Influence of Chronic Autoimmune Thyroiditis and Papillary Thyroid Cancer on Serum Calcitonin Levels

Abstract

Background:

Serum calcitonin (sCt) is measured in many patients with nodular thyroid disease, and the possibility of a false-positive result is a matter of concern, particularly in the case of mild hypercalcitoninemia. Among the conditions reported to cause sCt elevation, Hashimoto's thyroiditis (HT) and papillary thyroid carcinoma (PTC) are relevant. In view of the high frequency of these conditions in patients with nodular disease and the controversy regarding the extent to which they contribute to hypercalcitoninemia, the objective of this study was to determine the influence of the presence of HT and PTC on sCt levels.

Methods:

Three groups of patients >12 years of age were studied. The first group (group A, n=492) consisted of patients with nodular disease evaluated before thyroidectomy and without medullary thyroid carcinoma (MTC) upon histology. The second group (group B, n=583) consisted of subjects without nodules on ultrasound. The third group (group C, n=62) consisted of patients with PTC and distant metastases after total thyroidectomy. The levels of sCt and frequency of elevated sCt were compared in patients with versus without HT (groups A and B) and those with PTC>1 cm versus without PTC (group A).

Results:

No difference in sCt levels or in the frequency of elevated sCt was observed between patients with and without HT, irrespective of sex. Moreover, the presence of PTC>1 cm did not influence sCt levels or the frequency of hypercalcitoninemia. In fact, none of the 1075 patients in groups A and B had sCt>40 pg/mL, regardless of the presence of HT and PTC. Serum calcitonin was undetectable in any patient of group C.

Conclusions:

The finding of hypercalcitoninemia in patients with nodular disease should be interpreted as a suspicion of MTC, even in the presence of associated HT or cytology suggestive of PTC.

Introduction

C onsensus exists regarding the usefulness of serum calcitonin (sCt) in patients with nodular disease and family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasm type 2 (MEN 2), or with a cytological suspicion of MTC. Even when history and cytology are not suspicious for MTC, many authors recommend the measurement of sCt in all patients referred for thyroidectomy (1). Some authors even recommend routine measurement of sCt in subjects with thyroid nodules, irrespective of history, cytology, or surgical indication (1). It can be noted that sCt is measured in many patients with nodular thyroid disease.

Most patients with sCt concentrations above the reference range present with mild hypercalcitoninemia and, particularly in these cases, the possibility of a false-positive result is a matter of concern. Among the non-MTC conditions reported to cause sCt elevation, Hashimoto's thyroiditis (HT) and papillary thyroid carcinoma (PTC) are the most relevant (2,3). HT and PTC are frequent in subjects with nodular disease (coexisting or as a cause of nodules) and are a common result of cytology, raising doubts regarding the interpretation of hypercalcitoninemia in these cases (false-positive sCt result or false-negative cytological result for MTC). In addition, controversy exists whether these conditions indeed cause sCt elevation.

The objective of the present study was to determine the influence of the presence of HT and PTC on sCt levels.

Patients and Methods

Among patients consecutively seen at our institution (Santa Casa de Belo Horizonte), those who met the criteria of one of the following three groups were selected. The first group (group A) consisted of patients with nodular thyroid disease evaluated before thyroidectomy (n=494; 120 men, 374 women). The second group (group B) consisted of subjects submitted to ultrasound (US) screening of the thyroid because they had a sibling with PTC but did not have nodules themselves (n=583; 345 men, 238 women) (4). The third group (group C) consisted of patients with PTC evaluated after total thyroidectomy and remnant ablation with ¹³¹I, who presented with an elevated thyroglobulin and distant metastases (n=62; 22 men, 40 women). Next, exclusion criteria were applied, and patients who did not meet these criteria were included in the study. Excluded were (i) patients with a family history of MTC or MEN 2; (ii) patients with known presence of kidney failure, hyperparathyroidism, chronic atrophic gastritis, neuroendocrine tumor, or lung cancer; (iii) children and adolescents (age ≤12 years); and (iv) two patients of group A who had a postoperative (histological) diagnosis of MTC.

Serum calcitonin was measured in all patients. For sCt measurement, the patients were asked not to consume alcohol for at least 1 week and to discontinue the use of proton pump inhibitors for at least 4 weeks. None of the patients had apparent bacterial infection or hypercalcemia at the time of measurement. Anti-thyroid peroxidase antibodies (TPOAb) were measured in the same sample in subjects of groups A and B. The serum samples were obtained in the morning (∼8:00 a.m.) after an 8- to 10-hour fast and were analyzed immediately after collection at the same laboratory where they were collected. In the case of patients of group B, samples were collected 3–7 days after US showing the absence of nodules.

The study was approved by the local Research Ethics Committee.

