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Reference intervals for serum calcitonin in men, women, and children.

The strategy currently used to investigate thyroid nodules in most cases involves measurement of calcitonin to exclude the possibility of medullary thyroid cancer (MTC). Techniques used to measure calcitonin have become more reliable, sensitive, and easy to perform. Automated nonisotopic techniques now exist, such as the Advantage[R] system.

We found that some children have particularly high calcitonin. Previous reports also have shown that calcitonin is higher in young children (1-9), but most of these studies are now outdated and are based on immunoradiometric or even radioimmunologic (RIA) methods, which sometimes involve an extraction step. These techniques are also not very sensitive or specific (interference by procalcitonin). Because most studies addressing this subject investigated specific populations (premature infants, newborns, or hypotrophic or hypocalcemic children), we concluded that it would be useful to determine reference intervals for blood calcitonin in children with the Advantage system. Because the manufacturer (Nichols Institute Diagnostics) found a significant difference between men and women, we also evaluated this finding.

The Advantage is an automated multiparametric random-access system that uses an acridinium ester chemiluminescence technique and a magnetic separation step (10, 11). The monoclonal antibodies used recognize the 11-23 (capture monoclonal antibody) and 21-32 (labeled monoclonal antibody) fragments of human calcitonin. Results are obtained within 45 min.

The measurement is carried out using a serum sample (150 [micro]L). The sample is transported on ice and centrifuged at 4 [degrees]C. Serum samples can be stored at -20 [degrees]C until use. All samples were tested within 5 days of collection. According to the manufacturer, the detection limit of the system is 1 ng/L. The technique is linear up to 1500 ng/L, and there is no hook effect until 500 000 ng/L. There is no cross-reactivity with procalcitonin and calcitonin from other species (pig, salmon, chicken) at concentrations <40 mg/L. The reproducibility (CV) observed in our laboratory over a 17-month period (n = 160) was 11%, 9.8%, and 7.1%, respectively, at concentrations of 5, 20, and 190 ng/L.

We collected samples from 151 children (age range, 4 months to 15 years), hospitalized or consulting at Rouen University Hospital, with normal blood calcium and phosphate. Only leftover biological samples were used to measure blood calcitonin and, when possible, ionized calcium. These samples were treated, transported, and stored in our laboratory in accordance with good laboratory practice guidelines.


The samples used to determine usual values in adults were also leftover biological samples from adults with normal thyroid function. A total of 358 sera (282 from women and 76 from men) were evaluated.

According to the manufacturer, the reference intervals for calcitonin in adults are <11.5 ng/L for men and <4.6 ng/L for women. Our laboratory used a reference interval of <10 ng/L, as defined by GETC (French Calcitonin-Secreting Tumors Study Group). The difference in concentrations between men and women, described by Suzuki (12), was not addressed. Given the distribution obtained in 358 patients (Table 1), this threshold is probably too high for women.

The manufacturer did not supply any reference intervals for children. The results for our population of children are summarized in Fig. 1 and in Table 1: the reference values differed considerably between adults and children, particularly neonates.

The range of calcitonin values in children was so large that it was not possible to identify a significant sex ratio in these children. In addition, we observed no correlation between calcitonin concentration and other biological variables. Sample size was insufficient to measure serum parathyroid hormone, and we were able to measure ionized calcium in only 14 cases (results not shown).

When measured with the Advantage system, calcitonin concentrations are higher in young infants than in adults; similar results have already been obtained with an isotopic method, which showed that concentrations are particularly high during the first week of life (4, 5), in low-birth-weight children (3), and in premature infants (6,8). The RIA (1, 7) and the immunoradiometric assay (9) produced similar results for healthy infants.

Calcitonin concentrations are highest during the postnatal period, but high concentrations can also be observed in 6-month-old children. The child with the highest value in our series (75 ng/L at the age of 4.5 months) was retested 1 month later, and the value was halved (32.4 ng/L).

The pentagastrin test was also carried out on a child who presented with the clinical signs of MTC at the age of 6 months (persistent diarrhea, calcitonin concentration of 28 ng/L). The results of this test would have been considered suspicious or even abnormal in an adult (basal value, 9 ng/L; peak, 50 ng/L).

These two children had procalcitonin concentrations within the reference interval. This confirms that the substance measured was in fact probably calcitonin, as suggested by the specificity study carried out by the manufacturer, which confirmed no significant interference, in particular by procalcitonin. Although prophylactic thyroidectomy is not performed before the age of 3 years, evaluation of calcitonin in children younger than 6 month of age for MTC diagnosis is of more than casual clinical interest.

