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Calcitonin measurement and immunoassay interference: a case report and literature review

  • Simona Censi EMAIL logo , Elisabetta Cavedon , Sara Watutantrige Fernando , Susi Barollo , Loris Bertazza , Laura Zambonin , Martina Zaninotto , Diego Faggian , Mario Plebani ORCID logo and Caterina Mian
Published/Copyright: May 11, 2016

Abstract

Calcitonin (CT) is currently the most sensitive serological marker of C-cell disease [medullary thyroid carcinoma (MTC) and C-cell hyperplasia]. Starting with a report on a case that occurred at our institution, this review focuses on trying to explain the reasons behind the poor specificity and sensitivity of the various CT immunoassays. A 15-year-old patient was referred to our institution in May 2014 for moderately elevated CT levels. Thyroid ultrasonography (US) documented a colloidal goiter. Secondary causes of the hypercalcitoninemia (hyperCT) were ruled out. The mismatch between the clinical picture and the laboratory results prompted us to search for other reasons for the patient’s high CT levels, so we applied the heterophilic blocking tube (HBT) procedure to the patient’s sera before the CT assay. Using this pretreatment step, his serum CT concentration dropped to <1 ng/L, as measured at the same laboratory. Measuring plasma CT has an important role in screening for C-cell disease, but moderately elevated serum CT levels need to be placed in their clinical context, bearing in mind all the secondary causes of C-cell hyperplasia and the possibility of laboratory interference, before exposing patients to the risks and costs of further tests.


Corresponding author: Dr. Simona Censi, Endocrinology Unit, Department of Medical and Surgical Sciences, University of Padua, Via Ospedale n.105-35128 Padova, Italy, Tel.: (+39)049.8213003-04-00, Fax: (+39)049.657391

Acknowledgments:

We wish to thank Flaviano Favaro for his excellent technical assistance.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Becker KL, Nylén ES, White JC, Müller B, Snider RH Jr. Clinical review 167: procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: a journey from calcitonin back to its precursors. J Clin Endocrinol Metab 2004;89:1512–25.10.1210/jc.2002-021444Search in Google Scholar PubMed

2. Sturgeon CM, Viljoen A. Analytical error and interference in immunoassay: minimizing risk. Ann Clin Biochem 2011;48:418–32.10.1258/acb.2011.011073Search in Google Scholar PubMed

3. Mian C, Pennelli G, Barollo S, Cavedon E, Nacamulli D, Vianello F, et al. Combined RET and Ki-67 assessment in sporadic medullary thyroid carcinoma: a useful tool for patient risk stratification. Eur J Endocrinol 2011;164:9716.10.1530/EJE-11-0079Search in Google Scholar PubMed

4. Mian C, Perrino M, Colombo C, Cavedon E, Pennelli G, Ferrero S, et al. Refining calcium test for the diagnosis of medullary thyroid cancer: cutoffs, procedures, and safety. J Clin Endocrinol Metab 2014;99:1656–64.10.1210/jc.2013-4088Search in Google Scholar PubMed

5. Englebach M, Görges R, Forst T, Pfützner A, Dawood R, Heerdt S. Improved diagnostic methods in the follow-up of medullary thyroid carcinoma by highly specific calcitonin measurements. J Clin Endocinol Metab 2000;85:1890–4.10.1210/jcem.85.5.6601Search in Google Scholar

6. Berson SA, Yalow RS. General principles of radioimmunoassay. 1968. Clin Chim Acta 2006;369:125–43.10.1016/j.cca.2006.05.002Search in Google Scholar PubMed

7. Uwaifo GI, Remaley AT, Stene M, Reynolds JC, Yen PM, Snider RH, et al. A case of spurious hypercalcitoninemia: a cautionary tale on the use of plasma calcitonin assays in the screening of patients with thyroid nodules for neoplasia. J Endocrinol Invest 2001;24:361–9.10.1007/BF03343874Search in Google Scholar PubMed

8. Tommasi M, Raspanti S. Comparison of calcitonin determinations by polyclonal and monoclonal IRMAs. Clin Chem 2007;53:798–9.10.1373/clinchem.2006.083733Search in Google Scholar PubMed

9. Leboeuf R, Langlois MF, Martin M, Ahnadi CE, Fink GD. “Hook effect” in calcitonin immunoradiometric assay in patients with metastatic medullary thyroid carcinoma: case report and review of the literature. J Clin Endocrinol Metab. 2006;91:361–4.10.1210/jc.2005-1429Search in Google Scholar PubMed

10. Papapetrou PD, Polymeris A, Karga H, Vaiopoulos G. Heterophilic antibodies causing falsely high serum calcitonin values. J Endocrinol Invest 2006;29:919–23.10.1007/BF03349197Search in Google Scholar PubMed

