Summary

Findings of parathyroid surface proteins acting as calcium receptors have improved our understanding of the secretory dysfunctions leading to the hypercalcemia of HPT, and it is hoped that research on the regulation of function of these proteins will provide new treatments for HPT. The diagnosis of HPT has improved substantially since the introduction of sensitive and specific assays for the intact 84—amino acid peptide. Such immunoradiometric or immunochemolumi-nescent sandwich assays should accurately differentiate HPT from other causes of hypercalcemia. Moreover, these assays enable recognition of most patients with HPT, but their efficiency in this respect depends on applied criteria for biochemical recognition and operative confirmation of parathyroid disease.

REFERENCES

1. Brown EM. PTH secretion in vivo and in vitro: Regulation by calcium and other secretogogues. Miner Electrolyte Metab 1982;8:130.

2. Brown EM. Calcium receptor and regulation of parathyroid hormone secretion. Rev Endocr Metab Disord 2000; 1:307.

3. Brown EM, Leombruno R, Thatcher J, et al. The acute secretory response to alterations in extracellular calcium concentration and dopamine in perfused bovine parathyroid cells. Endocrinology 1985;116:1123.

4. Wallfelt C, Lindh E, Larsson R, et al. Kinetic evidence for cytoplasmic calcium as an inhibitory messenger in parathyroid hormone release. Biochim Biophys Acta 1988;969:257.

5. 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.

6. Wallfelt C, Gylfe E, Larsson R, et al. Relationship between external and cytoplasmic calcium concentrations, parathyroid hormone release and weight of parathyroid glands in human hyperparathyroidism. J Endocrinol 1988; 16:457.

7. Tohme JF, Bilezikian JP, Clemens TL, et al. Suppression of parathyroid hormone secretion with oral calcium in normal subjects and patients with primary hyperparathyroidism. J Clin Endocrinol Metab 1990;70:951.

8. Ljunghall S, Larsson K, Lindh E, et al. Disturbance of basal and stimulated serum levels of intact parathyroid hormone in primary hyperparathyroidism. Surgery 1991; 110:47.

9. Schwartz P, Sörensen HA, McNair P, et al. Cica-clamp technique: A method for quantifying parathyroid hormone secretion. A sequential citrate and calcium clamp study. Eur J Clin Invest 1993;23:546.

10. Logue FC, Fräser WD, Gallacher SJ, et al. The loss of circadian rhythm for intact parathyroid hormone and nephrogenous cyclic AMP in patients with primary hyperparathyroidism. Clin Endocrinol (Oxf) 1990;32:475.

11. Calvo MS, Eastell R, Offord KP, et al. Circadian variation in ionized calcium and intact parathyroid hormone: Evidence for sex differences in calcium homeostasis. J Clin Endocrinol Metab 1991 ;72:69.

12. Kitamura N, Shigeno C, Shiomi K, et al. Episodic fluctuation in serum intact parathyroid hormone concentration in men. J Clin Endocrinol Metab 1990;70:252.

13. Harms HM, Schlinke E, Neubauer O, et al. Pulse amplitude and frequency modulation of parathyroid hormone in primary hyperparathyroidism. J Clin Endocrinol Metab 1994;78:53.

14. Grant FD, Conlin PR, Brown EM. Rate and concentration dependence of parathyroid hormone dynamics during stepwise changes in serum ionized calcium in normal humans. J Clin Endocrinol Metab 1990;71:370.

15. Brent GA, LeBoff MS, Seely EW, et al. Relationship between the concentration and rate of change of calcium and serum intact parathyroid hormone levels in normal humans. J Clin Endocrinol Metab 1988;67:944.

16. Conlin PR, Fajtova VT, Mortensen RM, et al. Hysteresis in the relationship between serum ionized calcium and intact parathyroid hormone during recovery from induced hyper- and hypocalcemia in normal humans. J Clin Endocrinol Metab 1989;69:593.

