Routine measurement of serum calcitonin (CT) has been recently proposed for all patients with neoplastic thyroid disease to detect clinically occult medullary thyroid carcinoma (MTC). Data on the prevalence of elevated CT levels in nonneoplastic thyroid disease or in healthy subjects have non been reported to engagement. 4 hundred and fourteen consecutive patients with suspected thyroid disease and 362 good for you controls underwent thyroid examination with measurement of basal serum CT. Whenever serum CT was ten pg/ml or more, a pentagastrin (PG) stimulation examination was performed. Twenty-eight of 414 patients (6.eight%) showed elevated basal serum CT levels, 15 of them with nonneoplastic thyroid disease, and the remaining 13 subjects with neoplastic thyroid illness. Iv patients with abnormal PG testing (stimulated CT, ≥100 pg/ml) were identified. Three of them had biochemical and sonographical evidence of thyroiditis. Elevated basal CT levels were significantly more than frequent in patients with Hashimoto's thyroiditis (HT; P < 0.05). One female patient with HT had a 5-mm nodule, which was classified as MTC. None of the half dozen out of 362 salubrious controls with elevated basal CT (1.vii%) presented an abnormal PG test. Our information advise that basal CT measurements can be of use in the detection/screening of MTC not simply in subjects with neoplastic thyroid disorders, but likewise in patients with immunological evidence of HT. They too confirm earlier reports on the essential value of PG stimulation testing, even when basal plasma CT levels are only modestly elevated, with regard to establishing the diagnosis of MTC or its premalignant associated conditions (micro-MTC and neoplastic C cell hyperplasia).

MEDULLARY THYROID CARCINOMA (MTC) occurs in both nonhereditary (sporadic) and hereditary forms. Information technology is well known that serum calcitonin (CT) is a sensitive and authentic mark of MTC and that the increase in CT later pentagastrin (PG) injection is a specific feature of MTC (one–three). Sporadic MTC is usually diagnosed at the stage of nodal involvement, hence precluding definitive cure in most cases (4–half dozen). Routine measurement of serum CT was recently proposed for all patients with neoplastic thyroid disease (vii, 8). Especially, patients with basal and stimulated plasma CT levels greater than 100 pg/ml should exist considered for functioning (ix) considering they probably suffer either from MTC or C cell hyperplasia (CCH), a potential precancerous status even in the absence of germline mutations in the RET protooncogene (10, 11), which was termed neoplastic CCH (12). This strategy volition increase the probability of early on diagnosis of MTC, thus providing the chance of curative surgery (ix, 13). However, we do not agree with the supposition that only neoplastic thyroid illness is associated with MTC. Autopsy studies revealed a loftier prevalence of CCH in 33–66% of specimens obtained from deceased persons without known thyroid disease, perhaps reflecting an age-related issue (14–16). Despite the high prevalence of CCH, information technology must be emphasized that MTC is rare. It is well known that CCH may too be associated with a variety of (non) thyroidal diseases (12, 17). All the same, data on the prevalence of elevated CT levels in nonneoplastic thyroid affliction and its presumed human relationship to CCH and MTC are missing. Therefore, the aim of our report was to compare the distribution and relevance of elevated CT levels in referrals with nonneoplastic and neoplastic thyroid disease as well as in immature to middle-aged subjects without a history of thyroid disease. Indeed, in this study we expand for the first time the utility of basal plasma CT measurements in the detection/screening of MTC in patients with immunological prove of Hashimoto'south thyroiditis (HT).

Subjects and Methods

Patients with thyroid disease

Iv hundred and fourteen sequent patients (85 males and 329 females), aged 18–88 twelvemonth (mean age, 56 yr), referred to our out-patient department for the piece of work-up of various suspected thyroid disorders were included in the nowadays study (Tabular array 1). The clinical diagnosis was nonneoplastic thyroid disease in 219 (Graves' disease, HT, nontoxic diffuse goiter, or de Quervain'southward subacute thyroiditis) and neoplastic thyroid illness in 195 patients (uni- and multinodular affliction; Tabular array 1).

Table i.

