Calcitonin

Calcitonin, a hormone produced by the thyroid gland, serves as a crucial biomarker in clinical diagnostics. Understanding the role and significance of calcitonin is paramount in various medical contexts, particularly in the assessment and management of thyroid disorders and certain types of cancer. 

This article involves a comprehensive exploration of calcitonin as a biomarker, covering its physiological functions, laboratory testing procedures, related biomarkers, and clinical implications.

Calcitonin's involvement in calcium regulation and bone metabolism underscores its importance in maintaining overall health. Furthermore, its role in thyroid physiology and pathology, particularly in thyroid cancer, highlights its significance as a diagnostic and prognostic tool.

 By elucidating the functions and testing methodologies associated with calcitonin, healthcare professionals can better interpret test results, diagnose conditions accurately, and guide appropriate treatment strategies.

What is Calcitonin?

Calcitonin, a peptide hormone produced by the parafollicular cells (also known as C-cells) of the thyroid gland, plays a pivotal role in calcium homeostasis and bone metabolism. 

Definition and Role of Calcitonin

Calcitonin is a key regulator of calcium levels in the bloodstream, exerting its effects primarily on bone tissue. Its main role involves inhibiting osteoclast activity, which are cells responsible for breaking down bone tissue and releasing calcium into the bloodstream. 

By suppressing osteoclast function, calcitonin helps maintain bone density and prevents excessive calcium release from bones. 

In the kidneys, calcitonin increases diuresis and reduces calcium and phosphate reabsorption.   

Finally, calcitonin decreases calcium absorption in the GI tract.

Calcitonin has a short absorption half-life of 10–15 minutes and an elimination rate of 50–80 minutes. [MCLAUGHLIN>>>>

Physiological Functions of Calcitonin: What Does Calcitonin Do?  [5., 8., 11.]

The primary physiological function of calcitonin revolves around its role in counteracting the effects of parathyroid hormone (PTH) on calcium regulation. While PTH stimulates bone resorption and enhances calcium reabsorption in the kidneys, calcitonin opposes these actions by promoting calcium deposition in bones and enhancing renal excretion of calcium. 

Calcitonin Promotes Bone Health

• Inhibits bone resorption by directly slowing down osteoclast activity, maintaining bone density and preventing osteoporosis.
• Promotes calcium deposition in bone tissue, supporting bone remodeling and repair.
• Its absence in knockout mice results in increased bone mass, suggesting a role in bone metabolism.

Calcitonin Reduces Hypercalcemia

• Enhances calcium excretion by the kidneys, aiding in the regulation of blood calcium levels.
• Modulates gastrointestinal calcium absorption, contributing to systemic calcium homeostasis.

Calcitonin in the GI Tract

• Stimulated by increased serum calcium and gastrointestinal hormones like gastrin.
• Interaction with gastrointestinal hormones suggests a possible postprandial role in bone health.

Calcitonin in the Kidneys

• May increase renal production of 1,25 (OH)2 vitamin D (1,25D), particularly during pregnancy and lactation.
• Enhances the excretion of calcium by the kidneys.
• Helps regulate blood calcium levels by influencing calcium and phosphate reabsorption in the renal tubules.
• Plays a minor role in renal physiology compared to its effects on bone metabolism.

‍Calcitonin in Pregnancy

• Potentially aids in maternal-fetal calcium transfer and prevents bone loss during pregnancy and lactation.

This delicate balance between calcitonin and PTH ensures proper calcium homeostasis in the body, vital for various physiological processes such as muscle contraction, nerve function, and blood clotting.

Regulation of Calcitonin Secretion

Calcitonin secretion is tightly regulated by various factors, including serum calcium levels, hormonal signals, and neural inputs. 

High calcium in the blood raises calcitonin secretion.  Gastrin also increases calcitonin secretion.  [5.] 

Conversely, decreased blood calcium levels or high levels of other hormones such as thyroid-stimulating hormone (TSH) may inhibit calcitonin secretion. Additionally, neural inputs from the central nervous system can modulate calcitonin release, providing an additional layer of regulation to maintain calcium homeostasis.

Production of Calcitonin  [5., 8.]

The production of calcitonin occurs primarily within specialized cells located in the thyroid gland known as parafollicular cells or C-cells. 

Parafollicular Cells: Source of Calcitonin  [6.]

Parafollicular cells, situated within the thyroid gland's connective tissue between follicles containing thyroid hormone-producing cells (thyrocytes), are responsible for synthesizing and secreting calcitonin. 

