Horm Metab Res 2021; 53(06): 355-363
DOI: 10.1055/a-1487-6449
Review

Calcitonin Stimulation Tests: Rationale, Technical Issues and Side Effects: A Review

1   “C.I. Parhon” National Institute of Endocrinology, Bucharest, Romania
,
Cristina Alexandra Olariu
1   “C.I. Parhon” National Institute of Endocrinology, Bucharest, Romania
,
Gabriel Moldoveanu
1   “C.I. Parhon” National Institute of Endocrinology, Bucharest, Romania
2   “Carol Davila“ University of Medicine and Pharmacy, Bucharest, Romania
,
Cristina Corneci
1   “C.I. Parhon” National Institute of Endocrinology, Bucharest, Romania
,
Corin Badiu
1   “C.I. Parhon” National Institute of Endocrinology, Bucharest, Romania
2   “Carol Davila“ University of Medicine and Pharmacy, Bucharest, Romania
› Author Affiliations

Abstract

Calcitonin (CT) stimulation tests have great value and could help to: differentiate thyroid causes of elevated CT apart from non-thyroid sources, determine whether the patients with slightly elevated basal CT could/could not be candidates for surgery, and indicate the right moment for prophylactic thyroidectomy in children with MEN syndromes when with normal basal CT. This triggered the requests for development of CT stimulation tests, taking into consideration their safety and aimed us to write a systematic review of literature regarding the rationale, technical issues, and side effects of CT stimulating tests used for diagnosis of MTC. After a thorough review of the literature, we classified the reported side effects by severity, as defined by United States Food and Drug Administration. A statistical analysis was performed using IBM SPSS Statistics version 20. Various side effects were noticed during stimulation tests that differ by intensity, duration and severity, depending on types of substances and protocols used. The side effects after pentagastrin test were significantly more severe than those reported after calcium stimulation test (p=0.0396). There are also significant gender-specific differences in side effects induced by stimulation tests. In conclusion, we recommend performing Ca CT stimulation test when needed, considering preventive evaluation of some clinical, instrumental, and biochemical aspects of each patient. Precise instructions should be followed before a stimulation test and furthermore continuous cardiac monitoring is essential during and after the test to minimize the possibility of a serious event.



