The mutational analysis in the diagnostic work-up of thyroid nodules: the real impact in a center with large experience in thyroid cytopathology.

PURPOSE: Fine-needle aspiration (FNA) cytology is a mainstay in the evaluation of thyroid nodules, but fails to reach reliable results in 25-30% of cases. The role of molecular markers in helping clinical decisions has been investigated for the last years, but their clinical usefulness is still unsettled. METHODS: Mutation analysis of BRAF, RAS genes and TERT promoter was performed in a series of 617 consecutive cytological specimens undergoing FNA. RESULTS: The 617 nodules had the following cytological diagnosis: non diagnostic 22 (3.6%), benign 425 (68.9%), indeterminate 114 (18.5%), suspicious 11 (1.8%) and malignant 45 (7.3%). BRAF mutations were found in 31 cases (5.0%), all but two in suspicious and malignant nodules. RAS mutations were detected in 47 samples (7.6%): 25 benign (5.9%) and 19 indeterminate nodules (16.7%). TERT promoter mutation alone was detected in three samples. Histological outcome was available for 167 nodules, 81 of which proved malignant: all the 48 with suspicious or malignant cytology; 25 out of 56 (44.6%) with indeterminate and 8 out of 57 (14%) with benign cytology. BRAF mutations were associated with worse tumors pathological features. The presence of RAS mutations was indicative of follicular-patterned malignancies in 5 out of 8 benign nodules and 9 out of 11 indeterminate nodules. CONCLUSIONS: Our study established mutational rates for BRAF and RAS genes in a large series of FNA specimens. BRAF mutations were confirmed as highly specific but not able to improve cytological diagnosis, while RAS testing proved effective in assessing malignancy in nodules with indeterminate and benign cytology.

Thyroid ultrasonography reporting: consensus of Italian Thyroid Association (AIT), Italian Society of Endocrinology (SIE), Italian Society of Ultrasonography in Medicine and Biology (SIUMB) and Ultrasound Chapter of Italian Society of Medical Radiology (SIRM).

Thyroid ultrasonography (US) is the gold standard for thyroid imaging and its widespread use is due to an optimal spatial resolution for superficial anatomic structures, a low cost and the lack of health risks. Thyroid US is a pivotal tool for the diagnosis and follow-up of autoimmune thyroid diseases, for assessing nodule size and echostructure and defining the risk of malignancy in thyroid nodules. The main limitation of US is the poor reproducibility, due to the variable experience of the operators and the different performance and settings of the equipments. Aim of this consensus statement is to standardize the report of thyroid US through the definition of common minimum requirements and a correct terminology. US patterns of autoimmune thyroid diseases are defined. US signs of malignancy in thyroid nodules are classified and scored in each nodule. We also propose a simplified nodule risk stratification, based on the predictive value of each US sign, classified and scored according to the strength of association with malignancy, but also to the estimated reproducibility among different operators.

BRAF mutation analysis in thyroid nodules with indeterminate cytology: our experience on surgical management of patients with thyroid nodules from an area of borderline iodine deficiency.

PURPOSE: Fine-needle aspiration (FNA) with cytologic evaluation is the most reliable tool for malignancy prediction in thyroid nodules, but cytologic diagnosis remains indeterminate for 12-18 % of nodules. BRAF V600E mutation has been reported to show a high specificity for malignant thyroid nodules and the use of this marker to refine indeterminate FNA cytology results may be a useful diagnostic adjunctive tool in the pre-operative evaluation of thyroid nodules. The aim of this study was to estimate the prevalence of BRAF exon 15 mutation (V600E) and its clinical value as a diagnostic tool in a series of thyroid nodules with indeterminate cytology from an area of borderline iodine deficiency. SUBJECTS AND METHODS: One hundred and fifty-three thyroid samples obtained by FNA of thyroid nodules from 151 patients were subjected to the analysis of BRAF V600E mutation by direct sequencing. In the study 54 nodules with indeterminate cytology, 56 benign and 43 malignant thyroid nodules were included. RESULTS: V600E BRAF gene mutation was demonstrated in 19/43 malignant nodules, in 0/56 benign nodules and in only 1/54 indeterminate nodules that, after histology, turned out to be at a papillary thyroid carcinoma. CONCLUSIONS: The application of BRAF exon 15 analysis showed limitations when applied to discriminate thyroid nodules with indeterminate cytology if wild-type BRAF is found, and there is no role for avoiding diagnostic thyroid surgery.