These neuroendocrine cells possess distinctive ultrastructural features, including prominent Golgi apparatus and abundant secretory vesicles containing procalcitonin, the precursor molecule of calcitonin. Parafollicular cells exhibit specialized secretory machinery necessary for the efficient processing and release of calcitonin in response to physiological stimuli.

Regulation of Calcitonin Synthesis

Factors that Increase Calcitonin Secretion:

• Elevated serum calcium levels
• Calcitonin gene-related peptide (CGRP)
• Glucagon-like peptide 1 (GLP-1)
• Neural inputs from the autonomic nervous system, particularly adrenergic and cholinergic signals

Factors that Decrease Calcitonin Secretion:

• Adrenergic and cholinergic signals
• Low serum calcium levels
• Also, hypothyroidism is associated with low calcitonin secretion [10.]

Intracellular Processing of Procalcitonin  [2.]

Upon synthesis, procalcitonin undergoes post-translational modifications within the endoplasmic reticulum and Golgi apparatus of parafollicular cells. These modifications include cleavage of the procalcitonin molecule to generate mature calcitonin, along with the production of other peptide fragments.

Once processed, calcitonin is packaged into secretory vesicles and transported to the cell membrane for subsequent release into the bloodstream. The precise mechanisms underlying procalcitonin processing and trafficking within parafollicular cells ensure the efficient synthesis and secretion of biologically active calcitonin in response to physiological demands.

Environmental and Pathological Influences  [1.]

Various environmental and pathological factors can impact calcitonin production and secretion, although research is lacking on many of the environmental toxins that can affect calcitonin.   

For instance, exposure to certain chemicals, drugs, or environmental toxins may alter parafollicular cell function and disrupt calcitonin synthesis.  These include some heavy metals, tobacco smoking, and BPA.  [1.]

Additionally, pathological conditions such as thyroid tumors or thyroiditis can affect parafollicular cell activity, leading to aberrant calcitonin production and secretion. Additionally, bacterial infections reduce calcitonin secretion.  [2.]

Understanding the regulatory mechanisms and environmental influences governing calcitonin synthesis is essential for interpreting calcitonin levels accurately and diagnosing associated medical conditions.

Lab Testing for Calcitonin

Accurate measurement of calcitonin levels is essential for diagnosing and monitoring various thyroid disorders and conditions associated with abnormal calcitonin production.

Calcitonin is assessed with a blood test, which typically requires a venipuncture.  Fasting may be required for this test; it is important to consult your ordering provider for more information.  

Clinical Interpretation

Interpreting calcitonin test results requires consideration of various factors, including patient demographics, clinical history, and assay characteristics. Elevated calcitonin levels may indicate conditions such as medullary thyroid carcinoma (MTC), a rare form of thyroid cancer derived from parafollicular cells. 

However, elevated calcitonin levels can also occur in non-neoplastic conditions such as thyroid nodules, thyroiditis, or renal insufficiency. Therefore, clinical correlation and additional diagnostic tests may be necessary to determine the underlying cause of elevated calcitonin levels and guide appropriate management.

Clinical Indications

Calcitonin testing is primarily indicated in the evaluation of thyroid nodules and suspected thyroid cancer, particularly medullary thyroid cancer (MTC). 

Screening for elevated calcitonin levels may be recommended in individuals with a family history of MTC or multiple endocrine neoplasia type 2 (MEN2) syndrome. 

Additionally, calcitonin testing may be performed as part of routine thyroid function testing or in the assessment of patients with hypercalcemia, osteoporosis, or renal dysfunction. The clinical indications for calcitonin testing may vary based on individual patient characteristics and healthcare provider discretion.

Reference Range for Calcitonin

It is important to consult with the ordering lab company for their reference ranges used.  Common reference ranges are given as: [9.]

Basal (plasma):

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):

Males: ≤190 pg/mL or ≤190 ng/L

Females: ≤ 130 pg/mL or ≤ 130 ng/L

Testing Biomarkers Related to Calcitonin

In addition to calcitonin, several other biomarkers may be evaluated concurrently to provide a comprehensive assessment of thyroid function and associated pathologies. 

Thyroid Hormones: T3 and T4

Thyroid hormones triiodothyronine (T3) and thyroxine (T4) are key regulators of metabolism, growth, and development. 

Measurement of serum T3 and T4 levels provides valuable information about thyroid function and can help identify conditions such as hyperthyroidism or hypothyroidism. 

