Low Calcitonin Levels Research Articles

Impact of dietary, lifestyle and sociodemographic factors on calcitonin levels in a healthy population

Calcitonin (CT), a hormone secreted by thyroid parafollicular C cells, plays a role in calcium homeostasis and bone health. Understanding the relationship between CT levels and dietary, sociodemographic, and lifestyle factors is essential for public health and hormonal balance studies. This study encompassed 3323 healthy participants from the Croatian biobank. We utilized principal component analysis (PCA) to reduce food items into dietary patterns. Regression analysis was used to investigate the relationship between CT levels and data collected through questionnaires, accounting for age and sex. CT levels exhibited sex-specific differences, with higher values observed in males. Positive associations were found between CT levels and age, body mass index (BMI), as well as weekly consumption of white and red wine mixed with water. While height and sternal notch-finger length initially correlated positively with CT levels, this relationship reversed upon adjusting for age and sex. Regarding sport activities, CT levels were significantly increased in non-participants compared to occasional sport participants (p = 0.043). Dietary factors yielded intriguing findings, with frequent consumption of butter, animal fat and veal associated with lower CT levels, while higher CT levels were associated with the frequent consumption of white fish, blue fish, pasta, and rice. However, no significant correlation was found between CT levels and bone mineral density (BMD), weight, or body surface area (BSA). This study highlights the complex interplay of dietary, lifestyle, and sociodemographic factors influencing CT levels. These findings suggest that a broad range of factors should be considered in hormonal balance studies, underlining their potential implications for public health.

Medullary thyroid carcinoma (MTC): unusual metastatic sites.

SummaryMedullary thyroid carcinoma (MTC) has a varying clinical course; distant metastases are frequently present even at diagnosis. We present two MTC cases with unusual metastatic sites. Two female patients are presented with slow progressive MTC. The first case developed distant metastases 23 years after diagnosis and underwent locoregional therapies. At the same time a breast mass developed representing MTC metastasis. Treatment with vandetanib led to long-term disease stabilization. The second patient is presented with metastases in the pancreas 13 years after diagnosis. Shortly, a painful mass developed in the mandible and metastasis of MTC was diagnosed. Disease progression was recorded 20 months after the initiation of local and systemic therapy. Such cases have only rarely been reported in the literature and highlight the need for prompt recognition of unexpected MTC metastases.Learning pointsUnusual sites of metastasis may appear in patients with medullary thyroid carcinoma (MTC) years after the initial diagnosis.Although rare, unexpected MTC metastases highlight the need for prompt recognition and appropriate treatment.Local recurrences accompanied by inappropriately low calcitonin levels should prompt further investigation for possible distant metastatic disease.Systemic treatment with tyrosine kinase inhibitors may be effective even in patients with unusual metastases from MTC.

Serum miR-375 for Diagnostic and Prognostic Purposes in Medullary Thyroid Carcinoma.

PurposeHaving previously demonstrated that tissue miR-375 expression in medullary thyroid carcinoma (MTC) tissues is linked to prognosis, the aim of this study was to assess the diagnostic and prognostic value of circulating miR-375 levels in MTC patients.MethodsA series of 68 patients with MTC was retrospectively retrieved and assessed in terms of their clinicopathological characteristics. MiR-375 levels were measured in all patients’ presurgical blood samples. Both serum and tissue levels were tested prior to surgery in a subgroup of 57 patients. Serum miR-375 levels were also measured in serum from 49 patients with non-C-cell thyroid nodular diseases (non-CTN), 14 patients with pheochromocytoma, and 19 healthy controls.ResultsCirculating miR-375 levels were 101 times higher in the serum of patients with MTC than in all other patients and controls, with no overlap (P < 0.01). No correlation emerged between serum and tissue miR-375 levels. Serum miR-375 levels were higher in MTC patients with N0 than in those with N1 disease (P = 0.01), and also in patients who were biochemically cured than in those who were not (P = 0.02). In the whole series of patients and controls, calcitonin (CT) and serum miR-375 levels were correlated at diagnosis (R2 = 0.40, P < 0.01), but in a U-shaped manner: a positive correlation was found with low CT levels, then the correlation turns negative as CT rises (in MTC patients). A negative correlation was indeed found in MTC patients between serum miR-375 and CT (R2 = −0.10, P = 0.01). On ROC curve analysis, a cut-off of 2.1 for serum miR-375 proved capable of distinguishing between MTC patients and the other patients and controls with a 92.6% sensitivity and a 97.6% specificity (AUC: 0.978, P < 0.01).ConclusionsSerum miR-375 levels can serve as a marker in the diagnosis of MTC, with a remarkable specificity. Serum miR-375 also proved a novel marker of prognosis in this disease. Further in vitro experiments to corroborate our results are currently underway.