Salivary glands ultrasound examination after radioiodine-131 treatment for differentiated thyroid cancer.

BACKGROUND: The most important side effect of radioiodine ((131)I) therapy is sialoadenitis and xerostomy. AIM: To evaluate by ultrasound (US) parotid and submandibular glands after (131)I therapy for differentiated thyroid cancer (DTC). PATIENTS: Seventy-six subjects thyroidectomized for DTC submitted to salivary glands US examination. Forty-three of them had been previously treated with (131)I: 22 with 1.11 GBq (30 mCi) for remnant ablation, and 21 with higher doses [up to 44.4 GBq (1200 mCi)] for metastases. Thirty-three subjects studied before (131)I therapy served as controls. Parotid and submandibular volume, homogeneity, and echogenicity were determined. (131)I-treated patients filled a questionnaire about sialoadenitis symptoms. RESULTS: Parotid gland volume was significantly higher in treated patients (28.3±16.2 ml) than in untreated patients (20.7±10.4 ml, p=0.0154) and related to the time from last (131)I therapy. Three had parotid volume <1.5 ml and complained severe xerostomy. Submandibular gland volume was similar in treated (11.2±7.6 ml) and untreated patients (8.6±4.2 ml, p=0.0602). Homogeneity and echogenicity were similar in treated and untreated patients. Sialoadenitis symptoms were reported in 26% and were related to the (131)I cumulative dose. Symptoms were not related to gland volume. Hypoechogenicity and inhomogeneity of the parotids were more frequent in patients with salivary stickiness. CONCLUSION: Parotid, but not submandibular, volume is increased after (131)I treatment depending on the received activity and the time from irradiation but not on sialoadenitis symptoms. Xerostomy is associated to gland atrophy at US.

Genetic markers to discriminate benign and malignant thyroid nodules with undetermined cytology in an area of borderline iodine deficiency.

BACKGROUND: Fine needle aspiration (FNA) with cytologic evaluation is the most reliable tool for malignancy prediction in thyroid nodules, but cytologic diagnosis remains undetermined for 20% of nodules. AIM: We investigated the diagnostic potential of a set of 6 marker genes to distinguish benign and malignant thyroid nodules. SUBJECTS AND METHODS: The prospective study included 153 thyroid samples obtained by FNA of thyroid nodules from 151 patients (56 benign, 43 malignant, and 54 nodules with undetermined cytology). Gene expression was evaluated by quantitative realtime PCR and statistical analysis of data was performed. All samples were analyzed for V600E BRAF mutation. RESULTS: A decrease in TTF3 and HGD1 expression was observed in malignant nodules with respect to benign ones, while an increase in PLAB expression was demonstrated in these nodules. The decision model was valid for 88 of 99 cases of benign and malignant nodules, with a total of 11 false positive or negative predictions. The obtained malignant/benign phenotype prediction was also valid for 37 of 54 cases of nodules with undetermined cytology with a total of 8 false positive and 9 false negative predictions. V600E BRAF gene mutation was demonstrated in 19/43 malignant nodules, in 0/56 benign nodules, and in 1/54 undetermined nodules. CONCLUSIONS: The expression profiles of genes (TFF3, HGD1, and PLAB) allowed a good prediction for the differentiation of benign thyroid lesions and thyroid cancer starting from cells of FNA; however, this assay showed limitations when applied to discriminate thyroid nodules with undetermined cytology.

Papillary thyroid cancer, although strongly associated with lymphocytic infiltration on histology, is only weakly predicted by serum thyroid auto-antibodies in patients with nodular thyroid diseases.

