyroid gland. Parathyroid hormone causes increase in serum calcium.
  • Usually asymptomatic
  • Hypercalcemia detected on routine biochemical panel
Secondary hyperparathyroidism Increase in secretion of parathyroid hormone (PTH) from a secondary process. Parathyroid hormone causes increase in serum calcium after long periods.
Tertiary hyperparathyroidism Continuous elevation of parathyroid hormone (PTH) even after successful treatment of the secondary cause of elevated parathyroid hormone. Parathyroid hormone causes increase in serum calcium.
Familial hypocalciuric hypercalcemia This is a genetic disorder caused my mutation in calcium-sensing receptor gene.
  • A benign condition
  • Does not require treatment
Malignancy[3][4] Humoral hypercalcemia of malignancy[5][6][7][8] Tumor cells secretes parathyroid hormone-related protein (PTHrP) which has similar action as parathyroid hormone.
Osteolytic tumors[9][10] Multiple myeloma produces osteolysis of bones causing hypercalcemia. Osteolytic metasteses can cause bone resorption causing hypercalcemia.
Production of calcitirol[11] Some tumors has ectopic activity of 1-alpha-hydroxylase leading to increased production of calcitriol. Calcitriol is active form of vitamin D and causes hypercalcemia.
Ectopic parathyroid hormone[12] Some tumors leads to ectopic production of parathyroid hormone.
Medication induced Lithium[13] Lithium lowers urinary calcium and causes hypercalcemia. Lithium has been reported to cause an increase in parathyroid hormone and enlargement if parathyroid gland after weeks to months of therapy.
Thiazide diuretics[14] Thiazide diuretics lowers urinary calcium excretion and causes hypercalcemia.
Nutritional Milk-alkali syndrome Hypercalcemia is be caused by high intake of calcium carbonate.
Vitamin D toxicity[15][16][17] Excess vitamin D causes increased absorption of calcium from intestine causing hypercalcemia.
Granulomatous disease Sarcoidosis[20] Hypercalcemia is causes by endogeous production of calcitriol by disease-activated macrophages.

Gross Pathology

  • Hypercalcemia is most commonly caused by hyperparathyroidism. For gross pathology of hyperparathyroidism, click here.

Microscopic Pathology

  • Hypercalcemia is most commonly caused by hyperparathyroidism. For microscopic pathology of hyperparathyroidism, click here.


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  9. Roodman GD (2004). "Mechanisms of bone metastasis". N Engl J Med. 350 (16): 1655–64. doi:10.1056/NEJMra030831. PMID 15084698.
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  14. Griebeler ML, Kearns AE, Ryu E, Thapa P, Hathcock MA, Melton LJ; et al. (2016). "Thiazide-Associated Hypercalcemia: Incidence and Association With Primary Hyperparathyroidism Over Two Decades". J Clin Endocrinol Metab. 101 (3): 1166–73. doi:10.1210/jc.2015-3964. PMC 4803175. PMID 26751196.
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  19. Hoeck HC, Laurberg G, Laurberg P (1994). "Hypercalcaemic crisis after excessive topical use of a vitamin D derivative". J. Intern. Med. 235 (3): 281–2. PMID 8120527.
  20. Dusso AS, Kamimura S, Gallieni M, Zhong M, Negrea L, Shapiro S, Slatopolsky E (1997). "gamma-Interferon-induced resistance to 1,25-(OH)2 D3 in human monocytes and macrophages: a mechanism for the hypercalcemia of various granulomatoses". J. Clin. Endocrinol. Metab. 82 (7): 2222–32. doi:10.1210/jcem.82.7.4074. PMID 9215298.

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