Demographics of 414 referrals with thyroid disease

Males/females 85/329
Hateful age ± sd (yr) 56 ± 15
Nonneoplastic thyroid disease 219 (52.9)
Neoplastic thyroid disease 195 (47.ane)
Thyroid function
    Euthyroidism 309 (74.6)
    (Latent) hyperthyroidism 92 (22.2)
    (Latent) hypothyroidism 13 (3.2)
Basal CT level (pg/ml)
    <10 pg/ml 386 (93.2)
    ≥10 pg/ml 28 (half dozen.8)
Males/females 85/329
Mean age ± sd (twelvemonth) 56 ± xv
Nonneoplastic thyroid illness 219 (52.9)
Neoplastic thyroid disease 195 (47.1)
Thyroid office
    Euthyroidism 309 (74.6)
    (Latent) hyperthyroidism 92 (22.two)
    (Latent) hypothyroidism 13 (3.2)
Basal CT level (pg/ml)
    <ten pg/ml 386 (93.2)
    ≥10 pg/ml 28 (half-dozen.8)

Values are given as absolute numbers (with percentages in parentheses) if not otherwise specified.

TABLE 1.

Demographics of 414 referrals with thyroid disease

Males/females 85/329
Hateful historic period ± sd (yr) 56 ± 15
Nonneoplastic thyroid disease 219 (52.nine)
Neoplastic thyroid disease 195 (47.i)
Thyroid function
    Euthyroidism 309 (74.6)
    (Latent) hyperthyroidism 92 (22.2)
    (Latent) hypothyroidism 13 (iii.2)
Basal CT level (pg/ml)
    <10 pg/ml 386 (93.2)
    ≥ten pg/ml 28 (half-dozen.8)
Males/females 85/329
Mean age ± sd (yr) 56 ± 15
Nonneoplastic thyroid disease 219 (52.9)
Neoplastic thyroid disease 195 (47.1)
Thyroid office
    Euthyroidism 309 (74.half dozen)
    (Latent) hyperthyroidism 92 (22.2)
    (Latent) hypothyroidism 13 (3.2)
Basal CT level (pg/ml)
    <ten pg/ml 386 (93.2)
    ≥10 pg/ml 28 (6.8)

Values are given as absolute numbers (with percentages in parentheses) if not otherwise specified.

All patients underwent thyroid palpation, sonography, scintigraphy, and measurement of thyroid hormones (gratuitous Tfour and T3), TSH, and antithyroid autoantibodies. Immulite 2000 complimentary Tiv (EURO/DPC, Gwynedd, UK) was used for the quantitative measurement of nonprotein-bound Tfour. Serum levels of free T3 and homo TSH were measured using the Immulite 2000 costless T3 and Immulite 2000 third generation TSH (EURO/DPC). Immulite 2000 antithyroglobulin antibody and Immulite 2000 antithyroid peroxidase (EURO/DPC) were used for the quantitative measurement of autoantibodies to thyroglobulin and antithyroid peroxidase antibodies, respectively. TSH receptor autoantibody levels were measured using the TRAK-Assay (Brahms Diagnostica, Berlin, Germany).

Serum CT was determined with a commercially available luminescence assay (Nichols Advantage, Calcitonin Chemiluminescence Analysis, San Juan Capistrano, CA). Elevated CT was confirmed by an additional dilution examination. In rare cases of nonconformity, the results of the diluted sample are reported (xviii).

Analytic sensitivity was 1 pg/ml. The intraassay coefficient of variation was 3.v–6.two%, and the day to twenty-four hours variation was five.1–8.7% at boilerplate CT levels between x–553 pg/ml. Basal serum CT was adamant in each patient. Whenever serum CT was equal to or exceeded 10 pg/ml, a PG stimulation exam was performed. For this purpose, blood samples for the assessment of CT were fatigued through an indwelling catheter before and two and v min later on an iv bolus of 0.5 μg/kg PG (Pentagastrin Injection BP, Cambridge Laboratories, Tyne & Wear, UK). Abnormal and pathological PG stimulation test results were defined by CT levels betwixt 100–500 pg/ml and above 500 pg/ml, respectively.