OBJECTIVE: We evaluated the association between thyroid autoimmunity and thyroid cancer in a retrospective series of unselected thyroid nodules submitted to fine-needle aspiration (FNA) cytology. DESIGN: Anti-thyroid antibodies (TAb) were measured in patients with multinodular goiter (MNG) and single/isolated thyroid nodule (S/I) submitted to FNA. Thyroid lymphocytic infiltration (LI) on histology was studied in a subgroup of patients submitted to thyroidectomy; 13,021 patients were included: on cytology 622 had papillary thyroid cancer (c- PTC) and 12,399 benign thyroid nodular diseases (c-BTN). LI was evaluated in histological samples of 688 patients: 304 with PTC (h-PTC) and 384 with BTN (h-BTN). RESULTS: TAb prevalence was not different in c-BTN and c-PTC (38.7% vs 35.6%). TAb were more frequent in c-BTN than c-PTC in females with MNG (40.1% vs 32.5%, p=0.02), and in c-PTC than in c-BTN in males with S/I (31.2% vs 20.4%, p=0.02) and, although not significantly, in females younger than 30 yr (35.1% vs 30.7%). The frequency and severity of LI was significantly higher in h-PTC than h-BTN, both in MNG (82.5% vs 45.0%, p<0.001) and S/I (85.6% vs 71.0%, p<0.001), but a higher number of patients with h-PTC had negative circulating TAb, despite the presence of moderate/severe LI. CONCLUSIONS: TAb are weakly associated to PTC in males and young females, while they are more frequent in older females with BTN. The frequency and severity of LI is significantly higher in PTC than in BTN, but in cancer patients TAb are frequently negative, despite the evidence of histological thyroiditis. These data suggest that different kinds of immune response may be involved in PTC and BTN.

Elastography: new developments in ultrasound for predicting malignancy in thyroid nodules.

BACKGROUND: Elastography is a newly developed dynamic technique that uses ultrasound (US) to provide an estimation of tissue stiffness by measuring the degree of distortion under the application of an external force. US elastography has been applied to differentiate malignant from benign lesions. PATIENTS: This study included 92 consecutive patients with a single thyroid nodule who underwent surgery for compressive symptoms or suspicion of malignancy on fine needle aspiration cytology. Tissue stiffness on US elastography was scored from one (greatest elastic strain) to five (no strain). RESULTS: On US elastography: scores 1 and 2 were found in 49 cases, all benign lesions; score 3 in 13 cases, one carcinoma and 12 benign lesions; and scores 4 and 5 in 30 cases, all carcinomas. Thus, the elasticity scores 4-5 were highly predictive of malignancy (P < 0.0001), with a sensitivity of 97%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 98%. In 32 patients with an indeterminate fine needle aspiration result, the conventional US was not predictive of malignancy, while an US elastographic score of 4-5 was observed in six of seven (86%) patients with carcinoma on histology, and a score of 1-3 in all 25 patients with benign lesions. CONCLUSIONS: US elastography has great potential as an adjunctive tool for the diagnosis of thyroid cancer, especially in indeterminate nodules on cytology. Larger prospective studies are needed to confirm these results and establish the diagnostic accuracy of this new technique.

Outcomes and Risk Factors for Complications of Laser Ablation for Thyroid Nodules: A Multicenter Study on 1531 Patients.

BACKGROUND: Image-guided laser ablation therapy (LAT) of benign thyroid nodules demonstrated favorable results in randomized trials with fixed modalities of treatment. The aim of this retrospective multicenter study was to assess the effectiveness, tolerability, and complications of LAT in a large consecutive series of patients from centers using this technique in their routine clinical activity. PATIENTS: Clinical records of 1534 consecutive laser-treated nodules in 1531 patients from eight Italian thyroid referral centers were assessed. Inclusion criteria were as follows: solid or mixed nodules with fluid component up to 40%; benign cytological findings; and normal thyroid function. METHODS: LAT was performed with a fixed-power protocol, whereas the number of applicators and illumination times were different according to target size. From one to three illuminations with pullback technique and with a total energy delivery based on the nodule volume were performed during the same session. Patients were evaluated during LAT, within 30 days, and 12 months after the procedure. RESULTS: Total number of treatments was 1837; 1280 (83%) of nodules had a single LAT session. Mean nodule volume decreased from 27 ± 24 mL at baseline to 8 ± 8 mL 12 months after treatment (P < .001). Mean nodule volume reduction was 72% ± 11% (range 48%-96%). This figure was significantly greater in mixed nodules (79% ± 7%; range 70%-92%) because they were drained immediately before laser illumination. Symptoms improved from 49% to 10% of cases (P < .001) and evidence of cosmetic signs from 86% to 8% of cases (P < .001). Seventeen complications (0.9%) were registered. Eight patients (0.5%) experienced transitory voice changes that completely resolved at the ear-nose-throat examination within 2-84 days. Nine minor complications (0.5%) were reported. No changes in thyroid function or autoimmunity were observed. CONCLUSIONS: Real practice confirmed LAT as a clinically effective, reproducible, and rapid outpatient procedure. Treatments were well tolerated and risk of major complications was very low.

