Abstract
Primary hyperparathyroidism (PHPT) is a common disorder in which parathyroid hormone (PTH) is excessively secreted from one or more of the four parathyroid glands. A single benign parathyroid adenoma is the cause in most people. However, multiglandular disease is not rare and is typically seen in familial PHPT syndromes. The genetics of PHPT is usually monoclonal when a single gland is involved and polyclonal when multiglandular disease is present. The genes that have been implicated in PHPT include proto-oncogenes and tumour-suppressor genes. Hypercalcaemia is the biochemical hallmark of PHPT. Usually, the concentration of PTH is frankly increased but can remain within the normal range, which is abnormal in the setting of hypercalcaemia. Normocalcaemic PHPT, a variant in which the serum calcium level is persistently normal but PTH levels are increased in the absence of an obvious inciting stimulus, is now recognized. The clinical presentation of PHPT varies from asymptomatic disease (seen in countries where biochemical screening is routine) to classic symptomatic disease in which renal and/or skeletal complications are observed. Management guidelines have recently been revised to help the clinician to decide on the merits of a parathyroidectomy or a non-surgical course. This Primer covers these areas with particular attention to the epidemiology, clinical presentations, genetics, evaluation and guidelines for the management of PHPT.
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References
Cope, O. The study of hyperparathyroidism at the Massachusetts General Hospital. N. Engl. J. Med. 274, 1174–1182 (1966).
Pallan, S., Rahman, M. O. & Khan, A. A. Diagnosis and management of primary hyperparathyroidism. BMJ 344, e1013 (2012).
Bilezikian, J. P. & Silverberg, S. J. Clinical practice. Asymptomatic primary hyperparathyroidism. N. Engl. J. Med. 350, 1746–1751 (2004). This paper reports on the changing clinical presentation of PHPT from symptomatic to asymptomatic.
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).
Yeh, M. W. et al. Incidence and prevalence of primary hyperparathyroidism in a racially mixed population. J. Clin. Endocrinol. Metab. 98, 1122–1129 (2013). This is a recent survey of the prevalence of PHPT.
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).
Berger, C. et al. Characteristics of hyperparathyroid states in the Canadian multicentre osteoporosis study (CaMos) and relationship to skeletal markers. Clin. Endocrinol. (Oxf.) 82, 359–368 (2015).
Lee, P. K., Jarosek, S. L., Virnig, B. A., Evasovich, M. & Tuttle, T. M. Trends in the incidence and treatment of parathyroid cancer in the United States. Cancer 109, 1736–1741 (2007).
Palmer, M., Jakobsson, S., Akerstrom, G. & Ljunghall, S. Prevalence of hypercalcaemia in a health survey: a 14-year follow-up study of serum calcium values. Eur. J. Clin. Invest. 18, 39–46 (1988).
Abood, A. & Vestergaard, P. Increasing incidence of primary hyperparathyroidism in Denmark. Dan. Med. J. 60, A4567 (2013).
Yu, N., Donnan, P. T., Murphy, M. J. & Leese, G. P. Epidemiology of primary hyperparathyroidism in Tayside, Scotland, UK. Clin. Endocrinol. (Oxf.) 71, 485–493 (2009).
Bandeira, F., Griz, L., Caldas, G., Bandeira, C. & Freese, E. From mild to severe primary hyperparathyroidism: the Brazilian experience. Arq. Bras. Endocrinol. Metab. 50, 657–663 (2006).
Spivacow, F. R., Martinez, C. & Polonsky, A. [Primary hyperparathyroidism: postoperative long-term evolution]. Medicina (B. Aires) 70, 408–414 (in Spanish) (2010).
Eufrazino, C., Veras, A. & Bandeira, F. Epidemiology of primary hyperparathyroidism and its non-classical manifestations in the city of Recife, Brazil. Clin. Med. Insights Endocrinol. Diabetes 6, 69–74 (2013).
