Bestimmung von Kalzitonin

Zusammenfassung

Kalzitonin ist ein vergleichsweise sensitiver, spezifischer und reliabler Tumormarker, der bei der Primärdiagnostik und Nachsorge des C-Zellkarzinoms sowie der neoplastischen C-Zell-Hyperplasie einen zentralen Stellenwert besitzt. Wesentlich seltener wird Kalzitonin auch bei anderen Tumorarten nachgewiesen. Zur Messung sollten immunometrische Two-Site-Assays mit einer funktionellen Sensitivität um 1-2 pg/ml verwendet werden. Assays mit weitgehend selektiver Erfassung der monomeren Kalzitoninform bieten den Vorteil einer höheren Spezifität bezüglich des Erkennens von C-Zellkarzinomen. Unter diesen Voraussetzungen besitzen bereits Messungen des basalen Kalzitonins eine hohe diagnostische Aussagekraft. Die Durchführung eines Pentagastrintests kann die diagnostische Sensitivität und Spezifität der Kalzitoninbestimmung steigern, aber falsch positive Ergebnisse sind auch hierbei insbesondere bei C-Zellhyperplasie und Niereninsuffizienz von klinischer Relevanz. Bezüglich des Screenings der Familienmitglieder von Patienten mit C-Zellkarzinom hat die molekulargenetische Diagnostik in den letzten Jahren den Pentagastrintest weitgehend abgelöst. Als neues Einsatzgebiet rückt derzeit das Kalzitoninscreening bei Struma nodosa stärker in den Blickpunkt. Zwar können hierdurch nur bis 10 % der (ohnehin seltenen) Schilddrüsenmalignome erfasst werden, und bei den empfohlenen Interventionsschwellenwerten wird ein nicht unerheblicher Anteil unnötiger Schilddrüsenoperationen verursacht, aber die Chance kurativer Interventionen durch Erfassung früher Tumorstadien steigt.

Abstract

Calcitonin in serum is a comparatively highly sensitive, specific and reliable tumor marker of central relevance for the diagnosis and follow-up of medullary thyroidal C-cell carcinoma (MTC) and neoplastic C-cell hyperplasia (CCH). It is seen considerably less often in other tumor entities. For determination we recommend immunometric two-site assays of approximately 1-2 pg/ml sensitivity. Higher MTC specificity is achieved by assays focussing on a largely selective determination of monomeric calcitonin. If this is realized, basal calcitonin levels are already greatly relevant for MTC or CCH diagnosis. The diagnostic sensitivity and specificity of calcitonin determination may be further enhanced by means of pentagastrin test, but even then false positive results are clinically relevant especially in benign CCH and renal insufficiency. In family screening in case of MTC patients, moleculargenetic techniques have become the procedure of choice and have now largely replaced the pentagastrin test. Calcitonin screening in adenomatous goitre (struma nodosa) is making headway. Although this accounts for only 10 % of thyroidal malignomas (which are in fact rare), and the recommanded levels of intervention will result in many unnecessary surgical operations, early tumor staging definitely increases the chances for curative intervention.

Schlüsselwörter

Kalzitonin - Pentagastrintest - C-Zellkarzinom - Struma nodosa - Screening - Monomer

Key words

Calcitonin - pentagastrin test - medullary thyroid carcinoma - adenomatous goitre - screening - monomer