Serum calcitonin was measured by an immunochemiluminescent assay (Immulite, Diagnostic Products Corporation, Los Angeles, CA), with a sensitivity of 2 pg/mL and reference values of up to 5 pg/mL for women and 8.4 pg/mL for men. TPOAb were also measured by a chemiluminescent assay (Immulite), with a reference value of up to 35 IU/mL.

Sonography was performed with a linear multifrequency 10–12 MHz transducer for morphological analysis (B-mode).

In groups A and C, the smears (cytology and histology) were analyzed by pathologists experienced in thyroid pathology.

The levels of sCt and the frequency of elevated sCt were compared in patients with versus without HT (groups A and B) and with PTC>1 cm versus without PTC (group A) considering different cutoff values: 2 pg/mL (sensitivity of the assay), 5 pg/mL or 8.4 pg/mL (reference value of the method for women and men, respectively), 10 pg/mL, 15 pg/mL (5), and 20 pg/mL (6,7). In the last analysis, patients with papillary microcarcinoma were excluded. The following three parameters for the definition of HT were analyzed separately: presence of circulating TPOAb (titers above the reference value) in groups A and B, presence of lymphocytic thyroiditis on histology in group A, and diffuse hypoechogenicity on US in group B. All analyses were stratified by sex.

Mean and median values were compared between groups by the Student t test or the nonparametric Mann-Whitney U test. The Fisher exact test or χ² test was used to detect differences in the proportion of cases. A p value of <0.05 was considered to be significant.

Results

Group A (patients with nodular disease, n=492)

No difference in sCt levels or in the frequency of elevated sCt was observed between patients with and without circulating TPOAb, irrespective of sex (Table 1). The results were similar when patients with and without lymphocytic thyroiditis on histology were compared. Moreover, the presence of PTC>1 cm did not influence sCt levels or the frequency of hypercalcitoninemia (Table 2).

Table 1.

Serum Calcitonin Levels in Patients With Nodular Disease (Group A) with and Without Circulating Anti-Thyroperoxidase Antibodies

Basal sCt	TPOAb+	TPOAb−
Men^a (n=120)	18	102
>2 pg/mL	12 (66.6%)	70 (70%)
>8.4 pg/mL	1 (5.5%)	4 (4%)
>10 pg/mL	1 (5.5%)	2 (2%)
>15 pg/mL	0	2 (2%)
>20 pg/mL	0	2 (2%)
Women^b (n=372)	112	260
>2 pg/mL	36 (32.1%)	78 (30%)
>5 pg/mL	8 (7.1%)	15 (5.7%)
>10 pg/mL	2 (1.8%)	4 (1.5%)
>15 pg/mL	1 (0.9%)	3 (1.1%)
>20 pg/mL	1 (0.9%)	3 (1.1%)

Data are presented as number (percentage).

Median sCt levels (for both subsets of patients, TPOAb+ and TPOAb−): ^amen, 3.6 pg/mL; ^bwomen, ≤2 pg/mL.

sCt, serum calcitonin; TPOAb, anti-thyroperoxidase antibodies.

Table 2.

Serum Calcitonin Levels in Patients With Nodular Disease (Group A) with Papillary Thyroid Carcinoma of >1 cm and Without Papillary Thyroid Carcinoma

Basal sCt	PTC>1 cm	Without PTC
Men^a (n=105)	48	57
>2 pg/mL	32 (66.6%)	40 (70.1%)
>8.4 pg/mL	2 (4.1%)	2 (3.5%)
>10 pg/mL	1 (2%)	1 (1.75%)
>15 pg/mL	1 (2%)	1 (1.75%)
>20 pg/mL	1 (2%)	1 (1.75%)
Women^b (n=333)	120	213
>2 pg/mL	38 (31.6%)	64 (30.4%)
>5 pg/mL	8 (6.6%)	13 (6.1%)
>10 pg/mL	2 (1.6%)	3 (1.4%)
>15 pg/mL	1 (0.8%)	2 (0.9%)
>20 pg/mL	1 (0.8%)	2 (0.9%)

Data are presented as number (percentage).

Median sCt levels: men with PTC>1 cm, 3.6 pg/mL; men without PTC, 3.5 pg/mL.

Median sCt levels (for both subsets of women, with PTC>1 cm and without PTC): ≤2 pg/mL.

PTC, papillary thyroid carcinoma.

Group B (subjects without thyroid nodules, n=583)

No difference in sCt levels or in the frequency of hypercalcitoninemia was observed between patients with and without circulating TPOAb, irrespective of sex (Table 3). The same results were obtained when patients with and without diffuse hypoechogenicity on US were compared.

Table 3.