Healthy controls

Three hundred and sixty-two obviously salubrious controls without whatever history of thyroid affliction or whatever family unit history of MTC were studied. Healthy subjects have been exposed to low level radiation (<20 mSv/yr) and have been obliged to pass their statutory annual cheque-upward in our section. In addition, this bank check-up consists of a clinical test, including the inspection of head and cervix, a red and white blood cell count, and measurement of thyroid hormones, TSH, and thyroid autoantibodies. During the study flow calcitonin was included, and subjects gave their consent. Thyroid sonography and PG stimulation testing were performed simply in subjects with basal serum CT levels of 10 pg/ml or more. The mean age in these subjects was significantly lower than that in patients with thyroid illness (36 ± 10 vs. 56 ± 15 yr; P < 0.05).

The nerveless samples of patients and healthy controls were properly anonymized/masked for the performance of this study. Informed consent was obtained from all subjects. The written report and the informed consent were part of an canonical institutional review board protocol.

Sonography

Thyroid sonography was performed in all patients using a Sonoline Prima diagnostic ultrasound system (Siemens, Erlangen, Germany) or a LOGIC 400 pro series (General Electrical, Fairfield, CT), using a linear 7.five-MHz transducer by experienced physicians.

Scintigraphy

Planar acquisition was performed using a one-head γ-camera equipped with a dedicated low energy, high resolution, parallel hole collimator (ADAC Transcam, equipped with a defended collimator for thyroid scintigraphy). A planar image (anterior view) of the thyroid was obtained 20 min after iv administration of 74MBq Tc99m-pertechnetate (matrix, 128 × 128 pixels; 100 kcounts/image).

Surgery

Past definition (9) patients with aberrant PG tests were candidates for surgery. Total thyroidectomy with lymph node dissection along both recurrent nerves was the treatment of choice (9).

Histology and molecular genetic analysis

Submitted thyroidectomy specimens were blocked entirely. On each block a hematoxylin and eosin stain and immunohistochemistry were performed. Immunostains were made using the avidin-biotin-peroxidase method. The CT antibiotic (dilution, 1:600) was obtained commercially (Chemicon, Temecula, CA). CCH was divers according to the criteria of Rosai et al. (19), when there were more fifty C cells in a single low power field (×100 magnification) in both thyroid lobes. The search for germline mutations of the RET protooncogene should exclude hereditary types of C cell pathology in patients undergoing surgery past analyzing exons 10, 11, thirteen, 14, 15, and 16 of this gene on chromosome 10. DNA was obtained from peripheral blood using the DNAzol (Vienna Lab, Vienna, Austria) Deoxyribonucleic acid extraction procedure. PCR amplification and Deoxyribonucleic acid sequencing were performed every bit described previously (20).

Results

CT levels in referrals

As reported in Table 1, 28 of 414 patients (half dozen.8%) showed elevated serum CT levels, 15 of them with nonneoplastic and the remaining 13 subjects with clinically occult neoplastic thyroid affliction (Table 2). The ratios between males and females were 8:vii and 9:4 in patients with nonneoplastic and neoplastic thyroid disease, respectively. Patients with nonneoplastic thyroid illness were significantly younger than those with neoplastic thyroid illness. Thyroid function was not significantly different in both groups (Table ii). Basal CT and CT after PG stimulation were non different, nor was the thyroid book (Table 3). Iv of 28 patients with elevated basal CT levels revealed an increment in CT after PG stimulation to a higher place 100 pg/ml. A PG-stimulated CT betwixt 100 and less than 500 pg/ml was found in 3 cases, whereas only i patient showed a CT response greater than 500 pg/ml. Table iv details gender, historic period, and diagnosis of these patients. Patient 1 with HT and thyroid adenoma underwent surgery due to the pathological PG stimulation test with evidence of MTC in the final histological examination (tumor diameter, 3 mm; no lymph node metastases in 81 nodes tested). Follow-upwardly basal and stimulated CT levels were not detectable. Patient 2 was lost for follow-upward. Patient 3 suffered from de Quervain's subacute thyroiditis until clinical remission after therapy with corticosteroids. Patient 4 refused both surgery and fine needle aspiration for personal reasons. The patient is monitored clinically at regular intervals. Over a period of one yr, basal and stimulated CT levels have been decreasing, although they remain elevated. Seven of 28 patients with elevated basal CT had HT (25%), whereas the prevalence of the disease was 13.3% (P < 0.05) in all 414 patients.

