Calcitonin test: what the hormone does, the normal range and what a high calcitonin level means

A calcitonin above 100 pg/mL in someone with a thyroid nodule means medullary thyroid cancer with near certainty, and the number itself says something about the tumor: levels in the low hundreds usually come from a tumor under a centimeter confined to the thyroid, levels above 500 to 1,000 pg/mL make lymph node spread likely and distant spread possible, and levels in the tens of thousands indicate widespread disease. Before any surgery, two further tests are standard: plasma or urine metanephrines to exclude a pheochromocytoma (which must be removed first, because operating on someone with an undiagnosed adrenal tumor can trigger a hypertensive crisis), and calcium and PTH to check for hyperparathyroidism. Germline RET testing follows for everyone, because about 25 percent of medullary cancers are inherited as part of MEN2 and finding a mutation changes the management of the whole family.

Most high results are not that clear-cut. Values between the reference limit and 100 pg/mL are the common finding, and the majority of these are not cancer: chronic kidney disease raises calcitonin because the kidney clears it; proton pump inhibitors and other causes of high gastrin stimulate C cells and can double or triple the level; smoking, obesity, autoimmune thyroiditis, hypercalcemia, sepsis and some lung, pancreatic and other neuroendocrine tumors all raise it; and some people simply have more C cells (C-cell hyperplasia), particularly men. The first step with a gray-zone result is to repeat it properly, on a chilled sample, off proton pump inhibitors if possible, with a check of kidney function. If it is confirmed above the sex-specific thresholds (about 17 pg/mL in women and 26 in men), a calcium stimulation test and a careful thyroid ultrasound follow, and a stimulated peak above 100 to 130 pg/mL usually leads to surgery.

After surgery for medullary cancer the interpretation changes again. Calcitonin falls with a half-life of hours, and a level that is undetectable at 3 to 6 months means the operation removed all the tumor (a complete biochemical response), with a low long-term recurrence risk. A level that is detectable but under 150 pg/mL usually reflects small amounts of disease in the neck, found on ultrasound and often simply watched if it grows slowly. A level above 150 pg/mL prompts imaging of chest, liver and bone. The most useful number from then on is the doubling time: if calcitonin takes more than 2 years to double, 10-year survival is close to 100 percent; if it doubles in under 6 months, the disease is aggressive and systemic treatment (kinase inhibitors that target RET) is considered. CEA is followed alongside, and a CEA that rises faster than calcitonin suggests the tumor is losing differentiation.

Common causes

1. 1.

   Medullary thyroid cancer (sporadic)

   About 75 percent of medullary cancers arise without an inherited mutation, usually as a single nodule in someone aged 40–60. Calcitonin above 100 pg/mL is essentially diagnostic; the fine-needle biopsy is often misread as another thyroid tumor, so a calcitonin level or calcitonin staining on the biopsy is what secures the diagnosis.

2. 2.

   Hereditary medullary cancer and MEN2 (RET mutation)

   Multiple endocrine neoplasia type 2A combines medullary cancer with pheochromocytoma (about 50 percent) and hyperparathyroidism (20–30 percent); MEN2B adds mucosal neuromas and a Marfan-like build and causes aggressive cancer in early childhood. Calcitonin is used to time prophylactic thyroidectomy in children who carry the mutation.

3. 3.

   C-cell hyperplasia

   An increase in the number of normal C cells, more common in men, in Hashimoto's thyroiditis, with hypercalcemia or high gastrin, and in older people. It produces mildly raised basal and stimulated levels (usually under 50–100 pg/mL) and in the hereditary setting is the precursor of cancer; the sporadic form usually is not.

4. 4.

   Chronic kidney disease

   Calcitonin is cleared by the kidney, and levels rise as eGFR falls; people on dialysis commonly have values of 20–50 pg/mL and occasionally above 100 with no thyroid disease. The stimulation test is less reliable in kidney failure.

5. 5.

   Proton pump inhibitors and high gastrin

   Gastrin stimulates C cells. Omeprazole, pantoprazole and related drugs, pernicious anemia, atrophic gastritis and Zollinger-Ellison syndrome all raise calcitonin, usually to under 30 pg/mL but occasionally higher. Stopping the PPI for 2–4 weeks before a repeat test (where safe) clarifies.

6. 6.

   Other neuroendocrine tumors

   Small-cell and carcinoid lung cancers, pancreatic neuroendocrine tumors, pheochromocytoma, insulinoma and some breast and prostate cancers can secrete calcitonin ectopically, sometimes to levels above 100 pg/mL. A high calcitonin with a normal thyroid ultrasound and stimulation test points this way.