Serum Calcitonin Levels in Subjects Without Nodular Disease (Group B) With and Without Circulating Anti-Thyroid Peroxidase Antibodies

Basal sCt	TPOAb+	TPOAb−
Men^a (n=345)	42	303
>2 pg/mL	26 (62%)	185 (61%)
>8.4 pg/mL	2 (4.7%)	12 (4%)
>10 pg/mL	1 (2.4%)	8 (2.6%)
>15 pg/mL	1 (2.4%)	4 (1.3%)
>20 pg/mL	0	3 (1%)
Women^b (n=238)	60	178
>2 pg/mL	18 (30%)	56 (31.4%)
>5 pg/mL	3 (5%)	8 (4.5%)
>10 pg/mL	1 (1.6%)	3 (1.7%)
>15 pg/mL	0	1 (0.6%)
>20 pg/mL	0	0

Data are presented as number (percentage).

Median sCt levels: TPOAb+ men, 3.6 pg/mL; TPOAb− men, 3.5 pg/mL.

Median sCt levels (for both subsets of women, TPOAb+ and TPOAb−): ≤2 pg/mL.

There were no differences in sCt levels between patients with and without chronic thyroiditis or between patients with PTC>1 cm and without PTC, even when nonsmokers and smokers were analyzed separately. However, the last group was small (29 subjects in group A and 36 in group B).

In fact, none of the 1075 patients of groups A and B had a sCt level of >40 pg/mL.

Group C (thyroidectomized patients with distant metastases from PTC, n=62)

All patients presented highly elevated thyroglobulin levels (>10 ng/mL during levothyroxine therapy) and distant metastases. Despite extensive tumor disease, sCt was undetectable in all patients of this group.

Discussion

In patients with nodular thyroid disease, cytology can be falsely negative for MTC (6) and sCt can be elevated even in the absence of this tumor (2,3,5,7), especially if hypercalcitoninemia is moderate. Therefore, if cytology does not suggest MTC, but hypercalcitoninemia is present, the sCt result is false positive or cytology is false negative. The presence of some conditions known to be associated with sCt elevation, such as HT and PTC (2,3), supports the first hypothesis.

The knowledge of whether HT is indeed a cause of sCt elevation is particularly relevant because of the frequent association of this condition with nodular disease. Some series show that C-cell hyperplasia is common in patients with chronic thyroiditis and is accompanied by hypercalcitoninemia in some cases (8,9). Accordingly, a higher frequency of elevated sCt has been reported in patients with autoimmune thyroid disease when compared to normal subjects (10). In contrast, other authors found no difference in sCt concentration between patients with and without autoimmune thyroiditis (positive autoantibodies), even in the early stage of disease, that is, still with goiter and without overt hypothyroidism (11 –13). Moreover, there are studies showing that chronic thyroiditis is in fact accompanied by a reduction of C cells (14) and lower sCt concentrations in an advanced stage (15 –17), and that this deficiency in sCt is already present in the early stage of disease (15,16).

In the present series, we did not observe higher concentrations of sCt or a higher frequency of hypercalcitoninemia in patients with nodular disease with circulating TPOAb or with lymphocytic thyroiditis on histology, or in subjects without nodules with TPOAb or diffuse hypoechogenicity on US.

MTC may have a cytology that is interpreted as suggestive of PTC (6), and PTC has also been considered to be a cause of sCt elevation (2,3). Since the extent of surgery in early-stage PTC differs from that of MTC, it is important to know whether a cytology compatible with PTC can explain a sCt elevation, or whether its presence indeed suggests MTC and a failure to identify it accurately by cytology. Two obvious explanations for hypercalcitoninemia in patients with PTC are its association with occult medullary microcarcinomas, or that PTC is in fact a mixed tumor (papillary/medullary) (18). In the present series, sCt was undetectable in all thyroidectomized patients with advanced metastases from PTC and elevated thyroglobulin levels, indicating that Ct is not directly secreted by follicular tumor cells. In fact, it has been postulated that in cases of pure PTC, the elevation of sCt is due to the production of C-cell stimulating factors by the tumor (paracrine action) (3). However, we did not observe higher sCt concentrations or a higher frequency of hypercalcitoninemia in patients with PTC even before thyroidectomy (even when only tumors >1 cm were analyzed). In agreement with this finding, a recent study was also unable to show higher sCt levels in patients with nodular disease, and suspicious or malignant non-MTC cytology (12).

Finally, regardless of the presence of HT or PTC, sCt was less than 40 pg/mL in all 1075 subjects without chronic kidney disease or known nonthyroid tumor (potentially secreting Ct) who were not using proton pump inhibitors. Accordingly, in the absence of these conditions, basal sCt concentrations of >40 pg/mL were always associated with the presence of MTC in previous series (6,19 –25).

In conclusion, the finding of hypercalcitoninemia in patients with nodular disease should be interpreted as being suggestive of MTC, even in the presence of associated HT or cytology suggestive of PTC.

Footnotes

Author Disclosure Statement

The authors declare no conflicts of interest.

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