Primary hyperparathyroidism

Key Points

  • Primary hyperparathyroidism (PHPT), a common endocrine disorder characterized by hypercalcaemia and elevated or inappropriately normal levels of parathyroid hormone, is diagnosed based upon biochemical evaluation

  • Over the past 50 years, the clinical profile of PHPT has evolved from a highly symptomatic disease to one that is most often asymptomatic, albeit with evidence of subclinical target organ involvement

  • Even 'asymptomatic' patients can have skeletal deterioration (evident upon imaging; for example, dual-energy X-ray absorptiometry), and subclinical manifestations can include osteoporosis and hypercalciuria as well as clinically silent vertebral fractures and nephrolithiasis

  • The diagnosis of normocalcaemic PHPT can be made after eliminating secondary causes of hyperparathyroidism; however, data are limited on its natural history and appropriate criteria for and response to surgery

  • Parathyroidectomy by an experienced parathyroid surgeon is recommended for patients with symptomatic disease or subclinical end-organ involvement, as no single medical therapy addresses hypercalcaemia and the skeletal and renal consequences of PHPT

Abstract

In this Review, we describe the pathogenesis, diagnosis and management of primary hyperparathyroidism (PHPT), with a focus on recent advances in the field. PHPT is a common endocrine disorder that is characterized by hypercalcaemia and elevated or inappropriately normal serum levels of parathyroid hormone. Most often, the presentation of PHPT is asymptomatic in regions of the world where serum levels of calcium are routinely measured. In addition to mild hypercalcaemia, PHPT can manifest with osteoporosis and hypercalciuria as well as with vertebral fractures and nephrolithiasis, both of which can be asymptomatic. Other clinical forms of PHPT, such as classical disease and normocalcaemic PHPT, are less common. Parathyroidectomy, the only curative treatment for PHPT, is recommended in patients with symptoms and those with asymptomatic disease who are at risk of progression or have subclinical evidence of end-organ sequelae. Parathyroidectomy results in an increase in BMD and a reduction in nephrolithiasis. Various medical therapies can increase BMD or reduce serum levels of calcium, but no single drug can do both. More data are needed regarding the neuropsychological manifestations of PHPT and the pathogenetic mechanisms leading to sporadic PHPT, as well as on risk factors for complications of the disorder. Future work that advances our knowledge in these areas will improve the management of the disorder.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Relationship between serum levels of calcium and PTH.
Figure 2: Trabecular deterioration in PHPT.

References

  1. 1

    Cope, O. The study of hyperparathyroidism at the Massachusetts General Hospital. N. Engl. J. Med. 274, 1174–1182 (1966).

  2. 2

    Yeh, M. W. et al. Incidence and prevalence of primary hyperparathyroidism in a racially mixed population. J. Clin. Endocrinol. Metab. 98, 1122–1129 (2013).

  3. 3

    Wermers, R. A. et al. Incidence of primary hyperparathyroidism in Rochester, Minnesota, 1993–2001: an update on the changing epidemiology of the disease. J. Bone Miner. Res. 21, 171–177 (2006).

  4. 4

    Press, D. M. et al. The prevalence of undiagnosed and unrecognized primary hyperparathyroidism: a population-based analysis from the electronic medical record. Surgery 154, 1232–1237 (2013).

  5. 5

    Heath, H. 3rd, Hodgson, S. F. & Kennedy, M. A. Primary hyperparathyroidism. Incidence, morbidity, and potential economic impact in a community. N. Engl. J. Med. 302, 189–193 (1980).

  6. 6

    Wermers, R. A. et al. The rise and fall of primary hyperparathyroidism: a population-based study in Rochester, Minnesota, 1965–1992. Ann. Intern. Med. 126, 433–440 (1997).

  7. 7

    Griebeler, M. L. et al. Secular trends in the incidence of primary hyperparathyroidism over five decades. Bone 73, 1–7 (2015).