Literatur

• 1 Barbot N, Calmettes C, Schuffenecker I, Saint-Andre J P, Franc B, Rohmer V, Jallet P, Bigorgne J C. Pentagastrin stimulation test and early diagnosis of medullary thyroid carcinoma using an immunoradiometric assay of calcitonin: comparison with genetic screening in hereditary medullary thyroid carcinoma.  J Clin Endocrinol Metab. 1994;  78 114-120
• 2 Becker K L, Nash D, Silva O L, Snider R H, Moore C F. Increased serum and urinary calcitonin levels in patients with pulmonary disease.  Chest. 1981;  79 211-216
• 3 Bockhorn M, Frilling A, Rewerk S, Liedke M, Dirsch O, Schmid K W, Broelsch C E. Lack of elevated serum carcinoembryonic antigen and calcitonin in medullary thyroid carcinoma.  Thyroid. 2004;  14 468-470
• 4 Body J J, Chanoine J P, Dumon J C, Delange F. Circulating calcitonin levels in healthy children and subjects with congenital hypothyroidism from birth to adolescence.  J Clin Endocrinol Metab. 1993;  77 565-567
• 5 Borges M F, Abelin N M, Menezes F O, Dahia P L, Toledo S P. Calcitonin deficiency in early stages of chronic autoimmune thyroiditis.  Clin Endocrinol (Oxf). 1998;  49 69-75
• 6 Brauckhoff M, Gimm O, Brauckhoff K, Ukkat J, Thomusch O, Dralle H. Calcitonin kinetics in the early postoperative period of medullary thyroid carcinoma.  Langenbecks Arch Surg. 2001;  386 434-439
• 7 Conte N, Roiter I, Monco M A, Carniato A. Plasma immunoreactive calcitonin in acute and chronic lung diseases.  Minerva Endocrinol. 1984;  9 359-361
• 8 Cohen R, Modigliani E. Medullary thyroid carcinoma: 25 years on.  The Cancer Journal. 1993;  6 59-64
• 9 Copp D H, Cameron E C. Demonstration of a hypocalcemic factor (calcitonin) in commercial parathyroid extract.  Science. 1961;  134 2038
• 10 Dietlein M, Dressler J, Grünwald F, Joseph K, Leisner B, Moser E, Reiners C, Rendl J, Schicha H, Schneider P, Schober O. Leitlinie zur Schilddrüsendiagnostik (Version 2).  Nuklearmedizin. 2003;  43 109-115
• 11 Dietlein M, Moka D, Schmidt M, Theissen P, Schicha H. Prävention, Screening and Therapie gutartiger Schilddrüsenerkrankungen unter dem Aspekt von Kosten und Nutzen.  Nuklearmedizin. 2003;  42 181-189
• 12 Elisei R, Bottici V, Luchetti F, Di Coscio G, Romei C, Grasso L, Miccoli P, Iacconi P, Basolo F, Pinchera A, Pacini F. Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: experience in 10 864 patients with nodular thyroid disorders.  J Clin Endocrinol Metab. 2004;  89 163-168
• 13 Engelbach M, Görges R, Forst T, Pfutzner A, Dawood R, Heerdt S, Kunt T, Bockisch A, Beyer J. Improved diagnostic methods in the follow-up of medullary thyroid carcinoma by highly specific calcitonin measurements.  J Clin Endocrinol Metab. 2000;  85 1890-1894
• 14 Engelbach M, Heerdt S, Gorges R, Kunt T, Pfutzner A, Forst T, Diefenbach K, Walgenbach S, Beyer J. Is there an ectopic secretion of monomeric calcitonin in the human being?.  Langenbecks Arch Surg. 1998;  383 456-459
• 15 Erdogan M F, Gullu S, Baskal N, Uysal A R, Kamel N, Erdogan G. Omeprazole: calcitonin stimulation test for the diagnosis follow-up and family screening in medullary thyroid carcinoma.  J Clin Endocrinol Metab. 1997;  82 897-899
• 16 Franc S, Niccoli-Sire P, Cohen R, Bardet S, Maes B, Murat A, Krivitzky A, Modigliani E.. French Medullary Study Group (GETC) . Complete surgical lymph node resection does not prevent authentic recurrences of medullary thyroid carcinoma.  Clin Endocrinol (Oxf). 2001;  55 403-409
