Efficacy and safety of a 30-day methylprednisolone treatment protocol for subacute thyroiditis: a prospective study.

Objective: The optimal corticosteroid treatment regimen for subacute thyroiditis has not yet been established. To avoid side effects, tapering of the initial dose of corticosteroid is recommended. With reducing dose, the symptoms can recur. Design: In a prospective clinical study, a 30-day methylprednisolone (MPSL) treatment protocol with a starting dose of 24 mg/day and tapered by 4 mg every 5 days was assessed for effectiveness and safety regarding possible adrenal insufficiency. Methods: Fifty-nine patients with subacute thyroiditis were included. At visit 1, after establishing the diagnosis, a short stimulation adrenocorticotrophic hormone (ACTH) test was performed and methylprednisolone treatment was prescribed. At visit 2 (40 ± 5 days after visit 1), clinical, laboratory (including short stimulation ACTH test), and ultrasound evaluation were repeated. Results: Forty-eight patients (81.4%) were cured by the prescribed protocol, having significantly lower cortisol levels after stimulation at visit 1 than patients who were not cured (mean, 674.9 nmol/L and 764.0 nmol/L, respectively, P = 0.012). Seven patients (12.3%) developed adrenal insufficiency; this group had significantly lower cortisol levels after stimulation at visit 1 than patients without adrenal insufficiency development (mean, 561.5 nmol/L and 704.7 nmol/L, respectively, P = 0.005). Using stimulated cortisol level at visit 1 as the explanatory variable, logistic models were optimized to determine treatment efficacy (AUC = 0.745, optimal threshold 729 nmol/L, specificity 71%, sensitivity 73%) and adrenal function (AUC = 0.861, optimal threshold 629 nmol/L, specificity 73%, sensitivity 100%). Conclusions: The described protocol was efficient for more than 80% of patients. Using this protocol, the corticosteroid treatment interval is shorter than proposed in current guidelines. Significance statement: A short but effective protocol for treatment of subacute thyroiditis with methylprednisolone is presented in this article. Using this protocol, the treatment interval is shorter than proposed in current guidelines. Its safety regarding possible adrenal insufficiency is assessed.

First Estimation of Reference Intervals for Thyroid-Stimulating Hormone and Thyroid Hormones in Slovenian Population.

For thyroid function estimation and clinical decision making, use of appropriate reference intervals for thyroid-stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) is crucial. For each laboratory, establishment of own reference intervals is advised. For the first Slovenian estimation of reference intervals for thyroid hormones a large group of 1722 healthy individuals without thyroid disease was established retrospectively. Hormone analyses were performed on automated analyser Advia Centaur XP Immunoassay System (Siemens Healthineers), which reference intervals for TSH, fT4 and fT3 were 0.55-4.78 mIU/L, 11.5-22.7 pmol/L, and 3.5-6.5 pmol/L, respectively. Statistical analysis followed non-parametric percentile method. Our laboratory reference intervals for TSH, fT4 and fT3 are mostly narrower than intervals given by manufacturer. Median value, lower and upper limit for TSH, fT4 and fT3 were 1.98 (0.59-4.23) mIU/L, 14.5 (11.3-18.8) pmol/L and 4.82 (3.79-6.05) pmol/L, respectively. Most likely, an inclusion of a high number of healthy individuals without thyroid disease was a reason for such results.

Five-year follow-up and clinical outcome in euthyroid patients with thyroid nodules.

BACKGROUND: Thyroid nodule diagnosis has become increasingly frequent. Defining optimum surveillance intervals for patients with unsuspicious thyroid nodules remains a challenge. This was a single centre cohort study in which patients diagnosed with unsuspicious thyroid nodules in whom no treatment was indicated were invited for re-evaluation 5 years after the diagnosis. The primary end point of the study was to estimate the change in nodule size with thyroid ultrasound (US) and the secondary end point was to assess the need for clinical management 5 years after the diagnosis. PATIENTS AND METHODS: Baseline patient parameters and ultrasound characteristics of the nodules were retrospectively collected. At follow-up, thyroid ultrasound was performed. RESULTS: A hundred and eighteen (107 women / 11 men, aged 56.8 ± 13.4 years) patients were included in the study having 203 nodules at baseline, with mean largest nodule diameter 10.5 ± 7.4 mm. After 5 years, 58 (28.6%) nodules significantly increased in size, 27 (13.3%) decreased, and for 104 (51.2%) of nodules, no change in size was noted. Fourteen (6.9%) nodules disappeared. Additional 26 new nodules (mean largest diameter 7.7 ± 5.0 mm) in 16 patients were identified at follow-up. Regarding the clinical outcome, no new thyroid cancers were found. For 107 (90.7%) patients no further management was indicated. Five (4.2%) patients were referred to thyroidectomy because of the growth of the nodules. Two (1.7%) patients were treated for hyperthyroidism. Four (3.4%) patients did not complete the study. CONCLUSIONS: We report a single centre experience of the natural history of unsuspicious thyroid nodules. Our results showed that 71.4% of such nodules remained stable in size, decreased or even disappeared and that the vast majority of the patients remained clinically stable with no need for treatment 5 years after the diagnosis.

