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Omeprazole: Calcitonin Stimulation Test for the Diagnosis Follow-Up and Family Screening in Medullary Thyroid Carcinoma

Murat Faik Erdoan, Sevim Güllü, Nilgün Bakal, Ali Riza Uysal, Nuri Kamel and Gürbüz i Erdoan

Department of Endocrinology and Metabolism (M.F.E., S.G., N.B., A.R.U., N.K., G.E.) University of Ankara, School of Medicine, Ankara, Turkey

Address correspondence and requests for reprints to: Gürbüz Erdoan MD PhD, Merutiyet Cad. 29/3, Kizilay 06420, Ankara, Turkey.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Medullary thyroid carcinoma (MTC) occurs sporadically but may also be inherited as part of the multiple endocrine neoplasia (MEN) type 2 syndrome. Screening of the patients and first degree relatives annually with basal and provocative tests for serum immunoreactive calcitonin (CT) levels is essential and enables potentially curative disease. Pentagastrin and calcium are the usual provocative agents used worldwide. We used endogenous gastrin (GT) release achieved by omeprazole, 20 mg b.i.d., to stimulate CT in 9 MTC, in 3 MEN 2A family members, and in 50 healthy control subjects. A steady and significant increase both in GT and CT levels was achieved in 9 MTC patients and 3 of the 14 family members tested, whereas in healthy controls the CT increase stimulated by GT was insignificant.

Preliminary results showed that this new, safe, cheap, and outpatient-basis test can be used in MTC diagnosis, follow-up, and screening.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
MEDULLARY THYROID carcinoma (MTC) is a malignant tumor of the parafollicular cells of the thyroid gland. It occurs sporadically but may also be inherited as a part of the multiple endocrine neoplasia (MEN) type 2 syndrome.

Screening of first degree relatives annually with basal and provocative tests for serum immunoreactive calcitonin (CT) levels is essential and enables potentially curative surgical treatment (1, 2, 3, 4). CT is usually measured before and 2, 5, 7, 10, and 15 min after an iv bolus injection of pentagastrin (0.5 µg/kg body weight) (1, 2, 3, 4, 5, 6). Calcium, beta adrenergic catecholamines, and several peptides, including gastrin are also known to release CT (3).

Omeprazole is a substituted benzimidazole derivative, which markedly inhibits basal and stimulated gastric acid secretion. Short periods of treatment with omeprazole administered once daily resulted in elevated serum gastrin levels in several hours to days. This increase is secondary to the pronounced reduction in intragastric acidity and is therefore caused by the elimination of acid inhibition of gastrin release from the antrum (7, 8, 9, 10, 11, 12).

Our aim was to use the endogenous gastrin release achieved by omeprazole as a new, outpatient-basis provocative test for MTC.

	Subjects and Methods

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Gastrin assay

Gastrin (GT) was measured by double antibody GT RIA kit (Diagnostic Products Corp., Los Angeles, CA). The assay system utilizes a broad-spectrum antibody capable of recognizing the several forms of GT (G-14,G-17, G-34). The sensitivity was 4.7 ng/L. The coefficient of variation of the intraassay comparison was 5.2% for a mean of 200 ng/L, and that of the interassay comparison was 4.0% for 331 ng/L. On each study day fasting venous blood was taken at 0900, and plasma was separated immediately and stored at -20°C.

CT assay

Immunoreactive CT was measured by the DSL calcitonin RIA kit (Diagnostic Systems Laboratories, Webster, TX). The sensitivity was 14 ng/L. The coefficient of variation of the intraassay comparison was 5.3%, and that of the interassay comparison was 7.1% for 75 ng/L.

Omeprazole stimulation test

After fasting blood was taken for basal CT and GT determinations, omeprazole 20 mg b.i.d. was given for 3 days, and fasting blood samples for CT and GT were withdrawn every morning at 0900 (the fourth and the last morning of the test inclusive).

Healthy subjects

An omeprazole stimulation test was performed on 50 healthy Caucasian volunteers without known thyroid disease in their family. Twenty-five females and 25 males with a mean age of 27 yr (range 14–50) gave informed consent.