Surgical Curability of Medullary Thyroid Cancer in Multiple Endocrine Neoplasia 2B

This investigation aimed at exploring the suitability of nonendocrine manifestations preceding medullary thyroid cancer (MTC) for early diagnosis of multiple endocrine neoplasia type 2B (MEN 2B). MEN 2B patients, running a high risk of metastatic MTC, must be diagnosed early for biochemical cure. Forty-four MEN 2B patients carrying inherited (3 patients) and de novo (41 patients) M918T RET mutations were examined for signs and symptoms prompting MEN 2B. All 3 patients with inherited mutations were diagnosed before the age of 1 year and cured of their C-cell disease. Among 41 patients with de novo mutations, MEN 2B was diagnosed in 12 patients after recognition of nonendocrine manifestations [intestinal ganglioneuromatosis (6 patients), oral symptoms (5 patients), ocular ("tearless crying") (4 patients), and skeletal stigmata (1 patient) alone or concomitantly]. In the remaining 29 patients with de novo mutations, the diagnosis of MEN 2B was triggered by symptomatic MTC (28 patients) or pheochromocytoma (1 patient). The former patients, being significantly (P < 0.001) younger (means of 5.3 vs 17.6 years) and having lower calcitonin levels (means of 115 vs 25,519 pg/mL), smaller tumors (67% vs 0% were ≤10 mm) and less often extrathyroidal extension (0% vs 81%), lymph node (42% vs 100%), and distant metastases (8% vs 79%), were biochemically cured more often (58% vs 0%). MTC is curable in patients with de novo mutations when nonendocrine MEN 2B components are quickly appreciated and surgical intervention is performed before patients turn 4 years old.

Metachronous appearance of second malignancies in medullary thyroid carcinoma (MTC) patients: a diagnostic challenge and brief review of the literature

Medullary thyroid carcinoma (MTC) is a rare tumour which frequently occurs in the context of the multiple endocrine neoplasia syndromes, where it coexists with other usually benign tumours. The clinical picture varies and distant metastases are frequently present at diagnosis. Calcitonin levels are elevated in the presence of metastatic disease. Two MTC cases are presented, which had elevated postoperative calcitonin levels. Imaging revealed lung lesions which were originally attributed to metastatic disease from the MTC. However, at follow-up, these cases presented unusual features. The rapid increase in the lung lesions and the development of hypercalcaemia in the first patient suggested a second unrelated tumour. Biopsy of the lung lesion was compatible with lung adenocarcinoma. In the second patient, the appearance of a liver mass, although calcitonin levels remained stable, led to biopsy of the lesion: this was negative for calcitonin and compatible with metastatic lung adenocarcinoma. These MTC cases show that further malignancies may coexist with MTC and may obscure the clinical picture and influence the therapeutic decisions, especially in the case of metastatic disease. Features such as unusual imaging characteristics and the development of hypercalcemia, never encountered in MTC outside the MEN2 syndromes, as well as 'disproportionately' low calcitonin levels, incompatible with extensive metastatic disease, were the factors that led to further work-up. Both the cases subsequently proved to carry an unsuspected second malignancy. It is crucial to discriminate the metastatic lesion attributed to MTC from another coexisting primary malignancy, because different therapeutic strategies are needed for each setting.