17. Schwartz P, Sörensen HA, Transböl I. Interrelations between the calcium setpoints of Parfitt and Brown in primary hyperparathyroidism: A sequential citrate and calcium clamp study. Eur J Clin Invest 1994; 24:553.

18. Graf W, Rastad J, Äkerström G, et al. Dynamics of parathyroid hormone release and serum calcium regulation after surgery for primary hyperparathyroidism. World J Surg 1992;16:625.

19. Habener JT, Rosenblatt M, Potts JT. Parathyroid hormone: Biochemical aspects of biosynthesis, secretion, action, and metabolism. Physiol Rev 1984;64:985.

20. Reis A, Hecht W, Gröger R, et al. Cloning and sequence analysis of the human parathyroid hormone gene region. Hum Genet 1990;84:119.

21. Cohn DV, MacGregor RR. The biosynthesis, intracellular processing, and secretion of parathormone. Endocr Rev 1981 ;2:1.

22. Arnold A, Horst SA, Gardella TJ, et al. Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism. J Clin Invest 1990;86:1084.

23. Naveh-Many T, Friedlander MM, Mayer H, et al. Calcium regulates parathyroid hormone messenger ribonucleic acid (mRNA), but not calcitonin mRNA in vivo in the rat: Dominant role of 1,25-dihydroxy-vitamin D. Endocrinology 1989; 125:275.

24. Yamamoto M, Igarishi T, Muramatsu M, et al. Hypocalcemia increases and hypercalcemia decreases the steady state level of parathyroid hormone messenger ribonucleic acid in the rat. J Clin Invest 1989;83:1053.

25. Farrow SM, Karmali R, Gleed JH, et al. Regulation of preproparathyroid hormone messenger RNA and hormone synthesis in human parathyroid adenomata. J Endocrinol 1988; 117:133.

26. Shvil Y, Naveh-Many T, Barach P, et al. Regulation of parathyroid cell gene expression in experimental uremia. J Am Soc Nephrol 1990; 1:99.

27. Nygren P, Larsson R, Johansson H, et al. 1,25(OH)2D3 inhibits hormone secretion and proliferation but not functional dedifferentiation of cultured bovine parathyroid cells. Calcif Tissue Int 1988;43:213.

28. Delmez JA, Tindira C, Grooms P, et al. Parathyroid hormone suppression by intravenous 1,25-dihydroxyvitamin D: A role for increased sensitivity to calcium. J Clin Invest 1989;83:1349.

29. Farrow SM, Hawa NS, Karmali R, et al. Binding of the receptor for 1,25-dihydroxyvitamin D3 to the 5'-flanking region of the bovine parathyroid hormone gene. J Endocrinol 1990:126:355.

30. Rupp E, Mayer H, Wingender E. The promoter of the human parathyroid hormone gene contains a functional cyclic AMP-responsive element. Nucleic Acids Res 1990;18:5677.

31. 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.

32. Lasker RD, Spiegel AM. Endogenous substrates for cAMP-dependent phosphorylation in dispersed bovine parathyroid cells. Endocrinology 1982;111:1412.

33. Morrissey JJ, Cohn DV. Regulation of secretion of parathormone and secretory protein-I from separate intracellular pools by calcium, dibu-tyryl cyclic AMP, and (^-isoproterenol. J Cell Biol 1979;82:93.

34. Ridefelt P, Hellman P, Rastad J, et al. Fluoride interactions with stimulus-secretion coupling of normal and pathological parathyroid cells. Acta Physiol Scand 1992;145:275.

35. Johansson H, Larsson R, Nygren P, et al. Cytoplasmic Ca2+ concentration of single normal human and bovine parathyroid cells measured by dual wavelength microfluorometry. Biosci Rep 1987 ;7:705.

36. Nygren P, Larsson R, Lindh E, et al. Bimodal regulation of secretion by cytoplasmic Ca2+ as demonstrated by the parathyroid. FEBS Lett 1987;213:195.

