Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Pathogenesis and etiology of primary hyperparathyroidism

Ghada El-Hajj Fuleihan, MD, MPH
Andrew Arnold, MD
Section Editor
Clifford J Rosen, MD
Deputy Editor
Jean E Mulder, MD


Parathyroid hormone (PTH) is one of the two major hormones modulating calcium and phosphate homeostasis, the other being calcitriol (1,25-dihydroxyvitamin D). The minute-to-minute regulation of serum ionized calcium is exclusively regulated through PTH, maintaining the concentration of this cation within a narrow range, through stimulation of renal tubular calcium reabsorption and bone resorption. PTH secretion is, in turn, regulated by serum ionized calcium acting via an exquisitely sensitive calcium-sensing receptor (CaSR) on the surface of parathyroid cells.

Primary hyperparathyroidism is characterized by abnormal regulation of PTH secretion by calcium, resulting in hypersecretion of PTH relative to the serum calcium concentration. Experimental findings have advanced our understanding of the pathophysiology and causes of primary hyperparathyroidism. This topic will review these observations, beginning with a brief review of the basic aspects of parathyroid hormone and calcium homeostasis.

Other aspects of primary hyperparathyroidism are reviewed elsewhere.

(See "Primary hyperparathyroidism: Clinical manifestations".)

(See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Jan 12, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Brown EM. Extracellular Ca2+ sensing, regulation of parathyroid cell function, and role of Ca2+ and other ions as extracellular (first) messengers. Physiol Rev 1991; 71:371.
  2. Friedman PA, Gesek FA. Calcium transport in renal epithelial cells. Am J Physiol 1993; 264:F181.
  3. Gesek FA, Friedman PA. On the mechanism of parathyroid hormone stimulation of calcium uptake by mouse distal convoluted tubule cells. J Clin Invest 1992; 90:749.
  4. Brown EM. Four-parameter model of the sigmoidal relationship between parathyroid hormone release and extracellular calcium concentration in normal and abnormal parathyroid tissue. J Clin Endocrinol Metab 1983; 56:572.
  5. Brossard JH, Whittom S, Lepage R, D'Amour P. Carboxyl-terminal fragments of parathyroid hormone are not secreted preferentially in primary hyperparathyroidism as they are in other hypercalcemic conditions. J Clin Endocrinol Metab 1993; 77:413.
  6. Brown EM, Gamba G, Riccardi D, et al. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 1993; 366:575.
  7. Brown EM, Pollak M, Seidman CE, et al. Calcium-ion-sensing cell-surface receptors. N Engl J Med 1995; 333:234.
  8. Hosokawa Y, Pollak MR, Brown EM, Arnold A. Mutational analysis of the extracellular Ca(2+)-sensing receptor gene in human parathyroid tumors. J Clin Endocrinol Metab 1995; 80:3107.
  9. Cetani F, Pinchera A, Pardi E, et al. No evidence for mutations in the calcium-sensing receptor gene in sporadic parathyroid adenomas. J Bone Miner Res 1999; 14:878.
  10. Carling T, Szabo E, Bai M, et al. Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor. J Clin Endocrinol Metab 2000; 85:2042.
  11. Scillitani A, Guarnieri V, Battista C, et al. Primary hyperparathyroidism and the presence of kidney stones are associated with different haplotypes of the calcium-sensing receptor. J Clin Endocrinol Metab 2007; 92:277.
  12. Kifor O, Moore FD Jr, Wang P, et al. Reduced immunostaining for the extracellular Ca2+-sensing receptor in primary and uremic secondary hyperparathyroidism. J Clin Endocrinol Metab 1996; 81:1598.
  13. Gogusev J, Duchambon P, Hory B, et al. Depressed expression of calcium receptor in parathyroid gland tissue of patients with hyperparathyroidism. Kidney Int 1997; 51:328.
  14. Cetani F, Picone A, Cerrai P, et al. Parathyroid expression of calcium-sensing receptor protein and in vivo parathyroid hormone-Ca(2+) set-point in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 2000; 85:4789.
  15. Farnebo F, Enberg U, Grimelius L, et al. Tumor-specific decreased expression of calcium sensing receptor messenger ribonucleic acid in sporadic primary hyperparathyroidism. J Clin Endocrinol Metab 1997; 82:3481.