Effect of iodized salt on thyroid volume of children living in an area previously characterized by moderate iodine deficiency.

It is well established that an adequate iodine intake prevents iodine deficiency disorders. Prophylaxis through iodized salt is able to correct urinary iodine deficiency and to prevent goiter endemia, but scanty data are available about its effect on decreasing the thyroid size in goitrous children born before prophylaxis. The prevalence of goiter was evaluated by ultrasound in the school-children population of an area of Eastern Tuscany (Tiberina Valley) characterized by moderate iodine deficiency in 1985. At present, after the implementation of voluntary iodized salt consumption, iodine urinary excretion was borderline sufficient (median, 98 micrograms/L). Goiter prevalence was higher at ultrasound (17%) than by palpation (10%). The median thyroid volume ranged from 3.1 mL in 7-yr-old children to 9.2 mL in 14-yr-old children. In the 7-10 yr age class (i.e. in children born after iodine prophylaxis), no statistical difference in thyroid volume was found with respect to controls. In older children (11-14 yr) born before the institution of iodine prophylaxis, the median thyroid volume was significantly higher than that in age-matched controls. Moreover, in this cluster of subjects, the median thyroid volume in nongoitrous children was higher than that in controls. In conclusion, the data of the present study indicate that the iodized salt prophylaxis is able to prevent the development of goiter in children born after the implementation of iodized salt consumption and to further control thyroid enlargement in older children, but is less effective (or rapid) in reducing goiter size in children exposed to iodine deficiency in the first years of life.

Interleukin-6: a marker of thyroid-destructive processes?

Increased serum interleukin-6 (IL-6) concentrations have recently been reported in patients with subacute thyroiditis and in some patients with amiodarone-induced thyrotoxicosis, possibly because of cytokine release from damaged thyroid cells. In this study, serum IL-6 levels were determined by an enzyme-linked immunosorbent assay method in 18 patients given percutaneous intranodular ethanol injection (PIEI) for autonomously functioning thyroid nodule, 12 patients treated with radioactive iodine (RAI) for Graves' disease or toxic adenoma, and 23 patients submitted to fine needle aspiration (FNA) for nonfunctioning thyroid nodules. Baseline serum IL-6 levels did not differ in the 3 groups. PIEI was followed by a dramatic increase in median IL-6 values from 42 fmol/L (range, < 25 to 84) to 381 fmol/L (range, 61-9870; P < 0.0001); the peak value was attained as little as 10 min after injection. RAI was also followed by a significant (P < 0.0001) increase in IL-6 from 52 fmol/L (range, < 25 to 84) to 189 fmol/L (range, 119-1417 fmol/L); the increase after RAI was lower than that after PIEI (P < 0.05), and the peak value was attained later (after 24 h). FNA was also followed by a slight, but significant, increase in the serum IL-6 concentration from 21 fmol/L (range, < 25 to 103) to 109 fmol/L (range, < 25 to 360; P < 0.0001 vs. baseline). The increase in IL-6 was correlated with the size of nodule or goiter (P < 0.0001), but not with the amount of injected ethanol or the dose of radioiodine delivered to the thyroid. Serum thyroglobulin also increased after PIEI, RAI, or FNA, but no significant correlation could be demonstrated with the increase in IL-6. The results of this study support the concept that in the absence of nonthyroidal illnesses, which are often associated with increased serum concentrations of the cytokine, IL-6 can be regarded as a useful marker of thyroid-destructive processes.

Thyroid volume measurement by ultrasound in children as a tool for the assessment of mild iodine deficiency.