Effects of Adequate Iodine Supply on the Incidence of Iodine-Induced Thyroid Disorders in Slovenia.

BACKGROUND: This study aimed to establish the changes in the incidence and characteristics of iodine-induced hyperthyroidism (II-Hyper) and iodine-induced hypothyroidism (II-Hypo) in the two-year period before and the 10-year period after the increase in mandatory salt iodization from the previous 10 mg/kg of potassium iodide to 25 mg/kg in 1999. Furthermore, the aim was to determine the duration of treatment in II-Hyper patients, since no data regarding severity and treatment of II-Hyper with respect to iodine supply are available. METHODS: This retrospective study reviewed medical records of 885 Slovenian patients first diagnosed with II-Hyper or II-Hypo between 1998 and 2009 at the Thyroid Department of the University Medical Centre Ljubljana. II-Hyper and II-Hypo were diagnosed by one out of 10 senior internal medicine specialists. The diagnosis was based on an adequate patient history, and laboratory measurements of thyrotropin, thyroid hormones, and thyroid antibodies. In most cases, thyroid ultrasound and thyroid scintigraphy were performed. Demographic characteristics and the type and the duration of treatment were also reviewed. RESULTS: The incidence of II-Hypo was significantly higher after the increase in iodine supply than it was before (p < 0.001). After the increase in iodine supply, the incidence of II-Hyper was significantly lower than before the increase (p < 0.001). Furthermore, the portion of patients with overt hyperthyroidism decreased, predominantly due to the increased proportion of patients with subclinical hyperthyroidism (p = 0.007 and p = 0.015, respectively). The duration of treatment with antithyroid drugs and perchlorate was significantly shorter after the increase in iodine supply than it was before (p = 0.001 and p = 0.002, respectively). A significantly positive correlation between the year of the occurrence of excessive iodine intake (EII)-induced thyroid disease and the duration of treatment with amiodarone was found (R = 0.132; p = 0.048), suggesting that the longer the patients had an adequate iodine supply, the longer they could take amiodarone before EII-induced thyroid disorder developed. CONCLUSIONS: After the increase in iodine supply, a higher incidence of II-Hypo and a lower incidence of II-Hyper were observed than before the increase. Less severe II-Hyper, shorter duration of treatment of II-Hyper, as well as a longer thyroid disease-free period in patients on amiodarone are additional beneficial clinical consequences after the establishment of an adequate iodine supply.

An Advantageous Role of Spectral Doppler Sonography in the Evaluation of Thyroid Dysfunction During the Postpartum Period.

OBJECTIVES: To evaluate the diagnostic value of spectral Doppler sonography in women with thyroid dysfunction during the first postpartum year. METHODS: This prospective observational clinical study included 83 consecutive untreated women: 32 with hyperthyroid postpartum thyroiditis, 32 with hypothyroid postpartum thyroiditis, and 19 with Graves disease, which first appeared within 12 months after delivery. Thyrotropin, free thyroid hormones, thyroid peroxidase antibodies, thyroglobulin antibodies, and thyrotropin receptor antibodies were measured. With a 7.5-MHz linear transducer, we measured the thyroid volume and peak systolic velocity (PSV) at the level of intrathyroid arteries. RESULTS: Hyperthyroid postpartum thyroiditis appeared significantly earlier (mean ± SD, 4.4 ± 1.9 months after delivery) than hypothyroid postpartum thyroiditis (6.5 ± 2.1 months) and Graves disease (7.2 ± 2.7 months; P< .001). The thyroid volume in hyperthyroid postpartum thyroiditis (9.7 ± 6.3 mL) was significantly lower than in hypothyroid postpartum thyroiditis (14.7 ± 10.2 mL; P = .030) and Graves disease (19.4 ± 10.2 mL; P< .001). The PSV in hyperthyroid postpartum thyroiditis (9.4 ± 3.4 cm/s) was significantly lower than in hypothyroid postpartum thyroiditis (14.4 ± 3.9 cm/s; P < .001) and Graves disease (19.8 ± 7.0 cm/s; P < .001). With a cutoff level of 15 cm/s, the sensitivity and specificity of the PSV as a predictor of the correct diagnosis in hyperthyroid postpartum women were 94.7% and 96.8%, respectively. A multinomial logistic regression revealed PSV and the time after delivery at which the disorders presented as independent predictors of the differentiation between hyperthyroid postpartum thyroiditis and Graves disease (P = .003; P = .022). CONCLUSIONS: Spectral Doppler sonography was shown to be a useful and accurate method for thyroid dysfunction evaluation during the postpartum period.