Table ii.

Demographics and thyroid function data of 28 patients with thyroid affliction and elevated basal CT

Nonneoplastic thyroid disease (n = 219) Neoplastic thyroid illness (n = 195) P
Number (%) 15 (6.viii) 13 (6.7) NS
Male/female viii/7 9/4 NS
Historic period (yr ± sd) l ± 15 61 ± 14 0.05
Thyroid office 12 euthyroidism 12 euthyroidism
1 hyperthyroidism i hyperthyroidism
2 hypothyroidism
Nonneoplastic thyroid illness (n = 219) Neoplastic thyroid disease (due north = 195) P
Number (%) 15 (six.viii) 13 (half dozen.7) NS
Male/female 8/7 9/4 NS
Age (yr ± sd) 50 ± 15 61 ± 14 0.05
Thyroid role 12 euthyroidism 12 euthyroidism
1 hyperthyroidism 1 hyperthyroidism
two hypothyroidism

TABLE 2.

Demographics and thyroid function information of 28 patients with thyroid disease and elevated basal CT

Nonneoplastic thyroid illness (north = 219) Neoplastic thyroid disease (n = 195) P
Number (%) xv (six.8) 13 (half dozen.7) NS
Male/female person 8/7 9/4 NS
Age (year ± sd) 50 ± fifteen 61 ± 14 0.05
Thyroid function 12 euthyroidism 12 euthyroidism
i hyperthyroidism 1 hyperthyroidism
2 hypothyroidism
Nonneoplastic thyroid disease (north = 219) Neoplastic thyroid disease (due north = 195) P
Number (%) 15 (6.eight) 13 (6.7) NS
Male/female eight/7 9/4 NS
Age (yr ± sd) 50 ± 15 61 ± 14 0.05
Thyroid role 12 euthyroidism 12 euthyroidism
1 hyperthyroidism 1 hyperthyroidism
2 hypothyroidism

TABLE 3.

Basal and stimulated CT levels (pg/ml) and thyroid volume in patients with thyroid disease and elevated basal CT

Nonneoplastic thyroid disease Neoplastic thyroid disease P
Basal CT 17 (11–33) a sixteen (ten–61) NS
PG examination
CT 0 xi (half-dozen–23) 10 (half-dozen–68) NS
CT ii 58 (17–265) 60 (8–558) NS
CT 5 46 (thirteen–194) 50 (seven–403) NS
Volume (ml) 17 ± 15 b 21 ± 10 NS
Nonneoplastic thyroid disease Neoplastic thyroid disease P
Basal CT 17 (eleven–33) a sixteen (x–61) NS
PG test
CT 0 11 (vi–23) x (half dozen–68) NS
CT 2 58 (17–265) lx (eight–558) NS
CT 5 46 (13–194) 50 (vii–403) NS
Volume (ml) 17 ± 15 b 21 ± 10 NS

CT 0, 2, and five, CT levels 0, 2, and five min subsequently PG stimulation.

a

Values are the median (range).

b

Values are the mean ± sd.

TABLE 3.

Basal and stimulated CT levels (pg/ml) and thyroid volume in patients with thyroid disease and elevated basal CT

Nonneoplastic thyroid affliction Neoplastic thyroid disease P
Basal CT 17 (11–33) a 16 (10–61) NS
PG test
CT 0 11 (six–23) 10 (half-dozen–68) NS
CT 2 58 (17–265) 60 (8–558) NS
CT 5 46 (13–194) l (7–403) NS
Volume (ml) 17 ± 15 b 21 ± 10 NS
Nonneoplastic thyroid disease Neoplastic thyroid affliction P
Basal CT 17 (11–33) a 16 (10–61) NS
PG test
CT 0 11 (6–23) 10 (6–68) NS
CT ii 58 (17–265) 60 (8–558) NS
CT 5 46 (xiii–194) 50 (7–403) NS
Volume (ml) 17 ± 15 b 21 ± x NS

CT 0, 2, and five, CT levels 0, 2, and five min subsequently PG stimulation.

a

Values are the median (range).

b

Values are the mean ± sd.

