Calcitonin

Calcitonin reference ranges are dependent on the method used for assessment.

Basal (plasma) ^[1] :

• Males: ≤19 pg/mL or ≤19 ng/L (SI units)
• Females: ≤14 pg/mL or ≤14 ng/L (SI units)

Calcium infusion (2.4 mg/kg) ^[1] :

• Males: ≤190 pg/mL or ≤190 ng/L
• Females: ≤ 130 pg/mL or ≤ 130 ng/L

Pentagastrin injection (0.5 mcg/kg) ^[1] :

• Males: ≤ 110 pg/mL or ≤ 110 ng/L
• Females: ≤ 30 pg/mL or ≤ 30 ng/L

Age, pregnancy, lactation, and ingestion of food have been reported to influence calcitonin concentration in healthy individuals, but specific reference intervals have not been established. ^[2]

Diagnosis and monitoring of medullary thyroid carcinoma (MTC) is the main application of the serum calcitonin assay. Basal calcitonin levels are high in most patients with sporadic MTC but are normal in 30% of those with familial MTC (FMTC) or multiple endocrine neoplasia (MEN) type 2.

In these patients, a calcium infusion provocative test (short calcium infusion with blood drawing at 0, 5, and 10 min) was commonly required to demonstrate the abnormality; however, such testing has been largely superseded by RET mutation screening, to the point where calcium infusion tests are now considered necessary only in suspected familial cases involving the 5-10% of MEN/FMTC families that do not have detectable RET mutations. ^{[3, 4]}

After curative surgery for MTC, serum calcitonin levels fall to undetectable levels over several weeks. If they remain elevated postoperatively, this is usually an indicator of residual cancer, either from local lymph node spread or from distant metastases. In this situation, diagnostic imaging is generally required for further workup. If only local spread is identified, additional surgical procedures may be beneficial. It remains to be determined, however, whether such approaches actually improve survival.

A retrospective, observational study by Fanget et al reported that among patients who underwent surgery for MTC, the risk of disease recurrence was 25% when normalized postsurgical calcitonin levels were found, compared with 3% in patients who demonstrated undetectable levels of calcitonin. ^[5]

If previously undetectable or very low postoperative serum calcitonin levels are found to have increased, disease recurrence or spread is highly likely and further diagnostic evaluation is warranted.

The specifics of specimen collection are as follows:

• Preferred specimen – Serum (plasma also an acceptable specimen)

• Collection container/tube - Red top tube, SST, or green top tube (sodium or lithium heparin), depending on the method of testing

• Transfer container/tube - Plastic vial

• Specimen volume - 0.8 mL

• If hemolysis or lipemia is present, specimen should be rejected

• After drawing the specimen, it should be placed immediately in ice or under refrigeration

• Serum frozen 15 days

Measurement of calcitonin

Calcitonin is assessed in clinical laboratories using noncompetitive immunoassays of different formats: enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), and chemiluminescent immunoassays. The assays are heterogeneous, with different sensitivity and specificity, and often they recognize multiple forms of immunoreactive calcitonin. As consequence, the reference intervals are dependent on the method used for assessment.

Description

Calcitonin is produced and released by parafollicular cells of the thyroid (”the C cells”). Multiple forms of circulating calcitonin have been found in the serum of healthy and diseased individuals. They all are referred as “circulating immunoreactive calcitonin.” Calcitonin is derived from larger precursors. Precalcitonin (116 amino acids) is cleaved to procalcitonin, which is further cleaved to immature calcitonin (33 amino acids) and then to mature calcitonin, a monomer of a 3.5-kd peptide composed of 32 amino acids, which is the only biologically active form.

The full spectrum of calcitonin regulation is not completely understood, but its secretion is primarily regulated by the ionized calcium concentration, with increases in ionized calcium leading to increases in calcitonin, while pharmacological doses of calcitonin reduce serum calcium and phosphate concentrations by inhibiting osteoclastic bone resorption and reducing renal tubular reabsorption. Other potent calcitonin secretagogues include the gastrointestinal peptide hormones, gastrin in particular. A mild postprandial increase in calcitonin concentration occurs. ^[2]

Calcitonin's precise physiologic role in humans remains to be elucidated. It is known to act on the bones, kidneys, and gastrointestinal tract. Calcitonin binds directly to osteoclasts, thereby directly inhibiting osteoclastic bone resorption, an effect that is observed within minutes after calcitonin administration. Although this inhibition may be important in short-term control of calcium loads, it is transient and probably plays an insignificant role in overall calcium homeostasis. Calcitonin also inhibits the action of parathyroid hormone and vitamin D. ^[6]

Although some clinical studies suggest that the serum calcium concentration may be unaffected in patients with total thyroidectomy, others suggest that medullary thyroid carcinoma (MTC) and excess calcitonin can lead to marked hypocalcemia. Calcitonin induces increased renal clearance of calcium and phosphate. ^[7]

Indications/Applications

A calcitonin assay is helpful in identifying patients with nodular thyroid disease. ^{[8, 9, 10]} It is often performed in the hope of identifying early MTC, which may be seen in the setting of multiple endocrine neoplasia (MEN) type 2. Successful treatment of MTC depends on early detection; late detection confers a poor prognosis. ^[11] Slight elevations in calcitonin with subsequent surgical exploration of the thyroid may allow the clinician to identify this lesion in its early, nonpalpable stage of development.

In the United States, routine testing for calcitonin in patients with nodular thyroid disease was long considered not to be cost-effective. In Europe, however, studies have shown that this practice is in fact cost-effective. One analysis performed in the United States concluded that routine calcitonin testing in patients with nodular thyroid disease was as cost-effective as other screening tests, such as those for thyroid-stimulating hormone, breast cancer (mammography), and colon cancer (colonoscopy). ^[12]

The specificity of calcitonin testing increases with provocative testing. Pentagastrin stimulation before a calcitonin assay increases diagnostic sensitivity for MTC. Plasma or serum calcitonin levels higher than 100 pg/mL should raise the index of suspicion for this aggressive neoplasm.

Considerations

In addition to calcitonin testing being very useful for patients with MTC/familial MTC, calcitonin levels are reported to be increased in other malignancies, such as carcinoid tumors, lung carcinoma, melanoma, pancreatic and breast carcinoma, and pheochromocytoma.

Elevation of calcitonin has been reported in acute and chronic kidney injury, hypercalcemia, and severe illness.

A serum calcitonin assay is not useful for evaluating calcium or metabolic bone diseases.

Procalcitonin evaluation is used to aid antibiotic therapy decisions in chronic microbial infections. ^{[13, 14]}