Factors influencing the success of radioiodine therapy in patients with Graves' disease.

OBJECTIVE: The first dose of radioiodine (I) does not always cure hyperthyroidism in patients with Graves' disease (GD). Our aim was to evaluate the factors influencing the success of I therapy. PATIENTS AND METHODS: We reviewed the medical records of 724 patients who were first diagnosed with GD between 2005 and 2009 and were subsequently treated with I in a fixed-dose manner considering the thyroid volume (TV). TSH, fT(4), and fT(3) were measured. TV was measured by means of ultrasonography. Successful therapy was followed by euthyroidism or hypothyroidism. RESULTS: Out of 724 patients, 656 (90.5%) were successfully (Group 1) and 69 (9.5%) were unsuccessfully (Group 2) treated with the first dose of (131)I. In Group 1, the applied dose of (131)I was lower than that in Group 2 [626±107, 95% confidence interval (CI) 618-634, and 709±140, 95% CI 675-742 MBq, respectively; P<0.001]. At presentation, patients in Group 1 were younger than those in Group 2 (45.5±14.9, 95% CI 44.4-46.6, and 50.1±15.8, 95% CI 46.3-53.9 years, respectively; P=0.031). They had a lower fT(4) (54.9±26.1, 95% CI 52.9-56.9, and 72.1±34.1, 95% CI 63.9-80.3 pmol/l, respectively; P<0.001), a lower fT3 (20.9±8.2, 95% CI 20.3-21.5, and 23.9±8.2, 95% CI 21.9-25.9 pmol/l, respectively; P<0.001), and a smaller TV (21.5±13.2, 95% CI 20.2-22.8, and 35.6±22.3, 95% CI 28.2-42.9 ml, respectively; P<0.001). Before I therapy, patients in Group 1 had a lower fT(3) (9.6±6.0, 95% CI 9.2-10.1, and 11.3±7.6, 95% CI 9.5-13.2 pmol/l, respectively; P=0.038). CONCLUSION: Successfully treated GD patients were younger, less severely hyperthyroid, and had a smaller TV at presentation. They were also less severely hyperthyroid before I therapy.

Beneficial effects of adequate iodine supply on characteristics of thyroid autonomy.

OBJECTIVE: Our aim was to establish the characteristics of thyroid autonomy (TA) in Slovenian patients and the required therapeutic dose of radioiodine before and ten years after the increase in mandatory salt iodization from previous 10 mg of potassium iodide to 25 mg per kg in 1999 because almost no data about TA and radioiodine treatment with respect to iodine supply are available. DESIGN: Retrospective clinical study. PATIENTS: We reviewed records of all patients referred for the first time in 1998 and 2009 to the Thyroid Department at the University Medical Centre Ljubljana which is a tertiary referral centre with a stable catchment area for more than 20 years. METHODS: TA was diagnosed by thyroid function, ultrasound, scintigraphy and negative TSH receptor antibodies. Demographic characteristics and the applied dose of radioiodine were evaluated. RESULTS: In 1998, significantly more patients presented with TA than in 2009 (383 of 3243, 11·8% and 333 of 4546, 7·3%, respectively, P < 0·001). In 1998, the ratio between hyperthyroid and euthyroid patients was higher than in 2009 (6:1 and 2·1:1, respectively, P < 0·001). In 1998, patients were younger than in 2009 (mean 63·8 ± 13·9 and 66·8 ± 14·9 years, respectively, P < 0·004). Hyperthyroid patients were older than euthyroid in both years (P < 0·001). In 1998, mean applied dose of radioiodine was significantly lower than in 2009 (713 ± 306 and 791 ± 194 MBq, respectively, P = 0·003). CONCLUSIONS: In adequate iodine supply, TA is less frequent, patients are less often hyperthyroid, they are older and cured with higher doses of radioiodine than in mild iodine deficiency.