Tabular array 4.

Characteristics of four patients with thyroid disease and abnormal PG test

Patient no.
1 2 3 a 4
Sex f m m f
Age (yr) 47 81 39 31
Structure Neoplastic Neoplastic Nonneoplastic Nonneoplastic
Basal CT (pg/ml) 13 61 21, twenty, 20 26
Maximum CT (pg/ml) after PG test 558 403 231, 222, 104 265
Diagnosis HT desultory MTC (micocarcinoma) None De Quervain'south subacute thyroiditis (in remission) HT
Patient no.
1 two iii a 4
Sex f m 1000 f
Age (yr) 47 81 39 31
Structure Neoplastic Neoplastic Nonneoplastic Nonneoplastic
Basal CT (pg/ml) 13 61 21, 20, twenty 26
Maximum CT (pg/ml) afterward PG test 558 403 231, 222, 104 265
Diagnosis HT sporadic MTC (micocarcinoma) None De Quervain'south subacute thyroiditis (in remission) HT

a

PG testing was repeated 3 times during a catamenia of 2 year. f, Female; m, male.

Tabular array iv.

Characteristics of four patients with thyroid affliction and abnormal PG examination

Patient no.
one two iii a 4
Sex f m m f
Age (yr) 47 81 39 31
Structure Neoplastic Neoplastic Nonneoplastic Nonneoplastic
Basal CT (pg/ml) 13 61 21, 20, twenty 26
Maximum CT (pg/ml) after PG test 558 403 231, 222, 104 265
Diagnosis HT sporadic MTC (micocarcinoma) None De Quervain'due south subacute thyroiditis (in remission) HT
Patient no.
1 two 3 a 4
Sex f one thousand m f
Historic period (year) 47 81 39 31
Structure Neoplastic Neoplastic Nonneoplastic Nonneoplastic
Basal CT (pg/ml) thirteen 61 21, twenty, 20 26
Maximum CT (pg/ml) after PG exam 558 403 231, 222, 104 265
Diagnosis HT desultory MTC (micocarcinoma) None De Quervain'south subacute thyroiditis (in remission) HT

a

PG testing was repeated 3 times during a period of 2 yr. f, Female; m, male person.

Table v demonstrates that in contrast to patients with neoplastic thyroid illness, in those with diffuse goiter, basal CT levels were related to PG-stimulated CT levels.

Table v.

Correlations between basal and stimulated CT levels in patients with thyroid disease and elevated basal CT

Nonneoplastic thyroid disease Neoplastic thyroid disease
Basal CT vs. CT 0 0.89 a 0.79 a
CT 0 vs. CT 2 0.65 a 0.30
CT 0 vs. CT 5 0.92 a 0.31
Vs. Thyroid volume vs. basal CT 0.34 0.59 a
Nonneoplastic thyroid disease Neoplastic thyroid disease
Basal CT vs. CT 0 0.89 a 0.79 a
CT 0 vs. CT 2 0.65 a 0.30
CT 0 vs. CT 5 0.92 a 0.31
Vs. Thyroid volume vs. basal CT 0.34 0.59 a

Values are presented every bit coefficients of correlations.

CT 0, 2, and v, CT levels 0, two, and v min subsequently PG stimulation.

a

P < 0.05.

Tabular array 5.

Correlations between basal and stimulated CT levels in patients with thyroid affliction and elevated basal CT

Nonneoplastic thyroid illness Neoplastic thyroid affliction
Basal CT vs. CT 0 0.89 a 0.79 a
CT 0 vs. CT ii 0.65 a 0.30
CT 0 vs. CT 5 0.92 a 0.31
Vs. Thyroid book vs. basal CT 0.34 0.59 a
Nonneoplastic thyroid disease Neoplastic thyroid affliction
Basal CT vs. CT 0 0.89 a 0.79 a
CT 0 vs. CT ii 0.65 a 0.30
CT 0 vs. CT 5 0.92 a 0.31
Vs. Thyroid volume vs. basal CT 0.34 0.59 a

Values are presented as coefficients of correlations.