  16. Pollak MR, Brown EM, Chou YH, et al. Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 1993; 75:1297.
  17. Khosla S, Ebeling PR, Firek AF, et al. Calcium infusion suggests a "set-point" abnormality of parathyroid gland function in familial benign hypercalcemia and more complex disturbances in primary hyperparathyroidism. J Clin Endocrinol Metab 1993; 76:715.
  18. Wermers RA, Khosla S, Atkinson EJ, et al. Incidence of primary hyperparathyroidism in Rochester, Minnesota, 1993-2001: an update on the changing epidemiology of the disease. J Bone Miner Res 2006; 21:171.
  19. Griebeler ML, Kearns AE, Ryu E, et al. Secular trends in the incidence of primary hyperparathyroidism over five decades (1965-2010). Bone 2015; 73:1.
  20. Yeh MW, Ituarte PH, Zhou HC, et al. Incidence and prevalence of primary hyperparathyroidism in a racially mixed population. J Clin Endocrinol Metab 2013; 98:1122.
  21. Abood A, Vestergaard P. Increasing incidence of primary hyperparathyroidism in Denmark. Dan Med J 2013; 60:A4567.
  22. Beard CM, Heath H 3rd, O'Fallon WM, et al. Therapeutic radiation and hyperparathyroidism. A case-control study in Rochester, Minn. Arch Intern Med 1989; 149:1887.
  23. Tisell LE, Hansson G, Lindberg S, Ragnhult I. Hyperparathyroidism in persons treated with X-rays for tuberculous cervical adenitis. Cancer 1977; 40:846.
  24. McMullen T, Bodie G, Gill A, et al. Hyperparathyroidism after irradiation for childhood malignancy. Int J Radiat Oncol Biol Phys 2009; 73:1164.
  25. Boehm BO, Rosinger S, Belyi D, Dietrich JW. The parathyroid as a target for radiation damage. N Engl J Med 2011; 365:676.
  26. Schneider AB, Gierlowski TC, Shore-Freedman E, et al. Dose-response relationships for radiation-induced hyperparathyroidism. J Clin Endocrinol Metab 1995; 80:254.
  27. Fujiwara S, Sposto R, Ezaki H, et al. Hyperparathyroidism among atomic bomb survivors in Hiroshima. Radiat Res 1992; 130:372.
  28. Tezelman S, Rodriguez JM, Shen W, et al. Primary hyperparathyroidism in patients who have received radiation therapy and in patients who have not received radiation therapy. J Am Coll Surg 1995; 180:81.
  29. Wilson SD, Doffek KM, Wang TS, et al. Primary hyperparathyroidism with a history of head and neck irradiation: the consequences of associated thyroid tumors. Surgery 2011; 150:869.
  30. Woll M, Sippel RS, Chen H. Does previous head and neck irradiation increase the chance of multigland disease in patients with hyperparathyroidism? Ann Surg Oncol 2011; 18:2240.
  31. Ippolito G, Palazzo FF, Sebag F, Henry JF. Long-term follow-up after parathyroidectomy for radiation-induced hyperparathyroidism. Surgery 2007; 142:819.
  32. Rahbari R, Sansano IG, Elaraj DM, et al. Prior head and neck radiation exposure is not a contraindication to minimally invasive parathyroidectomy. J Am Coll Surg 2010; 210:942.
  33. Colaço SM, Si M, Reiff E, Clark OH. Hyperparathyroidism after radioactive iodine therapy. Am J Surg 2007; 194:323.
  34. Fjälling M, Dackenberg A, Hedman I, Tisell LE. An evaluation of the risk of developing hyperparathyroidism after 131I treatment for thyrotoxicosis. Acta Chir Scand 1983; 149:681.
  35. Paik JM, Curhan GC, Taylor EN. Calcium intake and risk of primary hyperparathyroidism in women: prospective cohort study. BMJ 2012; 345:e6390.
  36. Shattuck TM, Välimäki S, Obara T, et al. Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med 2003; 349:1722.
  37. Westin G, Björklund P, Akerström G. Molecular genetics of parathyroid disease. World J Surg 2009; 33:2224.
  38. Costa-Guda J, Arnold A. Hyperparathyroidism. In: Genetics of Bone Biology and Skeletal Disease, Thakker RV, Whyte MP, Eisman JA, Igarashi T. (Eds), Academic Press/Elsevier, London, UK/San Diego, CA 2013. p.397.
