Determination of Calcitonin Levels in C-cell Disease: Clinical Interest and Potential Pitfalls

Giuseppe Costante; Cosimo Durante; Zélia Francis; Martin Schlumberger; Sebastiano Filetti

Nat Clin Pract Endocrinol Metab. 2009;5(1):35-44.

Calcitonin Stimulation Tests

Some patients with limited C-cell disease might have normal basal calcitonin levels; however, measurement of stimulated hormone levels can disclose the C-cell abnormality in these individuals.^[7,14]

The method most widely used to stimulate calcitonin secretion involves the slow intravenous administration of pentagastrin (0.5 µg/kg).^[7] Serum calcitonin levels are measured before infusion and then at 3 min and 5 min after initiation of the infusion.^[7] This test can cause unpleasant, or potentially dangerous, adverse effects (e.g. tachycardia, bradycardia, nausea, vomiting, dizziness, flushing, and substernal tightness). As a consequence, it is contraindicated in patients with hypertension and/or coronary artery disease, and it is not recommended in individuals greater than 60 years of age.^[7]

Peak stimulated calcitonin levels <10 ng/l are detected in 80% of healthy individuals, whereas peak stimulated calcitonin levels <30 ng/l are detected in 95% of healthy individuals. Of note, mean stimulated calcitonin levels are higher in men than in women. Stimulated levels >100 ng/l are suggestive of C-cell disease ( Table 3 ), but moderate elevations (30-100 ng/l) have been reported in adults with other thyroid abnormalities.^[7] For patients with MTC who exhibit elevated basal calcitonin levels, the peak observed after pentagastrin stimulation is usually 5-10 times higher than the basal level.^[7] By contrast, pentagastrin produces a more limited response (two-fold or less) in patients with other types of neuroendocrine tumors (e.g. gastroenteropancreatic).^[15]

Calcitonin secretion can also be provoked by a short intravenous calcium infusion.^[7,16,17] This approach provides a useful alternative to pentagastrin stimulation in countries where pentagastrin is unavailable, such as the US. In addition, calcium stimulation can be combined with pentagastrin testing in order to enhance the sensitivity of the latter test.^[14,18] Both in healthy individuals and in patients with C-cell disease, serum calcitonin levels measured after a 30-sec infusion of calcium gluconate (2.5 mg/kg) are of a similar magnitude to those produced by pentagastrin administration.^[7] The main problem with calcium stimulation, however, is that this approach has never been evaluated with assays specific for the mature form of calcitonin.

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Clinical Interests and Pitfalls of Basal Calcitonin Measurement in C-cell Disease
Indications	Clinical interest	Pitfall	Reference basal value
Screening and/or diagnosis	Early detection of MTC Greater sensitivity than FNAC	Low PPV Need to retest using provocative testing No proven clinical benefit	Normal: <10 ng/l Indeterminate: 10-100 ng/l Suspected MTC: >100 ng/l
Follow-up monitoring and prognostic assessment	Detection of residual disease Correlation with tumor burden Correlation between calcitonin doubling time and survival	Lack of correlation with tumor burden and imaging studies for low calcitonin levels Assay hook effect	No residual tumor tissue: <10 ng/l Possible local disease (i.e. neck): <150 ng/l Possible distant metastases: >150 ng/l
Assessment of treatment response	Evaluation of the response to systemic treatment	Lack of correlation with tumor burden and imaging studies Assay hook effect	ND

Abbreviations: FNAC = fine-needle aspiration cytology; MTC = medullary thyroid cancer; ND = not determined; PPV = positive predictive value.

Positive Predictive Values of Peak Levels of Calcitonin After Pentagastrin Stimulation: A Review of the Literature
Study	Number of patients	Diagnostic criteria			MTC		Basal CT		Pg-stimulated CT
Study	Number of patients	Method	Sensitivity (ng/l)	Cut-off (ng/l)	Number of patients with positive histology at surgery	Prevalence (%)	Patients with increased CT (%)	PPV ^a (%)	Number of patients with CT elevated above cut-off level	PPV ^a (%)
Pacini et al. (1994)^[20]	1,385	IRMA	2.0	20	8	0.58	0.58	100.0	8	100.0
Niccoli et al. (1997)^[22]	1,167	IRMA	2.0	10	14	1.19	3.00	26.5	NA	NA
Vierhapper et al. (1997)^[23]	1,062	IRMA	1.0	5	6	0.56	6.70	8.4	14	42.8
Hahm et al. (2001)^[25]	1,448	IRMA	0.8	10	10	0.69	3.80	17.8	23	43.5
Iacobone et al. (2002)^[26]	7,276	IRMA	2.0	10	45	0.62	0.90	68.2	NA	NA
Elisei et al. (2004)^[27]	10,864	IRMA	2.0	20	44	0.40	0.43	93.6	44	100.0
Karanikas et al. (2004)^[28]	414	ILMA	1.0	10	1	0.24	6.80	12.5	28	25.0
Gibelin et al. (2005)^[29]	5,018	IRMA	2.0	10	29	0.58	1.30	43.3	NA	NA
Vierhapper et al. (2005)^[30]	10,157	IRMA	2.0	10	32	0.32	4.90	6.3	103	42.7
Papi (2006)^[31]	1,425	ILMA	1.0	10	10	0.68	1.61	39.1	19	83.3
Costante et al. (2007)^[32]	5,817	ILMA	1.0	20	15	0.26	1.15	23.1	17	40.0

^aPPV was calculated exclusively from positive values in patients who underwent surgery.
Abbreviations: CT = calcitonin; ILMA = immunoluminometric assay; IRMA = immunoradiometric assay; MTC = medullary thyroid carcinoma; NA = data not available or not suitable for precise calculation of PPV; Pg = pentagastrin; PPV = positive predictive value.