  8. 8

    Silverberg, S. J., Shane, E., Jacobs, T. P., Siris, E. & Bilezikian, J. P. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N. Engl. J. Med. 341, 1249–1255 (1999).

  9. 9

    Rao, S. D. et al. Hyperparathyroidism following head and neck irradiation. Arch. Intern. Med. 140, 205–207 (1980).

  10. 10

    Bendz, H., Sjodin, I., Toss, G. & Berglund, K. Hyperparathyroidism and long-term lithium therapy — a cross-sectional study and the effect of lithium withdrawal. J. Intern. Med. 240, 357–365 (1996).

  11. 11

    Newey, P. J. et al. Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas. J. Clin. Endocrinol. Metab. 97, E1995–E2005 (2012).

  12. 12

    Costa-Guda, J. & Arnold, A. Genetic and epigenetic changes in sporadic endocrine tumors: parathyroid tumors. Mol. Cell. Endocrinol. 386, 46–54 (2014).

  13. 13

    Pardi, E. et al. Aryl hydrocarbon receptor interacting protein (AIP) mutations occur rarely in sporadic parathyroid adenomas. J. Clin. Endocrinol. Metab. 98, 2800–2810 (2013).

  14. 14

    Arnold, A. M. & Levine, M. A. in The Parathyroids: Basic and Clinical Concepts (ed. Bilezikian, J. P.) 279–297 (Academic Press, 2015).

  15. 15

    Marx, S. J. et al. Hyperparathyroidism in hereditary syndromes: special expressions and special managements. J. Bone Miner. Res. 17 (Suppl. 2), N37–N43 (2002).

  16. 16

    Thakker, R. V. Genetics of parathyroid tumours. J. Intern. Med. 280, 574–583 (2016).

  17. 17

    Guan, B. et al. GCM2-activating mutations in familial isolated hyperparathyroidism. Am. J. Hum. Genet. 99, 1034–1044 (2016).

  18. 18

    Yu, W. et al. Whole-exome sequencing studies of parathyroid carcinomas reveal novel PRUNE2 mutations, distinctive mutational spectra related to APOBEC-catalyzed DNA mutagenesis and mutational enrichment in kinases associated with cell migration and invasion. J. Clin. Endocrinol. Metab. 100, E360–E364 (2015).

  19. 19

    Corbetta, S. et al. Differential expression of microRNAs in human parathyroid carcinomas compared with normal parathyroid tissue. Endocr. Relat. Cancer 17, 135–146 (2010).

  20. 20

    Brown, E. M. Role of the calcium-sensing receptor in extracellular calcium homeostasis. Best Pract. Res. Clin. Endocrinol. Metab. 27, 333–343 (2013).

  21. 21

    Mahoney, E. J., Monchik, J. M., Donatini, G. & De Lellis, R. Life-threatening hypercalcemia from a hepatocellular carcinoma secreting intact parathyroid hormone: localization by sestamibi single-photon emission computed tomographic imaging. Endocr. Pract. 12, 302–306 (2006).

  22. 22

    Nussbaum, S. R., Gaz, R. D. & 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. 323, 1324–1328 (1990).

  23. 23

    D'Amour, P. et al. Amino-terminal form of parathyroid hormone (PTH) with immunologic similarities to hPTH(1–84) is overproduced in primary and secondary hyperparathyroidism. Clin. Chem. 49, 2037–2044 (2003).

  24. 24

    Eastell, R. et al. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J. Clin. Endocrinol. Metab. 99, 3570–3579 (2014).

  25. 25

    Wilhelm, S. M. et al. The American Association of Endocrine Surgeons Guidelines for definitive management of primary hyperparathyroidism. JAMA Surg. 151, 959–968 (2016).

  26. 26

    Eastell, R. et al. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J. Clin. Endocrinol. Metab. 94, 340–350 (2009).

  27. 27

    Nesbit, M. A. et al. Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia. N. Engl. J. Med. 368, 2476–2486 (2013).