  39. Arnold A, Marx SJ. Familial primary hyperparathyroidism including MEN, FHH, and HPT-JT. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 8th ed, Rosen CJ. (Ed), John Wiley & Sons, Hoboken, NJ 2013. p.553.
  40. Arnold A, Kim HG, Gaz RD, et al. Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma. J Clin Invest 1989; 83:2034.
  41. Hsi ED, Zukerberg LR, Yang WI, Arnold A. Cyclin D1/PRAD1 expression in parathyroid adenomas: an immunohistochemical study. J Clin Endocrinol Metab 1996; 81:1736.
  42. Rosenberg CL, Kim HG, Shows TB, et al. Rearrangement and overexpression of D11S287E, a candidate oncogene on chromosome 11q13 in benign parathyroid tumors. Oncogene 1991; 6:449.
  43. Hemmer S, Wasenius VM, Haglund C, et al. Deletion of 11q23 and cyclin D1 overexpression are frequent aberrations in parathyroid adenomas. Am J Pathol 2001; 158:1355.
  44. Vasef MA, Brynes RK, Sturm M, et al. Expression of cyclin D1 in parathyroid carcinomas, adenomas, and hyperplasias: a paraffin immunohistochemical study. Mod Pathol 1999; 12:412.
  45. Imanishi Y, Hosokawa Y, Yoshimoto K, et al. Primary hyperparathyroidism caused by parathyroid-targeted overexpression of cyclin D1 in transgenic mice. J Clin Invest 2001; 107:1093.
  46. Mallya SM, Gallagher JJ, Wild YK, et al. Abnormal parathyroid cell proliferation precedes biochemical abnormalities in a mouse model of primary hyperparathyroidism. Mol Endocrinol 2005; 19:2603.
  47. Agarwal SK, Kester MB, Debelenko LV, et al. Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum Mol Genet 1997; 6:1169.
  48. Heppner C, Kester MB, Agarwal SK, et al. Somatic mutation of the MEN1 gene in parathyroid tumours. Nat Genet 1997; 16:375.
  49. Carling T, Correa P, Hessman O, et al. Parathyroid MEN1 gene mutations in relation to clinical characteristics of nonfamilial primary hyperparathyroidism. J Clin Endocrinol Metab 1998; 83:2960.
  50. Farnebo F, Teh BT, Kytölä S, et al. Alterations of the MEN1 gene in sporadic parathyroid tumors. J Clin Endocrinol Metab 1998; 83:2627.
  51. Costa-Guda J, Marinoni I, Molatore S, et al. Somatic mutation and germline sequence abnormalities in CDKN1B, encoding p27Kip1, in sporadic parathyroid adenomas. J Clin Endocrinol Metab 2011; 96:E701.
  52. Costa-Guda J, Soong CP, Parekh VI, et al. Germline and somatic mutations in cyclin-dependent kinase inhibitor genes CDKN1A, CDKN2B, and CDKN2C in sporadic parathyroid adenomas. Horm Cancer 2013; 4:301.
  53. Pellegata NS, Quintanilla-Martinez L, Siggelkow H, et al. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Natl Acad Sci U S A 2006; 103:15558.
  54. Agarwal SK, Mateo CM, Marx SJ. Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. J Clin Endocrinol Metab 2009; 94:1826.
  55. Falchetti A, Marini F, Giusti F, et al. DNA-based test: when and why to apply it to primary hyperparathyroidism clinical phenotypes. J Intern Med 2009; 266:69.
  56. Cetani F, Pardi E, Borsari S, et al. Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors. J Clin Endocrinol Metab 2004; 89:5583.
  57. Krebs LJ, Shattuck TM, Arnold A. HRPT2 mutational analysis of typical sporadic parathyroid adenomas. J Clin Endocrinol Metab 2005; 90:5015.
  58. Pausova Z, Soliman E, Amizuka N, et al. Role of the RET proto-oncogene in sporadic hyperparathyroidism and in hyperparathyroidism of multiple endocrine neoplasia type 2. J Clin Endocrinol Metab 1996; 81:2711.
  59. Padberg BC, Schröder S, Jochum W, et al. Absence of RET proto-oncogene point mutations in sporadic hyperplastic and neoplastic lesions of the parathyroid gland. Am J Pathol 1995; 147:1600.