Publication History

Received: 29 December 2020

Accepted after revision: 14 April 2021

Article published online:
21 June 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Medullary thyroid cancer: Surgical treatment and prognosis – UpToDate n.d https://www.uptodate.com/contents/medullary-thyroid- cancer-surgical-treatment-and-prognosis?search = Medullary thyroid cancer: Treatment and prognosis.&source = search_ result&selectedTitle = 1~88&usage_type = default&display_rank = 1 (accessed October 19 2020)
  • 2 Toledo SPA, Lourenço DM, Santos MA. et al. Hypercalcitoninemia is not pathognomonic of medullary thyroid carcinoma. Clinics 2009; 64: 699-706
  • 3 Papadakis G, Keramidas I, Triantafillou E. et al. Association of basal and calcium-stimulated calcitonin levels with pathological findings after total thyroidectomy. Anticancer Res 2015; 35: 4251-4258
  • 4 Colombo C, Verga U, Mian C. et al. Comparison of calcium and pentagastrin tests for the diagnosis and follow-up of medullary thyroid cancer. J Clin Endocrinol Metab 2012; 97: 905-913
  • 5 Niederle MB, Scheuba C, Gessl A. et al. Calcium-stimulated calcitonin - The “new standard” in the diagnosis of thyroid C-cell disease-clinically relevant gender-specific cut-off levels for an “old test.”. Biochem Med (Zagreb) 2018; 28: 030710
  • 6 Niederle MB, Scheuba C, Riss P. et al. Early Diagnosis of Medullary Thyroid Cancer: Are Calcitonin Stimulation Tests Still Indicated in the Era of Highly Sensitive Calcitonin Immunoassays?. Thyroid 2020; 30: 974-984
  • 7 Fugazzola L, Di Stefano M, Censi S. et al. Basal and stimulated calcitonin for the diagnosis of medullary thyroid cancer: updated thresholds and safety assessment. J Endocrinol Invest 2020; 44: 587-597
  • 8 Costante G, Meringolo D, Durante C. et al. Predictive value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab 2007; 92: 450-455
  • 9 Wells SA, Asa SL, Dralle H. et al. Revised American thyroid association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015; 25: 567-610
  • 10 Russo M, Scollo C, Padova G. et al. Cardiac arrest after intravenous calcium administration for calcitonin stimulation test. Thyroid 2014; 24: 606-607
  • 11 Niederle B, Sebag F, Brauckhoff M. Timing and extent of thyroid surgery for gene carriers of hereditary C cell disease - A consensus statement of the European Society of Endocrine Surgeons (ESES). Langenbeck’s Arch Surg 2014; 399: 185-197
  • 12 Moher D, Liberati A, Tetzlaff J. et al. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. BMJ 2009; 339: 332-336
  • 13 CFR - Code of Federal Regulations Title 21 n.d https://www. accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr = 312.32 accessed October 19 2020;
  • 14 Hofer AM, Brown EM. Extracellular calcium sensing and signalling. Nat Rev Mol Cell Biol 2003; 4: 530-538
  • 15 Garrett JE, Tamir H, Kifor O. et al. Calcitonin-secreting cells of the thyroid express an extracellular calcium receptor gene. Endocrinology 1995; 136: 5202-5211
  • 16 Gardner DG, Shoback DM. Greenspan’s Basic & Clinical Endocrinology. Ninth Edition; New York: McGraw-Hill; 2011
  • 17 Freichel M, Zink-Lorenz A, Holloschi A. et al. Expression of a calcium-sensing receptor in a human medullary thyroid carcinoma cell line and its contribution to calcitonin secretion. Endocrinology 1996; 137: 3842-3848
  • 18 Ceglia L, Harris SS, Rasmussen HM. et al. Activation of the calcium sensing receptor stimulates gastrin and gastric acid secretion in healthy participants. Osteoporos Int 2009; 20: 71-78
  • 19 Ubl P, Gincu T, Keilani M. et al. Comparison of side effects of pentagastrin test and calcium stimulation test in patients with increased basal calcitonin concentration: The gender-specific differences. Endocrine 2014; 46: 549-553
  • 20 Pentagastrin | DrugBank Online n.d https://go.drugbank.com/drugs/ (accessed February 22, 2021)
  • 21 Reubi JC, Schaer JC, Waser B. Cholecystokinin(CCK)-A and CCK-B/gastrin receptors in human tumors. Cancer Res 1997; 57: 1377-1386
  • 22 Thiem U, Marculescu R, Cejka D. et al. Low-dose calcium versus pentagastrin for stimulation of calcitonin in chronic hemodialysis patients: A pilot study. J Clin Endocrinol Metab 2014; 99: 4704-4711
  • 23 Farndon JR, Lewis KR, Dale JK. et al. Histamine and calcitonin release from medullary thyroid carcinoma. Cancer 1983; 51: 1221-1225
  • 24 Wells SA, Baylin SB, Linehan WM. et al. Provocative agents and the diagnosis of medullary carcinoma of the thyroid gland. Ann Surg 1978; 188: 139-141
  • 25 Emmertsen K, Nielsen HE, Mosekilde L. et al. Pentagastrin, calcium and whisky stimulated serum calcitonin in medullary carcinoma of the thyroid. Acta Oncol (Madr) 1980; 19: 85-89
  • 26 Gharib H, Kao PC, Heath H. Determination of Silica-Purified Plasma Calcitonin for the Detection and Management of Medullary Thyroid Carcinoma: Comparison of Two Provocative Tests. Mayo Clin Proc 1987; 62: 373-378