  28. 28

    Nesbit, M. A. et al. Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. Nat. Genet. 45, 93–97 (2013).

  29. 29

    Lowe, H., McMahon, D. J., Rubin, M. R., Bilezikian, J. P. & Silverberg, S. J. Normocalcemic primary hyperparathyroidism: further characterization of a new clinical phenotype. J. Clin. Endocrinol. Metab. 92, 3001–3005 (2007).

  30. 30

    Albright, F., Aub, J. & Bauer, W. Hyperparathyroidism: common and polymorphic condition as illustrated by seventeen proven cases in one clinic. JAMA 102, 1276 (1934).

  31. 31

    Silverberg, S. J. et al. Current issues in the presentation of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J. Clin. Endocrinol. Metab. 99, 3580–3594 (2014).

  32. 32

    Usta, A., Alhan, E., Cinel, A., Turkyilmaz, S. & Erem, C. A 20-year study on 190 patients with primary hyperparathyroidism in a developing country: Turkey experience. Int. Surg. 100, 648–655 (2015).

  33. 33

    Mallette, L. E., Bilezikian, J. P., Heath, D. A. & Aurbach, G. D. Primary hyperparathyroidism: clinical and biochemical features. Med. (Baltimore) 53, 127–146 (1974).

  34. 34

    Liu, J. M. et al. Primary hyperparathyroidism: a tale of two cities revisited — New York and Shanghai. Bone Res. 1, 162–169 (2013).

  35. 35

    Malabu, U. H. & Founda, M. A. Primary hyperparathyroidism in Saudi Arabia: a review of 46 cases. Med. J. Malaysia 62, 394–397 (2007).

  36. 36

    Paruk, I. M., Esterhuizen, T. M., Maharaj, S., Pirie, F. J. & Motala, A. A. Characteristics, management and outcome of primary hyperparathyroidism in South Africa: a single-centre experience. Postgrad. Med. J. 89, 626–631 (2013).

  37. 37

    Shah, V. N., Bhadada, S., Bhansali, A., Behera, A. & Mittal, B. R. Changes in clinical and biochemical presentations of primary hyperparathyroidism in India over a period of 20 years. Indian J. Med. Res. 139, 694–699 (2014).

  38. 38

    Zhao, L. et al. The changing clinical patterns of primary hyperparathyroidism in Chinese patients: data from 2000 to 2010 in a single clinical center. J. Clin. Endocrinol. Metab. 98, 721–728 (2013).

  39. 39

    Bandeira, F. & Cassibba, S. Hyperparathyroidism and bone health. Curr. Rheumatol. Rep. 17, 48 (2015).

  40. 40

    Oliveira, U. E. et al. Analysis of the diagnostic presentation profile, parathyroidectomy indication and bone mineral density follow-up of Brazilian patients with primary hyperparathyroidism. Braz. J. Med. Biol. Res. 40, 519–526 (2007).

  41. 41

    Spivacow, F. R., Martinez, C. & Polonsky, A. [Primary hyperparathyroidism: postoperative long-term evolution]. Medicina (B. Aires) 70, 408–414 (in Spanish) (2010).

  42. 42

    Walker, M. D. et al. Low vitamin D levels have become less common in primary hyperparathyroidism. Osteoporos. Int. 26, 2837–2843 (2015).

  43. 43

    Moosgaard, B. et al. Vitamin D status, seasonal variations, parathyroid adenoma weight and bone mineral density in primary hyperparathyroidism. Clin. Endocrinol. (Oxf.) 63, 506–513 (2005).

  44. 44

    Boudou, P., Ibrahim, F., Cormier, C., Sarfati, E. & Souberbielle, J. C. A very high incidence of low 25 hydroxy-vitamin D serum concentration in a French population of patients with primary hyperparathyroidism. J. Endocrinol. Invest. 29, 511–515 (2006).