Pentagastrin-stimulated Calcitonin Values in Thyroid Nodular Disease
Stimulated calcitonin peak (ng/l)	Clinical significance
<10	Absence of C-cell disease
>10 but <100	Indeterminate (probable false-positive result)
>100 but <500	Probable C-cell hyperplasia
>500 but <1,000	Probable medullary thyroid carcinoma
>1,000	Medullary thyroid carcinoma

Positive Predictive Values of Peak Levels of Calcitonin After Pentagastrin Stimulation: A Review of the Literature
Study	Number of patients	Diagnostic criteria			MTC		Basal CT		Pg-stimulated CT
Study	Number of patients	Method	Sensitivity (ng/l)	Cut-off (ng/l)	Number of patients with positive histology at surgery	Prevalence (%)	Patients with increased CT (%)	PPV ^a (%)	Number of patients with CT elevated above cut-off level	PPV ^a (%)
Pacini et al. (1994)^[20]	1,385	IRMA	2.0	20	8	0.58	0.58	100.0	8	100.0
Niccoli et al. (1997)^[22]	1,167	IRMA	2.0	10	14	1.19	3.00	26.5	NA	NA
Vierhapper et al. (1997)^[23]	1,062	IRMA	1.0	5	6	0.56	6.70	8.4	14	42.8
Hahm et al. (2001)^[25]	1,448	IRMA	0.8	10	10	0.69	3.80	17.8	23	43.5
Iacobone et al. (2002)^[26]	7,276	IRMA	2.0	10	45	0.62	0.90	68.2	NA	NA
Elisei et al. (2004)^[27]	10,864	IRMA	2.0	20	44	0.40	0.43	93.6	44	100.0
Karanikas et al. (2004)^[28]	414	ILMA	1.0	10	1	0.24	6.80	12.5	28	25.0
Gibelin et al. (2005)^[29]	5,018	IRMA	2.0	10	29	0.58	1.30	43.3	NA	NA
Vierhapper et al. (2005)^[30]	10,157	IRMA	2.0	10	32	0.32	4.90	6.3	103	42.7
Papi (2006)^[31]	1,425	ILMA	1.0	10	10	0.68	1.61	39.1	19	83.3
Costante et al. (2007)^[32]	5,817	ILMA	1.0	20	15	0.26	1.15	23.1	17	40.0

Positive Predictive Values of Peak Levels of Calcitonin After Pentagastrin Stimulation: A Review of the Literature
Study	Number of patients	Diagnostic criteria			MTC		Basal CT		Pg-stimulated CT
Study	Number of patients	Method	Sensitivity (ng/l)	Cut-off (ng/l)	Number of patients with positive histology at surgery	Prevalence (%)	Patients with increased CT (%)	PPV ^a (%)	Number of patients with CT elevated above cut-off level	PPV ^a (%)
Pacini et al. (1994)^[20]	1,385	IRMA	2.0	20	8	0.58	0.58	100.0	8	100.0
Niccoli et al. (1997)^[22]	1,167	IRMA	2.0	10	14	1.19	3.00	26.5	NA	NA
Vierhapper et al. (1997)^[23]	1,062	IRMA	1.0	5	6	0.56	6.70	8.4	14	42.8
Hahm et al. (2001)^[25]	1,448	IRMA	0.8	10	10	0.69	3.80	17.8	23	43.5
Iacobone et al. (2002)^[26]	7,276	IRMA	2.0	10	45	0.62	0.90	68.2	NA	NA
Elisei et al. (2004)^[27]	10,864	IRMA	2.0	20	44	0.40	0.43	93.6	44	100.0
Karanikas et al. (2004)^[28]	414	ILMA	1.0	10	1	0.24	6.80	12.5	28	25.0
Gibelin et al. (2005)^[29]	5,018	IRMA	2.0	10	29	0.58	1.30	43.3	NA	NA
Vierhapper et al. (2005)^[30]	10,157	IRMA	2.0	10	32	0.32	4.90	6.3	103	42.7
Papi (2006)^[31]	1,425	ILMA	1.0	10	10	0.68	1.61	39.1	19	83.3
Costante et al. (2007)^[32]	5,817	ILMA	1.0	20	15	0.26	1.15	23.1	17	40.0

Pentagastrin-stimulated Calcitonin Values in Thyroid Nodular Disease
Stimulated calcitonin peak (ng/l)	Clinical significance
<10	Absence of C-cell disease
>10 but <100	Indeterminate (probable false-positive result)
>100 but <500	Probable C-cell hyperplasia
>500 but <1,000	Probable medullary thyroid carcinoma
>1,000	Medullary thyroid carcinoma

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