Diagnostic Utility of Procalcitonin for Sporadic Medullary Thyroid Carcinoma in Patients with Nodular Disease and Mild or Moderate Hypercalcitoninemia.

Many authors recommend the measurement of serum calcitonin (Ctn) to screen for sporadic medullary thyroid carcinoma (MTC) in patients with thyroid nodules. In this situation, procalcitonin (pro-Ctn) would have greater utility in patients with hypercalcitoninemia<100 pg/ml. The aim of this study was to evaluate the utility of pro-Ctn in patients with thyroid nodules and without a suspicion of familial MTC or type 2 multiple endocrine neoplasia who had mild or moderate hypercalcitoninemia without an apparent cause. Consecutive patients with nodular thyroid disease assessed routinely by Ctn measurement were selected. Sixty patients with basal Ctn>10 pg/ml but<100 pg/ml were included. Nine patients (15%) had MTC, with cytology being diagnostic in only four. Among the 51 patients without MTC, pro-Ctn was<0.1 ng/ml in 46 (90.2%). All patients with MTC had pro-Ctn>0.1 ng/ml. Basal Ctn was>24.6 pg/ml in all patients with MTC and in 42 patients (82.3%) without MTC. It is noteworthy that among patients with basal Ctn>24.6 pg/ml (n=18) pro-Ctn>0.1 ng/ml identified all patients with MTC and 64.2% of subjects with these pro-Ctn concentrations had this tumor. In conclusion, we did not find superiority of pro-Ctn over Ctn for the diagnosis of sporadic MTC in patients with nodular disease and mild or moderate hypercalcitoninemia. However, in the case of patients with hypercalcitoninemia in the gray zone, pro-Ctn has an excellent negative predictive value while the data regarding its positive predictive value are not uniform.

Subclinical Hypothyroidism with TSH>7 mIU/l and≤10 mIU/l and Coronary Artery Disease.

The association of subclinical hypothyroidism (SCH) with increased cardiovascular risk is controversial when thyroid-stimulating hormone (TSH) concentration is<10 mIU/l, as well as its association with a higher coronary artery calcium score (CACS) in individuals with low cardiovascular risk. This study evaluated coronary artery disease (CAD) by CACS in asymptomatic, low-cardiovascular risk women with SCH and TSH>7 mIU/l and≤10 mIU/l untreated for 5 years after diagnosis. The CACS was obtained for two groups of women with low cardiovascular risk. Group A consisted of 32 women with mild SCH (TSH>7 mIU/l and≤10 mIU/l) who remained untreated for 5 years, and group B consisted of 32 euthyroid women matched for age and body mass index to group A. The CACS ranged from 0 to 350 (median 0, 25-75% interval: 0-10) in group A and from 0 to 280 (median 0, 25-75% interval: 0-0) in group B. Scores>0 and≥10 were significantly more frequent in group A (40.6 vs. 12.5% and 25 vs. 3.1%, respectively). A CACS≥100 was also more frequent in group A (18.75 vs. 3.1%), but the difference was not significant (p=0.1). The results of the study suggest that long-term SCH with TSH>7 mIU/l and ≤ 10 mIU/l is associated with a higher risk of CAD in individuals≤65 years, even in those with low cardiovascular risk.

Usefulness of Serum Calcitonin in Patients with Thyroid Nodules ≤ 1 cm Without an Indication for Fine-Needle Aspiration.

Fine-needle aspiration (FNA) is not necessary in adults with nodules ≤ 1 cm without apparent extrathyroidal extension (ETE) or lymph node (LN) involvement on ultrasonography (US). In the absence of FNA and serum calcitonin (Ctn) measurement, medullary thyroid microcarcinomas (microMTC) are not diagnosed. The aim of this prospective study was to evaluate Ctn levels in adults with a low clinical risk of MTC and nodules ≤ 1 cm without ETE or LN involvement on US. A total of 506 consecutively seen adults who had nodules with two or more suspicious features were included. Patients with elevated basal Ctn underwent a calcium stimulation test and FNA. Basal Ctn was normal in 490 patients (96.8%). In the 16 patients with elevated basal Ctn, FNA revealed MTC in only one patient and MTC was not suspected in the 15 patients with elevated basal Ctn. Three patients with stimulated Ctn<100 pg/ml and benign cytology were not submitted to surgery. MTC was excluded by histology in three patients with stimulated Ctn<100 pg/ml and indeterminate or suspicious cytology and in eight patients with stimulated Ctn>100 pg/ml. One patient with stimulated Ctn>100 pg/ml had MTC. Ctn was undetectable 6 months after surgery in two patients with MTC. Although uncommon, even subjects without a suspicious history and with nodules ≤ 1 cm without ETE or LN involvement on US, but with suspicious findings, can have microMTC. The measurement of Ctn permits the diagnosis of these cases.