Correlation between Calcitonin Levels and [F18]FDG-PET/CT in the Detection of Recurrence in Patients with Sporadic and Hereditary Medullary Thyroid Cancer

Purpose. Measurement of serum calcitonin is important in the followup of patients with medullary thyroid carcinoma (MTC) and reliably reflects the presence of the disease. This is the largest study so far in bibliography investigating the diagnostic accuracy of combined [18F]FDG-PET/CT in patients with MTC and elevated calcitonin levels. Methods. Between February 2007 and February 2011, 59 [18F]FDG-PET/CT were performed on 51 patients with MTC and elevated calcitonin levels for localization of recurrent disease. Conventional morphologic imaging methods were negative or showed equivocal findings. Results. Among the 59 [18F]FDG-PET/CT, 29 were positive (26 had true-positive and 3 false-positive findings) and 30 negative. The overall per-patient sensitivity of [18F]FDG-PET/CT was 44.1%. Using as cut-off point the calcitonin value of 1000 pg/ml, in patients with calcitonin exceeding this value, sensitivity raised to 86.7%. The overall sensitivity of [18F]FDG-PET/CT was lower (23%) in patients with MEN IIA syndrome. Conclusion. The findings of this paper show that [18F]FDG-PET/CT is valuable for the detection of recurrence in patients with highly elevated calcitonin levels, >1000 pg/mL, but in patients with lower calcitonin levels, its contribution is questionable. Also, there is evidence that the sensitivity of [18F]FDG-PET/CT is lower in patients with MTC as part of MEN IIA syndrome.

Interpretation of serum calcitonin in patients with chronic autoimmune thyroiditis

Calcitonin (CT) is an important clinical marker for the diagnosis and follow-up of medullary thyroid carcinoma, although it is not absolutely specific. Some authors have reported C-cell hyperplasia in a number of thyroid specimens affected by Hashimoto's thyroiditis. The association between thyroiditis and hypercalcitoninemia is still controversial because some authors have reported low CT levels. The aim of this study is to evaluate the basal CT values in patients with and without thyroid autoimmunity. From May 2005 to February 2010, 1073 patients underwent ultrasonography-guided fine-needle aspiration cytology at the Thyroid Center of Sapienza University of Rome, with evaluation of basal serum FT4, FT3, TSH, and antithyroid peroxidase (anti-TPO) antibodies as well as CT levels. Forty-one patients presented a basal CT level above the reference upper limit. The mean serum CT was significantly lower in women than in men (4.28 ± 6.63 vs 7.50 ± 25.50 pg/ml; P<0.01). Basal serum CT was not significantly higher in patients showing anti-TPO Ab positivity (4.71 ± 6.46 vs 4.84 ± 13.11 pg/ml; P>0.05). Importantly, the rate of 'suspicious' CT values (above the 10 pg/ml cutoff) was not significantly different between patients with or without thyroid autoimmunity (3.9 vs 3.0%). Patients with hypercalcitoninemia suffering from chronic autoimmune thyroiditis should undergo the same clinical evaluation procedure as patients do without thyroid autoimmunity.

Medullary Thyroid Cancer: A Retrospective Analysis of a Cohort Treated at a Single Tertiary Care Center Between 1970 and 2005

To identify prognostic factors of clinical outcome and long-term survival in medullary thyroid cancer (MTC). Retrospective case series of 51 consecutive patients (mean age 46.9 years, 57% female) treated at a single tertiary university medical center from 1970 to 2005. Medical records were reviewed for demographic data, laboratory and clinical course, treatment, and long-term outcome. At presentation, 25 patients (49%) had local disease and 26 (51%) had metastatic disease (three with distant metastases). RET mutations were identified in nine of 23 patients tested. The patients with hereditary disease were younger than the patients with sporadic disease (p < 0.001) and had lower calcitonin levels at diagnosis (p = 0.004) and more multicentric tumors (p = 0.02). Initial surgery consisted of total thyroidectomy in 47 patients, with neck dissection in 26; 22 patients achieved long-term remission. The 5-, 10- and 15-year survival rates were 88%, 85%, and 77%, respectively. On univariate analysis, distant metastases during the course of the disease and elevated calcitonin levels postoperatively were significant prognostic factors of reduced survival (p = 0.001 and 0.016, respectively). Lymph node involvement at initial surgery was associated with a lower remission rate (p = 0.016) but had no impact on long-term survival (p = 0.269). Patients with MTC have a generally favorable outcome, perhaps owing to recent advances in diagnosis and treatment. Although postoperative serum calcitonin level and distant metastases are the only determinants of long-term survival, the presence of cervical metastases is predictive of a higher risk of recurrent or persistent disease.