Pradeep, P. V., Jayashree, B., Mishra, A. & Mishra, S. K. Systematic review of primary hyperparathyroidism in India: the past, present, and the future trends. Int. J. Endocrinol. 2011, 921814 (2011).
Bilezikian, J. P., Meng, X., Shi, Y. & Silverberg, S. J. Primary hyperparathyroidism in women: a tale of two cities — New York and Beijing. Int. J. Fertil. Womens Med. 45, 158–165 (2000).
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).
Liu, J. M. et al. Primary hyperparathyroidism: a tale of two cities revisited — New York and Shanghai. Bone Res. 1, 162–169 (2013).
Lo, C. Y. et al. Surgical treatment for primary hyperparathyroidism in Hong Kong: changes in clinical pattern over 3 decades. Arch. Surg. 139, 77–82 (2004).
Gopal, R. A. et al. Clinical profile of primary hyperparathyroidism from western India: a single center experience. J. Postgrad. Med. 56, 79–84 (2010).
Malabu, U. H. & Founda, M. A. Primary hyperparathyroidism in Saudi Arabia: a review of 46 cases. Med. J. Malaysia 62, 394–397 (2007).
Prasarttong-Osoth, P., Wathanaoran, P., Imruetaicharoenchoke, W. & Rojananin, S. Primary hyperparathyroidism: 11-year experience in a single institute in Thailand. Int. J. Endocrinol. 2012, 952426 (2012).
Hamidi, S., Soltani, A., Hedayat, A. & Kamalian, N. Primary hyperparathyroidism: a review of 177 cases. Med. Sci. Monit. 12, CR86-9 (2006).
Biyabani, S. R. & Talati, J. Bone and renal stone disease in patients operated for primary hyperparathyroidism in Pakistan: is the pattern of disease different from the west? J. Pak. Med. Assoc. 49, 194–198 (1999).
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).
Kobayashi, T., Sugimoto, T. & Chihara, K. Clinical and biochemical presentation of primary hyperparathyroidism in Kansai district of Japan. Endocr. J. 44, 595–601 (1997).
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).
Clifton-Bligh, P. B. et al. Mortality associated with primary hyperparathyroidism. Bone 74, 121–124 (2015).
Lundgren, E. et al. Increased cardiovascular mortality and normalized serum calcium in patients with mild hypercalcemia followed up for 25 years. Surgery 130, 978–985 (2001).
Wermers, R. A. et al. Survival after the diagnosis of hyperparathyroidism: a population-based study. Am. J. Med. 104, 115–122 (1998).
Brown, E. M. et al. Dispersed cells prepared from human parathyroid glands: distinct calcium sensitivity of adenomas versus primary hyperplasia. J. Clin. Endocrinol. Metab. 46, 267–275 (1978).
Silverberg, S. J. in Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism (eds Rosen, C. J. et al.) 543–552 (John Wiley & Sons, 2014).
Brown, E. M. Role of the calcium-sensing receptor in extracellular calcium homeostasis. Best Pract. Res. Clin. Endocrinol. Metab. 27, 333–343 (2013). This is a recent review that highlights the role of the CASR in physiological and pathological conditions.
Segersten, U. et al. 25-hydroxyvitamin D3-1α-hydroxylase expression in normal and pathological parathyroid glands. J. Clin. Endocrinol. Metab. 87, 2967–2972 (2002).
Naveh-Many, T., Rahamimov, R., Livni, N. & Silver, J. Parathyroid cell proliferation in normal and chronic renal failure rats. The effects of calcium, phosphate, and vitamin D. J. Clin. Invest. 96, 1786–1793 (1995).
Moallem, E., Kilav, R., Silver, J. & Naveh-Many, T. RNA-protein binding and post-transcriptional regulation of parathyroid hormone gene expression by calcium and phosphate. J. Biol. Chem. 273, 5253–5259 (1998).