  60. Samander EH, Arnold A. Mutational analysis of the vitamin D receptor does not support its candidacy as a tumor suppressor gene in parathyroid adenomas. J Clin Endocrinol Metab 2006; 91:5019.
  61. Rao DS, Honasoge M, Divine GW, et al. Effect of vitamin D nutrition on parathyroid adenoma weight: pathogenetic and clinical implications. J Clin Endocrinol Metab 2000; 85:1054.
  62. Björklund P, Lindberg D, Akerström G, Westin G. Stabilizing mutation of CTNNB1/beta-catenin and protein accumulation analyzed in a large series of parathyroid tumors of Swedish patients. Mol Cancer 2008; 7:53.
  63. Costa-Guda J, Arnold A. Absence of stabilizing mutations of beta-catenin encoded by CTNNB1 exon 3 in a large series of sporadic parathyroid adenomas. J Clin Endocrinol Metab 2007; 92:1564.
  64. Cetani F, Pardi E, Banti C, et al. Beta-catenin activation is not involved in sporadic parathyroid carcinomas and adenomas. Endocr Relat Cancer 2010; 17:1.
  65. Haglund F, Andreasson A, Nilsson IL, et al. Lack of S37A CTNNB1/β-catenin mutations in a Swedish cohort of 98 parathyroid adenomas. Clin Endocrinol (Oxf) 2010; 73:552.
  66. Guarnieri V, Baorda F, Battista C, et al. A rare S33C mutation of CTNNB1 encoding β-catenin in a parathyroid adenoma found in an Italian primary hyperparathyroid cohort. Endocrine 2012; 41:152.
  67. Starker LF, Fonseca AL, Akerström G, et al. Evidence of a stabilizing mutation of β-catenin encoded by CTNNB1 exon 3 in a large series of sporadic parathyroid adenomas. Endocrine 2012; 42:612.
  68. Cromer MK, Starker LF, Choi M, et al. Identification of somatic mutations in parathyroid tumors using whole-exome sequencing. J Clin Endocrinol Metab 2012; 97:E1774.
  69. Newey PJ, Nesbit MA, Rimmer AJ, et al. Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas. J Clin Endocrinol Metab 2012; 97:E1995.
  70. Nussbaum SR, Gaz RD, Arnold A. Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma with rearrangement of the gene for parathyroid hormone. N Engl J Med 1990; 323:1324.
  71. VanHouten JN, Yu N, Rimm D, et al. Hypercalcemia of malignancy due to ectopic transactivation of the parathyroid hormone gene. J Clin Endocrinol Metab 2006; 91:580.
  72. Salti GI, Fedorak I, Yashiro T, et al. Continuing evolution in the operative management of primary hyperparathyroidism. Arch Surg 1992; 127:831.
  73. Bartsch D, Nies C, Hasse C, et al. Clinical and surgical aspects of double adenoma in patients with primary hyperparathyroidism. Br J Surg 1995; 82:926.
  74. Ruda JM, Hollenbeak CS, Stack BC Jr. A systematic review of the diagnosis and treatment of primary hyperparathyroidism from 1995 to 2003. Otolaryngol Head Neck Surg 2005; 132:359.
  75. Maret A, Bourdeau I, Ding C, et al. Expression of GCMB by intrathymic parathyroid hormone-secreting adenomas indicates their parathyroid cell origin. J Clin Endocrinol Metab 2004; 89:8.
  76. Wynne AG, van Heerden J, Carney JA, Fitzpatrick LA. Parathyroid carcinoma: clinical and pathologic features in 43 patients. Medicine (Baltimore) 1992; 71:197.
  77. Marx SJ, Simonds WF, Agarwal SK, et al. Hyperparathyroidism in hereditary syndromes: special expressions and special managements. J Bone Miner Res 2002; 17 Suppl 2:N37.
  78. Mallette LE, Malini S, Rappaport MP, Kirkland JL. Familial cystic parathyroid adenomatosis. Ann Intern Med 1987; 107:54.
  79. Simonds WF, Robbins CM, Agarwal SK, et al. Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome. J Clin Endocrinol Metab 2004; 89:96.
  80. Simonds WF, James-Newton LA, Agarwal SK, et al. Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds. Medicine (Baltimore) 2002; 81:1.