Thyroid ultrasound was used to measure thyroid volume in children and compared with thyroid palpation for the assessment of the prevalence of goiter in an area of mild iodine deficiency. School children, 6-14 yr old, were from control areas (n = 2693; urinary iodine excretion, 110 micrograms/L) or from an area of mild iodine deficiency (IDA; n = 278; urinary iodine excretion, 72 micrograms/L). Thyroid volume determined by ultrasound in control children increased with age (r = 0.62; P < 0.0001) and was significantly correlated with height (r = 0.51; P < 0.0001) and body weight (r = 0.126; P < 0.0001). Both median and mean thyroid volumes were greater in IDA children than in controls. The prevalence of goiter determined by ultrasound was 68 of 268 children (25.3%) in IDA and 105 of 2693 children (3.9%) in the control area (chi 2 = 204; P < 0.0001). Thyroid enlargement, as assessed by palpation, was found in 59 of 268 children (22%) in the IDA group and in 165 of 2693 (6.1%) subjects in the control area (chi 2 = 88; P < 0.0001). Some subjects of the IDA who were judged goitrous by palpation (11.2%) had a normal thyroid volume at ultrasound, and 12.7% of subjects with an abnormal thyroid volume at ultrasound were judged nongoitrous by palpation. In conclusion, 1) thyroid volume in children, as assessed by ultrasound, increases with age and is closely related to the parameters of body growth; 2) in every age group, thyroid ultrasound shows greater thyroid volume in an IDA group than in controls; and 3) a discrepancy between palpation and ultrasound is found in 23.9% of children living in an IDA, confirming that palpation is relatively inaccurate for assessing the prevalence of goiter in mild iodine deficiency. These data indicate that thyroid volume measurement by ultrasound in children provides a useful tool for the assessment of goiter in mild iodine deficiency.

Detection of thyroid-stimulating antibody using Chinese hamster ovary cells transfected with cloned human thyrotropin receptor.

A clone of Chinese hamster ovary (CHO) cells transfected with the cloned human TSH receptor (CHO-R) was used to optimize an assay for thyroid-stimulating antibody (TSAb), measuring adenylate cyclase stimulation by purified immunoglobulin G from patients with Graves' disease. Optimal sensitivity to bovine TSH (1 mU/L) and TSAb was obtained using hypotonic buffer and measuring extracellular cAMP. In time-response experiments, TSAb stimulation was maximal after 2 h of incubation in hypotonic buffer. Under these conditions, a significant stimulation by Graves' immunoglobulin G was obtained with 33 of 35 (94%) samples from patients with untreated Graves' disease and with 21 of 23 (91%) from patients who relapsed after a course of antithyroid drugs. On the other hand, TSAb was detected in only 12 of 20 (60%) patients who were euthyroid during methimazole treatment and in 4 of 11 (36%) who were euthyroid after a course of antithyroid drugs. All samples from Graves' patients were also tested for TSAb activity on FRTL-5 cells. The results of cAMP stimulation in FRTL-5 and CHO-R showed a fairly good correlation (r = 0.60; P < 0.0001). In particular, of the 58 patients with active Graves' disease (35 with untreated hyperthyroidism and 23 relapsed after methimazole), 43 (74%) were positive in both assays, 3 (5%) were negative in both, 11 (19%) were negative in FRTL-5 and positive in CHO-R, and 1 (1.7%) was negative in CHO-R and positive in FRTL-5. In conclusion, CHO cells transfected with the cloned human TSH receptor are suitable for the clinical assay of TSAb. The sensitivity of this assay is higher than that obtained using FRTL-5 cells, having the additional advantages of expressing the human TSH receptor and requiring less cumbersome procedures for cell culture.

Treatment of solitary autonomous thyroid nodules by percutaneous ethanol injection: results of an Italian multicenter study. The Multicenter Study Group.