37. Shoback D, Membreno L, McGhee J. High calcium and other divalent cations increase inositol trisphosphate in bovine parathyroid cells. Endocrinology 1988; 123:382.

38. Enyedi P, Brown E, Williams G. Distinct binding sites for Ins(l,4,5)P3 and Ins(l,3,4,5)P4 in bovine parathyroid glands. Biochim Biophys Res Commun 1989; 159:200.

39. Wallfelt C, Larsson R, Johansson H, et al. Stimulus-secretion coupling of parathyroid hormone release: Studies of 45Ca and 86Rb fluxes. Acta Physiol Scand 1985:124:239.

40. Bergsten P, Grapengiesser E, Gylfe E, et al. Synchronous oscillations of cytoplasmic Ca2+ and insulin release in glucose-stimulated pancreatic islets. J Biol Chem 1994;269:8749.

41. Racke FK, Nemeth EF. Protein kinase C modulates hormone secretion regulated by extracellular polycations in bovine parathyroid cells. J Physiol 1993;468:163.

42. Kifor O, Brown EM. Relationship between diacylglycerol levels and extracellular Ca2+ in dispersed bovine parathyroid cells. Endocrinology 1988;123:2723.

43. Kobayashi N, Russell J, Lettieri D, et al. Regulation of protein kinase C by extracellular calcium in bovine parathyroid cells. Proc Natl Acad Sci USA 1988;85:4857.

44. Lopez-Bameo J, Armstrong CM. Depolarizing response of rat parathyroid cells to divalent cations. J Gen Physiol 1983;82:269.

45. Larsson R, Akerstrom G, Gylfe E, et al. Paradoxical effects of K+ and D-600 on parathyroid hormone secretion and cytoplasmic Ca2+ in normal bovine and pathological human parathyroid cells. Biochim Biophys Acta 1985;847:263.

46. Gylfe E, Johansson H, Larsson R, et al. Activation of Ca2+ influx into parathyroid cells by external cation binding. In: Cohn DV, Martin TJ, Meunier TJ (eds), Calcium Regulation and Bone Metabolism. Amsterdam, Elsevier, 1987, p 33.

47. Ridefelt P, Hellman P, Ljunggren O, et al. Ga3+ inhibits parathyroid hormone release without interacting with the Ca2+ receptor of the parathyroid cell. Biochim Biophys Res Commun 1992;186:556.

48. Juhlin C, Lundgren S, Johansson H, et al. 500-Kilodalton calcium sensor regulating cytoplasmic Ca2+ in cytotrophoblast cells of human placenta. J Biol Chem 1990;265:8275.

49. Juhlin C, Holmdahl R, Johansson H, et al. Monoclonal antibodies with exclusive reactivity against parathyroid cells and tubule cells of the kidney. Proc Natl Acad Sci USA 1987;84:2990.

50. Juhlin C, Johansson H, Holmdahl R, et al. Monoclonal anti-parathyroid antibodies interfering with a Ca2+-sensor of human parathyroid cells. Biochem Biophys Res Commun 1987;143:570.

51. Nygren P, Gylfe E, Larsson R, et al. Modulation of the Ca2+-sensing function of parathyroid cells in vitro and in hyperparathyroidism. Biochim Biophys Acta 1988;968:253.

52. Lundgren S, Hjalm G, Hellman P, et al. A protein involved in calcium sensing of the human parathyroid and placental cytotrophoblast cells belongs to the LDL-receptor protein superfamily. Exp Cell Res 1994;212:344.

53. Hellman P, Hellman B, Juhlin C, et al. Regulation of proliferation in JEG-3 cells by a 500-kDa Ca2+ sensor and parathyroid hormone-related protein. Arch Biochem Biophys 1993;307:379.

