Hypercalcemia pathophysiology

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

Overview

Pathophysiology

Mineral Homeostasis

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

Decrease in serum calcium concentration stimulates parathyroid hormone.
Calcium provides negative feedback on parathyroid hormone.
Magnesium provides negative feedback on parathyroid hormone.
Vitamin D decreases the concentration of parathyroid hormone.

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

Effect on parathyroid hormone on calcium metabolism:
- Direct effect:
  - Increased resorption of bones.
  - Decreases excretion from kidney.
- Indirect effect:
  - Increases conversion of inactive 25-hydroxy vitamin D to the active 1,25-dihydroxy vitamin D which increases absorption of calcium from gut. Decreased phosphate concentration also increases this conversion process. Vitamin D shows synergism with parathyroid hormone action on bone.
  - Decreased serum inorganic phosphate concentration prevents precipitation of calcium phosphate in bones.
- Both these direct and indirect mechanism results in an increased serum calcium concentration.
Effect of parathyroid hormone on inorganic phosphate metabolism:
- Increases excretion of inorganic phosphate from kidney resulting in decreased serum concentration of phosphate.
Effect of parathyroid hormone on magnesium concentration:
- Decreases excretion of magnesium resulting in increased serum magnesium concentretion.

The Sequence of Events in Mineral Homeostasis

Parathyroid hormone

Kidney

Bone

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

Pathogenesis

Differential diagnosis of hyperparathyroidism on the basis of hypercalcemia
Disorder		Mechanism of hypercalcemia	Clinical features	Laboratory findings				Imaging & diagnostic modalities
Disorder		Mechanism of hypercalcemia	Clinical features	PTH	Calcium	Phosphate	Other findings	Imaging & diagnostic modalities
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	↑	↑	↓/Normal	Normal/↑ calcitriol	Findings of bone resorption: X-ray Dual energy X-ray absorptiometry (DXA) Preoperative localization of hyperfunctioning parathyroid gland: Non-Invasive Tc-99m sestamibi scintigraphy Neck ultrasound 4D-CT SPECT(P-SPECT) PET MRI Invasive: Super sensitive venous sampling Selective arteriography Angiography Predicting post-operative success: Intraoperative parathyroid hormone monitoring
	Secondary hyperparathyroidism	Increase in secretion of parathyroid hormone (PTH) from a secondary process. Parathyroid hormone causes increase in serum calcium after long periods.	May present with history of: Chronic renal failure Vitamin D deficiency	↑	↓/Normal	↑	--
	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.	Usually present with history of kidney transplant Usually hyperplasia of all four parathyroid glands	↑	↑	↑	--
Familial hypocalciuric hypercalcemia		This is a genetic disorder caused my mutation in calcium-sensing receptor gene.	A benign condition Does not require treatment	Normal/↑	Normal/↑	--	--	Urinary calcium/creatinine clearance ratio
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.	Most common cause of malignancy related hypercalcemia Usually present with solid tumors	--	↑	↓/Normal	↑ PTHrP Normal/↑ calcitriol	Chest X-ray CT scan MRI
	Osteolytic tumors^[9]^[10]	Multiple myeloma produces osteolysis of bones causing hypercalcemia. Osteolytic metasteses can cause bone resorption causing hypercalcemia.	Commonly present in multiple myeloma and breast cancer	↓	↑	--	--	DXA X-ray Mammography Ultrasound ESR Serum protein electrophoresis
	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.	Commonly present in lymphomas and in some ovarian germ cell tumors	--	↑	--	↑ Calcitriol	CT scan MRI
	Ectopic parathyroid hormone^[12]	Some tumors leads to ectopic production of parathyroid hormone.	In rare instances, small cell carcinoma of lung may produce hypercalcemia by this process	↑	↑	↓/Normal	Normal/↑ calcitriol	Chest X-ray CT scan MRI
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.	History of mood disorder	↑	↑	--	--	Lithium levels
Medication induced	Thiazide diuretics^[14]	Thiazide diuretics lowers urinary calcium excretion and causes hypercalcemia.	History of cardiac disorder Rarely causes hypercalcemia	--	↑	--	--	--
Nutritional	Milk-alkali syndrome	Hypercalcemia is be caused by high intake of calcium carbonate.	History of High milk intake Excess calcium intake for treating: Osteoporosis Dyspepsia May lead to metabolic alkalosis and renal insufficiency.	--	↑	--	↓ calcitriol	Renal function tests
Nutritional	Vitamin D toxicity^[15]^[16]^[17]	Excess vitamin D causes increased absorption of calcium from intestine causing hypercalcemia.	History of: Excess intake vitamin D Excess milk fortified with vitamin D^[18] Topical application of vitamin D analogue calcipotriol^[19]	--	↑	--	↑ Vitamin D (calcidiol and/or calcitriol)	--
Granulomatous disease	Sarcoidosis^[20]	Hypercalcemia is causes by endogeous production of calcitriol by disease-activated macrophages.	History of: Cough Dyspnea Chest pain Tiredness or weakness Fever Weight loss	--	↑	--	↑ Calcitriol ↑ ACE levels	Chest X-ray Biopsy