  45. 45

    Clements, M. R. et al. The role of 1,25-dihydroxyvitamin D in the mechanism of acquired vitamin D deficiency. Clin. Endocrinol. (Oxf.) 37, 17–27 (1992).

  46. 46

    Clements, M. R. et al. Metabolic inactivation of vitamin D is enhanced in primary hyperparathyroidism. Clin. Sci. (Lond.) 73, 659–664 (1987).

  47. 47

    Rao, D. S. et al. Effect of vitamin D nutrition on parathyroid adenoma weight: pathogenetic and clinical implications. J. Clin. Endocrinol. Metab. 85, 1054–1058 (2000).

  48. 48

    Silverberg, S. J., Shane, E., Dempster, D. W. & Bilezikian, J. P. The effects of vitamin D insufficiency in patients with primary hyperparathyroidism. Am. J. Med. 107, 561–567 (1999).

  49. 49

    Tassone, F. et al. Vitamin D status in primary hyperparathyroidism: a Southern European perspective. Clin. Endocrinol. (Oxf.) 79, 784–790 (2013).

  50. 50

    Viccica, G., Cetani, F., Vignali, E., Miccoli, M. & Marcocci, C. Impact of vitamin D deficiency on the clinical and biochemical phenotype in women with sporadic primary hyperparathyroidism. Endocrine 55, 256–265 (2017).

  51. 51

    Walker, M. D. et al. Vitamin D in primary hyperparathyroidism: effects on clinical, biochemical, and densitometric presentation. J. Clin. Endocrinol. Metab. 100, 3443–3451 (2015).

  52. 52

    Yamashita, H. et al. Vitamin D status in Japanese patients with hyperparathyroidism: seasonal changes and effect on clinical presentation. World J. Surg. 26, 937–941 (2002).

  53. 53

    Ozbey, N. et al. Correlations between vitamin D status and biochemical/clinical and pathological parameters in primary hyperparathyroidism. World J. Surg. 30, 321–326 (2006).

  54. 54

    Jayasena, C. N. et al. Associations of serum 25-hydroxyvitamin D with circulating PTH, phosphate and calcium in patients with primary hyperparathyroidism. Clin. Endocrinol. (Oxf.) 78, 838–843 (2013).

  55. 55

    Inoue, Y. et al. Vitamin D status affects osteopenia in postmenopausal patients with primary hyperparathyroidism. Endocr. J. 55, 57–65 (2008).

  56. 56

    Moosgaard, B. et al. Plasma 25-hydroxyvitamin D and not 1,25-dihydroxyvitamin D is associated with parathyroid adenoma secretion in primary hyperparathyroidism: a cross-sectional study. Eur. J. Endocrinol. 155, 237–244 (2006).

  57. 57

    Moosgaard, B. et al. Vitamin D metabolites and skeletal consequences in primary hyperparathyroidism. Clin. Endocrinol. (Oxf.) 68, 707–715 (2008).

  58. 58

    Shah, V. N., Shah, C. S., Bhadada, S. K. & Rao, D. S. Effect of 25 (OH) D replacements in patients with primary hyperparathyroidism (PHPT) and coexistent vitamin D deficiency on serum 25(OH) D, calcium and PTH levels: a meta-analysis and review of literature. Clin. Endocrinol. (Oxf.) 80, 797–803 (2014).

  59. 59

    Rolighed, L. et al. Vitamin D treatment in primary hyperparathyroidism: a randomized placebo controlled trial. J. Clin. Endocrinol. Metab. 99, 1072–1080 (2014).

  60. 60

    Silverberg, S. J. et al. Skeletal disease in primary hyper- parathyroidism. J. Bone Miner. Res. 4, 283–291 (1989).

  61. 61

    Parisien, M. et al. The histomorphometry of bone in primary hyperparathyroidism: preservation of cancellous bone structure. J. Clin. Endocrinol. Metab. 70, 930–938 (1990).

