Download PDF
Horm Metab Res 2016; 48(03): 163-168
DOI: 10.1055/s-0035-1559723
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Clinical Expression of Calcium Sensing Receptor Polymorphism (A986S) in Normocalcemic and Asymptomatic Hyperparathyroidism

G. Díaz-Soto
1   Endocrinology and Nutrition Service, University Hospital of Valladolid, Centro de Investigación de Endocrinología y Nutrición-University of Valladolid, Valladolid, Spain
,
E. Romero
1   Endocrinology and Nutrition Service, University Hospital of Valladolid, Centro de Investigación de Endocrinología y Nutrición-University of Valladolid, Valladolid, Spain
,
J. L.P. Castrillón
2   Internal Medicine Service, Centro de Investigación de Endocrinología y Nutrición, Hospital Universitario Rio Hortega, Valladolid, Spain
,
O. I. Jauregui
1   Endocrinology and Nutrition Service, University Hospital of Valladolid, Centro de Investigación de Endocrinología y Nutrición-University of Valladolid, Valladolid, Spain
,
D. de Luis Román
1   Endocrinology and Nutrition Service, University Hospital of Valladolid, Centro de Investigación de Endocrinología y Nutrición-University of Valladolid, Valladolid, Spain
› Author Affiliations
Further Information

Publication History

received 10 April 2015

accepted 27 July 2015

Publication Date:
02 September 2015 (online)

Also available at
   Permissions and Reprints

Abstract

Normocalcemic and asymptomatic hyperparathyroidism diagnosis are becoming more common. However, their pathophysiology is incompletely known. The aim of the present study was to evaluate the clinical effect of calcium-sensing receptor polymorphism (A986S) in normocalcemic and asymtomatic HPT. Prospective study conducted with 61 consecutive normocalcemic and asymptomatic HPT patients was followed up during a minimum period of 1 year. Secondary causes of hyperparathyroidism were ruled out. Calcium and phosphorus metabolism parameters were evaluated in at least 2 determinations during follow-up to classify as normocalcemic or asymptomatic hyperparathyroidism. Bone mineral density and A986S polymorphism genotype were also analyzed. Thiry-eight patients (62.3%) had the genotype A986A, and 23 (36.7%) patients had A986S (20 patients, 32.8%) or S986S (3 patients, 4.9%). Age, sex, and genotype distributions were comparable in both normocalcemic and asymptomatic hyperparathyroidism. In normocalcemic patients, S allele genotype was associated to statistically significant higher level of intact PTH: 92.0 (SD 18.5) vs. 110.6 (SD 24.4) pg/ml, p<0.05; and remained significant after adjustment by multiple linear regression. In asymptomatic hyperparathyroidism, A986A genotype resulted in a statistically significant higher level of intact PTH, alkaline phosphatase and procollagen amino-terminal propeptide; but only serum calcium remained as an independent predictor of serum intact PTH levels after a multiple linear regression. Bone mineral densitometry between genotypes did not show statistically significant differences. A986S polymorphism of CaSR is an independent predictor of PTH level in normocalcemic hyperparathyroidism patients, but not in asymptomatic hyperparathyroidism. More studies are needed to evaluate the effect of other polymorphisms in normocalcemic and asymptomatic hyperparathyroidism.