54. Brown EM, Gamba G, Riccardi D, et al. Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid. Nature 1993;366:575.

55. Chou Y-HW, Brown EM, Levi T, et al. The gene responsible for familial hypocalciuric hypercalcemia maps to chromosome 3q in four unrelated families. Nat Genet 1992; 1:295.

56. Pollak MR, Brown EM, Wu Chou Y-H, et al. Mutations in the human Ca2+-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 1993;75; 1297.

57. Arnold A, Shattuck TM, Mallya SM, et al. Molecular pathogenesis of primary hyperparathyroidism. J Bone Miner Res 2002;2:N30.

58. Larsson R, Wallfelt C, Abrahamsson H, et al. Defective regulation of the cytosolic Ca2+ activity in parathyroid cells from patients with hyperparathyroidism. Biosci Rep 1984;4:909.

59. LeBoff MS, Shoback D, Brown EM, et al. Regulation of parathyroid hormone release and cytosolic calcium by extracellular calcium in dispersed and cultured bovine and pathological human parathyroid cells. J Clin Invest 1985;75:49.

60. Nygren P. Functional dedifferentiation of parathyroid cells results both from a defective regulation and action of cytoplasmic Ca2+. Biosci Rep 1986;6; 1057.

61. Corbetta S, Mantovani G, Lania A, et al. Calcium-sensing receptor expression and signalling in human parathyroid adenomas and primary hyperplasia. Clin Endocrinol (Oxf) 2000;52:339.

62. Brown EM, Gardner DG, Brennan MF, et al. Calcium-regulated parathyroid hormone release in primary hyperparathyroidism: Studies in vitro with dispersed parathyroid cells. Am J Med 1979; 66:923.

63. Wallfelt C, Ljunghall S, Bergstróm R, et al. Clinical characteristics and surgical treatment of sporadic primary hyperparathyroidism. Surgery 1990;107:13.

64. Benson L, Rastad J, Ljunghall S, et al. Parathyroid hormone release in vitro in hyperparathyroidism associated with multiple endocrine neoplasia type 1. Acta Endocrinol (Copenh) 1987;114:12.

65. Wallfelt CH, Larsson R, Gylfe E, et al. Secretory disturbance in hyperplastic parathyroid nodules of uremic hyperparathyroidism: Implication for parathyroid autotransplantation. World J Surg 1988;12:431.

66. Johansson H, Rastad J, Bjemeroth G, et al. Microfluorometric measurements of cytoplasmic calcium in chief and oxyphil parathyroid cells of adenomatous and hyperplastic glands and of normal-sized glands associated with adenomas. Surgery 1989;106:517.

67. Juhlin C, Rastad J, Klareskog L, et al. Parathyroid histology and cytology with monoclonal antibodies recognizing a calcium sensor of parathyroid Cells. Am J Pathol 1989;135:321.

68. Williams JG, Wheeler MH, Aston JP, et al. The relationship between adenoma weight and intact (1-84) parathyroid hormone level in primary hyperparathyroidism. Am J Surg 1992;163:301.

69. Mittendorf EA, McHenry CR. Persistent parathyroid hormone elevation following curative parathyroidectomy for primary hyperparathyroidism. Arch Otolaryngol Head Neck Surg 2002;128:275.

70. Mozzon M, Mortier PE, Jacob PM, et al. Surgical management of primary hyperparathyroidism: The case for giving up quick intraoperative PTH assay in favor of routine PTH measurement the morning after. Ann Surg 2004;240:949.

71. Larsson R, Wallfelt C, Akerstrom G, et al. Normalizing effect of Ca2+ ionophore on cytoplasmic Ca2+ and parathyroid hormone release of dispersed parathyroid cells from patients with hyperparathyroidism. Mol Cell Endocrinol 1986;45:191.

72. Juhlin C, Klareskog L, Nygren P, et al. Hyperparathyroidism is associated with reduced expression of a parathyroid calcium receptor mechanism defined by monoclonal antiparathyroid antibodies. Endocrinology 1988;122:2999.