  62. 62

    Cipriani, C. et al. Prevalence of kidney stones and vertebral fractures in primary hyperparathyroidism using imaging technology. J. Clin. Endocrinol. Metab. 100, 13091315 (2015).

  63. 63

    Khosla, S. et al. Primary hyperparathyroidism and the risk of fracture: a population-based study. J. Bone Miner. Res. 14, 1700–1707 (1999).

  64. 64

    Vignali, E. et al. Morphometric vertebral fractures in postmenopausal women with primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 94, 2306–2312 (2009).

  65. 65

    Mosekilde, L. Primary hyperparathyroidism and the skeleton. Clin. Endocrinol. (Oxf.) 69, 1–19 (2008).

  66. 66

    De Geronimo, S., Romagnoli, E., Diacinti, D., D'Erasmo, E. & Minisola, S. The risk of fractures in postmenopausal women with primary hyperparathyroidism. Eur. J. Endocrinol. 155, 415–420 (2006).

  67. 67

    Stein, E. M. et al. Primary hyperparathyroidism is associated with abnormal cortical and trabecular microstructure and reduced bone stiffness in postmenopausal women. J. Bone Miner. Res. 28, 1029–1040 (2013).

  68. 68

    Walker, M. D. et al. Effect of concomitant vitamin D deficiency or insufficiency on lumbar spine volumetric bone mineral density and trabecular bone score in primary hyperparathyroidism. Osteoporos. Int. 27, 3063–3071 (2016).

  69. 69

    Hansen, S., Hauge, E. M., Rasmussen, L., Jensen, J. E. & Brixen, K. Parathyroidectomy improves bone geometry and microarchitecture in female patients with primary hyperparathyroidism. A 1-year prospective controlled study using high resolution peripheral quantitative computed tomography. J. Bone Miner. Res. 27, 1150–1158 (2012).

  70. 70

    Nordenstrom, E., Westerdahl, J., Lindergard, B., Lindblom, P. & Bergenfelz, A. Multifactorial risk profile for bone fractures in primary hyperparathyroidism. World J. Surg. 26, 1463–1467 (2002).

  71. 71

    Bilezikian, J. P. et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J. Clin. Endocrinol. Metab. 99, 3561–3569 (2014).

  72. 72

    Lundstam, K. et al. Effects of parathyroidectomy versus observation on the development of vertebral fractures in mild primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 100, 1359–1367 (2015).

  73. 73

    Rejnmark, L., Vestergaard, P. & Mosekilde, L. Nephrolithiasis and renal calcifications in primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 96, 2377–2385 (2011).

  74. 74

    Cassibba, S. et al. Silent renal stones in primary hyperparathyroidism: prevalence and clinical features. Endocr. Pract. 20, 1137–1142 (2014).

  75. 75

    Odvina, C. V. et al. Biochemical characterization of primary hyperparathyroidism with and without kidney stones. Urol. Res. 35, 123–128 (2007).

  76. 76

    Berger, A. D. et al. Patients with primary hyperparathyroidism — why do some form stones? J. Urol. 181, 2141–2145 (2009).

  77. 77

    Tassone, F., Gianotti, L., Emmolo, I., Ghio, M. & Borretta, G. Glomerular filtration rate and parathyroid hormone secretion in primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 94, 4458–4461 (2009).

  78. 78

    Walker, M. D. et al. Predictors of renal function in primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 99, 1885–1892 (2014).

  79. 79

    Walker, M. D. et al. Effect of renal function on skeletal health in primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 97, 1501–1507 (2012).

  80. 80

    Rao, D. S., Wilson, R. J., Kleerekoper, M. & Parfitt, A. M. Lack of biochemical progression or continuation of accelerated bone loss in mild asymptomatic primary hyperparathyroidism: evidence for biphasic disease course. J. Clin. Endocrinol. Metab. 67, 1294–1298 (1988).