Abnormalities in thyroid hormone levels may influence calcitonin secretion and thyroid tumor development, highlighting the importance of assessing thyroid hormone status alongside calcitonin testing.

Thyroid-Stimulating Hormone (TSH)

Thyroid-stimulating hormone (TSH), also known as thyrotropin, is produced by the pituitary gland and regulates thyroid hormone synthesis and secretion. 

TSH levels are inversely correlated with thyroid hormone levels, with elevated TSH indicating hypothyroidism and suppressed TSH suggesting hyperthyroidism. 

Measurement of TSH levels alongside calcitonin testing can help differentiate primary thyroid disorders from secondary or tertiary causes of thyroid dysfunction and guide appropriate management strategies.

Parathyroid Hormone (PTH)

Parathyroid hormone (PTH) regulates calcium and phosphate homeostasis by influencing bone metabolism, renal calcium reabsorption, and intestinal calcium absorption. Abnormalities in PTH levels can impact calcitonin secretion and bone remodeling processes. 

Measurement of serum PTH levels alongside calcitonin testing is essential for evaluating calcium disorders, such as hyperparathyroidism or hypoparathyroidism, and assessing bone health in individuals with thyroid disorders or renal dysfunction.

Serum Calcium and Phosphate

Serum calcium and phosphate levels are tightly regulated by hormonal signals, including calcitonin, PTH, and vitamin D. Dysregulation of calcium and phosphate metabolism can impact calcitonin secretion and bone mineralization processes. 

Monitoring serum calcium and phosphate levels alongside calcitonin testing is critical for assessing mineral metabolism disorders, such as hypercalcemia, hypocalcemia, hyperphosphatemia, or hypophosphatemia, and guiding appropriate treatment interventions.

Clinical Significance of Calcitonin Testing  [3., 4.]

Diagnosis of Medullary Thyroid Carcinoma (MTC)

Calcitonin testing serves as a cornerstone in the diagnosis of medullary thyroid carcinoma (MTC), a rare form of thyroid cancer arising from parafollicular cells. Elevated serum calcitonin levels are characteristic of MTC and play a central role in its diagnosis. 

Measurement of basal calcitonin levels and/or stimulated calcitonin levels following pentagastrin or calcium stimulation tests can aid in the detection of MTC, particularly in individuals with thyroid nodules or a family history of MTC. Early diagnosis of MTC allows for timely intervention and improved prognosis.

Screening for Familial MTC and Multiple Endocrine Neoplasia Type 2 (MEN2)

Calcitonin testing is instrumental in screening individuals with a family history of MTC or multiple endocrine neoplasia type 2 (MEN2) syndrome, an inherited cancer syndrome characterized by MTC, pheochromocytoma, and hyperparathyroidism. Regular monitoring of serum calcitonin levels in at-risk individuals enables early detection of MTC or preclinical disease, facilitating timely intervention and genetic counseling for affected families. Screening protocols typically involve periodic measurement of basal calcitonin levels and/or genetic testing for mutations associated with MEN2.

Evaluation of Thyroid Nodules and Indeterminate Thyroid Cytology

Calcitonin testing may be employed in the evaluation of thyroid nodules and indeterminate thyroid cytology findings on fine-needle aspiration biopsy (FNAB). Elevated calcitonin levels in the setting of thyroid nodules may raise suspicion for MTC or other thyroid malignancies, prompting further diagnostic workup and management. Calcitonin testing can help differentiate benign thyroid nodules from potentially malignant lesions, guiding treatment decisions and minimizing unnecessary interventions.

Monitoring Thyroid Cancer Recurrence and Response to Treatment

Serial monitoring of serum calcitonin levels is essential for assessing disease recurrence and treatment response in patients with MTC or other forms of thyroid cancer. Following surgical resection or adjuvant therapy, regular measurement of calcitonin levels allows for early detection of disease recurrence and timely intervention. Trends in calcitonin levels over time provide valuable prognostic information and guide treatment decisions, such as the initiation of salvage therapies or participation in clinical trials.

Prognostic Marker in Thyroid Cancer

Calcitonin levels also serve as a prognostic marker in thyroid cancer, particularly in MTC. Higher baseline calcitonin levels and persistent elevation following treatment are associated with increased disease burden, metastatic spread, and reduced survival rates. Serial monitoring of calcitonin levels enables clinicians to assess disease progression, predict outcomes, and optimize patient management strategies accordingly.