73. Ridefelt P, Nygren P, Hellman P, et al. Regulation of parathyroid hormone release in normal and pathological parathyroid cells exposed to modulators of protein kinase C. Acta Endocrinol (Copenh) 1992; 126:505.

74. Fukuda N, Tanaka H, Tominaga Y, et al. Decreased 1,25-dihydroxy-vitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest 1993:92:1436.

75. Chan Y-K, McKay C, Dye E, et al. The effect of 1,25-dihydroxychole-calciferol on parathyroid hormone secretion by monolayer cultures of bovine parathyroid cells. Calcif Tissue Int 1986:38:27.

76. Brown AJ, Dusso A, Lopez-Hilker S, et al. l,25-(OH)2D receptors are decreased in parathyroid glands from chronically uremic dogs. Kidney Int 1989;35:19.

77. Kebebew E, Duh QY, Clark OH. Parathyroidectomy for primary hyperparathyroidism in octogenarians and nonagenarians: A plea for early surgical referral. Arch Surg 2003;138:867.

78. Quesada JM, Coopmans W, Ruiz B, et al. Influence of vitamin D on parathyroid function in the elderly. J Clin Endocrinol Metab 1992;75:494.

79. Parfitt AM, Willgoss D, Jacobi J, et al. Cell kinetics in parathyroid adenomas: Evidence for decline in rates of cell birth and tumour growth, assuming clonal origin. Clin Endocrinol (Oxf) 1991;35:151.

80. 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.

81. Sakaguchi K, Santora A, Zimering M, et al. Functional epithelial cell line cloned from rat parathyroid glands. Proc Nad Acad Sci USA 1987;84:3269.

82. Boonen S, Vanderschueren D, Pelemans W, Bouillon R. Primary hyperparathyroidism: Diagnosis and management in the older individual. Eur J Endocrinol 2004; 151:297.

83. Nygren P, Larsson R, Johansson H, et al. Inhibition of cell growth retains differentiated function of bovine parathyroid cells in monolayer culture. Bone Miner 1988;4:123.

84. Brandi ML, Aurbach GD, Fitzpatrick LA, et al. Parathyroid mitogenic activity in plasma from patients with familial multiple endocrine neoplasia type 1. N Engl J Med 1986;314:1287.

85. Karges W, Schaaf L, Dralle H, Boehm BO. Clinical and molecular diagnosis of multiple endocrine neoplasia type 1. Langenbecks Arch Surg 2002;386:547.

86. Bystróm C, Larsson C, Blomberg C, et al. Localization of the gene for multiple endocrine neoplasia type 1 to a small region within chromosome llql3 by deletion mapping in tumors. Proc Natl Acad Sci USA 1990;87:1968.

87. Friedman E, de Marco L, Gejman PV, et al. Allelic loss from chromosome 11 in parathyroid tumors. Cancer Res 1992;52:6804.

88. Rosenberg CL, Kim HG, Shows TB, et al. Rearrangement and overexpression of D11S287E, a candidate oncogene on chromosome llql3 in benign parathyroid tumors. Oncogene 1991;6:449.

89. Arnold A, Kim HG, Gaz RD, et al. Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in parathyroid adenoma. J Clin Invest 1989;83:2034.

90. Motokura T, Bloom T, Kim HG, et al. A novel cyclin encoded by a bell-linked candidate oncogene. Nature 1991;350:512.

91. Arnold A, Staunton CE, Kim HG, et al. Monoclonality and abnormal parathyroid hormone genes in parathyroid adenomas. N Engl J Med 1988;318:658.

92. Friedman E, Sakaguchi K, Bale AE, et al. Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1. N Engl J Med 1989:321:213.

93. Friedman E, Bale AE, Marx SJ, et al. Genetic abnormalities in sporadic parathyroid adenomas. J Clin Endocrinol Metab 1990; 71:293.