Ben-Dov, I. Z. et al. The parathyroid is a target organ for FGF23 in rats. J. Clin. Invest. 117, 4003–4008 (2007).
Witteveen, J. E., van Lierop, A. H., Papapoulos, S. E. & Hamdy, N. A. Increased circulating levels of FGF23: an adaptive response in primary hyperparathyroidism? Eur. J. Endocrinol. 166, 55–60 (2012).
Silva, B. C. & Kousteni, S. in The Parathyroids. Basic and Clincial Concepts (eds Bilezikian, J. P. et al.) 127–137 (Academic Press, 2015).
Goltzman, D. in The Parathyroids. Basic and Clincial Concepts (eds Bilezikian, J. P. et al.) 139–152 (Academic Press, 2015).
Carpinteri, R. et al. Glucocorticoid-induced osteoporosis and parathyroid hormone. J. Endocrinol. Invest. 33, 16–21 (2010).
Silverberg, S. J. & Bilezikian, J. P. in The Parathyroids. Basic and Clinical Concepts (eds Bilezikian, J. P. et al.) 317–327 (Academic Press, 2015).
Marcocci, C. & Cetani, F. Clinical practice. Primary hyperparathyroidism. N. Engl. J. Med. 365, 2389–2397 (2011).
Arnold, A. & Levine, A. in The Parathyroids. Basic and Clincial Concepts (eds Bilezikian, J. P. et al.) 279–296 (Academic Press, 2015). This is a recent comprehensive chapter on the molecular pathogenesis of parathyroid tumours.
Attie, J. N., Bock, G. & Auguste, L. J. Multiple parathyroid adenomas: report of thirty-three cases. Surgery 108, 1014–1019 (1990).
Cohen, J., Gierlowski, T. C. & Schneider, A. B. A prospective study of hyperparathyroidism in individuals exposed to radiation in childhood. JAMA 264, 581–584 (1990).
Boehm, B. O., Rosinger, S., Belyi, D. & Dietrich, J. W. The parathyroid as a target for radiation damage. N. Engl. J. Med. 365, 676–678 (2011).
Szalat, A., Mazeh, H. & Freund, H. R. Lithium-associated hyperparathyroidism: report of four cases and review of the literature. Eur. J. Endocrinol. 160, 317–323 (2009).
Arnold, A., Staunton, C. E., Kim, H. G., Gaz, R. D. & Kronenberg, H. M. Monoclonality and abnormal parathyroid hormone genes in parathyroid adenomas. N. Engl. J. Med. 318, 658–662 (1988).
Friedman, E. in Molecular Biology of the Parathyroid (ed. Naveh-Many, T. ) 128–139 (Plenum Publisher New York, 2005).
Arnold, A. et al. Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia. J. Clin. Invest. 95, 2047–2053 (1995).
Friedman, E. et al. Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1. N. Engl. J. Med. 321, 213–218 (1989).
Thakker, R. V. et al. Association of parathyroid tumors in multiple endocrine neoplasia type 1 with loss of alleles on chromosome 11. N. Engl. J. Med. 321, 218–224 (1989).
Chandrasekharappa, S. C. et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276, 404–407 (1997).
Lemos, M. C. & Thakker, R. V. Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum. Mutat. 29, 22–32 (2008).
Agarwal, S. K. et al. Menin molecular interactions: insights into normal functions and tumorigenesis. Horm. Metab. Res. 37, 369–374 (2005).
Gracanin, A., Dreijerink, K. M., van der Luijt, R. B., Lips, C. J. & Hoppener, J. W. Tissue selectivity in multiple endocrine neoplasia type 1-associated tumorigenesis. Cancer Res. 69, 6371–6374 (2009).
Karnik, S. K. et al. Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Proc. Natl Acad. Sci. USA 102, 14659–14664 (2005).
Milne, T. A. et al. MLL associates specifically with a subset of transcriptionally active target genes. Proc. Natl Acad. Sci. USA 102, 14765–14770 (2005).