Percutaneous intranodular ethanol injection (PEI) has been proposed for the therapy of autonomously functioning thyroid nodules. In 1992, an Italian multicenter study was undertaken to confirm the usefulness and the feasibility of this procedure. The study included 429 patients: 242 (56.4%) were affected by a toxic adenoma (TA) and 187 (43.5%) by pretoxic adenoma (PTA). Free thyroid hormone levels (FT4, FT3) and thyroid stimulating hormone (TSH) were measured before and 3, 6, 12 months after the end of treatment; thyroid ultrasound and thyroid scintiscan were performed in the majority of patients before and after treatment. Patients underwent 2-12 sessions of ethanol injection under sonographic guidance (median 4). The total amount of ethanol administered per patient (1.5 mL/mL nodular volume) was 2-50 mL (mean +/- SD, 17 +/- 9 mL), and the amount per each injection was 1-8 mL (3.2 +/- 1.3 mL). The treatment was judged successful when both TSH and free thyroid hormone serum levels returned within the normal range and recovery of tracer uptake in extranodular tissue was observed at scintiscan, at any time during the follow-up period. The treatment was considered unsuccessful when no change was observed at scintiscan and/or serum TSH levels remained less than 0.4 mU/L. A successful treatment was achieved in 66.5% of patients with TA and in 83.4% of patients with PTA, when assessed after a 12-month follow-up. In all cases a reduction of the nodular size was observed. Almost all positive results were obtained in nodules whose initial volume was less than 15 mL; large nodules responded less favorably. The treatment was generally well tolerated, only transient side-effects, mainly local pain at the time of injection, were observed. Once normalization of scintigraphic image and of FT4, FT3 and TSH serum concentrations was achieved, no recurrence of hyperthyroidism nor development of hypothyroidism were observed for the length of the study. In conclusion, percutaneous ethanol injection for treatment of autonomously functioning thyroid nodules is effective and safe. Better results are obtained in patients with PTA than in patients with TA, particularly when the initial volume of the nodule is less than or equal to 15 mL. PEI may be considered as an alternative to surgery and to radioiodine for treatment of autonomously functioning thyroid nodules.

The spectrum of thyroid disorders in an iodine-deficient community: the Pescopagano survey.

We carefully assessed thyroid status and goiter by ultrasound in 1411 subjects virtually representing the entire resident population of Pescopagano, an iodine-deficient village of Southern Italy. Median urinary iodine excretion was 55 microg/L. The prevalence of goiter was 16.0% in children and 59.8% in adults. Thyroid nodularity was 0.5% in children and progressively increased with age to 28.5% in the 56- to 65-yr-old group. The prevalence of present or past hyperthyroidism was 2.9%, including 9 cases with toxic diffuse goiter and 20 with toxic nodular goiter. Functional autonomy was rare in children, progressively increased with age up to 15.4% in the elderly, and was related to nodular goiter. The prevalences of overt and subclinical hypothyroidism in the adults were 0.2% and 3.8%, respectively. Serum autoantibodies to thyroglobulin and thyroperoxidase were detected in 12.6% of the entire population. The prevalence of diffuse autoimmune thyroiditis was 3.5%, being very low in children. Thyroid cancer was found in only 1 case. In conclusion, in the present survey of an iodine-deficient community, a progressive increase with age of goiter prevalence, thyroid nodularity, and functional autonomy was observed. Hyperthyroidism was twice as high as that reported in iodine-sufficient areas, mainly due to an increased frequency of toxic nodular goiter. Although low titer serum thyroid antibodies were relatively frequent, the prevalences of both overt and subclinical autoimmune hypothyroidism were not different from those observed in iodine-sufficient areas.

Outcome of thyroid function in Graves' patients treated with radioiodine: role of thyroid-stimulating and thyrotropin-blocking antibodies and of radioiodine-induced thyroid damage.