  81. Starker LF, Akerström T, Long WD, et al. Frequent germ-line mutations of the MEN1, CASR, and HRPT2/CDC73 genes in young patients with clinically non-familial primary hyperparathyroidism. Horm Cancer 2012; 3:44.
  82. Huang SM, Duh QY, Shaver J, et al. Familial hyperparathyroidism without multiple endocrine neoplasia. World J Surg 1997; 21:22.
  83. Christensson T, Hellström K, Wengle B. Hypercalcemia and primary hyperparathyroidism. Prevalence in patients receiving thiazides as detected in a health screen. Arch Intern Med 1977; 137:1138.
  84. Wermers RA, Kearns AE, Jenkins GD, Melton LJ 3rd. Incidence and clinical spectrum of thiazide-associated hypercalcemia. Am J Med 2007; 120:911.e9.
  85. Mallette LE, Eichhorn E. Effects of lithium carbonate on human calcium metabolism. Arch Intern Med 1986; 146:770.
  86. Mak TW, Shek CC, Chow CC, et al. Effects of lithium therapy on bone mineral metabolism: a two-year prospective longitudinal study. J Clin Endocrinol Metab 1998; 83:3857.
  87. McKnight RF, Adida M, Budge K, et al. Lithium toxicity profile: a systematic review and meta-analysis. Lancet 2012; 379:721.
  88. Mallette LE, Khouri K, Zengotita H, et al. Lithium treatment increases intact and midregion parathyroid hormone and parathyroid volume. J Clin Endocrinol Metab 1989; 68:654.
  89. Lehmann SW, Lee J. Lithium-associated hypercalcemia and hyperparathyroidism in the elderly: what do we know? J Affect Disord 2013; 146:151.
  90. Bendz H, Sjödin I, Toss G, Berglund K. Hyperparathyroidism and long-term lithium therapy--a cross-sectional study and the effect of lithium withdrawal. J Intern Med 1996; 240:357.
  91. El-Hajj Fuleihan G, Brown EM, Heath H III. The Familial Benign Hypocalciuric Hypercalcemic Syndromes. In: Principles of Bone Biology, Bilezikian JP, Raisz LG, Rodan GA (Eds), Academic Press, San Diego 1996.
  92. Brown EM. Lithium induces abnormal calcium-regulated PTH release in dispersed bovine parathyroid cells. J Clin Endocrinol Metab 1981; 52:1046.
  93. Haden ST, Stoll AL, McCormick S, et al. Alterations in parathyroid dynamics in lithium-treated subjects. J Clin Endocrinol Metab 1997; 82:2844.
  94. McHenry CR, Lee K. Lithium therapy and disorders of the parathyroid glands. Endocr Pract 1996; 2:103.
  95. Racke F, McHenry CR, Wentworth D. Lithium-induced alterations in parathyroid cell function: insight into the pathogenesis of lithium-associated hyperparathyroidism. Am J Surg 1994; 168:462.
  96. McHenry CR, Stenger DB, Racke F. Investigation of calcium-induced hydrolysis of phosphoinositides in normal and lithium-treated parathyroid cells. Am J Surg 1995; 170:484.
  97. Nordenström J, Strigård K, Perbeck L, et al. Hyperparathyroidism associated with treatment of manic-depressive disorders by lithium. Eur J Surg 1992; 158:207.
  98. Järhult J, Ander S, Asking B, et al. Long-term results of surgery for lithium-associated hyperparathyroidism. Br J Surg 2010; 97:1680.
  99. Awad SS, Miskulin J, Thompson N. Parathyroid adenomas versus four-gland hyperplasia as the cause of primary hyperparathyroidism in patients with prolonged lithium therapy. World J Surg 2003; 27:486.
  100. Plenge P, Rafaelsen OJ. Lithium effects on calcium, magnesium and phosphate in man: effects on balance, bone mineral content, faecal and urinary excretion. Acta Psychiatr Scand 1982; 66:361.
  101. Christiansen C, Baastrup PC, Transbøl I. Development of 'primary' hyperparathyroidism during lithium therapy: longitudinal study. Neuropsychobiology 1980; 6:280.
  102. Nordenström J, Elvius M, Bågedahl-Strindlund M, et al. Biochemical hyperparathyroidism and bone mineral status in patients treated long-term with lithium. Metabolism 1994; 43:1563.