Belar, O. et al. Novel mutations in MEN1, CDKN1B and AIP genes in patients with multiple endocrine neoplasia type 1 syndrome in Spain. Clin. Endocrinol. (Oxf.) 76, 719–724 (2012).
Arnold, A. & Marx, S. J. in Primer on the Metabolic Bone Disease and Disorders of Mineral Metabolism (eds Rosen, C. J. et al.) 553–561 (John Wiley & Sons, 2014).
Wohllk, N. et al. Multiple endocrine neoplasia type 2. Best Pract. Res. Clin. Endocrinol. Metab. 24, 371–387 (2010).
Pellegata, N. S. et al. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc. Natl Acad. Sci. USA 103, 15558–15563 (2006).
Thakker, R. V. in The Parathyroids. Basic and Clinical Concepts (eds Bilezikian, J. P. et al.) 341–364 (Academic Press, 2015).
Marinoni, I. & Pellegata, N. S. p27kip1: a new multiple endocrine neoplasia gene? Neuroendocrinology 93, 19–28 (2011).
Molatore, S. & Pellegata, N. S. The MENX syndrome and p27: relationships with multiple endocrine neoplasia. Prog. Brain Res. 182, 295–320 (2010).
Lee, J. & Kim, S. S. The function of p27KIP1 during tumor development. Exp. Mol. Med. 41, 765–771 (2009).
Carpten, J. D. et al. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat. Genet. 32, 676–680 (2002).
Howell, V. M. et al. HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours. J. Med. Genet. 40, 657–663 (2003).
Newey, P. J., Bowl, M. R. & Thakker, R. V. Parafibromin — functional insights. J. Intern. Med. 266, 84–98 (2009).
Cetani, F. et al. Genetic analyses in familial isolated hyperparathyroidism: implication for clinical assessment and surgical management. Clin. Endocrinol. (Oxf.) 64, 146–152 (2006).
Miedlich, S., Lohmann, T., Schneyer, U., Lamesch, P. & Paschke, R. Familial isolated primary hyperparathyroidism — a multiple endocrine neoplasia type 1 variant? Eur. J. Endocrinol. 145, 155–160 (2001).
El-Hajj Fuleihan, G. & Brown, E. M. in The Parathyroids. Basic and Clincial Concepts (eds Bilezikian, J. P. et al.) 365–387 (Academic Press, 2015).
Pollak, M. R. et al. Mutations in the human Ca2+-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 75, 1297–1303 (1993).
Nesbit, M. A. et al. Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. Nat. Genet. 45, 93–97 (2013).
Ho, C. et al. A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nat. Genet. 11, 389–394 (1995).
Arnold, A. et al. Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma. J. Clin. Invest. 83, 2034–2040 (1989).
Mallya, S. M., Wu, H. I., Saria, E. A., Corrado, K. R. & Arnold, A. Tissue-specific regulatory regions of the PTH gene localized by novel chromosome 11 rearrangement breakpoints in a parathyroid adenoma. J. Bone Miner. Res. 25, 2606–2612 (2010).
Cetani, F. et al. Six novel MEN1 gene mutations in sporadic parathyroid tumors. Hum. Mutat. 16, 445 (2000).
Farnebo, F. et al. Alterations of the MEN1 gene in sporadic parathyroid tumors. J. Clin. Endocrinol. Metab. 83, 2627–2630 (1998).
Cromer, M. K. et al. Identification of somatic mutations in parathyroid tumors using whole-exome sequencing. J. Clin. Endocrinol. Metab. 97, E1774–E1781 (2012).
Cetani, F. et al. Should parafibromin staining replace HRTP2 gene analysis as an additional tool for histologic diagnosis of parathyroid carcinoma? Eur. J. Endocrinol. 156, 547–554 (2007).