Normocalcemic Primary Hyperparathyroidism in Adults Without a History of Nephrolithiasis or Fractures: A Prospective Study.

The prevalence and the diagnostic criterion of "normocalcemic" primary hyperparathyroidism (NPHPT) are still uncertain and there is no consensual definition. This prospective study evaluated the prevalence of NPHPT in 676 adults without a history of fractures or nephrolithiasis and who would be submitted to thyroidectomy, the impact of adopting different cut-off values for 25-hydroxyvitamin D and estimated glomerular filtration rate (eGFR), and the agreement between biochemical diagnosis and the surgical finding of altered parathyroid glands. NPHPT was diagnosed in patients with normal total and ionized calcium and elevated PTH (in 2 measurements) and without a known cause of secondary HPT, including eGFR<40 ml/min/1.73 m2 and 25-hydroxyvitamin D<20 ng/dl. The 4 parathyroid glands were fully explored in these patients. Forty-six patients (6.8%) had a laboratory diagnosis of NPHPT. Altered parathyroid glands were detected in only 4 patients, corresponding to 0.6% of all patients and to 8.7% of those with a biochemical diagnosis of NPHPT. The latter was confirmed in 0/174 men, 1/252 premenopausal women, and 3/250 postmenopausal women. Among the 42 patients with elevated PTH and without altered parathyroid glands, 25 had 25-hydroxyvitamin D between 20 and 30 ng/dl, 7 had eGFR between 40 and 60 ml/min/1.73 m2, and 9 had both. The prevalence of NPHPT was 0.74% in this adult population without a history of nephrolithiasis or fractures. The diagnostic criterion using eGFR>60 ml/min/1.73 m2 and 25-hydroxyvitamin D>30 ng/dl was more appropriate considering the agreement with the surgical finding of altered parathyroid glands.

Definition of the Response to Initial Therapy with Radioiodine in Patients with Differentiated Thyroid Carcinoma: Basal or Stimulated Thyroglobulin?

Basal thyroglobulin (b-Tg) measured with second-generation assay or stimulated Tg (s-Tg) can be used to define the response to therapy of differentiated thyroid carcinoma. However, they do not always define the same category and guidelines do not establish "if" or "when" s-Tg needs to be obtained. We studied 304 patients without clinically apparent disease or disease detected by neck ultrasonography and without anti-Tg antibodies 9-12 months after therapy. Based on b-Tg, 196 patients had an excellent response and 108 had an indeterminate response. Based on s-Tg, a change in category occurred in 10.2% of the patients with an initial excellent response (all to indeterminate response) and in half the patients with an initial indeterminate response (44.4% to excellent response and 5.5% to biochemical incomplete response). One case of recurrence was observed among patients with an initial excellent response but whose response changed to indeterminate after s-Tg, while no disease was detected among those who remained in the initial category; however, this difference was not significant. In patients with an initial indeterminate response, no recurrence was detected among those whose response changed to excellent after s-Tg, while 11.1 and 33.3% of those who remained in the initial category or whose response changed to biochemical incomplete, respectively, had structural disease. This study suggest that, in low- or intermediate-risk patients, s-Tg better defines the response to therapy with 131I when it is classified as indeterminate based on b-Tg using second-generation assay. However, s-Tg is not necessary when b-Tg defines the response as excellent.

Active Surveillance in Adults with Low-Risk Papillary Thyroid Microcarcinomas: A Prospective Study.