7. 7.

   Hypercalcemia and hyperparathyroidism

   High blood calcium is the physiological stimulus for calcitonin, so untreated hyperparathyroidism raises it modestly; it normalizes when calcium is corrected.

8. 8.

   Smoking, alcohol and obesity

   Smokers have higher basal and stimulated calcitonin than non-smokers, probably through C-cell stimulation by nicotine; heavy alcohol use and higher body weight also push values up by a few pg/mL. These shift a result from the top of normal into the gray zone rather than to diagnostic levels.

9. 9.

   Autoimmune thyroiditis

   Hashimoto's thyroiditis is associated with C-cell hyperplasia and mildly raised calcitonin in a minority of people; a thyroid ultrasound and stimulation test separate this from a small medullary cancer.

10. 10.

    Sepsis, systemic inflammation and heterophile antibodies

    Severe infection raises procalcitonin (the precursor) and, on some assays, the measured calcitonin. Heterophile antibodies can bridge the assay antibodies and create a false positive, suspected when the level does not fit and confirmed by rerunning with blocking reagents or on a different platform.

Symptoms that can go with it

• Usually none; most high calcitonin levels are found during the work-up of a painless thyroid nodule or on screening
• A firm lump in the lower neck, sometimes with enlarged lymph nodes along the side of the neck
• Hoarseness, difficulty swallowing or a pressure sensation in the neck with larger tumors
• Watery diarrhea and flushing, which occur when calcitonin levels are very high (often above several thousand pg/mL) with advanced medullary cancer
• Episodes of headache, pounding heartbeat, sweating and high blood pressure, which suggest a pheochromocytoma in MEN2
• Kidney stones, bone pain or fatigue from hyperparathyroidism in MEN2A
• Bumps on the lips and tongue, a tall thin build and bowel problems from infancy in MEN2B
• Heartburn or indigestion treated with a proton pump inhibitor, or known kidney disease, when the elevation is benign

A low or undetectable calcitonin is the expected result in a healthy adult and carries no health meaning on its own. Many people, especially women, have levels below the detection limit of the assay (often 1 or 2 pg/mL), and there is no recognized calcitonin deficiency state: after total thyroidectomy the hormone disappears from the blood and calcium balance, bone density and kidney function are maintained by parathyroid hormone and vitamin D. The historical concern that people without a thyroid would lose bone through lack of calcitonin has not been borne out in long-term studies, where bone loss after thyroidectomy is explained by over-replacement with levothyroxine rather than by missing calcitonin.

The one setting where 'undetectable' is actively good news is after surgery for medullary thyroid cancer. An undetectable calcitonin 3 to 6 months after the operation (allowing time for the hormone to clear and for the postoperative stress response to settle) means no tumor remains that is capable of secreting it, which is the definition of a complete biochemical response. People in this group are followed with yearly calcitonin and CEA, and about 95 percent remain free of recurrence at 10 years. A level that is low but detectable does not count as a complete response; it is followed with doubling-time calculations and imaging as described above. A falsely low result can occur if the sample sat at room temperature before being separated, which is why borderline post-surgical results are repeated with proper handling before anyone is reassured.

Common causes

1. 1.

   Normal health

   Low calcitonin is the norm; most healthy women and many men have values below the assay's detection limit. No action is needed.

2. 2.

   Total thyroidectomy

   Removal of the whole gland removes the C cells; calcitonin becomes undetectable within days. Calcium regulation continues normally through PTH and vitamin D.

3. 3.

   Successful surgery for medullary thyroid cancer

   An undetectable level at 3–6 months after operation defines a complete biochemical response; follow-up continues yearly because late recurrence, though uncommon, can occur.

4. 4.

   Sample handling

   Calcitonin degrades at room temperature; a sample that was not chilled and separated promptly can read falsely low. Borderline results are repeated with correct handling.

5. 5.

   Medication effects

   Salmon calcitonin nasal spray or injections (used for Paget's disease, hypercalcemia or osteoporosis) are detected by some assays and not others, and chronic use can suppress the person's own C cells; mention it to the lab.

Symptoms that can go with it

• None; low calcitonin does not cause symptoms and is not treated
• Tingling, cramps or muscle spasms after thyroid surgery are due to low calcium from parathyroid injury, not to low calcitonin, and need prompt calcium and PTH testing