Juhlin, C. C. & Hoog, A. Parafibromin as a diagnostic instrument for parathyroid carcinoma-lone ranger or part of the posse? Int. J. Endocrinol. 2010, 324964 (2010).
Costa-Guda, J., Marinoni, I., Molatore, S., Pellegata, N. S. & Arnold, A. Somatic mutation and germline sequence abnormalities in CDKN1B, encoding p27Kip1, in sporadic parathyroid adenomas. J. Clin. Endocrinol. Metab. 96, E701–E706 (2011).
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).
Bjorklund, P., Lindberg, D., Akerstrom, 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 7, 53 (2008).
Cetani, F. et al. β-catenin activation is not involved in sporadic parathyroid carcinomas and adenomas. Endocr. Relat. Cancer 17, 1–6 (2010).
Giusti, L. et al. A proteomic approach to study parathyroid glands. Mol. Biosyst. 7, 687–699 (2011).
Cryns, V. L. et al. Loss of the retinoblastoma tumor-suppressor gene in parathyroid carcinoma. N. Engl. J. Med. 330, 757–761 (1994).
Cetani, F. 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. 89, 5583–5591 (2004).
Shattuck, T. M. et al. Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N. Engl. J. Med. 349, 1722–1729 (2003).
Hahn, M. A. et al. CDC73/HRPT2 CpG island hypermethylation and mutation of 5′-untranslated sequence are uncommon mechanisms of silencing parafibromin in parathyroid tumors. Endocr. Relat. Cancer 17, 273–282 (2010).
Singh Ospina, N., Sebo, T. J., Thompson, G. B., Clarke, B. L. & Young, W. F. Jr. Prevalence of parathyroid carcinoma in 348 patients with multiple endocrine neoplasia type 1 — case report and review of the literature. Clin. Endocrinol. (Oxf.) http://dx.doi.org/10.1111/cen.12714 (2014).
Corbetta, S. et al. Differential expression of microRNAs in human parathyroid carcinomas compared with normal parathyroid tissue. Endocr. Relat. Cancer 17, 135–146 (2010).
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).
Hansen, S., Beck Jensen, J. E., Rasmussen, L., Hauge, E. M. & Brixen, K. Effects on bone geometry, density, and microarchitecture in the distal radius but not the tibia in women with primary hyperparathyroidism: a case–control study using HR-pQCT. J. Bone Miner. Res. 25, 1941–1947 (2010).
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). This paper reports on the use of high-resolution skeletal imaging to detect trabecular bone disease in PHPT.
Romagnoli, E. et al. “Trabecular Bone Score” (TBS): an indirect measure of bone micro-architecture in postmenopausal patients with primary hyperparathyroidism. Bone 53, 154–159 (2013).
Silva, B. C. et al. Trabecular bone score (TBS) — a novel method to evaluate bone microarchitectural texture in patients with primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 98, 1963–1970 (2013).
Khosla, S. et al. Primary hyperparathyroidism and the risk of fracture: a population-based study. J. Bone Miner. Res. 14, 1700–1707 (1999).
Vignali, E. et al. Morphometric vertebral fractures in postmenopausal women with primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 94, 2306–2312 (2009).
Kulak, C. A. et al. Marked improvement in bone mass after parathyroidectomy in osteitis fibrosa cystica. J. Clin. Endocrinol. Metab. 83, 732–735 (1998).
Albright, F. & Reifenstein, E. C. Jr. The Parathyroid Glands and Metabolic Bone Diseases: Selected Studies (Williams & Wilkins, 1948).
Mallette, L. E., Bilezikian, J. P., Heath, D. A. & Aurbach, G. D. Primary hyperparathyroidism: clinical and biochemical features. Medicine (Baltimore) 53, 127–146 (1974).
Starup-Linde, J., Waldhauer, E., Rolighed, L., Mosekilde, L. & Vestergaard, P. Renal stones and calcifications in patients with primary hyperparathyroidism: associations with biochemical variables. Eur. J. Endocrinol. 166, 1093–1100 (2012).