References

↑ HARRISON MT (1964). "INTERRELATIONSHIPS OF VITAMIN D AND PARATHYROID HORMONE IN CALCIUM HOMEOSTASIS". Postgrad Med J. 40: 497–505. PMC 2482768. PMID 14184232.
↑ Nussey, Stephen (2001). Endocrinology : an integrated approach. Oxford, UK Bethesda, Md: Bios NCBI. ISBN 1-85996-252-1.
↑ Mirrakhimov AE (2015). "Hypercalcemia of Malignancy: An Update on Pathogenesis and Management". N Am J Med Sci. 7 (11): 483–93. doi:10.4103/1947-2714.170600. PMC 4683803. PMID 26713296.
↑ Stewart AF (2005). "Clinical practice. Hypercalcemia associated with cancer". N Engl J Med. 352 (4): 373–9. doi:10.1056/NEJMcp042806. PMID 15673803.
↑ Ratcliffe WA, Hutchesson AC, Bundred NJ, Ratcliffe JG (1992). "Role of assays for parathyroid-hormone-related protein in investigation of hypercalcaemia". Lancet. 339 (8786): 164–7. doi:10.1016/0140-6736(92)90220-W. PMID 1346019.
↑ Ikeda K, Ohno H, Hane M, Yokoi H, Okada M, Honma T, Yamada A, Tatsumi Y, Tanaka T, Saitoh T (1994). "Development of a sensitive two-site immunoradiometric assay for parathyroid hormone-related peptide: evidence for elevated levels in plasma from patients with adult T-cell leukemia/lymphoma and B-cell lymphoma". J. Clin. Endocrinol. Metab. 79 (5): 1322–7. doi:10.1210/jcem.79.5.7962324. PMID 7962324.
↑ Horwitz MJ, Tedesco MB, Sereika SM, Hollis BW, Garcia-Ocaña A, Stewart AF (2003). "Direct comparison of sustained infusion of human parathyroid hormone-related protein-(1-36) [hPTHrP-(1-36)] versus hPTH-(1-34) on serum calcium, plasma 1,25-dihydroxyvitamin D concentrations, and fractional calcium excretion in healthy human volunteers". J. Clin. Endocrinol. Metab. 88 (4): 1603–9. doi:10.1210/jc.2002-020773. PMID 12679445.
↑ Stewart AF, Vignery A, Silverglate A, Ravin ND, LiVolsi V, Broadus AE; et al. (1982). "Quantitative bone histomorphometry in humoral hypercalcemia of malignancy: uncoupling of bone cell activity". J Clin Endocrinol Metab. 55 (2): 219–27. doi:10.1210/jcem-55-2-219. PMID 7085851.
↑ Roodman GD (2004). "Mechanisms of bone metastasis". N Engl J Med. 350 (16): 1655–64. doi:10.1056/NEJMra030831. PMID 15084698.
↑ Guise TA, Yin JJ, Taylor SD, Kumagai Y, Dallas M, Boyce BF; et al. (1996). "Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis". J Clin Invest. 98 (7): 1544–9. doi:10.1172/JCI118947. PMC 507586. PMID 8833902.
↑ Seymour JF, Gagel RF, Hagemeister FB, Dimopoulos MA, Cabanillas F (1994). "Calcitriol production in hypercalcemic and normocalcemic patients with non-Hodgkin lymphoma". Ann Intern Med. 121 (9): 633–40. PMID 7944070.
↑ VanHouten JN, Yu N, Rimm D, Dotto J, Arnold A, Wysolmerski JJ, Udelsman R (2006). "Hypercalcemia of malignancy due to ectopic transactivation of the parathyroid hormone gene". J. Clin. Endocrinol. Metab. 91 (2): 580–3. doi:10.1210/jc.2005-2095. PMID 16263810.
↑ Mallette LE, Khouri K, Zengotita H, Hollis BW, Malini S (1989). "Lithium treatment increases intact and midregion parathyroid hormone and parathyroid volume". J. Clin. Endocrinol. Metab. 68 (3): 654–60. doi:10.1210/jcem-68-3-654. PMID 2918061.
↑ 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.
↑ 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.
↑ Jacobus CH, Holick MF, Shao Q, Chen TC, Holm IA, Kolodny JM, Fuleihan GE, Seely EW (1992). "Hypervitaminosis D associated with drinking milk". N. Engl. J. Med. 326 (18): 1173–7. doi:10.1056/NEJM199204303261801. PMID 1313547.
↑ Sharma OP (1996). "Vitamin D, calcium, and sarcoidosis". Chest. 109 (2): 535–9. PMID 8620732.
↑ Jacobus CH, Holick MF, Shao Q, Chen TC, Holm IA, Kolodny JM, Fuleihan GE, Seely EW (1992). "Hypervitaminosis D associated with drinking milk". N. Engl. J. Med. 326 (18): 1173–7. doi:10.1056/NEJM199204303261801. PMID 1313547.
↑ 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.
↑ 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.

Template:WS Template:WH

[pmid14184232-1] HARRISON MT (1964). "INTERRELATIONSHIPS OF VITAMIN D AND PARATHYROID HORMONE IN CALCIUM HOMEOSTASIS". Postgrad Med J. 40: 497–505. PMC 2482768. PMID 14184232.