CT 0, 2, and 5, CT levels 0, 2, and 5 min after PG stimulation.

a

P < 0.05.

CT levels in healthy controls

Six (v males and one female) of 362 salubrious controls (1.7%) had elevated basal CT levels, ranging from 10–12 pg/ml. Figure ane shows the gender-related CT distribution pattern, demonstrating higher normal values in males compared with females. None of the 6 subjects had an abnormal PG stimulation test or evidence of functional or morphological thyroid abnormalities.

Fig. 1.

CT levels in healthy volunteers (M, male; F, female; all, females and males together).

CT levels in healthy volunteers (M, male person; F, female; all, females and males together).

Fig. i.

CT levels in healthy volunteers (M, male; F, female; all, females and males together).

CT levels in healthy volunteers (M, male person; F, female; all, females and males together).

Discussion

To improve the prognosis of MTC, an early on diagnosis is essential. It is believed that CCH is a potential precancerous condition even in the absence of germline mutations in the RET protooncogene (10, xi). CT screening in neoplastic thyroid disease is a common approach to solve this issue, yet it is unclear whether subjects with nonneoplastic thyroid illness should also be candidates for CT screening, considering pathological studies revealed the presence of both CCH and MTC in thyroid tissue without evidence of nodules (11). The overall prevalence of elevated basal CT in referrals was 28 of 414 (6.8%) and was not different in neoplastic and nonneoplastic thyroid disease. In healthy controls, 6 of 362 (one.65%) had elevated basal CT levels. In our subjects, including both referrals and salubrious controls, CCH, as divers biochemically by an aberrant PG stimulation exam (>100–500 pg/ml), was a rare condition (iii of 414 and 0 of 362 subjects, respectively). Absolutely, healthy controls were significantly younger than referrals, which is a limitation of our study.

But 1 of 28 referrals with an elevated basal CT had a terminal histological diagnosis of MTC. In the study group of referrals, the prevalence of MTC reached 0.24%, which was lower than in previously published trials, where it ranged from 0.58% (7) to ane.37% (21). Therefore, in agreement with before studies no rationale exists for full general CT screening, because these programs should be performed for common diseases, withal this is clearly not true for MTC (22, 23). However, subjects with neoplastic or nonneoplastic thyroid disease correspond a different population. In fact, the frequency of an abnormal PG test was every bit high in subjects with neoplastic (2 of 195, ane%) and nonneoplastic (2 of 219, 0.9%) thyroid disease and was comparable with that in other studies (7, 8, 13, 21). At the end, 4 subjects with aberrant or pathological PG testing were identified, at to the lowest degree i of them with a final diagnosis of MTC. This patient had only 1 nonpalpable nodule, 5 mm in bore, which might have been missed if patients were selected by clinical criteria. Importantly, this female was one of three patients with aberrant PG testing and show of thyroiditis (ii subjects with HT and 1 subject with de Quervain's subacute thyroiditis). Niccoli's study (21) revealed that 8 (50%) of sixteen patients with MTC had histopathological signs of thyroiditis, whereas other groups did not comment upon the frequency of thyroiditis. An clan between CCH and HT has been described (24–27). Firstly, Barbot (27) reported increased serum CT levels and all-encompassing CCH in histology subsequently thyroidectomy in three of 24 patients with HT. In extended studies, Guyetant (24) reported the occurrence of CCH in 20% of HT patients. The pathophysiological link between CCH and HT may involve an immunopathological mechanism or an effect of the inflammatory mediators and cytokines secreted past infiltrating lymphocytes in the thyroid parenchyma. Information technology is important to state that our information suggest that CT measurements should exist carried out in all patients with HT.

The office of a C cell growth factor whose factor is overexpressed in hyperplastic C cells next to follicular tumors is hypothesized (24). Interestingly, basal CT levels were related to stimulated CT levels in nonneoplastic, but not in neoplastic, thyroid disease, and the PG-stimulated increase in CT was lower in nonneoplastic thyroid disease. Perry et al. (12) postulated the concept of physiological and neoplastic CCH. One might hypothesize that the increment in CT reflects a cause-effect human relationship in HT, a physiological response of all C cells in the thyroid gland in nonneoplastic disease, yet no biochemical markers exist for the distinction between physiological and neoplastic CCH.