  81. 81

    Kristoffersson, A., Backman, C., Granqvist, K. & Jarhult, J. Pre- and postoperative evaluation of renal function with five different tests in patients with primary hyperparathyroidism. J. Intern. Med. 227, 317–324 (1990).

  82. 82

    Ambrogini, E. et al. Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial. J. Clin. Endocrinol. Metab. 92, 3114–3121 (2007).

  83. 83

    Bollerslev, J. et al. Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial. J. Clin. Endocrinol. Metab. 92, 1687–1692 (2007).

  84. 84

    Ogino, K., Burkhoff, D. & Bilezikian, J. P. The hemodynamic basis for the cardiac effects of parathyroid hormone (PTH) and PTH-related protein. Endocrinology 136, 3024–3030 (1995).

  85. 85

    Collip, J. B. & Clark, E. P. Further studies on the physiological action of a parathyroid hormone. J. Biol. Chem. 64, 4485–507 (1925).

  86. 86

    Walker, M. D. et al. Carotid vascular abnormalities in primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 94, 3849–3856 (2009).

  87. 87

    Walker, M. D. & Silverberg, S. J. Parathyroidectomy in asymptomatic primary hyperparathyroidism: improves “bones” but not “psychic moans”. J. Clin. Endocrinol. Metab. 92, 1613–1615 (2007).

  88. 88

    Talpos, G. B. et al. Randomized trial of parathyroidectomy in mild asymptomatic primary hyperparathyroidism: patient description and effects on the SF-36 health survey. Surgery 128, 1013–1020 (2000).

  89. 89

    Perrier, N. D. et al. Prospective, randomized, controlled trial of parathyroidectomy versus observation in patients with “asymptomatic” primary hyperparathyroidism. Surgery 146, 1116–1122 (2009).

  90. 90

    Walker, M. D. & Silverberg, S. J. Cardiovascular aspects of primary hyperparathyroidism. J. Endocrinol. Invest. 31, 925–931 (2008).

  91. 91

    Soreide, J. A. et al. Survival after surgical treatment for primary hyperparathyroidism. Surgery 122, 1117–1123 (1997).

  92. 92

    Wermers, R. A. et al. Survival after the diagnosis of hyperparathyroidism: a population-based study. Am. J. Med. 104, 115–122 (1998).

  93. 93

    Vestergaard, P. et al. Cardiovascular events before and after surgery for primary hyperparathyroidism. World J. Surg. 27, 216–222 (2003).

  94. 94

    Streeten, E. A. et al. Coronary artery calcification in patients with primary hyperparathyroidism in comparison with control subjects from the multi-ethnic study of atherosclerosis. Endocr. Pract. 14, 155–161 (2008).

  95. 95

    Kepez, A. et al. Evaluation of subclinical coronary atherosclerosis in mild asymptomatic primary hyperparathyroidism patients. Int. J. Cardiovasc. Imag. 25, 187–193 (2009).

  96. 96

    Stefenelli, T. et al. Primary hyperparathyroidism: incidence of cardiac abnormalities and partial reversibility after successful parathyroidectomy. Am. J. Med. 95, 197–202 (1993).

  97. 97

    Iwata, S. et al. Aortic valve calcification in mild primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 97, 132–137 (2012).

  98. 98

    Walker, M. D. et al. Effect of parathyroidectomy on subclinical cardiovascular disease in mild primary hyperparathyroidism. Eur. J. Endocrinol. 167, 277–285 (2012).

  99. 99

    McMahon, D. J. et al. Effect of parathyroidectomy upon left ventricular mass in primary hyperparathyroidism: a meta-analysis. J. Clin. Endocrinol. Metab. 100, 4399–4407 (2015).

  100. 100

    Nilsson, I. L., Aberg, J., Rastad, J. & Lind, L. Endothelial vasodilatory dysfunction in primary hyperparathyroidism is reversed after parathyroidectomy. Surgery 126, 1049–1055 (1999).