94. Bjerneroth G, Juhlin C, Grimelius L, et al. Improvement in histological diagnosis of primary hyperparathyroidism with a monoclonal antiparathyroid antibody. Endocr Pathol 1992;3:83.

95. Arnold A, Brown M, Urena P, et al. X-inactivation analysis of clonality in primary and secondary parathyroid hyperplasia [Abstract]. J Bone Miner Res 1992;7(Suppl 1):S153.

96. Falchetti A, Bale AE, Amorosi A, et al. Progression of uremic hyperparathyroidism involves allelic loss on chromosome 11. J Clin Endocrinol Metab 1993;76:139.

97. Cryns V, Thor A, Xu HJ, et al. Loss of the retinoblastoma tumor-suppressor gene in parathyroid carcinoma. N Engl J Med 1994;330:757.

98. Kramer R, Bolivar I, Golzman D, et al. Influence of calcium and 1,25-dihydroxycholecalciferol on proliferation and proto-oncogene expression in primary cultures of bovine parathyroid cells. Endocrinology 1989:125:935.

99. Shattuck TM, Valimaki 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.

100. Tanaka R, Tsushima T, Murakami H, et al. Insulin-like growth factor 1 receptors and insulin-like growth factor-binding protein in human parathyroid tumors. World J Surg 1994; 18:635.

101. Sakaguchi K. Acidic fibroblast growth factor autocrine system as a mediator of calcium-regulated parathyroid cell growth. J Biol Chem 1992;267:24554.

102. Mignatti P, Morimoto T, Rifkin DB. Basic fibroblast growth factor, a protein devoid of secretory signal sequence, is released by cells via a pathway independent of the endoplasmic reticulum-Golgi complex. J Cell Physiol 1992:151:81.

103. Cohn DV, Zangerle R, Fischer-Colbie R, et al. Similarity of secretory protein-I from parathyroid gland to chromogranin A from adrenal medulla. Proc Natl Acad Sci USA 1982:79:6056.

104. Fasciotto BH, Gorr S-U, DeFranco DJ, et al. Pancreastatin, a presumed product of chromogranin-A (secretory protein I) processing, inhibits secretion from porcine parathyroid cells in culture. Endocrinology 1989:125:1617.

105. Mouland AJ, Hendy GN. Regulation of synthesis and secretion of chromogranin-A by calcium and 1,25-dihydroxycholecalciferol in cultured bovine parathyroid cells. Endocrinology 1991:128:441.

106. Ridgeway RD, MacGregor RR. Opposite effects of l,25-(OH)2D3 on synthesis and release of PTH with secretory protein I. Am J Physiol 1988;254:E279.

107. Fasciotto BH, Trauss CA, Greeley GH, et al. Parastatin (porcine chromogranin A347-419), a novel chromogranin A-derived peptide, inhibits parathyroid cell secretion. Endocrinology 1993; 133:461.

108. Drees BM, Hamilton JW. Pancreastatin and bovine parathyroid cell secretion. Bone Miner 1992:17:335.

109. Ridefelt P, Hellman P, Stridsberg M, et al. Different secretory actions of pancreastatin in bovine and human parathyroid cells. Biosci Rep 1994:16:221.

110. Kitazawa R, Kitazawa S, Maeda S, Kobayashi A. Expression of parathyroid hormone-related protein (PTHrP) in parathyroid tissue under normal and pathological conditions. Histol Histopathol 2002:17:179.

111. Sakaguchi K, Ikeda K, Curcio F, et al. Subclones of a rat parathyroid cell line (PT-r): Regulation of growth and production of parathyroid hormone-related peptide (PTHRP). J Bone Miner Res 1990;5:863.

112. Fuji Y, Moreira JE, Orlando C, et al. Endothelin as an autocrine factor in the regulation of parathyroid cells. Proc Natl Acad Sci USA 1991:88:4235.