UNLABELLED: We investigated the interrelationship and the influence of thyroid-stimulating antibodies (TSAb), TSH-blocking antibodies (TSHBAb), and of radioiodine (131I)-induced thyroid damage in the early (within 1 yr) outcome of thyroid function in hyperthyroid patients with Graves' disease (GD) treated with 131I. TSAb, TSHBAb, and ultrasound thyroid volume (as an index of thyroid damage) were simultaneously measured before and at 1, 3, 6, and 12 months after 131I in 31 GD patients. One year after radioiodine, 9.7% of patients were hyperthyroid (Hyper-group), requiring methimazole; 12.9% were euthyroid (Eu-group); and 77.4% were hypothyroid (Hypo-group). Pretreatment thyroid volume in the Eu-group and Hyper-group was significantly greater (P = 0.009) than in the Hypo-group. Pre-131I TSAb levels were higher in the Hyper-group vs. the Hypo-group (P = 0.01) or the Eu-group (P = 0.03). A significant post-131I increase in TSAb levels occurred in 66% of patients developing hypothyroidism but not in those remaining hyperthyroid. After 131I, TSHBAb appeared in 7 patients, in all but one associated with high levels of TSAb. One year after radioiodine: 1) the mean percent reduction in thyroid volume was greater in the Hypo-group (80.7%) or the Eu-group (83.5%) than in the Hyper-group (35.7%) (P = 0.007 and 0.0033 respectively); 2) hypothyroid patients had smaller (P = 0.0058) post-131I thyroids than hyperthyroid patients; and 3) TSAb were still elevated in 75% hypothyroid patients, but all of them had a thyroid volume < or = 8 mL, indicating major postradioiodine gland damage. IN CONCLUSION: 1) the early outcome of thyroid function after 131I for GD is mainly related to pretreatment thyroid volume and to the degree of its reduction after therapy; 2) high TSAb levels before 131I are associated with a relative resistance to therapy; 3) a postradioiodine increase in TSAb levels is related to the development of hypothyroidism; and 4) the concomitant appearance of TSHBAb and disappearance of TSAb are not frequent after 131I and play a role in the development of early postradioiodine hypothyroidism only in a minority of patients.

Role of conventional ultrasonography and color flow-doppler sonography in predicting malignancy in 'cold' thyroid nodules.

The aim of the present study was to establish the usefulness of conventional thyroid ultrasonography (US) and color flow-doppler (CFD) sonography in the assessment of 'cold' thyroid nodules. One hundred and four consecutive patients with thyroid nodules who were to undergo surgery were examined by US and CFD before thyroidectomy. Conventional US evaluated the presence of a halo sign, hypoechogenicity and microcalcifications. The vascular pattern on CFD was classified as follows: Type I, absence of blood flow; Type II, perinodular blood flow; Type III, marked intranodular blood flow. On histology, 30 nodules were diagnosed as malignant (carcinoma, CA) and 74 as benign nodules (BN). On US, the echographic pattern most predictive for malignancy was absent halo sign, which was found in 20/30 CA and in 17/72 BN (P = 0.0001; specificity 77.0%; sensitivity 66.6%). The most specific combination on US, absent halo sign/microcalcifications, was found in 8/30 CA and in 5/74 BN (P < 0.005; specificity 93.2%, sensitivity 26.6%). The Type III pattern on CFD was found in 20/30 CA and 38/74 BN (not statistically significant). The combination of absent halo sign on US with Type III pattern on CFD was found in 15/30 CA and in 8/74 BN (P < 0.0001; specificity 89.0%, sensitivity 50.0%). The combination of absent halo sign/microcalcifications on US with Type III pattern on CFD was the most specific combination of the two techniques, being found in 5/30 CA and in only 2/74 BN (P < 0.01; specificity 97.2%, sensitivity 16.6%). In conclusion, findings on US and CFD become highly predictive for malignancy only when multiple signs are simultaneously present in a thyroid nodule. Thus the predictive value of these techniques increases at the expense of their sensitivity. Only in a small proportion of patients with thyroid carcinoma is US and CFD information highly predictive of malignancy.

Surgical treatment of Graves' disease: subtotal or total thyroidectomy?

BACKGROUND: The extent of thyroidectomy in Graves' disease is still controversial. We compared the outcome of two groups of patients with Graves' disease who underwent total and subtotal thyroidectomy, respectively. METHODS: One hundred forty patients were treated by subtotal (ST, n = 80) or total thyroidectomy (TT, n = 60) between 1988 and 1994 for a large goiter or recurrence of hyperthyroidism after antithyroid drugs. Surgical complications, relapse of hyperthyroidism, and serum levels of antibodies were evaluated. RESULTS: Thyroid-stimulating hormone receptor and thyroperoxidase antibodies significantly decreased in 44 of 60 and in 27 of 60, respectively, of TT patients and in 65 of 80 and 8 of 80, respectively, of ST patients. Thyroid-stimulating hormone antibody levels increased in three ST patients who had relapse of hyperthyroidism and in no TT patients; thyroperoxidase antibodies increased in nine ST patients (four with relapse of hyperthyroidism) and in no TT patients. Vocal cord palsy occurred in two ST (2.5%) and in 1 TT (1.7%) patients; hypoparathyroidism occurred in three ST (3.8%) and in two (3.3%) TT patients. CONCLUSIONS: Total thyroidectomy does not present more complications with respect to subtotal thyroidectomy, but it avoids the worsening of thyroid humoral autoimmunity and the relapse of hyperthyroidism. Thus it could represent the treatment of choice in Graves' disease.