  101. 101

    Kosch, M. et al. Studies on flow-mediated vasodilation and intima–media thickness of the brachial artery in patients with primary hyperparathyroidism. Am. J. Hypertens. 13, 759–764 (2000).

  102. 102

    Lumachi, F. et al. Intima-media thickness measurement of the carotid artery in patients with primary hyperparathyroidism. A prospective case–control study and long-term follow-up. In Vivo 20, 887–890 (2006).

  103. 103

    Fallo, F. et al. Ultrasound evaluation of carotid artery in primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 88, 2096–2099 (2003).

  104. 104

    Rosa, J. et al. Pulse wave velocity in primary hyperparathyroidism and effect of surgical therapy. Hypertens. Res. 34, 296–300 (2011).

  105. 105

    Schillaci, G. et al. Large-artery stiffness: a reversible marker of cardiovascular risk in primary hyperparathyroidism. Atherosclerosis 218, 96–101 (2011).

  106. 106

    Rubin, M. R., Maurer, M. S., McMahon, D. J., Bilezikian, J. P. & Silverberg, S. J. Arterial stiffness in mild primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 90, 3326–3330 (2005).

  107. 107

    Ragno, A. et al. Chronic constipation in hypercalcemic patients with primary hyperparathyroidism. Eur. Rev. Med. Pharmacol. Sci. 16, 884–889 (2012).

  108. 108

    Pepe, J. et al. The effect of parathyroidectomy on chronic constipation in patients affected by primary hyperparathyroidism. J. Bone Miner. Metab. 31, 690–694 (2013).

  109. 109

    Ludvigsson, J. F. et al. Primary hyperparathyroidism and celiac disease: a population-based cohort study. J. Clin. Endocrinol. Metab. 97, 897–904 (2012).

  110. 110

    Bilezikian, J. P., Khan, A. A. & Potts, J. T. Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J. Clin. Endocrinol. Metab. 94, 335–339 (2009).

  111. 111

    Cusano, N. E. et al. Normocalcemic hyperparathyroidism and hypoparathyroidism in two community-based nonreferral populations. J. Clin. Endocrinol. Metab. 98, 2734–2741 (2013).

  112. 112

    Maruani, G., Hertig, A., Paillard, M. & Houillier, P. Normocalcemic primary hyperparathyroidism: evidence for a generalized target-tissue resistance to parathyroid hormone. J. Clin. Endocrinol. Metab. 88, 4641–4648 (2003).

  113. 113

    Rejnmark, L., Amstrup, A. K., Mollerup, C. L., Heickendorff, L. & Mosekilde, L. Further insights into the pathogenesis of primary hyperparathyroidism: a nested case–control study. J. Clin. Endocrinol. Metab. 98, 87–96 (2013).

  114. 114

    Tuna, M. M. et al. Normocalcemic hyperparathyroidism is associated with complications similar to those of hypercalcemic hyperparathyroidism. J. Bone Miner. Metab. 34, 331–335 (2016).

  115. 115

    Koumakis, E. et al. Bone mineral density evolution after successful parathyroidectomy in patients with normocalcemic primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 98, 3213–3220 (2013).

  116. 116

    Abdulla, A. G., Ituarte, P. H., Harari, A., Wu, J. X. & Yeh, M. W. Trends in the frequency and quality of parathyroid surgery: analysis of 17,082 cases over 10 years. Ann. Surg. 261, 746–750 (2015).

  117. 117

    Stavrakis, A. I., Ituarte, P. H., Ko, C. Y. & Yeh, M. W. Surgeon volume as a predictor of outcomes in inpatient and outpatient endocrine surgery. Surgery 142, 887–899 (2007).

  118. 118

    Kluijfhout, W. P. et al. Fluorine-18 fluorocholine PET–CT localizes hyperparathyroidism in patients with inconclusive conventional imaging: a multicenter study from the Netherlands. Nucl. Med. Commun. 37, 1246–1252 (2016).