Cassibba, S. et al. Silent renal stones in primary hyperparathyroidism: prevalence and clinical features. Endocr. Pract. 20, 1137–1142 (2014).
Cipriani, C. et al. Prevalence of kidney stones and vertebral fractures in primary hyperparathyroidism using imaging technology. J. Clin. Endocrinol. Metab. 100, 1309–1315 (2015). This paper re-evaluates the presence of kidney stones in PHPT.
Patten, B. M. et al. Neuromuscular disease in primary hyperparathyroidism. Ann. Intern. Med. 80, 182–193 (1974).
Turken, S. A. et al. Neuromuscular involvement in mild, asymptomatic primary hyperparathyroidism. Am. J. Med. 87, 553–557 (1989).
Diniz, E. T. et al. Primary hyperparathyroidism is associated with subclinical peripheral neural alterations. Endocr. Pract. 19, 219–225 (2013).
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).
Linos, D. A., van Heerdan, J. A., Abboud, C. F. & Edis, A. J. Primary hyperparathyroidism and peptic ulcer disease. Arch. Surg. 113, 384–386 (1978).
Bess, M. A., Edis, A. J. & van Heerden, J. A. Hyperparathyroidism and pancreatitis. Chance or a causal association? JAMA 243, 246–247 (1980).
Vaidya, A., Curhan, G. C., Paik, J. M., Kronenberg, H. & Taylor, E. N. Hypertension, antihypertensive medications, and risk of incident primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 100, 2396–2404 (2015).
Walker, M. D. et al. Cardiac structure and diastolic function in mild primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 95, 2172–2179 (2010).
Iwata, S. et al. Aortic valve calcification in mild primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 97, 132–137 (2012).
Eastell, R. et al. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J. Clin. Endocrinol. Metab. 99, 3570–3579 (2014). Conference proceedings from the Fourth International Workshop on the Management of Asymptomatic PHPT.
Rubin, M. R. et al. An N-terminal molecular form of parathyroid hormone (PTH) distinct from hPTH(1–84) is overproduced in parathyroid carcinoma. Clin. Chem. 53, 1470–1476 (2007).
Caron, P. et al. Nontruncated amino-terminal parathyroid hormone overproduction in two patients with parathyroid carcinoma: a possible link to HRPT2 gene inactivation. Clin. Endocrinol. (Oxf.) 74, 694–698 (2011).
Bandeira, F. & Cassibba, S. Hyperparathyroidism and bone health. Curr. Rheumatol. Rep. 17, 48 (2015).
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). Conference proceedings from the Fourth International Workshop on the Management of Asymptomatic PHPT.
Ketteler, M. et al. Revisiting KDIGO clinical practice guideline on chronic kidney disease–mineral and bone disorder: a commentary from a Kidney Disease: Improving Global Outcomes controversies conference. Kidney Int. 87, 502–528 (2015).
Bandeira, F. et al. Prevalence of cortical osteoporosis in mild and severe primary hyperparathyroidism and its relationship with bone markers and vitamin D status. J. Clin. Densitom. 12, 195–199 (2009).
Udelsman, R., Lin, Z. & Donovan, P. The superiority of minimally invasive parathyroidectomy based on 1650 consecutive patients with primary hyperparathyroidism. Ann. Surg. 253, 585–591 (2011).
Van Udelsman, B. & Udelsman, R. Surgery in primary hyperparathyroidism: extensive personal experience. J. Clin. Densitom. 16, 54–59 (2013).
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).
Vestergaard, P. & Mosekilde, L. Parathyroid surgery is associated with a decreased risk of hip and upper arm fractures in primary hyperparathyroidism: a controlled cohort study. J. Intern. Med. 255, 108–114 (2004).
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).
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).
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).
