Calcitonin

Calcitonin is a 32 amino acid peptide hormone made by the parafollicular C cells of the thyroid. Its physiological role in adults is minor, and loss of the thyroid does not cause calcium disturbance. It is the most sensitive and specific marker of C-cell disease: medullary thyroid carcinoma (MTC) and C-cell hyperplasia. It is measured by two site immunoassay in serum or plasma and reported in ng/L (pg/mL), or pmol/L (1 ng/L is about 0.29 pmol/L).

The test is used to evaluate thyroid nodules in selected patients, to screen carriers of RET variants, to judge extent of disease before surgery, and to monitor after thyroidectomy. Basal and stimulated values determine the extent of surgery and the likelihood of cure.

Medullary thyroid carcinoma makes up 1 to 2% of thyroid cancers. About 75% are sporadic and 25% hereditary, as multiple endocrine neoplasia type 2A or 2B or familial MTC, caused by activating RET variants. Roughly 0.3 to 1% of patients with thyroid nodules have MTC. Ten year survival is about 95% when disease is confined to the thyroid and under 40% with distant metastases.

Indications. Thyroid nodule with suspicious cytology for MTC, family history of MTC or MEN 2, a RET variant in the patient or family, unexplained chronic diarrhoea with a thyroid mass, flushing with a thyroid mass, follow up after thyroidectomy for MTC, and assessment of residual disease after surgery.

Specimen. Serum or EDTA plasma, taken after an overnight fast and separated and frozen promptly, since calcitonin is unstable at room temperature (a delay of over 1 hour lowers the result). Record medicines, smoking and pregnancy.

Ranges are assay specific and sex specific.

Basal calcitonin. In most assays, under 10 ng/L in women and under 18 ng/L in men, with higher values in men due to larger C-cell mass. Many centres use under 10 ng/L for both sexes.

• Under 10 ng/L: MTC is very unlikely.
• 10 to 100 ng/L: C-cell hyperplasia, small MTC, or non-thyroid causes. Stimulation testing or repeat measurement is needed.
• Over 100 ng/L: MTC likely, with positive predictive value of 90 to 100%.
• Over 500 ng/L: lymph node metastases in the neck and mediastinum are likely, and over 1000 ng/L suggests distant metastases.

Stimulated calcitonin. Intravenous calcium gluconate (2.5 mg/kg of elemental calcium over 30 seconds) or pentagastrin (where available) with sampling at 2, 5 and 10 minutes. A peak under 30 ng/L excludes MTC, 30 to 100 ng/L is indeterminate, and over 100 ng/L supports MTC. In asymptomatic RET carriers, the test timing helps decide the age of prophylactic thyroidectomy.

Doubling time. Calcitonin and CEA doubling times over 24 months have a good prognosis, 6 to 24 months an intermediate prognosis, and under 6 months an aggressive course with a five year survival of about 25%.

Post-operative monitoring.

• After total thyroidectomy with neck dissection, calcitonin should fall to undetectable (under 2 ng/L) within 3 to 6 months. Half life is about 1 hour, but clearance after surgery takes weeks.
• Undetectable basal and stimulated calcitonin indicates biochemical cure, with recurrence of under 3% in 10 years.
• A detectable or rising value indicates residual or recurrent disease and prompts neck ultrasound, cross-sectional imaging and PET.
• Monitoring is every 6 months in the first years and then yearly.

Causes of raised calcitonin other than MTC.

• Physiological and technical: men (higher), smoking, heterophile antibodies, hypergastrinaemia and macro-calcitonin.
• C-cell hyperplasia (reactive in chronic thyroiditis, hyperparathyroidism or follicular tumours).
• Kidney failure (reduced clearance, values usually under 50 ng/L).
• Proton pump inhibitors and other causes of hypergastrinaemia, and atrophic gastritis.
• Neuroendocrine tumours of the lung, gut and pancreas (small cell lung cancer, carcinoid, pancreatic neuroendocrine tumours).
• Hypercalcaemia, Zollinger-Ellison syndrome, pernicious anaemia, sepsis (procalcitonin cross-reaction in some assays), and chronic inflammatory conditions.
• Beta blockers, glucocorticoids, omeprazole, and calcium or glucagon infusion, which stimulate release.

Critical values and findings needing immediate action.

• Calcitonin over 100 ng/L with a thyroid nodule: urgent staging and surgical planning. Phaeochromocytoma must be excluded with plasma metanephrines before any surgery, since MEN 2 causes it.
• Diarrhoea, flushing or Cushing syndrome from ectopic ACTH in advanced MTC.
• A RET variant carrier of MEN 2B (codon 918), who needs thyroidectomy in the first year of life.
• Rising calcitonin with bone pain, hepatomegaly or dyspnoea.

Interferences and pitfalls.

• Routine calcitonin in all thyroid nodules finds more disease but also false positives, and is used by risk.
• Heterophile antibodies give false elevation, and very high calcitonin gives a falsely low reading (hook effect), so dilution is needed when the clinical picture does not match.
• Biotin interferes with some immunoassays.
• Calcitonin negative MTC is rare (about 1%) and occurs with poorly differentiated tumours, and CEA is then useful.
• Proton pump inhibitors raise basal values modestly.
• Assays differ in reference limits and are not interchangeable.
• Delay in processing falsely lowers the value.
• Procalcitonin is a different molecule and does not substitute.

Special groups.

• Children with RET variants: testing starts early. MEN 2B from birth to 1 year, high risk codon 634 or 883 before 5 years, and other variants by calcitonin from age 5 years or later.
• Pregnancy: calcitonin rises, and interpretation needs care.
• Men: reference limits are higher.
• Kidney failure: modest elevation.
• Regions: late presentation with advanced disease is common where thyroid imaging and genetic testing are limited.

Follow up tests. Repeat basal calcitonin, stimulated calcitonin, CEA, RET germline sequencing, plasma free metanephrines, serum calcium and parathyroid hormone, neck ultrasound with fine needle aspiration (calcitonin washout), CT or MRI of neck, chest and liver, PET, and bone scan.