Serum Basal and Stimulated Calcitonin

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Calcitonin is the most specific and sensitive medullary thyroid tumor marker, both before and after thyroidectomy [2,82,83]. It is a small polypeptide hormone of 32 amino acids normally produced almost exclusively by C cells. The gene encoding for calcitonin is located on chromosome 11p and yields two distinct messenger RNAs (mRNA) by alternative splicing: calcitonin and calcitonin gene-related peptide (CGRP) [84,85]. Calcitonin mRNA is found almost exclusively in the thyroid and CGRP mRNA in the nervous system. However, aberrant expression of CGRP may be observed in medullary thyroid carcinoma [86-88].

Release and secretion of calcitonin is mainly regulated by extracellular calcium concentration [89]. Other substances, such as pentagastrin, b-adrenergic agonists, growth hormone-releasing hormone and other gastrointestinal peptides [90-92],can stimulate cal-citonin release from C cells.

The physiological role of calcitonin is still not well defined. It binds specifically to the osteo-clasts and inhibits bone resorption in this site [93]. Experimental data obtained from mice

Figure 21.7 Cytological appearance of MTC. A Cells with abundant cytoplasm are visible; arrow indicates one cell with two nuclei, eccentrically localized (Papanicolaou staining, x500). B Positive cytoplasmic staining for calcitonin confirms the suspicion of medullary carcinoma (immunocytochemistry for calcitonin, x630). (Kindly provided by Dr G. Di Coscio, Department of Pathology,Uni-versity of Pisa, Italy.)

Figure 21.7 Cytological appearance of MTC. A Cells with abundant cytoplasm are visible; arrow indicates one cell with two nuclei, eccentrically localized (Papanicolaou staining, x500). B Positive cytoplasmic staining for calcitonin confirms the suspicion of medullary carcinoma (immunocytochemistry for calcitonin, x630). (Kindly provided by Dr G. Di Coscio, Department of Pathology,Uni-versity of Pisa, Italy.)

homozygous null for the calcitonin gene have demonstrated a significant increase in bone formation at 1 and 3 months of age [94]. However, in normal adult human subjects even quite large doses of calcitonin have little effect on serum calcium levels. It is only in subjects with an increased bone turnover that calcitonin treatment acutely inhibits bone resorption and lowers the serum calcium [95]. Recently, evidence has been reported suggesting that the actions of calcitonin may not be limited to bone. Calcitonin receptors have also been identified in the central nervous system, testes, skeletal muscle, lymphocytes, and the placenta [96].

Ten years after the recognition of medullary thyroid carcinoma as a distinct histological type of thyroid carcinoma [1], high levels of calci-tonin were demonstrated to be present both in the tumoral tissue and serum of patients with medullary thyroid carcinoma [2]. Elevated basal levels of serum calcitonin are diagnostic of medullary thyroid carcinoma. However, there are several other conditions, both physiological and pathological, in which basal levels of serum calcitonin may be found to be elevated and a differential diagnosis may be indicated [45,97101]. Since the release of calcitonin in these diseases does not appear to be regulated by the same factors that stimulate calcitonin release in the C cells, differential diagnosis can be performed by either the calcium (2mg/kg) or pentagastrin (0.5mg/kg intravenously) rapid stimulation test [102]. While in patients with medullary thyroid carcinoma and elevated basal levels of calcitonin, the pentagastrin stimulation determines a 5-10-fold increase in serum levels of calcitonin, in other diseases the calcitonin increase is limited or absent. In patients with an endocrine tumor of another origin, an increase may be observed but is not usually greater than twofold [43,102].

Routine measurement of serum calcitonin in nodular thyroid diseases allows the preopera-tive diagnosis of unsuspected sporadic medullary thyroid carcinoma [36-42]. Calcitonin screening determines the early diagnosis of medullary thyroid carcinoma, usually when the tumor is still at stage I, thus favoring successful surgical treatment. A comparison of the outcome of two groups of patients, one diagnosed by serum calcitonin screening and the other by cytology or histology, has demon-

Years

Figure 21.8 Significant difference in survival rate between patients with MTC diagnosed by serum calcitonin screening (dashed line) and those with MTC diagnosed at surgery and/or by preoperative cytology (solid line). (Modified from Elisei at al. [50].)

Years

Figure 21.8 Significant difference in survival rate between patients with MTC diagnosed by serum calcitonin screening (dashed line) and those with MTC diagnosed at surgery and/or by preoperative cytology (solid line). (Modified from Elisei at al. [50].)

strated a significantly better prognosis in the first group [50] (Figure 21.8).

It is worth noting that calcitonin precursors (pre- and pro-calcitonin) and post-translational deriving peptides (katacalcin and N-terminal peptide) are also present in the blood and may interfere in the measurement of serum calci-tonin. Artifactual recognition of larger calci-tonin precursors is commonly observed with one-site radioimmunoassay. This problem seems to be overcome by the most recent generation of calcitonin two-site immunoradiomet-ric assays (IRMA) that are able to specifically recognize the mature molecule of calcitonin [103]. Artifacts may be also determined by the presence of heterophilic antibodies in the blood of patients, which can interfere with the assay, thus producing false-positive results [47]. The absence of a significant increase in the serum calcitonin levels after pentagastrin or calcium stimulation test strongly suggests the artifactual nature of these false-positive values.

As an additional tool for the diagnosis of medullary thyroid carcinoma, calcitonin measurement in the washout of the needle used for the puncture of a suspected thyroid nodule may be useful. This approach is of particular diagnostic utility to ascertain the nature of neck lymph nodes, especially before thyroidectomy, to plan the surgical approach or the most appropriate therapeutic strategies.

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Responses

  • faizan campbell
    What is a basal calcitonen?
    4 months ago

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