Clinical features of patients with Graves' disease undergoing remission after antithyroid drug treatment.

The clinical course of 306 Graves' patients treated with methimazole (MMI) was reviewed with the aim of establishing criteria able to predict remission of hyperthyroidism after medical treatment. One hundred and ninety-four (149 females, 45 males) of 306 (63.4%) patients had relapse of hyperthyroidism after antithyroid drug (ATD) withdrawal. Relapse was more frequent during the first months of the follow-up, but still it was observed 3 years after MMI withdrawal. The relapse rate was dependent on the age of the patient, the size of goiter, and the level of TSH-receptor antibody (TRAb) at diagnosis, being observed in 40 of 47 (85%) patients with high (> 30 U/L) TRAb level and in 54 of 101 (53%) patients with low TRAb level (< or = 30 U/L; p <.0002). Remission was more frequent (43.3%) in patients having the combination goiter size < or = 40 mL, TRAb level < or = 30 U/L, than in patients with goiter size > 40 mL and high TRAb levels (9%). In the subgroup of patients with the combination: goiter < or = 40 mL- TRAb < or = 30 U/L - age at onset > 40 years, the remission rate was 80%, and all relapses occurred within the first 9 months after MMI withdrawal. In conclusion, our study confirms that hyperthyroidism relapses in the majority of patients with Graves' disease treated with ATD. Among different clinical and laboratory features, age at onset of hyperthyroidism, goiter size and TRAb level are particularly helpful in identifying those patients who are more prone to undergo a remission of hyperthyroidism after medical treatment and may be useful to select the minority of Graves' patients who will benefit from antithyroid drug treatment as a first choice.

Results of coeliac disease screening in Estonia in 1990-1994.

In the period of 1990-94, 2895 individuals (629 children with suspicion of coeliac disease selected throughout Estonia; 700 consecutively hospitalized children; 105 children with atopic dermatitis; 1461 inhabitants of a small Estonian town) were serologically screened for coeliac disease. The enzyme-linked immunosorbent assay was used for antigliadin antibody determinations and R1-type antireticulin antibodies were detected using an indirect immunofluorescence method. Coeliac disease was diagnosed according to recent criteria recommended by the European Society for Paediatric Gastroenterology and Nutrition. Antigliadin antibody testing was positive in 44 (3.1%) of 1434 children studied, and in 33 of whom coeliac disease was confirmed. In all the coeliac patients R1-type antireticulin antibody test was positive. However, 52 (3.5%) of 1461 adults studied who did not have coeliac disease had positive antigliadin antibody test but negative antireticulin antibody test. Thus, in Estonia, the antigliadin antibody test can be used in screening for coeliac disease in children but not in adults.

[Physiopathology of iodine deficiency]. / Fisiopatologia della carenza iodica.

The process of goitrogenesis is likely to be the consequence of an increased TSH stimulation linked to an initial reduction of circulating thyroid hormone caused by iodine deficiency (ID). Other growth factors associated to TSH may have a role in the pathogenesis of goiter. Natural history of goiter is the evolution towards nodularity and functional autonomy. This phenomenon is due to the heterogeneity of thyroid follicular cells, some of which, with an intrinsic elevated growth rate, under the stimulation of ID progress to nodule formation and hyperfunction. In multinodular goiter TSH receptor mutations activating adenylate cyclase-cAMP pathway were found. In a recent epidemiological survey it was shown that nodular goiter increased with the age, being about 1% in schoolchildren and 23% in the adults (56-75 years). Also nodular autonomy and hyperthyroidism were more frequent in the 36-75 year age group. Severe ID is also cause of endemic cretinism. In Europe minor neuropsychological impairments and cognitive deficits were described in areas of moderate ID. The exposure to a mild ID during fetal life causes minor neuropsychological damage. In conclusion, ID is responsible of goiter and its evolution towards nodularity and functional autonomy. Severe ID is also cause of endemic cretinism, while cognitive deficits and minor neuropsychological impairments were found in mild to moderate ID.