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). This is a RCT of parathyroidectomy on QOL in individuals with PHPT.
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).
Udelsman, R. et al. The surgical management of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J. Clin. Endocrinol. Metab. 99, 3595–3606 (2014).
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).
Ross, A. C., Taylor, C. L., Yaktine, A. L. & Del Valle, H. B. (eds) Dietary Reference Intakes for Calcium and Vitamin D (The National Academies Press, 2011).
Rolighed, L. et al. Vitamin D treatment in primary hyperparathyroidism: a randomized placebo controlled trial. J. Clin. Endocrinol. Metab. 99, 1072–1080 (2014).
European Medicines Agency. Mimpara. EMA http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000570/WC500028901.pdf (2009).
Food and Drug Administration. Sensipar. FDA http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021688s017lbl.pdf (2011).
Peacock, M. et al. Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 90, 135–141 (2005).
Peacock, M. et al. Cinacalcet treatment of primary hyperparathyroidism: biochemical and bone densitometric outcomes in a five-year study. J. Clin. Endocrinol. Metab. 94, 4860–4867 (2009).
Iglesias, P. et al. Acute and one-year effects of cinacalcet in patients with persistent primary hyperparathyroidism after unsuccessful parathyroidectomy. Am. J. Med. Sci. 335, 111–114 (2008).
Cetani, F. et al. Cinacalcet efficacy in patients with moderately severe primary hyperparathyroidism according to the European Medicine Agency prescription labeling. J. Endocrinol. Invest. 35, 655–660 (2012).
Luque-Fernandez, I., Garcia-Martin, A. & Luque-Pazos, A. Experience with cinacalcet in primary hyperparathyroidism: results after 1 year of treatment. Ther. Adv. Endocrinol. Metab. 4, 77–81 (2013).
Khan, A. A. et al. Alendronate in primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial. J. Clin. Endocrinol. Metab. 89, 3319–3325 (2004).
Khan, A. A. et al. Alendronate therapy in men with primary hyperparathyroidism. Endocr. Pract. 15, 705–713 (2009).
Marcus, R., Madvig, P., Crim, M., Pont, A. & Kosek, J. Conjugated estrogens in the treatment of postmenopausal women with hyperparathyroidism. Ann. Intern. Med. 100, 633–640 (1984).
Faggiano, A. et al. Cinacalcet hydrochloride in combination with alendronate normalizes hypercalcemia and improves bone mineral density in patients with primary hyperparathyroidism. Endocrine 39, 283–287 (2011).
Keutgen, X. M. et al. Calcimimetics versus parathyroidectomy for treatment of primary hyperparathyroidism: retrospective chart analysis of a prospective database. Ann. Surg. 255, 981–985 (2012).
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).
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).
Cesareo, R. et al. Effects of alendronate and vitamin D in patients with normocalcemic primary hyperparathyroidism. Osteoporos. Int. 26, 1295–1302 (2015).
Aberg, V. et al. Health-related quality of life after successful surgery for primary hyperparathyroidism: no additive effect from vitamin D supplementation: results of a double-blind randomized study. Eur. J. Endocrinol. 172, 181–187 (2015).
Amstrup, A. K., Rejnmark, L. & Mosekilde, L. Patients with surgically cured primary hyperparathyroidism have a reduced quality of life compared with population-based healthy sex-, age-, and season-matched controls. Eur. J. Endocrinol. 165, 753–760 (2011).
Babinska, D. et al. Evaluation of selected cognitive functions before and after surgery for primary hyperparathyroidism. Langenbecks Arch. Surg. 397, 825–831 (2012).
Benge, J. F. et al. Cognitive and affective sequelae of primary hyperparathyroidism and early response to parathyroidectomy. J. Int. Neuropsychol. Soc. 15, 1002–1011 (2009).