  119. 119

    Udelsman, R. & Donovan, P. I. Remedial parathyroid surgery: changing trends in 130 consecutive cases. Ann. Surg. 244, 471–479 (2006).

  120. 120

    Rao, D. S., Phillips, E. R., Divine, G. W. & Talpos, G. B. Randomized controlled clinical trial of surgery versus no surgery in patients with mild asymptomatic primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 89, 5415–5422 (2004).

  121. 121

    Rolighed, L. et al. BMD improvements after operation for primary hyperparathyroidism. Langenbecks Arch. Surg. 398, 113–120 (2013).

  122. 122

    Mollerup, C. L. et al. Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study. BMJ 325, 807 (2002).

  123. 123

    Rubin, M. R. et al. The natural history of primary hyperparathyroidism with or without parathyroid surgery after 15 years. J. Clin. Endocrinol. Metab. 93, 3462–3470 (2008).

  124. 124

    Zanocco, K. A., Wu, J. X. & Yeh, M. W. Parathyroidectomy for asymptomatic primary hyperparathyroidism: A revised cost-effectiveness analysis incorporating fracture risk reduction. Surgery 161, 16–24 (2017).

  125. 125

    Locker, F. G., Silverberg, S. J. & Bilezikian, J. P. Optimal dietary calcium intake in primary hyperparathyroidism. Am. J. Med. 102, 543–550 (1997).

  126. 126

    Paik, J. M., Curhan, G. C. & Taylor, E. N. Calcium intake and risk of primary hyperparathyroidism in women: prospective cohort study. BMJ 345, e6390 (2012).

  127. 127

    Marcocci, C., Bollerslev, J., Khan, A. A. & Shoback, D. M. Medical management of primary hyperparathyroidism: proceedings of the fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism. J. Clin. Endocrinol. Metab. 99, 3607–3618 (2014).

  128. 128

    Jorde, R., Szumlas, K., Haug, E. & Sundsfjord, J. The effects of calcium supplementation to patients with primary hyperparathyroidism and a low calcium intake. Eur. J. Nutr. 41, 258–263 (2002).

  129. 129

    Tsvetov, G. et al. Thiazide treatment in primary hyperparathyroidism — a new indication for an old medication? J. Clin. Endocrinol. Metab. 102, 1270–1276 (2017).

  130. 130

    Riss, P. et al. The influence of thiazide intake on calcium and parathyroid hormone levels in patients with primary hyperparathyroidism. Clin. Endocrinol. (Oxf.) 85, 196–201 (2016).

  131. 131

    Farquhar, C. W., Spathis, G. S., Barron, J. L. & Levin, G. E. Failure of thiazide diuretics to increase plasma calcium in mild primary hyperparathyroidism. Postgrad. Med. J. 66, 714–716 (1990).

  132. 132

    Grey, A. B., Stapleton, J. P., Evans, M. C., Tatnell, M. A. & Reid, I. R. Effect of hormone replacement therapy on bone mineral density in postmenopausal women with mild primary hyperparathyroidism. A randomized, controlled trial. Ann. Intern. Med. 125, 360–368 (1996).

  133. 133

    Tournis, S. et al. Effect of parathyroidectomy versus risedronate on volumetric bone mineral density and bone geometry at the tibia in postmenopausal women with primary hyperparathyroidism. J. Bone Miner. Metab. 32, 151–158 (2014).

Download references

Acknowledgements

The authors acknowledge the National Institiutes of Health (NIH; Grants DK074457 and DK084986 to S.J.S. and DK104105 to M.D.W.).

Author information

M.D.W. and S.J.S. researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission.

Correspondence to Shonni J. Silverberg.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Walker, M., Silverberg, S. Primary hyperparathyroidism. Nat Rev Endocrinol 14, 115–125 (2018). https://doi.org/10.1038/nrendo.2017.104

Download citation

Further reading