Patients

We studied 12 patients; 9 with fine needle aspiration biopsy diagnosis of MTC before thyroidectomy. Some had metastatic disease (Table 1). All had elevated (over 42 ng/L) preoperative basal values of CT. The preoperative diagnoses were confirmed histopathologically as MTC postoperatively (Table 1). One subject had MEN-2A (patient 3) and another patient had pheochromocytoma (patient 8).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Healthy subjects

Fifty normal subjects with normal levels of fasting GT (35.40 ± 29.21 ng/L) showed significant and steady increase, starting from day 1, after gastric acidity inhibition by omeprazole, reaching a mean value of 99.72 ± 83.43 ng/L by day 3 (Table 2).

Patients

Patients showed a similar GT response to omeprazole from a mean basal level of 29.87 ± 17.66 ng/L, reaching to 98.50 ± 76.35 ng/L on day 3 (Table 2).

The first nine patients with proven MTC (some metastatic, Table 1) had elevated baseline CT levels (mean = 647 ± 919 ng/mL). After gastric acid inhibition by omeprazole, a steady and significant increase in CT levels was achieved, reaching to a mean value of 1351 ± 1257 ng/L by day 3 of the test (Table 2). Using the Wilcoxon matched-pairs test, P values were found to be 0.05 and 0.01 by days 2 and 3 respectively (Table 2).

The last three patients who were from MEN 2A families with no clinically or ultrasonographically demonstrated thyroid disease, had normal basal CT levels, and showed 46-, 16-, and 10-fold increases on the third day of omeprazole stimulation (Table 1). One of these patients (patient 10) had a 5-fold increase from the basal CT level (33 ng/L up to 168 ng/L) on the fifth minute of standard iv pentagastrin stimulation as well. He had a total thyroidectomy and C cell hyperplasia was histopathologically proven. The other two subjects (patients 11 and 12) refused thyroidectomy.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Pentagastrin stimulation with DNA polymorphism analysis in a MEN 2A kindred enabled us to predict gene carrier status with 90–99% certainty (5). RET mutations were found in MEN 2A patients (13). Characterization of the same mutations in relatives of MEN 2A patients may make it possible to rapidly determine gene carrier status.

Despite the molecular techniques, basal and stimulated CT values measured by RIA or IRMA still have a very important place in the diagnosis, follow-up, and family screening of MTC.

We used the endogenous GT increase achieved by gastric acid inhibition by omeprazole as a stimulation test for MTC, MEN 2A patients, and MEN 2A kindred for the first time. Patients and some kindred showed very significant CT increases measured by RIA, while controls showed a slight, insignificant increase below 42 ng/L (%98). Our preliminary results are compatible with the classical pentagastrin test (2, 5, 14). We performed pentagastrin stimulation in only one of our patients, who had a 5-fold increased level of CT. Histopathological examination revealed C cell hyperplasia.

Basal control values of our test are higher than those published by Barbot et al. (5). This may be explained by the method. We used RIA, which recognizes the several circulating forms of the hormone, whereas they used IRMA, which by using two monoclonal antibodies measures only the CT monomer.

The pentagastrin test is a 15–30 min test. In our new test GT levels increase significantly by the first day and stay elevated for three days, which may enable a more continuous stimulation and distinctive CT release.

Omeprazole is an inexpensive and safe drug, widely approved for use in peptic ulcer disease and Zollinger-Ellison syndrome. The test is an outpatient-basis one and can be done by measuring a baseline CT and third day CT after 20 mg omeprazole b.i.d. for 3 days. Continuing the medication will result in a further increase in gastrin levels (15), which may be used in difficult cases to increase the sensitivity of the test.

These are the preliminary results of a new stimulation test for MTC and family screening. Further studies with larger number of patients and histopathological results are needed to establish the test. At the moment the test seems to be a cheap, easy, and safe one.

Received March 28, 1996.

Revised July 23, 1996.

Revised October 29, 1996.

Accepted November 8, 1996.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Erdogan, M. F. Articles by Erdogan, G. i Search for Related Content PubMed PubMed Citation Articles by Erdogan, M. F. Articles by Erdogan, G. i Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CALCITONIN, SALMON OMEPRAZOLE PENTAGASTRIN Medline Plus Health Information Thyroid Cancer