Calcitonin and parathyroid hormone: an evening seminar of the 17th Annual Meeting of the Japanese Society for Bone and Mineral Research, July 29, 1999.

and neurodegenerative diseases as a consequence of the paradoxical calcium overload due to age-related calcium deficiency. The main biologic action of calcitonin has resulted from its successful use in disease states characterized by increased bone resorption. Calcitonin is approved by the Food and Drug Administration (FDA) for the treatment of osteoporosis. The main biologic effect of calcitonin is to inhibit osteoclastic bone resorption. This effect is mediated by a calcitonin receptor, which is strongly expressed by osteoclasts. Thyroid C cells, which are neural crest derivatives, are the primary source of calcitonin in mammals. However, other tissue sources of calcitonin have been described, notably the pituitary cells and widely distributed neuroendocrine cells. Since the concentration of calcitonin at its several sites of biosynthesis may be sufficiently high, calcitonin may be expected to have paracrine effects at these sites. The demonstration of calcitonin and its receptors at intracranial sites may qualify calcitonin as a neurotransmitter. Most investigators find that women have lower calcitonin levels than men. The mechanism for this difference may be accounted for in part by a stimulating effect of gonadal steroids on calcitonin secretion. Analgesia is a commonly reported effect of calcitonin treatment in osteoporosis and bone malignant metastasis. In experimental studies using animals, calcitonin has acute antinociceptive effects when administered into the central nervous system. However, the effects of centrally administered calcitonin do not necessarily explain the clinical effects of intramuscular calcium injections. In this symposium, Dr. Yoshimura further focuses on the modulation of pain sensation at the level of the spinal cord in cases where there is an estrogen deficiency. By using a rat model, he initially observed the inducement of hyperalgesia after ovariectomy and the antinociceptive effect after intramuscular injections of elcatonin. He confirmed the involvement of the Parathyroid hormone and calcitonin are the principal regulators of bone and calcium metabolism in humans and most likely all terrestrial vertebrates. In bone, parathyroid hormone stimulates the resorption of bone, releasing calcium and phosphate. In the kidney, this hormone stimulates the reabsorption of calcium and inhibits the reabsorption of phosphate. Parathyroid hormone stimulates the activity of renal 1-αhydroxylase, thereby enhancing synthesis of the active form of vitamin D, which in turn increases intestinal calcium and phosphate. As a result of these parathyroid hormone-dependent actions, blood calcium concentration increases and phosphate concentration decreases. The extracellular calcium concentration is the most important regulator of parathyroid hormone secretion, and it is maintained at a constant level despite variation in the amount of daily calcium intake. In chronic calcium-deficient conditions, however, the homeostatic regulation of extracellular calcium level by parathyroid hormone seems to threaten the skeleton and nonskeletal soft tissues as well. Increased parathyroid hormone secretion readily leads to osteoporosis, which is a decrease in bone calcium content. On the other hand, a variety of cells in the extraskeletal soft tissues are exposed to the constant calcium overflow from bone so their intracellular calcium levels tend to increase. As a consequence, serious disturbance of cell function occurs, giving rise to various diseases. While systemic calcium deficiency is certainly expected to cause skeletal calcium deficiency, the associated increase of calcium within cells of nonskeletal tissue may appear to be paradoxical. In this symposium, Dr. Fujita focuses on this paradoxical calcium overload of the nonskeletal tissues and relates it to calcium deficiency. He attempts to explain the cause of various soft tissue disorders including cardiovascular diseases

Serum levels of calcitonin in Cushing's syndrome.

