Calcitonin (thyrocalcitonin)

Calcitonin Overview

Calcitonin, also known as thyrocalcitonin, is a hormone primarily involved in calcium and phosphate metabolism. In humans, it is produced mainly by the parafollicular cells (also called C-cells) of the thyroid gland.

While its physiological role in normal calcium homeostasis in adults is considered relatively minor compared to Parathyroid Hormone (PTH) and Vitamin D, calcitonin levels become clinically significant as a highly sensitive and specific tumor marker for Medullary Thyroid Carcinoma (MTC), a cancer originating from the C-cells.

Biology and Function

Calcitonin is a polypeptide hormone consisting of 32 amino acids, with a molecular weight of approximately 3500 Daltons (3.5 kDa).

Its main physiological action is to lower blood calcium levels, opposing the effects of PTH. It achieves this primarily by:

• Inhibiting the activity of osteoclasts (cells that break down bone tissue), thus reducing the release of calcium from bone into the blood.
• Potentially increasing calcium excretion by the kidneys (though this effect is generally considered weak in humans).

Secretion of calcitonin is stimulated mainly by high blood calcium levels.

Clinical Indications for Calcitonin Testing

Measuring calcitonin levels in the blood (serum or plasma) is indicated primarily for:

1. Diagnosis of Medullary Thyroid Carcinoma (MTC): Elevated calcitonin is the hallmark of MTC. Testing is crucial in evaluating thyroid nodules, especially if MTC is suspected based on fine-needle aspiration (FNA) cytology or family history.
2. Monitoring Patients with MTC: Serial calcitonin measurements are used after surgery (thyroidectomy) and other treatments to:
   • Assess for residual disease (persistent elevation).
   • Detect recurrence (rising levels over time).
   • Monitor response to systemic therapy for metastatic MTC.
3. Screening High-Risk Individuals: Testing family members of patients with hereditary forms of MTC (associated with Multiple Endocrine Neoplasia type 2 - MEN 2A and MEN 2B, or Familial MTC - FMTC) due to mutations in the RET proto-oncogene. Early detection in these individuals allows for prophylactic thyroidectomy.
4. Provocative Testing: In cases where basal calcitonin levels are borderline or equivocal, stimulation tests (using intravenous calcium gluconate or pentagastrin - though pentagastrin is often unavailable) can be performed. An exaggerated rise in calcitonin after stimulation strongly suggests C-cell hyperplasia or MTC.

Interpretation of Calcitonin Levels

Interpretation depends heavily on the clinical context and the specific laboratory assay used.

• Normal Range: Basal (unstimulated) calcitonin levels are generally very low in healthy individuals. Typical upper limits of normal vary but are often around:
  • Men: < 8.4 - 15 pg/mL (Note: Original text uses ng/L which is the same unit numerically as pg/mL. Values here reflect common ranges, but lab specifics matter).
  • Women: < 5.0 - 10 pg/mL.
  • Always refer to the reference range provided by the specific laboratory performing the test.
• Elevated Levels:
  • Significantly Elevated Basal Levels: Levels substantially above the upper limit of normal (e.g., > 100 pg/mL) are highly suggestive of Medullary Thyroid Carcinoma (MTC). The level often correlates with tumor burden (size and extent of spread).
  • Moderately Elevated or Borderline Levels: May indicate early MTC, C-cell hyperplasia (a precancerous condition), or potentially a benign condition (see below). Provocative testing may be helpful in these cases.
  • Post-Operative Levels: After total thyroidectomy for MTC, calcitonin levels should ideally become undetectable or fall to very low levels. Persistently elevated or rising levels indicate residual or recurrent disease.

Factors Affecting Calcitonin Levels

While highly specific for MTC when significantly elevated, calcitonin levels can be influenced by other factors:

• Medullary Thyroid Carcinoma (MTC): The primary cause of markedly elevated levels.
• C-cell Hyperplasia: Precursor to MTC, can cause mild to moderate elevations.
• Renal Failure: Impaired kidney function can lead to decreased clearance and moderately elevated calcitonin levels.
• Other Neuroendocrine Tumors: Rarely, other neuroendocrine tumors (e.g., carcinoid tumors, pancreatic neuroendocrine tumors) can produce calcitonin.
• Hypercalcemia/Hyperparathyroidism: High calcium levels stimulate calcitonin release, potentially causing mild elevations.
• Medications: Proton pump inhibitors (PPIs), glucagon, beta-agonists, and possibly others can sometimes cause mild elevations.
• Pregnancy: Levels may be slightly higher during pregnancy.
• Benign Lung Diseases: Slight increases have been reported in some cases.
• Benign Thyroid Conditions: Occasionally seen in Hashimoto's thyroiditis or other goiters, but usually only mild elevations.
• Smoking: Some studies suggest smokers may have slightly higher baseline levels.
• Assay Interference: Heterophile antibodies or other interfering substances can rarely affect test results.

The Calcitonin Blood Test Procedure

• Sample Type: Blood serum or plasma.
• Preparation: For basal calcitonin levels, fasting is usually required (e.g., overnight) as food intake (especially calcium or protein) can stimulate calcitonin release. Check specific lab instructions. Provocative testing requires specific protocols involving IV infusions.
• Collection: Standard venipuncture to draw a blood sample from a vein in the arm. Samples may need special handling (e.g., collection on ice, prompt separation and freezing) as calcitonin can degrade; follow lab requirements strictly.
• Analysis: Measured in the laboratory using sensitive immunoassays (e.g., chemiluminescence immunoassays - CLIA).

References

1. American Thyroid Association (ATA) Guidelines Task Force on Medullary Thyroid Carcinoma (Wells Jr, S. A., Asa, S. L., Dralle, H., Elisei, R., Evans, D. B., ... & Moley, J. F.). (2015). Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. *Thyroid*, 25(6), 567–610. https://doi.org/10.1089/thy.2014.0335
2. National Cancer Institute (NCI). (n.d.). Thyroid Cancer Treatment (PDQ®)–Health Professional Version. Retrieved from https://www.cancer.gov/types/thyroid/hp/thyroid-treatment-pdq
3. Mayo Clinic Laboratories. (n.d.). Test ID: CALCA - Calcitonin, Serum. Test Catalog. Retrieved from https://www.mayocliniclabs.com/test-catalog/Overview/81719 (Example lab reference)
4. Costante, G., Meringolo, D., Durante, C., Bianchi, D., Zivi, A., Tumino, S., ... & Filetti, S. (2009). Predictive value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with thyroid nodules. *The Journal of Clinical Endocrinology & Metabolism*, 94(10), 3866–3872. https://doi.org/10.1210/jc.2009-0671
5. Leboulleux, S., Baudin, E., Travagli, J. P., & Schlumberger, M. (2004). Medullary thyroid carcinoma. *Clinical Endocrinology*, 61(3), 299–310. https://doi.org/10.1111/j.1365-2265.2004.02098.x