  • 27 McLean GW, Rabin D, Moore L. et al. Evaluation of provocative tests in suspected medullary carcinoma of the thyroid: Heterogeneity of calcitonin responses to calcium and pentagastrin. Metabolism 1984; 33: 790-796
  • 28 Hennessy JF, Wells SA, Ontjes DA. et al. A comparison of pentagastrin injection and calcium infusion as provocative agents for the detection of medullary carcinoma of the thyroid. J Clin Endocrinol Metab 1974; 39: 487-495
  • 29 Graze K, Spiler IJ, Tashjian AH. et al. Natural History of Familial Medullary Thyroid Carcinoma: Effect of a Program for Early Diagnosis. N Engl J Med 1978; 299: 980-985
  • 30 Vainas I, Marthopoulos A, Chrisoulidou A. et al. Calcitonin stimulation tests for the early diagnosis and follow-up of patients with C cell disease: A descriptive analysis. Hippokratia 2013; 17: 246-251
  • 31 Doyle P, Düren C, Nerlich K. et al. Potency and tolerance of calcitonin stimulation with high-dose calcium versus pentagastrin in normal adults. J Clin Endocrinol Metab 2009; 94: 2970-2974
  • 32 Telenius-Berg M, Almqvist S, Berg B. et al. Screening for medullary carcinoma of the thyroid in families with Sipple’s syndrome: evaluation of new stimulation tests. Eur J Clin Invest 1977; 7: 7-16
  • 33 Rude RK, Singer FR. Comparison of serum calcitonin levels after a 1-minute calcium injection and after pentagastrin injection in the diagnosis of medullary thyroid carcinoma. J Clin Endocrinol Metab 1977; 44: 980-983
  • 34 Simpson WJ, Carruthers JS, Malkin D. Results of a screening program for c-cell disease (medullary thyroid cancer and c-cell hyperplasia). Cancer 1990; 65: 1570-1576
  • 35 Cohen SL, Grahame-Smith D, Macintyre I. et al. Alcohol-stimulated calcitonin release in medullary carcinoma of the thyroid. Lancet 1973; 302: 1172-1174
  • 36 Mian C, Perrino M, Colombo C. et al. Refining calcium test for the diagnosis of medullary thyroid cancer: Cutoffs, procedures, and safety. J Clin Endocrinol Metab 2014; 99: 1656-1664
  • 37 Drucker D. Atrial Fibrillation after Administration of Calcium and Pentagastrin. New Engl J Med 1981; 304: 1427-1428
  • 38 Morimoto S, Onishi T, Okada Y. et al. Comparison of Human Calcitonin Secretion After Calcium Infusion in Young Normal and in Elderly Subjects. Endocrinol Jpn 1979; 26: 207-211
  • 39 Aylward M, Bourke JB. A possible reaction to pentagastrin. Lancet 1969; 2: 267
  • 40 Barrowman JA, Herxheimer A, Kits TP. Unwanted effects of pentagastrin. Clin Pharmacol Ther 1970; 11: 862-868
  • 41 Ewers HR, Brouwers HP, Merguet P. et al. [Side effects after stimulation of gastric secretion with pentagastrin (author’s transl)]. Med Klin 1976; 71: 19-23
  • 42 McCloy RF. Acute reaction to Pentagastrin. Lancet 1977; 1: 548
  • 43 Acar O, Schwizer W, Hauri D. Demonstration of acid secretion in the gastric pouch through the pentagastrin stimulation test. Urol Int 2003; 70: 178-180
  • 44 Ahlman H, Dahlström A, Grönstad K. et al. The pentagastrin test in the diagnosis of the carcinoid syndrome. J Cardiovasc Pharmacol 1985; 7: S86-S88
  • 45 Brunt LM, Mazoujian G, O’Dorisio TM. et al. Stimulation of vasoactive intestinal peptide and neurotensin secretion by pentagastrin in a patient with VIPoma syndrome. Surgery 1994; 115: 362-369
  • 46 Radu D, Åhlin A, Svanborg P. et al. Pentagastrin test for anxiety - Psychophysiology and personality. Psychopharmacology (Berl) 2003; 166: 139-145
  • 47 Somers G, Pipeleers-Marichal M, Gepts W. et al. A case of duodenal somatostatinoma: diagnostic usefulness of calcium--pentagastrin test. Gastroenterology 1983; 85: 1192-1198
  • 48 Budmiger H, Bühler H, Häcki W. et al. Comparative diagnostic value of the calcium-pentagastrin test versus the tolbutamide test in a patient with a somatostatinoma. Gastroenterology 1987; 92: 800-804
  • 49 Rosario PW, Calsolari MR. Basal Serum Calcitonin, After Calcium Stimulation, and in the Needle Washout of Patients with Thyroid Nodules and Mild or Moderate Basal Hypercalcitoninemia. Horm Metab Res 2017; 49: 129-134
  • 50 Parthemore JG, Deftos LJ. A short calcium (Ca) infusion in the diagnosis of medullary thyroid carcinoma (MTC). J Clin Endocrinol Metab 1974; 22: 108-111
  • 51 Bevilacqua M, Dominguez LJ, Righini V. et al. Dissimilar PTH, gastrin, and calcitonin responses to oral calcium and peptones in hypocalciuric hypercalcemia, primary hyperparathyroidism, and normal subjects: A useful tool for differential diagnosis. J Bone Miner Res 2006; 21: 406-412
  • 52 Wells SA, Ontjes DA, Cooper CW. et al. The early diagnosis of medullary carcinoma of the thyroid gland in patients with multiple endocrine neoplasia type II. Ann Surg 1975; 182: 362-370
  • 53 Verdy M, Cholette JP, Cantin J. et al. Calcium infusion and pentagastrin injection in diagnosis of medullary thyroid carcinoma. Can Med Assoc J 1978; 119: 29-35
  • 54 van Lathem JJM, Vermaak WJH, Kuyl JM. et al. Experience with a provocative test of calcitonin release as a prospective screening for preclinical medullary thyroid carcinoma in men type 2A family members. J Clin Lab Anal 1992; 6: 384-390