Key words

parathyroid hormone - calcium sensing receptor - calcium - hyperparathyroidism
 

  • References

  • 1 Díaz-Soto G, Julián MT, Puig-Domingo M. Normocalcemic primary hyperparathyroidism: a newly emerging disease needing therapeutic intervention. Hormones (Athens) 2012; 11: 390-396
    CrossrefPubMedGoogle Scholar
  • 2 Bilezikian JP, Khan AA, Potts JT. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab 2009; 94: 335-339
    CrossrefPubMedGoogle Scholar
  • 3 Cusano NE, Silverberg SJ, Bilezikian JP. Normocalcemic primary hyperparathyroidism. J Clin Densitom Off J Int Soc Clin Densitom 2013; 16: 33-39
    PubMedGoogle Scholar
  • 4 Eastell R, Arnold A, Brandi ML, Brown EM, D’Amour P, Hanley DA, Rao DS, Rubin MR, Goltzman D, Silverberg SJ, Marx SJ, Peacock M, Mosekilde L, Bouillon R, Lewiecki EM. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab 2009; 94: 340-350
    CrossrefPubMedGoogle Scholar
  • 5 Silverberg SJ, Bilezikian JP. “Incipient” primary hyperparathyroidism: a “forme fruste” of an old disease. J Clin Endocrinol Metab 2003; 88: 5348-5352
    CrossrefPubMedGoogle Scholar
  • 6 Tordjman KM, Greenman Y, Osher E, Shenkerman G, Stern N. Characterization of normocalcemic primary hyperparathyroidism. Am J Med 2004; 117: 861-863
    CrossrefPubMedGoogle Scholar
  • 7 Lowe H, McMahon DJ, Rubin MR, Bilezikian JP, Silverberg SJ. Normocalcemic primary hyperparathyroidism: further characterization of a new clinical phenotype. J Clin Endocrinol Metab 2007; 92: 3001-3005
    CrossrefPubMedGoogle Scholar
  • 8 García-Martín A, Reyes-García R, Muñoz-Torres M. Normocalcemic primary hyperparathyroidism: one-year follow-up in one hundred postmenopausal women. Endocrine 2012; 42: 764-766
    CrossrefPubMedGoogle Scholar
  • 9 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 2003; 88: 4641-4648
    CrossrefPubMedGoogle Scholar
  • 10 Cole DE, Peltekova VD, Rubin LA, Hawker GA, Vieth R, Liew CC, Hwang DM, Evrovski J, Hendy GN. A986S polymorphism of the calcium-sensing receptor and circulating calcium concentrations. Lancet 1999; 353: 112-115
    CrossrefPubMedGoogle Scholar
  • 11 Cole DE, Vieth R, Trang HM, Wong BY, Hendy GN, Rubin LA. Association between total serum calcium and the A986S polymorphism of the calcium-sensing receptor gene. Mol Genet Metab 2001; 72: 168-174
    CrossrefPubMedGoogle Scholar
  • 12 Heath H, Odelberg S, Jackson CE, Teh BT, Hayward N, Larsson C, Buist NR, Krapcho KJ, Hung BC, Capuano IV, Garrett JE, Leppert MF. Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains. J Clin Endocrinol Metab 1996; 81: 1312-1317
    PubMedGoogle Scholar
  • 13 O’Seaghdha CM, Yang Q, Glazer NL, Leak TS, Dehghan A, Smith AV, Kao WHL, Lohman K, Hwang S-J, Johnson AD, Hofman A, Uitterlinden AG, Chen Y-DI, Brown EM, Siscovick DS, Harris TB, Psaty BM, Coresh J, Gudnason V, Witteman JC, Liu YM, Kestenbaum BR, Fox CS, Köttgen A. Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels. Hum Mol Genet 2010; 19: 4296-4303
    CrossrefPubMedGoogle Scholar
  • 14 Bilezikian JP, Brandi ML, Eastell R, Silverberg SJ, Udelsman R, Marcocci C, Potts JT. Guidelines for the Management of Asymptomatic Primary Hyperparathyroidism: Summary Statement from the Fourth International Workshop. J Clin Endocrinol Metab 2014; 99: 3561-3569
    CrossrefPubMedGoogle Scholar
  • 15 Eastell R, Brandi ML, Costa AG, D’Amour P, Shoback DM, Thakker RV. Diagnosis of Asymptomatic Primary Hyperparathyroidism: Proceedings of the Fourth International Workshop. J Clin Endocrinol Metab 2014; 99: 3570-3579
    CrossrefPubMedGoogle Scholar
  • 16 Bilezikian JP, Silverberg SJ. Normocalcemic primary hyperparathyroidism. Arq Bras Endocrinol Metabol 2010; 54: 106-109
    CrossrefPubMedGoogle Scholar
  • 17 Hernández JL, Olmos JM, Pariente E, Nan D, Martínez J, Llorca J, Valero C, Obregón E, González-Macías J. Influence of vitamin D status on vertebral fractures, bone mineral density, and bone turnover markers in normocalcemic postmenopausal women with high parathyroid hormone levels. J Clin Endocrinol Metab 2013; 98: 1711-1717
    CrossrefPubMedGoogle Scholar
  • 18 Koumakis E, Souberbielle J-C, Sarfati E, Meunier M, Maury E, Gallimard E, Borderie D, Kahan A, Cormier C. Bone Mineral Density Evolution After Successful Parathyroidectomy in Patients With Normocalcemic Primary Hyperparathyroidism. J Clin Endocrinol Metab 2013; 98: 3213-3220
    CrossrefPubMedGoogle Scholar
  • 19 Brown EM, Hebert SC. Calcium-receptor-regulated parathyroid and renal function. Bone 1997; 20: 303-309
    CrossrefPubMedGoogle Scholar
  • 20 He Y, Han L, Li W, Shu X, Zhao C, He Y, Bi M, Li Y, Sun C. Effects of the calcium-sensing receptor A986S polymorphism on serum calcium and parathyroid hormone levels in healthy individuals: a meta-analysis. Gene 2012; 491: 110-115
    CrossrefPubMedGoogle Scholar
  • 21 Miedlich S, Lamesch P, Mueller A, Paschke R. Frequency of the calcium-sensing receptor variant A986S in patients with primary hyperparathyroidism. Eur J Endocrinol 2001; 145: 421-427
    CrossrefPubMedGoogle Scholar
  • 22 Cetani F, Borsari S, Vignali E, Pardi E, Picone A, Cianferotti L, Rossi G, Miccoli P, Pinchera A, Marcocci C. Calcium-sensing receptor gene polymorphisms in primary hyperparathyroidism. J Endocrinol Invest 25: 614-619
    PubMedGoogle Scholar
  • 23 Corbetta S, Eller-Vainicher C, Filopanti M, Saeli P, Vezzoli G, Arcidiacono T, Loli P, Syren ML, Soldati L, Beck-Peccoz P, Spada A. R990G polymorphism of the calcium-sensing receptor and renal calcium excretion in patients with primary hyperparathyroidism. Eur J Endocrinol 2006; 155: 687-692
    CrossrefPubMedGoogle Scholar
  • 24 Nordenström E, Katzman P, Bergenfelz A. Biochemical diagnosis of primary hyperparathyroidism: Analysis of the sensitivity of total and ionized calcium in combination with PTH. Clin Biochem 2011; 44: 849-852
    CrossrefPubMedGoogle Scholar
  • 25 Kanzawa M, Sugimoto T, Kobayashi T, Kobayashi A, Chihara K. Parathyroid hormone gene polymorphisms in primary hyperparathyroidism. Clin Endocrinol (Oxf) 1999; 50: 583-588
    CrossrefPubMedGoogle Scholar