11. Tommasi M, Brocchi A, Cappellini A, Raspanti S, Mannelli M. False serum calcitonin high levels using a non-competitive two-site IRMA. J Endocrinol Invest 2001;24:356–60.10.1007/BF03343873Search in Google Scholar PubMed

12. Kim JM, Ching KM, Kim SW, Choi SH, Min HS, Kim JN, et al. Spurious hypercalcitoninemia in patients with nodular thyroid disease induced by heterophilic antibodies. Head Neck 2010;32:68–75.10.1002/hed.21145Search in Google Scholar

13. Giovanella L, Suriano S. Spurious hypercalcitoninemia and heterophilic antibodies in patients with thyroid nodules. Head Neck 2011;33:95–7.10.1002/hed.21405Search in Google Scholar

14. Alves TG, Kasamatsu TS, Yang JH, Meneghetti MC, Mendes A, Kunii IS, et al. Macrocalcitonin is a novel pitfall in the routine of serum calcitonin immunoassay. J Clin Endocrinol Metab 2016;101:653–8.10.1210/jc.2015-3137Search in Google Scholar

15. Miles LE, Hales CN. Labelled Antibodies and immunological assay systems. Nature 1968;219:186–9.10.1038/219186a0Search in Google Scholar

16. American Thyroid Association Guidelines Task Force, Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 2009;19:565–612.10.1089/thy.2008.0403Search in Google Scholar

17. Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015;25:567–610.10.1089/thy.2014.0335Search in Google Scholar

18. Kaplan IV, Levinson SS. When is a heterophile antibody not a heterophile antibody? When it is an antibody against a specific immunogen. Clin Chem 1999;45:616–8.10.1093/clinchem/45.5.616Search in Google Scholar

19. Boscato LM, Stuart MC. Heterophilic antibodies: a problem for all immunoassays. Clin Chem 1988;34:27–33.10.1093/clinchem/34.1.27Search in Google Scholar

20. Sharma SK, Bagshawe KD, Melton RG, Sherwood RF. Human immune to monoclonal antibody-enzyme conjugates in ADEPT pilot clinical trial. Cell Biophys 1992;21:109–20.10.1007/BF02789482Search in Google Scholar

21. Baum RP, Niesen A, Hertel A, Nancy A, Hess H, Donnerstag B, et al. Activating anti-idiotypic human anti-mouse antibodies for immunotherapy of ovarian carcinoma. Cancer 1994;73:1121–5.10.1002/1097-0142(19940201)73:3+<1121::AID-CNCR2820731353>3.0.CO;2-QSearch in Google Scholar

22. Levinson SS, Miller JJ. Towards a better understanding of heterophile (and the like) antibody interference with modern immunoassays. Clin Chim Acta 2002;325:1–15.10.1016/S0009-8981(02)00275-9Search in Google Scholar

23. Kricka LJ. Human anti-animal antibody interferences in immunological assays. Clin Chem 1999;45:942–56.10.1093/clinchem/45.7.942Search in Google Scholar

24. Hawkins BR, Saueracker GC, Dawkins RL, Davey MG, O’Connor KJ. Population study of heterophile antibodies. Vox Sang 1980;39:339–42.10.1111/j.1423-0410.1980.tb02973.xSearch in Google Scholar

25. Schaison G, Thomopoulos P, Moulias R, Feinstein MC. False hyperthyrotropinemia induced by heterophilic antibodies against rabbit serum. J Clin Endocrinol Metab 1981;53:200–2.10.1210/jcem-53-1-200Search in Google Scholar

26. Howanitz PJ, Howanitz JH, Lamberson HV, Ennis KM. Incidence and mechanism of spurious increase in serum thyrotropin. Clin Chem 1982;28:427–31.10.1093/clinchem/28.3.427Search in Google Scholar

27. Ismail AA. A radical approach is needed to eliminate interference from endogenous antibodies in immunoassays. Clin Chem. 2005;51:25.10.1373/clinchem.2004.042523Search in Google Scholar

28. Ismail AA, Walker PL, Cawood ML, Barth JH. Interference in immunoassay is ad underestimated problem. Ann Clin Biochem 2002;39:366–73.10.1258/000456302760042128Search in Google Scholar

29. Marks V. False-positive immunoassay results: a multi center survey of erroneous immunoassay results from assays of 74 analytes in 10 donors from 66 laboratories in seven countries. Clin Chem 2002;48:2008–16.10.1093/clinchem/48.11.2008Search in Google Scholar

30. Rotmensch S, Cole LA. False diagnosis and needless therapy of presumed malignant disease in women with false-positive human chorionic gonadotropin concentrations. Lancet 2000;355:712–5.10.1016/S0140-6736(00)01324-6Search in Google Scholar