CT measurement contains numerous methodological aspects. Mature CT is formed by posttranslational proteolytic processing of a large forerunner molecule, and diverse split products of prepro-CT may also exist in the apportionment (28). Conceivably, for MTC screening only tests free of cantankerous-reactions with young CT should exist used (29). There are several reports in the literature on rarely assay-dependent CT elevations, which may be partly explained by the presence of heterophilic antibodies within the sample matrix (18, thirty, 31). To block such interference, most noncompetitive immunoassays, including the test used in this study, contain an excess of nonimmune-competent immunoglobulin Chiliad of the same animal species. Despite this, we observed that several lots of the assay used were still susceptible to immunological interference, making either dilution testing or addition of an external blocking amanuensis necessary to obtain correct results (xviii). Our findings are in agreement with reported data, and the assay used throughout this report has been demonstrated to be a reliable and sensitive assay (32).

Identification of subjects at risk for MTC relies on an appropriate cutting-off value for basal and stimulated CT. From experience in our establishment a cutting-off of 100 pg/ml was appropriate to identify CCH (9). To stimulate CT secretion nosotros routinely use pentagastrin and have established criteria for test interpretation, which have been clinically validated (ix).

In our study a cut-off value of ten pg/ml was set up up for performing PG tests regardless of gender. Vierhapper et al. (xiii) used a cut-off of 5 pg/ml, and 72 of 1062 patients exceeded this value, yet in simply 11 of 34 patients with greater than 10 pg/ml was CCH or MTCfound. In Pacini's written report all subjects with MTC had a basal CT level greater than 55 pg/ml (7). Niccoli noted that 2 (0.17%) of sixteen patients with MTC had a basal CT ranging betwixt 5–10 pg/ml using of a less sensitive CT assay (21). Co-ordinate to our data, any higher CT cutting-off point would substantially decrease the sensitivity of basal CT measurements for the detection of (neoplastic) CCH.

Still, less is known almost the physiological variation in CT levels. They might be related to the subject's nutritional status (fasting/nonfasting) or influenced by blood sample collection. In our institution, as in many others, basal CT was measured kickoff during thyroid work-up in a nonfasting state with the patient seated. This is in contrast to the standardized conditions during PG stimulation testing. These differences might account for the variation in basal CT levels observed in our patients. Eighteen of 28 patients had basal CT values of 10 pg/ml or less at the time of PG stimulation. It is noteworthy that in our study basal CT levels were only moderately elevated in subjects with either abnormal or pathological PG testing. Equally reported recently (ix), patients with abnormal PG testing should undergo functioning. This strategy is supported past findings that metastatic MTC might occur fifty-fifty in patients with microcarcinoma (11).

Patient iii, suffering from de Quervain'southward subacute thyroiditis, is an example of the demand to obtain clinical information for interpretation of CT levels. Even after a follow-up period of 2 twelvemonth in clinical remission, this patient however showed evidence of elevated basal and stimulated CT, with a trendwise decrease over time. For that reason, interpretation of CT and PG exam results should exist made charily and with respect to the underlying condition. Nevertheless, this patient is nevertheless a candidate for surgery to exclude definitely micro-MTC.

Clinical conclusion

In accordance with previous studies and recommendations (13), CT measurements should exist performed in all subjects with neoplastic thyroid disease equally evidenced by sonography. Our data suggest that the number of basal CT measurements should be increased by extending them to all HT patients. This might alter the cost-effectiveness of basal CT screening. PG testing is essential even when basal CT levels are only moderately elevated to diagnose MTC or its premalignant conditions. However, by accumulating evidence for the impact of CT measurement for early diagnosis of nonhereditary MTC, farther studies are necessary to define how often CT levels should be assessed in patients with neoplastic thyroid disease, considering this data implies substantial consequences in terms of toll effectiveness. Furthermore, the effects of various forms of thyroiditis on CT levels and its potential touch on on the outcome of CT measurements demand to be investigated.

Abbreviations:

  • CCH,

  • CT,

  • HT,

  • MTC,

    medullary thyroid carcinoma;

  • PG,

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