113. Eguchi S, Hirata Y, Imai T, et al. Endothelin receptors in human parathyroid gland. Biochem Biophys Res Commun 1992;184:1448.

114. Juppner H, Potts JT Jr. Immunoassays for the detection of parathyroid hormone. J Bone Miner Res 2002;17:N81.

115. Martin KJ, Hruska KA, Freitag JJ, et al. The peripheral metabolism of parathyroid hormone. N Engl J Med 1979;302:1092.

116. D'Amour P, Lazure C, LaBelle F. Metabolism of radioiodinated carboxy-terminal fragments of bovine parathyroid hormone in normal and anephric rats. Endocrinology 1985:117:127.

117. Abou-Samra AB, Jüppner H, Force T, et al. Expression cloning of a common receptor for parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells; a single receptor stimulates intracellular accumulation of both cAMP and inositol trisphosphates and increases intracellular free calcium. Proc Natl Acad Sci USA 1992;89:2732.

118. Tregear GW, van Rietschoten J, Greene E, et al. Bovine parathyroid hormone: Minimum chain length of synthetic peptide required for biological activity. Endocrinology 1973:93:1349.

119. Rao LG, Murray TM. Binding of intact parathyroid hormone to rat osteosarcoma cells; major contribution of binding sites for the carboxy-terminal region of the hormone. Endocrinology 1985;117:1632.

120. Urena P, Kubrusly M, Mannstadt M, et al. The renal PTH/PTHrP receptor is down-regulated in rats with chronic renal failure. Kidney Int 1994;45:605.

121. Teitelbaum AP, Silve CM, Nyiredy KO, et al. Down-regulation of parathyroid hormone (PTH) receptors in cultured bone cells is associated with agonist-specific intracellular processing of PTH-receptor complexes. Endocrinology 1986;118:595.

122. Pun KK, Ho PWM, Nissenson RA, et al. Desensitization of parathyroid hormone receptors on cultured bone cells. J Bone Miner Res 1990:5:1193.

123. Levine MA. Clinical spectrum and pathogenesis of pseudohypoparathyroidism. Rev Endocr Metab Disord 2000:1:265.

124. Broadus AE. Nephrogenous cyclic AMP. Recent Prog Horm Res 1981:37:667.

125. Goltzman D, Henderson B, Loveridge N. Cytochemical bioassay of parathyroid hormone: Characteristics of the assay and analysis of circulating hormonal forms. J Clin Invest 1980:65:1309.

126. Endres DB, Villanueva R, Sharp CF, et al. Measurement of parathyroid hormone. Endocrinol Metab Clin North Am 1989;18:611.

127. Orloff JJ, Wu TL, Stewart AF. Parathyroid hormone-like proteins: Biochemical responses and receptor interactions. Endocr Rev 1989:10:476.

128. Nussbaum SR, Potts JT. Immunoassays for parathyroid hormone 1-84 in the diagnosis of hyperparathyroidism. J Bone Miner Res 1991;6(Suppl 2):S43.

129. Endres DB, Villanueva R, Sharp CF, et al. Immunochemilumino-metric and immunoradiometric determinations of intact and total immunoreactive parathyrin: Performance in the differential diagnosis of hypercalcemia and hypoparathyroidism. Clin Chem 1991; 37:162.

130. Body JJ, Dumon JC, Thirion M, et al. Circulating PTHrP concentrations in tumor-induced hypercalcemia: Influence on the response to bisphosphonate and changes after therapy. J Bone Miner Res 1992:8:701.

131. Blind E, Schmidt-Gayk H, Armbruster FP, et al. Measurement of intact human parathyrin by an extracting two-site immunoradiometric assay. Clin Chem 1987;33:1376.

132. Brown RC, Aston JP, Weeks I, et al. Circulating intact parathyroid hormone measured by a two-site immunochemiluminometric assay. J Clin Endocrinol Metab 1987;65:407.