The acceptance and results of active surveillance in patients with low-risk papillary thyroid microcarcinomas (PTMC) are unknown in populations other than the Japanese population. This was the objective of the present prospective study. We selected patients ≥20 years who had thyroid nodules ≤1.2 cm with intermediate or high suspicion for malignancy on ultrasonography (US), not located near the recurrent laryngeal nerve and without extrathyroidal invasion or apparent lymph node metastases, whose cytology was suspicious (Bethesda V) or diagnostic (Bethesda VI) of papillary thyroid carcinoma. Patients who opted for active surveillance were followed up by biannual US. Fifteen patients (18.7%) readily opted for surgery and 12 (15%) for active surveillance. Fifty-three patients (66.2%) delegated the decision or wished to know the doctor's preference before deciding. After the doctor had declared his/her preference for active surveillance, 50 patients decided to have this management and three to have surgery. Only 1/70 patients exhibited tumor progression (growth associated with a suspicion of extrathyroidal invasion) after 30 months of follow-up. Two patients decided to have surgery during follow-up, although the indication was not defined by the study. A>50% reduction in tumor volume was observed in three patients. The study shows that active surveillance can be well accepted if doctors were convinced that it is the best option for patients with low-risk PTMC. At least the short-term results reproduced those observed in other populations, with tumor progression being uncommon.

Risk of Malignancy in Thyroid Nodules Using the American College of Radiology Thyroid Imaging Reporting and Data System in the NIFTP Era.

Recently, the American College of Radiology (ACR) proposed a Thyroid Imaging Reporting and Data System (TI-RADS) for thyroid nodules based on ultrasonographic features. It is important to validate this classification in different centres. The present study evaluated the risk of malignancy in solid nodules>1 cm using ACR TI-RADS. The risk of malignancy was defined including noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and after its exclusion from malignant tumours. For the present study, the original images were revised, and each nodule was assigned to one of the TI-RADS levels proposed for solid nodules: TR3, TR4, or TR5. This risk of malignancy was significantly different for the three levels: 1.7%, 11.2%, and 60.6% for TR3, TR4, and TR5, respectively, when NIFTP was included, and 0.6%, 7.9%, and 60.2% for TR3, TR4, and TR5, respectively, when NIFTP was excluded from malignant tumours. The nodules corresponding to NIFTP were classified according to ACR as TR3 in 28.5% of cases, TR4 in 67.8%, and TR5 in only 3.5%. The nodules corresponding to cancer were classified according to ACR as TR3 in only 2.3% of cases, TR4 in 27%, and TR5 in 70.5%. In conclusion, this study shows the validity of the ACR TI-RADS for solid thyroid nodules, even after the exclusion of NIFTP from malignant tumours.

Long-Term Follow-Up in Patients with Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP) Without a Suspicion of Persistent Disease in Postoperative Assessment.

The objective was to determine whether negative assessment after surgery is a predictor of no relevant change of the results in subsequent evaluations in patients with noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Six months after surgery, "absence of persistent disease" was defined when concentration of thyroglobulin (Tg) is ≤2 ng/ml in patients undergoing total thyroidectomy and ≤10 ng/ml in those undergoing lobectomy, in the absence of antithyroglobulin antibodies (TgAb), and neck ultrasonography (US) without abnormalities. One hundred thirteen patients met the definition of "absence of persistent disease". The patients were followed up for 18-150 months. None of the patients developed structural disease. In the 56 patients undergoing total thyroidectomy, 380 Tg measurements were obtained and an increase in concentrations was not observed in any of them. During the same period, 332 US scans were performed and a suspicious lymph node was detected on only one occasion, but was not metastatic on fine needle aspiration (FNA). In the 57 patients undergoing lobectomy, 382 Tg measurements were obtained and increases or persistent concentrations>10 ng/ml were not observed in any patient. During the same period, 376 US scans were performed and nodules with an indication for FNA were detected in 4 patients, but malignancy was not confirmed in any of them. Finally, TgAb were not elevated in any of the 762 measurements obtained from the 113 patients. After complete resection of NIFTP, negative postoperative assessment can be used to exclude the need for long-term repetition of these tests.