31. Preissner CM, Dodge LA, O’Kane DJ, Singh RJ, Grebe SK. Prevalence of heterophilic antibody interference in eight automated tumor marker immunoassays. Clin Chem 2005;51: 208–10.10.1373/clinchem.2004.040501Search in Google Scholar PubMed

32. Martinetti A, Seregni E, Ferrari L, Pallotti F, Aliberti G, Coliva A, et al. Evaluation of circulating calcitonin: analytical aspects. Tumori 2003;89:566–8.10.1177/030089160308900525Search in Google Scholar

33. D’Herbomez M, Caron P, Bauters C, Do Cao C, Schlienger JL, Sapin R, et al. Reference range serum calcitonin levels in humans: influence of calcitonin assay, sex, age, and cigarette smoking. Eur J Endocrinol 2007;157:749–55.10.1530/EJE-07-0566Search in Google Scholar PubMed

34. Giovanella L, Imperiali M, Ferrari A, Palumbo A, Lippa L, Peretti A, et al. Thyroid volume influences serum calcitonin levels in a thyroid-healthy population: results of a 3-assay, 519 subjects study. Clin Chem Lab Med 2012;50:895–900.10.1515/cclm-2011-0920Search in Google Scholar PubMed

35. Guyétant S, Rousselet MC, Durigon M, Chappard D, Franc B, Guerin O, et al. Sex-related C cell hyperplasia in the normal human thyroid: a quantitative autopsy study. J Clin Endocrinol Metab 1997;82:42–7.10.1210/jcem.82.1.3684Search in Google Scholar PubMed

36. Doyle P, Düren C, Nerlich K, Verburg FA, Grelle I, Jahn H, et al. Potency and tolerance of calcitonin stimulation with high-dose calcium versus pentagastrin in normal adults. J Clin Endocrinol Metab 2009;94:2970–4.10.1210/jc.2008-2403Search in Google Scholar PubMed

37. Colombo C, Verga U, Mian C, Ferrero S, Perrino M, Vicentini L, et al. Comparison of calcium and pentagastrin tests for the diagnosis and follow-up of medullary thyroid cancer. J Clin Endocrinol Metab 2012;97:905–13.10.1210/jc.2011-2033Search in Google Scholar PubMed

38. Basuyau JP, Mallet E, Leroy M, Brunelle P. Reference intervals for serum calcitonin in men, women, and children. Clin Chem 2004;50:1828–30.10.1373/clinchem.2003.026963Search in Google Scholar PubMed

39. Castagna MG, Fugazzola L, Maino F, Covelli D, Memmo S, Sestini F, et al. Reference range of serum calcitonin in pediatric population. J Clin Endocrinol Metab.2015;100:1780–4.10.1210/jc.2014-4508Search in Google Scholar PubMed

40. Trimboli P, Treglia G, Guidobaldi L, Romanelli F, Nigri G, Valabrega S, et al. Detection rate of FNA cytology in medullary thyroid carcinoma: a meta-analysis. Clin Endocrinol (Oxf) 2015;82:280–5.10.1111/cen.12563Search in Google Scholar PubMed

41. Trimboli P, Cremonini N, Ceriani L, Saggiorato E, Guidobaldi L, Romanelli F, et al. Calcitonin measurement in aspiration needle washout fluids has higher sensitivity than cytology in detecting medullary thyroid cancer: a retrospective multicentre study. Clin Endocrinol (Oxf) 2014;80:135–40.10.1111/cen.12234Search in Google Scholar PubMed

42. Trimboli P, Guidobaldi L, Bongiovanni M, Crescenzi A, Alevizaki M, Giovanella L. Use of fine-needle aspirate calcitonin to detect medullary thyroid carcinoma: A systematic review. Diagn Cytopathol 2016;44:45–51.10.1002/dc.23375Search in Google Scholar PubMed

43. Trimboli P, Seregni E, Treglia G, Alevizaki M, Giovanella L. Procalcitonin for detecting medullary thyroid carcinoma: a systematic review. Endocr Relat Cancer 2015;22:157–64.10.1530/ERC-15-0156Search in Google Scholar PubMed

44. Giovanella L, Verburg FA, Imperiali M, Valabrega S, Trimboli P, Ceriani L. Comparison of serum calcitonin and procalcitonin in detecting medullary thyroid carcinoma among patients with thyroid nodules. Clin Chem Lab Med 2013;51:1477–81.10.1515/cclm-2012-0610Search in Google Scholar PubMed

45. Russo M, Scollo C, Padova G, Vigneri R, Pellegriti G. Cardiac arrest after intravenous calcium administration for calcitonin stimulation test. Thyroid 2014;24:606–7.10.1089/thy.2013.0394Search in Google Scholar PubMed

Received: 2015-11-23
Accepted: 2016-4-13
Published Online: 2016-5-11
Published in Print: 2016-12-1

©2016 Walter de Gruyter GmbH, Berlin/Boston

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