• 17 Frank-Raue K, Raue F, Buhr H J, Baldauf G, Lorenz D, Ziegler R. Localization of occult persisting medullary thyroid carcinoma before microsurgical reoperation: high sensitivity of selective venous catheterization.  Thyroid. 1992;  2 113-117
• 18 Gimm O, Ukkat J, Dralle H. Determinative factors of biochemical cure after primary and reoperative surgery for sporadic medullary thyroid carcinoma.  World J Surg. 1998;  22 562-567
• 19 Görges R. The changing epidemiology of thyroid cancer. In: Biersack HJ, Grünwald F (eds). Thyroid cancer. Springer, Berlin, Heidelberg 2001
• 20 Grauer A, Raue F, Ziegler R. Clinical usefulness of a new chemiluminescent two-site immunoassay for human calcitonin.  Exp Clin Endocrinol Diabetes. 1998;  106 353-359
• 21 Guyetant S, Wion-Barbot N, Rousselet M C, Franc B, Bigorgne J C, Saint-Andre J P. C-cell hyperplasia associated with chronic lymphocytic thyroiditis: a retrospective quantitative study of 112 cases.  Hum Pathol. 1994;  25 514-521
• 22 Hadjadj S, Nunez S, Bohme P, Goulet Salmon B, Klein M, Weryha G, Leclere J. False elevated serum level of circulating calcitonin induced by omeprazole.  Presse Med. 1997;  26 1859
• 23 Henriksen J H, Schifter S, Moller S, Bendtsen F. Increased circulating calcitonin in cirrhosis. Relation to severity of disease and calcitonin gene-related peptide.  Metabolism. 2000;  49 47-52
• 24 Hernandez G, Simo R, Oriola J, Mesa J. False-positive results of basal and pentagastrin-stimulated calcitonin in non-gene carriers of multiple endocrine neoplasia type 2 A.  Thyroid. 1997;  7 51-54
• 25 Karges W, Dralle H, Raue F, Mann K, Reiners C, Grussendorf M, Hüfner M, Niederle B, Brabant G.. German Society for Endocrinology (DGE) - Thyroid Section . Calcitonin measurement to detect medullary thyroid carcinoma in nodular goiter: German evidence-based consensus recommendation.  Exp Clin Endocrinol Diabetes. 2004;  112 52-58
• 26 Kebebew E, Ituarte P H, Siperstein A E, Duh Q Y, Clark O H. Related Articles, Links Abstract Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems.  Cancer. 2000;  88 1139-1148
• 27 Kotzmann H, Schmidt A, Scheuba C, Kaserer K, Watschinger B, Soregi G, Niederle B, Vierhapper H. Basal calcitonin levels and the response to pentagastrin stimulation in patients after kidney transplantation or on chronic hemodialysis as indicators of medullary carcinoma.  Thyroid. 1999;  9 943-947
• 28 Lind L, Bucht E, Ljunghall S. Pronounced elevation in circulating calcitonin in critical care patients is related to the severity of illness and survival.  Intensive Care Med. 1995;  21 63-66
• 29 Lissak B, Baudin E, Cohen R, Barbot N, Meyrier A, Niccoli P, Bouyge N, Modigliani E. Pentagastrin testing in patients with renal insufficiency: normal responsivity of mature calcitonin.  Thyroid. 1998;  8 265-268
• 30 Marsh D J, McDowall D, Hyland V J, Andrew S D, Schnitzler M, Gaskin E L, Nevell D F, Diamond T, Delbridge L, Clifton-Bligh P, Robinson B G. The identification of false positive responses to the pentagastrin stimulation test in RET mutation negative members of MEN 2 A families.  Clin Endocrinol (Oxf). 1996;  44 213-220
• 31 Marrinan M, Skrabanek P, Moriarty M, McPartlin J, Powell D. Hypercalcitoninaemia in medullary carcinoma of the thyroid and other malignancies: value of calcitonin as tumour marker.  Horm Metab Res. 1982;  14 213-215
• 32 Martinetti A, Seregni E, Ferrari L, Pallotti F, Aliberti G, Coliva A, Fracassi S, Bombardieri E. Evaluation of circulating calcitonin: analytical aspects.  Tumori. 2003;  89 566-568