The reference interval for serum calcitonin is wider in children, especially newborns, than in adults (1-9). Our results suggest the following reference intervals:


* <40 ng/L in children under 6 months of age

* <15 ng/L in children between 6 months and 3 years of age

* Over 3 years of age, the values are indistinguishable from those observed in adults


* <5 ng/L for females

* <12 ng/L for males

The highly significant difference between men and women was described by Suzuki (12) but ignored in the consensus definition of reference values. It is necessary, however, to exclude the unlikely possibility that this difference is not an artifact of the technique used.

Values that would be considered to be highly suggestive of MTC in adults are not in newborns. We propose that high values do not necessarily indicate a need for a pentagastrin test, especially in infants less than 1 year: the basal value should be confirmed several weeks later before performing this type of additional testing.

We thank Richard Medeiros, Rouen University Hospital Medical Editor, for advice in editing the manuscript. We also thank Professor Comte-Devolx for interesting observations regarding calcitonin measurements.


(1.) Samaan NA, Anderson GD, Adam-Mayne ME. Immunoreactive calcitonin in the mother, neonate, child and adult. Am J Obstet Gynecol 1975;121: 622-5.

(2.) Cannarozzi DB, Canale DD, Donabedian RK. Hypercalcitoninemia in infancy. Clin Chim Acta 1976;66:387-92.

(3.) David L, Salle B, Chopard P, Grafmeyer D. Studies on circulating immunoreactive calcitonin in low birth weight infants during the first 48 hours of life. Hely Paediatr Acta 1977;32:39-48.

(4.) Bagnoli F, Sardelli S, Vispi L, Buonocore G, Berti D, Vanni MG, Facchinetti F. Serum calcitonin in full-term infants. Boll Soc Ital Biol Sper 1982;58:556-61.

(5.) Branchi M, Patriarca PL, Bordoni P. Radioimmunologic analysis of calcitonin and PTH in the study of calcium homeostasis in the newborn infant during the first day of life. Pediatr Med Chir 1982;4:635-8.

(6.) Hillman LS, Hoff N, Walgate J, Haddad JG. Serum calcitonin concentrations in premature infants during the first 12 weeks of life. Calcif Tissue Int 1982;34:470-3.

(7.) Klein GL, Wadlington EL, Collins ED, Catherwood BD, Deftos U. Calcitonin levels in sera of infants and children: relations to age and periods of bone growth. Calcif Tissue Int 1984;36:635-8.

(8.) Bruchi S, Scattoni M, Buonocore G, Zani S, Bagnoli F. Serum concentrations of calcitonin and PTH in the cord blood of premature infants. Boll Soc Ital Biol Sper 1984;60:1703-8.

(9.) Body JJ, Chanoine JP, Dumon JC, Delange F. Circulating calcitonin level in healthy children and subjects with congenital hypothyroidism from birth to adolescence. J Clin Endocrinol Metab 1993;77:465-7.

(10.) Grauer A, Raue F, Ziegler R. Clinical usefulness of a new chemiluminescent two-site immunoassay for human calcitonin. Exp Clin Endocrinol Diabetes 1998;106:353-9.

(11.) D'Herbomez M, Leclerc L, Vantyghem MC, Fourrier F, Proye C, Wemeau JL. Clinical evaluation of a new sensitive calcitonin assay : study of specificity. Clin Chim Acta 2003;311:149-55.

(12.) Suzuki H. Calcitonin levels in normal individuals with new highly sensitive chemiluminescent enzyme immunoassay [Erratum published in: J Clin Lab Anal 1998;12:325]. J Clin Lab Anal 1998;12:218-22.

Jean-Pierre Basuyau, [1] * Eric Mallet, [2] Marcelle Leroy, [1] and Philippe Brunelle [1]

[1] Laboratoire de Biologie Clinique et de Radioanalyse, Centre Henri-Becquerel, Rouen, France; [2] Service de Pediatric, Hopital Charles-Nicolle, CHU de Rouen, France; * author for correspondence: fax 33-2-32-082590, e-mail

DOI: 10.1373/clinchem.2003.026963
Table 1. Distribution of calcitonin concentrations for
151 infants and 358 adults.


 Women Men Total

n 282 76 358
Calcitonin, ng/L
 Median 1.78 3.3 2.01
 95th percentile 5.3 11.7 8.0
 Minimum-maximum UD (a) to 10.3 0.13-18.4 UD to 18.4


 [less than or
 equal to] 6 months >6 months to 3 years

n 39 112
Calcitonin, ng/L
 Median 20 3.9
 95th percentile 41 13.7
 Minimum-maximum 4.4-75.0 0.1-18.0

(a) UD, undetectable.
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Title Annotation:Technical Briefs
Author:Basuyau, Jean-Pierre; Mallet, Eric; Leroy, Marcelle; Brunelle, Philippe
Publication:Clinical Chemistry
Date:Oct 1, 2004
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