Serum levels of calcitonin (CT) were studied in 21 patients with Cushing's syndrome (CS), 18 females and 3 males aging from 16 to 59 years, and in 70 age and sex matched normal subjects. Patients with CS showed CT values significantly lower than those found in controls (9.9 +/- 5.0 pg/ml vs. 15.9 +/- 6.3 pg/ml, mean +/- SD; p less than 0.01), while no difference was observed in total serum calcium and phosphate and calcium corrected for albumin. No correlation between CT and serum calcium and phosphate, serum cortisol and urinary free cortisol was found. It is possible that low CT levels are involved in the pathogenesis of bone loss observed in CS.

Relation of doubling time of plasma calcitonin levels to prognosis and recurrence of medullary thyroid carcinoma.

Plasma calcitonin (CT) levels were measured serially in 54 patients surgically treated for medullary thyroid carcinoma. Patients with postoperative basal CT levels higher than 1 ng/ml measured within 1 month after surgery had a higher recurrence rate than those with lower CT levels (p less than 0.002). Patients with postoperative basal CT levels higher than 2 ng/ml had a lower survival rate than those with lower CT levels (p less than 0.01). However, preoperative basal CT levels had no significant correlation with life expectancy or recurrence during the present observation period. Serial measurements in 23 patients with elevated postoperative CT levels showed exponential increases in basal CT levels in 19 patients (p less than 0.05 in nine patients, 0.05 less than p less than 0.1 in four patients) and slight decreases in four (p less than 0.05 in one patient). Doubling time of CT levels calculated from the regression line in each patient showed the highest correlation with 3-year survival, recurrence within 5 years, and time interval between surgery and clinical recurrence of the tumor, allowing quantitative prediction of the prognosis.

Parathyroid function and serum calcitonin in children receiving anticonvulsant drugs.

Serum calcitonin (CT) levels and other aspects of calcium metabolism were investigated in 40 epileptic children receiving long-term treatment with phenytoin and/or other anticonvulsant drugs, and in 38 age-matched controls. In the patients CT levels were significantly lower. Immunoreactive parathyroid hormone (iPTH) was significantly elevated exceeding the upper limit of controls in 11 patients. We also observed a highly significant correlation between iPTH and urinary cyclic AMP (cAMP) excretion but a lack of such a correlation with the renal handling of phosphate; this indicates to us a dissociation between cAMP production and phosphaturia. A significant correlation between iPTH levels and urinary hydroxyproline excretion points to a normal action of PTH on bone in the patients. The low CT levels are not due to hypocalcemia and may be directly attributed to the effects of anticonvulsant drugs. As the primary effect of CT is a direct inhibition of PTH induced calcium loss from bone, the drug-related low CT levels in association with secondary hyperparathyroidism possibly is an additional factor in anticonvulsant bone disease.

Tumor Growth and Calcitonin during Serial Transplantation of Rat Medullary Thyroid Carcinoma*

We have recently reported immunochemical methods for the measurement and purification of rat calcitonin (CT). To identify a convenient source of CT-producing cells for studies of rat CT biosynthesis, we have propagated 16 transplantable series of medullary thyroid carcinoma (MTC) from 2 types of WAG/Rij rat MTC from The Netherlands. Tumor CT concentrations and growth and plasma CT accumulation were studied in successive transplant generations of each MTC series. Although most MTC series maintained characteristic predictable tumor CT levels, some MTC series acquired nearly 90% lower CT levels. While related MTC series tended to maintain similar predictable growth rates, several spontaneous and propagatable increases (up to 5-fold) in tumor growth rates were noted. These increases occurred with and without concomitant decreases in tumor CT. Tumor CT production ranged over 20-fold among these 16 MTC series. Serial plasma CT analyses can be used to estimate tumor growth and CT production in live MTC rats. Using serial plasma CT analyses, we can select for serial transplantation tumors with specific growth and CT characteristics. This should facilitate propagation of MTC series needed for particular studies of CT production and cancer.