• 33 Mendelsohn G, Wells Jr S A, Baylin S B. Relationship of tissue carcinoembryonic antigen and calcitonin to tumor virulence in medullary thyroid carcinoma. An immunohistochemical study in early, localized, and virulent disseminated stages of disease.  Cancer. 1984;  54 657-662
• 34 Modigliani E, Cohen R, Campos J M,. et al . Prognostic factors for survival and biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group.  Clin Endocrinol (Oxf). 1998;  48 265-273
• 35 Niccoli P, Brunet P, Roubicek C, Roux F, Baudin E, Lejeune P J, Berland Y, Conte-Devolx B. Abnormal calcitonin basal levels and pentagastrin response in patients with chronic renal failure on maintenance hemodialysis.  Eur J Endocrinol. 1995;  132 75-81
• 36 Oishi S, Shimada T, Tajiri J, Inoue J, Sato T. Elevated serum calcitonin levels in patients with thyroid disorders.  Acta Endocrinol (Copenh). 1984;  107 476-481
• 37 Pedrazzoni M, Ciotti G, Davoli L, Pioli G, Girasole G, Palummeri E, Passeri M. Meal-stimulated gastrin release and calcitonin secretion.  J Endocrinol Invest. 1989;  12 409-412
• 38 Poppe K, Verbruggen L A, Velkeniers B, Finne E, Body J J, Vanhaelst L. Calcitonin reserve in different stages of atrophic autoimmune thyroiditis.  Thyroid. 1999;  9 1211-1214
• 39 Raue F. German MTC/MEN Study Group . German medullary thyroid carcinoma/multiple endocrine neoplasia registry.  Langenbecks Arch Surg. 1998;  383 334-336
• 40 Redding A H, Levine S N, Fowler M R. Normal preoperative calcitonin levels do not always exclude medullary thyroid carcinoma in patients with large palpable thyroid masses.  Thyroid. 2000;  10 919-922
• 41 Saeger H D, Pistorius S, Fitze G, Schackert H K. Prädiktive Medizin für das operative Fach.  Deutsches Ärzteblatt. 2002;  99 441
• 42 Sagulin G B, Bucht E, Gilljam H, Sjoberg H, Roomans G M. Plasma calcitonin levels in patients with cystic fibrosis.  Res Commun Chem Pathol Pharmacol. 1990;  69 325-334
• 43 Saller B, Görges R, Reinhardt W, Haupt K, Janssen O E, Mann K. Sensitive calcitonin measurement by two-site immunometric assays: implications for calcitonin screening in nodular thyroid disease.  Clin Lab. 2002;  48 191-200
• 44 Saller B, Moeller L, Görges R, Janssen O E, Mann K. Role of conventional ultrasound and color Doppler sonography in the diagnosis of medullary thyroid carcinoma.  Exp Clin Endocrinol Diabetes. 2002;  110 403-407
• 45 Schmid K W, Sheu S Y, Görges R, Ensinger C, Tötsch M. Tumoren der Schilddrüse.  Pathologe. 2003;  24 357-372
• 46 Sheu S Y, Görges R, Schmid K W. Hyperplasien der Schilddrüse.  Pathologe. 2003;  24 348-356
• 47 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;  24 356-360
• 48 Ukkat J, Gimm O, Brauckhoff M, Bilkenroth U, Dralle H. Single center experience in primary surgery for medullary thyroid carcinoma.  World J Surg. 2004;  28 1271-1274
• 49 Vitale G, Ciccarelli A, Caraglia M, Galderisi M, Rossi R, Del Prete S, Abbruzzese A, Lupoli G. Comparison of two provocative tests for calcitonin in medullary thyroid carcinoma: omeprazole vs pentagastrin.  Clin Chem. 2002;  48 1505-1510
• 50 Zaidi M, Inzerillo A M, Moonga B S, Bevis P J, Huang C L. Forty years of calcitonin - where are we now? A tribute to the work of Iain Macintyre, FRS.  Bone. 2002;  30 655-663
• 51 Zwermann O, Piepkorn B, Engelbach M, Beyer J, Kann P. Abnormal pentagastrin response in a patient with pseudohypoparathyroidism.  Exp Clin Endocrinol Diabetes. 2002;  110 86-91