[2] Nussey, Stephen (2001). Endocrinology : an integrated approach. Oxford, UK Bethesda, Md: Bios NCBI. ISBN 1-85996-252-1.

[pmid26713296-3] Mirrakhimov AE (2015). "Hypercalcemia of Malignancy: An Update on Pathogenesis and Management". N Am J Med Sci. 7 (11): 483–93. doi:10.4103/1947-2714.170600. PMC 4683803. PMID 26713296.

[pmid15673803-4] Stewart AF (2005). "Clinical practice. Hypercalcemia associated with cancer". N Engl J Med. 352 (4): 373–9. doi:10.1056/NEJMcp042806. PMID 15673803.

[pmid1346019-5] Ratcliffe WA, Hutchesson AC, Bundred NJ, Ratcliffe JG (1992). "Role of assays for parathyroid-hormone-related protein in investigation of hypercalcaemia". Lancet. 339 (8786): 164–7. doi:10.1016/0140-6736(92)90220-W. PMID 1346019.

[pmid7962324-6] Ikeda K, Ohno H, Hane M, Yokoi H, Okada M, Honma T, Yamada A, Tatsumi Y, Tanaka T, Saitoh T (1994). "Development of a sensitive two-site immunoradiometric assay for parathyroid hormone-related peptide: evidence for elevated levels in plasma from patients with adult T-cell leukemia/lymphoma and B-cell lymphoma". J. Clin. Endocrinol. Metab. 79 (5): 1322–7. doi:10.1210/jcem.79.5.7962324. PMID 7962324.

[pmid12679445-7] Horwitz MJ, Tedesco MB, Sereika SM, Hollis BW, Garcia-Ocaña A, Stewart AF (2003). "Direct comparison of sustained infusion of human parathyroid hormone-related protein-(1-36) [hPTHrP-(1-36)] versus hPTH-(1-34) on serum calcium, plasma 1,25-dihydroxyvitamin D concentrations, and fractional calcium excretion in healthy human volunteers". J. Clin. Endocrinol. Metab. 88 (4): 1603–9. doi:10.1210/jc.2002-020773. PMID 12679445.

[pmid7085851-8] Stewart AF, Vignery A, Silverglate A, Ravin ND, LiVolsi V, Broadus AE; et al. (1982). "Quantitative bone histomorphometry in humoral hypercalcemia of malignancy: uncoupling of bone cell activity". J Clin Endocrinol Metab. 55 (2): 219–27. doi:10.1210/jcem-55-2-219. PMID 7085851.

[pmid15084698-9] Roodman GD (2004). "Mechanisms of bone metastasis". N Engl J Med. 350 (16): 1655–64. doi:10.1056/NEJMra030831. PMID 15084698.

[pmid8833902-10] Guise TA, Yin JJ, Taylor SD, Kumagai Y, Dallas M, Boyce BF; et al. (1996). "Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis". J Clin Invest. 98 (7): 1544–9. doi:10.1172/JCI118947. PMC 507586. PMID 8833902.

[pmid7944070-11] Seymour JF, Gagel RF, Hagemeister FB, Dimopoulos MA, Cabanillas F (1994). "Calcitriol production in hypercalcemic and normocalcemic patients with non-Hodgkin lymphoma". Ann Intern Med. 121 (9): 633–40. PMID 7944070.

[pmid16263810-12] VanHouten JN, Yu N, Rimm D, Dotto J, Arnold A, Wysolmerski JJ, Udelsman R (2006). "Hypercalcemia of malignancy due to ectopic transactivation of the parathyroid hormone gene". J. Clin. Endocrinol. Metab. 91 (2): 580–3. doi:10.1210/jc.2005-2095. PMID 16263810.

[pmid2918061-13] Mallette LE, Khouri K, Zengotita H, Hollis BW, Malini S (1989). "Lithium treatment increases intact and midregion parathyroid hormone and parathyroid volume". J. Clin. Endocrinol. Metab. 68 (3): 654–60. doi:10.1210/jcem-68-3-654. PMID 2918061.

[pmid26751196-14] 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.

[pmid81205272-15] 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.

[pmid13135472-16] Jacobus CH, Holick MF, Shao Q, Chen TC, Holm IA, Kolodny JM, Fuleihan GE, Seely EW (1992). "Hypervitaminosis D associated with drinking milk". N. Engl. J. Med. 326 (18): 1173–7. doi:10.1056/NEJM199204303261801. PMID 1313547.

[pmid8620732-17] Sharma OP (1996). "Vitamin D, calcium, and sarcoidosis". Chest. 109 (2): 535–9. PMID 8620732.

[pmid1313547-18] Jacobus CH, Holick MF, Shao Q, Chen TC, Holm IA, Kolodny JM, Fuleihan GE, Seely EW (1992). "Hypervitaminosis D associated with drinking milk". N. Engl. J. Med. 326 (18): 1173–7. doi:10.1056/NEJM199204303261801. PMID 1313547.

[pmid8120527-19] 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.

[pmid9215298-20] 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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