Blanchard, C. et al. Quality of life is modestly improved in older patients with mild primary hyperparathyroidism postoperatively: results of a prospective multicenter study. Ann. Surg. Oncol. 21, 3534–3540 (2014).
Espiritu, R. P. et al. Depression in primary hyperparathyroidism: prevalence and benefit of surgery. J. Clin. Endocrinol. Metab. 96, E1737–E1745 (2011).
Hermsen, A. et al. Perioperative changes in cortical excitability, mood, and quality of life in patients with primary hyperparathyroidism: a pilot study using transcranial magnetic stimulation. Eur. J. Endocrinol. 170, 201–209 (2014).
Kahal, H. et al. The effect of parathyroidectomy on neuropsychological symptoms and biochemical parameters in patients with asymptomatic primary hyperparathyroidism. Clin. Endocrinol. (Oxf.) 76, 196–200 (2012).
Roman, S. A. et al. The effects of serum calcium and parathyroid hormone changes on psychological and cognitive function in patients undergoing parathyroidectomy for primary hyperparathyroidism. Ann. Surg. 253, 131–137 (2011).
Ryhanen, E. M. et al. Health-related quality of life is impaired in primary hyperparathyroidism and significantly improves after surgery: a prospective study using the 15D instrument. Endocr. Connect. 4, 179–186 (2015).
Tsukahara, K., Sugitani, I., Fujimoto, Y. & Kawabata, K. Surgery did not improve the subjective neuropsychological symptoms of patients with incidentally detected mild primary hyperparathyroidism. Eur. Arch. Otorhinolaryngol. 265, 565–569 (2008).
Walker, M. D. et al. Neuropsychological features in primary hyperparathyroidism: a prospective study. J. Clin. Endocrinol. Metab. 94, 1951–1958 (2009). This is a detailed study of neurocognitive features of PHPT.
Pasieka, J. L. et al. Patient-based surgical outcome tool demonstrating alleviation of symptoms following parathyroidectomy in patients with primary hyperparathyroidism. World J. Surg. 26, 942–949 (2002).
Webb, S. M. et al. Development of a new tool for assessing health-related quality of life in patients with primary hyperparathyroidism. Health Qual. Life Outcomes 11, 97 (2013).
Perrier, N. D. et al. Prospective, randomized, controlled trial of parathyroidectomy versus observation in patients with “asymptomatic” primary hyperparathyroidism. Surgery 146, 1116–1122 (2009).
Rolighed, L. et al. No beneficial effects of vitamin D supplementation on muscle function or quality of life in primary hyperparathyroidism: results from a randomized controlled trial. Eur. J. Endocrinol. 172, 609–617 (2015).
Bilezikian, J. P. et al. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J. Clin. Endocrinol. Metab. 87, 5353–5361 (2002).
Morrissey, J. J. & Cohn, D. V. Regulation of secretion of parathormone and secretory protein-I from separate intracellular pools by calcium, dibutyryl cyclic AMP, and (1)-isoproterenol. J. Cell Biol. 82, 93–102 (1979).
Acknowledgements
This work was supported, in part, by the NIH grant DK 32333.
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Introduction (J.P.B.); Epidemiology (J.-M.L. and A.A.K.); Mechanisms/pathophysiology (C.M.); Diagnosis, screening and prevention (F.B.); Management (J.P.B. and N.E.C.); Quality of life (N.E.C.); Outlook (J.P.B.); Overview of Primer (J.P.B.).
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J.P.B. is a consultant for Merck, Amgen, Shire Pharmaceuticals and Radius, and receives research support from Shire Pharmaceuticals. A.A.K. receives research grants from Amgen and Shire Pharmaceuticals. All other authors declare no competing interests.
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Bilezikian, J., Cusano, N., Khan, A. et al. Primary hyperparathyroidism. Nat Rev Dis Primers 2, 16033 (2016). https://doi.org/10.1038/nrdp.2016.33
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DOI: https://doi.org/10.1038/nrdp.2016.33
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