133. Nussbaum SP, Zahradnik RJ, Lavigne JP, et al. Highly sensitive two-site immunoradiometric analysis of parathyrin, and its clinical utility in evaluating patients with hypercalcemia. Clin Chem 1987;33:1364.

134. Bouillon R, Coopmans W, Degrotte DEH, et al. Immunoradiometric assay of parathyrin with polyclonal and monoclonal region-specific antibodies. Clin Chem 1990;36:271.

135. Nussbaum SR, Potts JT. Advances in immunoassays for parathyroid hormone: Clinical applications to skeletal disorders of bone and mineral metabolism. In: Bilezikian JP, Levine MA, Marcus R (eds). The Parathyroids. New York, Raven Press, 1994, p 157.

136. Nussbaum SR, Thompson AR, Hutcheson KA, et al. Intraoperative measurement of PTH 1-84: A potential use of the clearance of PTH to assess surgical cure of hyperparathyroidism. Surgery 1988:104:1121.

137. Irvin GL, Dembrow VD, Prudhomme DL, et al. Clinical usefulness of an intraoperative "quick parathyroid hormone" assay. Surgery 1993;114:1019.

138. Ryan MF, Jones SR, Barnes AD. Clinical evaluation of a rapid parathyroid hormone assay. Ann Clin Biochem 1992:29:48.

139. Nussbaum S, Gaz R, 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.

140. Yoshimoto K, Yamasaki R, Hideki S, et al. Ectopic production of parathyroid hormone by small cell lung cancer in a patient with hypercalcemia. J Clin Endocrinol Metab 1989;68:976.

141. Strewler GJ, Budayer AA, Clark OH, et al. Production of parathyroid hormone by a malignant nonparathyroid tumor in a hypercalcemia patient. J Clin Endocrinol Metab 1993:76:1373.

142. Rizzoli R, Pache JC, Burger A, et al. A thymoma as a cause of true ectopic hyperparathyroidism. J Clin Endocrinol Metab 1994;79:912.

143. Rastad J, Akerstrom G. Secondary hyperparathyroidism. In: Aker-strom G, Rastad J, Juhlin C (eds), Current Controversy in Parathyroid Operation and Reoperation. Austin, Tex, RG Landes, 1994, p 167.

Diagnosis of Primary Hyperparathyroidism and Indications for Parathyroidectomy

Primary hyperparathyroidism is a relatively common problem, and reportedly 100,000 new cases are detected each year in the United States.1 One of every 500 women and 1 of every 2000 men older than 40 years have primary hyperparathyroidism. A population-based study in Sweden suggested that about 2% of postmenopausal women have hyperparathyroidism.2 The disease entities to be considered in the differential diagnosis of hypercalcemia are shown in Table 40-1. Primary hyperparathyroidism and malignancy account for 90% of all patients with hypercalcemia. Primary hyperparathyroidism is the most common cause of hypercalcemia in outpatients, whereas malignancy is the most common cause of hypercalcemia in hospitalized patients.3

Malignancy-associated hypercalcemia has traditionally been considered to include three distinct syndromes: (1) humoral hypercalcemia of malignancy, (2) hypercalcemia associated with bone metastases, and (3) hypercalcemia associated with hematologic malignancy (multiple myeloma). Humoral hypercalcemia of malignancy occurs in patients with solid tumors of the lung, breast, kidney, head and neck, and ovary without bone metastases and is known to be mediated primarily by parathyroid hormone-related peptide (PTHrP).4 A comparison of the biochemical characteristics of primary hyperparathyroidism and humoral hypercalcemia of malignancy is shown in Table 40-2. PTHrP also plays a role in the hypercalcemia associated with bone metastases5 and multiple myeloma.6 Interestingly, primary bone tumors such as osteogenic sarcoma seldom cause hypercalcemia.7

Primary hyperparathyroidism may be distinguished from the other causes of hypercalcemia by careful history, physical examination, and laboratory investigations.

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