Ultrasonography Classification of the American Thyroid Association for Predicting Malignancy in Thyroid Nodules >1cm with Indeterminate Cytology: A Prospective Study.

The objective of this prospective study was to evaluate the ultrasonography classification of the American Thyroid Association (ATA) for predicting malignancy in thyroid nodules >1 cm with indication for fine-needle aspiration (FNA) whose cytology was indeterminate. Additionally, the combination of the ATA classification with Doppler analysis was evaluated. All patients with thyroid nodules >1 cm were eligible. Each nodule was assigned to one of the ATA categories. Exclusively or predominantly intranodular vascularity was considered suspicious. One hundred and thirty-seven patients with 143 nodules underwent FNA and those with indeterminate cytology (Bethesda category III or IV) were selected. All patients were referred for surgery. Among the 143 nodules evaluated, 92 were benign, 33 were malignant, 13 were noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), and 5 were tumors of uncertain malignant potential (TUMP). The rate of malignancy, including NIFTP and TUMP in this definition, was 80%, 42.8%, 13%, 10%, and 23% for nodules with a high suspicion, intermediate suspicion, low suspicion, very low suspicion, and undefined ultrasonographic pattern, respectively. Considering NIFPT and TUMP as benign, these rates were 72%, 22.4%, 4.3%, 0%, and 15.4%, respectively. The addition of Doppler analysis did not significantly improve the prediction of malignancy obtained with the ATA classification alone. The results of this prospective study show the usefulness of the ATA ultrasonographic classification for predicting malignancy specifically in thyroid nodules >1 cm with indeterminate cytology. The ATA category of the nodule should influence the decision for follow-up, molecular tests, or surgery.

Symptoms of thyrotoxicosis, bone metabolism and occult atrial fibrillation in older women with mild endogenous subclinical hyperthyroidism.

OBJECTIVE: The objective of this study was to evaluate symptoms of thyrotoxicosis, bone turnover, bone mineral density (BMD) and occult atrial fibrillation (AF) in women ≥65 years with mild endogenous subclinical hyperthyroidism (SCH). DESIGN: Cross-sectional and case-control study. PATIENTS: Signs and symptoms of thyrotoxicosis, serum carboxyterminal telopeptide (CTx) and procollagen type I N-terminal propeptide (PINP), BMD, resting electrocardiogram (ECG) and 72-h ECG monitoring were evaluated in 180 women ≥65 years, including 90 with mild SCH (TSH between 0·1 and 0·4 mIU/l) and 90 euthyroid controls matched for age and body mass index. RESULTS: Symptom Rating Scale scores did not differ between patients and controls. None of the patients with SCH scored 20 points, a score compatible with clinical thyrotoxicosis. Eighty patients with SCH (89%) obtained seven or fewer points, a score compatible with euthyroidism. No difference in serum CTx or PINP concentrations was observed between patients and controls. There was also no correlation between these markers and TSH, free T4 or total T3 levels. Finally, no difference in femoral neck or lumbar spine BMD was observed between patients with SCH and controls. Three patients with SCH (3·3%) and two euthyroid women (2·2%) had known AF or AF in the resting ECG. ECG monitoring for 72 h revealed episodes of occult AF in 1/87 patients with SCH and in 1/88 euthyroid women (1·1%). CONCLUSIONS: Mild endogenous SCH (TSH between 0·1 and 0·4 mIU/l) was not associated with symptoms of thyrotoxicosis, altered bone metabolism or a higher prevalence of occult AF in women ≥65 years.

Can the follow-up of patients with papillary thyroid carcinoma of low and intermediate risk and excellent response to initial therapy be simplified using second-generation thyroglobulin assays?

OBJECTIVE: In view of the low probability of recurrence, the cost-effective follow-up of patients with papillary thyroid carcinoma (PTC) of low or intermediate risk and excellent response to initial therapy represents a challenge. This study evaluated the cases of structural recurrence among these patients. PATIENTS: The sample comprised 578 patients with PTC of low or intermediate risk, who were submitted to total thyroidectomy with or without (131) I therapy and exhibited an excellent response to initial therapy defined based on nonstimulated thyroglobulin (Tg) ≤0·2 ng/ml and negative neck ultrasonography (US). RESULTS: Twelve patients (2%) showed structural recurrence. At the time when recurrence was 'confirmed', Tg elevation had not occurred in only two patients, one with lymph node metastases <1 cm detected by US and the other with pulmonary metastases. Antithyroglobulin antibodies (TgAb) were undetectable in both patients. The first alteration observed in patients with recurrence was Tg elevation in six patients, Tg elevation associated with suspicious US in three, and suspicious US in two. An increase in TgAb was not the first alteration in any of the patients. Among the 560 patients who continued to have Tg ≤ 0·2 ng/ml, US permitted the detection of only one neck recurrence. Measurement of TgAb did not detect any recurrence. CONCLUSION: Our results confirm that in patients with PTC of low or intermediate risk an excellent response to initial therapy can be defined based on nonstimulated Tg ≤ 0·2 ng/ml. Follow-up consisting only of clinical examination and periodic measurement of Tg with a second-generation assay may be sufficient.

Low postoperative nonstimulated thyroglobulin as a criterion for the indication of low radioiodine activity in patients with papillary thyroid cancer of intermediate risk 'with higher risk features'.

OBJECTIVE: This study evaluated low-activity (131) I therapy in patients with papillary thyroid carcinoma (PTC) of intermediate risk 'with higher risk features' who had low nonstimulated thyroglobulin (Tg) after thyroidectomy. DESIGN AND PATIENTS: This was a prospective study including 102 patients with tumours >1 cm and aggressive histology; and/or >3 positive lymph node (LN) or LN >1·5 cm or exhibiting macroscopic extracapsular extension, and clinically apparent (cN1); and/or a combination of a tumour >4 cm, microscopic extrathyroidal extension and LN metastases (cN1). After thyroidectomy, all patients had nonstimulated Tg < 0·3 ng/ml and negative antithyroglobulin antibodies (TgAb) and neck ultrasonography (US). The patients were treated with a low activity of (131) I (1110 or 1850 MBq). RESULTS: Post-therapy whole-body scanning (RxWBS) showed ectopic uptake in four patients. When evaluated 12 months after (131) I therapy, nonstimulated Tg ≤ 0·2 ng/ml with negative TgAb and US, defined as excellent response to initial therapy, was achieved in 101 patients (99%). Only one patient with positive initial RxWBS had structural disease. During follow-up, four patients (4%) relapsed, including LN metastases in two, pulmonary metastases in one, and elevated Tg in one. The other 98 patients remained with nonstimulated Tg ≤ 0·2 ng/ml and negative TgAb and US. There was no case of death due to the tumour. CONCLUSIONS: We conclude that in intermediate-risk patients 'with higher risk features', low nonstimulated Tg measured with a second-generation assay can be used as criterion for the administration of low (131) I activities (1850 MBq or less).

Screening for acromegaly by application of a simple questionnaire evaluating the enlargement of extremities in adult patients seen at primary health care units.

The objective of this study was to screen for acromegaly by application of a simple questionnaire in patients seen at primary health care units. A total of 17,000 patients of both genders >18 and <70 years seen by general practitioner were interviewed. Patients with known pituitary disease and pregnant women were excluded. A simple questionnaire was applied to the patients: Has your shoe size increased over the last 5 years? Did you have to change your wedding ring or ring over the last 5 years because it became tight? In one patient, the diagnosis of acromegaly was suspected by the physician. Among the remaining patients, 178 (1%) responded positively to one of the items of the questionnaire and were submitted to IGF-1 measurement. Five patients had persistently elevated IGF-1 and inadequate suppression of GH in the OGTT (without other conditions associated with GH or IGF-1 elevation). One of these patients presented a normal pituitary upon magnetic resonance imaging and adenoma was detected in the other four; two presented the typical facies and two others reported changes in physiognomy (confirmed by the comparison of photographs), in addition to the enlargement of extremities. The present investigation suggests a much higher prevalence of acromegaly in the adult population than that reported traditionally. We propose that screening based on phenotypic alterations is cost-effective since these changes occur early and almost universally in acromegaly and are uncommon in the general population.