Ten-year follow-up of thyroid epidemiology in Slovenia after increase in salt iodization.

AIM: To assess iodine supply and follow thyroid epidemiology for ten years after an iodine increase from 10 to 25 mg of potassium iodide per kilogram of salt in 1999. METHODS: In 2002 and 2003, we determined the thyroid size by palpation and ultrasound and measured urinary iodine concentration (UIC) in 676 schoolchildren from 34 schools throughout Slovenia. From 1999 to 2009, we followed the incidence of diffuse and nodular goiter, thyroid autonomy, Graves' disease, and Hashimoto's thyroiditis among adults in the stable catchment area of the University Medical Centre Ljubljana with 1000000 inhabitants. RESULTS.:In children, only 1% had a goiter grade 2 (visible and palpable thyroid gland), median thyroid volume was 5.8 mL, and median UIC was 148 µg/L. In adults, the incidence of diffuse goiter and thyroid autonomy decreased significantly (2009 vs 1999, rate ratio [RR], 0.16; 95% confidence interval [CI], 0.12-0.21 and RR, 0.73; 95% CI, 0.62-0.86, respectively), with a lower incidence in younger participants in 2009 (P<0.001). The incidence of multinodular goiter and solitary nodule increased (2009 vs 1999, RR, 1.55; 95% CI, 1.35-1.79 and RR, 1.72; 95% CI, 1.49-1.99, respectively). No long-term changes were observed for Graves' disease (2009 vs 1999, RR, 0.95; 95% CI, 0.81-1.13), while the incidence of Hashimoto's thyroiditis increased strongly (2009 vs 1999, RR, 1.86; 95% CI, 1.64-2.12). CONCLUSIONS: The change from mildly deficient to sufficient iodine supply was associated with a marked change in the incidence of thyroid epidemiology - a significant decline in the incidence of diffuse goiter and thyroid autonomy and a marked increase in the incidence of Hashimoto's thyroiditis.

The outcome of 131I treatment in Graves' patients pretreated or not with methimazole.

Despite extensive use of iodine-131 ((131)I) treatment for Graves' hyperthyroidism, the optimal regimen of pretreatment with antithyroid drugs is still a matter of discussion. Our aim was to evaluate the success of (131)I treatment in patients with Graves' disease without and with pretreatment with methimazole (MMI). In a prospective randomized study 156 patients with Graves' disease were treated with fixed activity of 550 MBq (131)I. First group of 59 patients received only (131)I. The second group of 50 patients received MMI which was stopped seven days before (131)I. The third group of 47 patients received MMI until (131)I application. Patients were followed clinically and biochemically 1, 3, 6 and 12 months after (131)I treatment. Absorbed dose of (131)I and thyroid volume were measured in each patient. Our result showed that (131)I treatment success after twelve months was equally effective in the first and second group (96.6% and 96%, respectively), while in the third group, success was significantly lower (63.8%). Accordingly, the absorbed dose of (131)I was significantly higher in the first and in second group (144±104 Gy and 164±107 Gy, respectively), and lower in the third group (105±58 Gy). Thyroid volume gradually decreased without any significant difference between the three groups. In conclusion, our study provides evidence that application of (131)I is equally effective in the nonpretreated with MMI group and in the group discontinuing MMI one week before (131)I treatment, and it is more effective in these two groups as compared to the group in which pretreatment with MMI was administered till the day of (131)I application.

49A/G and CT60 polymorphisms of the cytotoxic T-lymphocyte-associated antigen 4 gene associated with autoimmune thyroid disease.

Single nucleotide polymorphisms in the CTLA-4 gene have been suggested as genetic factors in the susceptibility to autoimmune thyroid disease (AITD). In our case-control study, patients with Graves' disease, Hashimoto's thyroiditis, and postpartum thyroiditis and control subjects have been genotyped for two A/G single nucleotide polymorphisms (49A/G and CT60) of the CTLA-4 gene. The 49A/G polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism method using the enzyme BseXI and the CT60 polymorphism by real-time polymerase chain reaction. Results were analyzed by chi(2) test and linkage disequilibrium analysis. In a comparison of frequencies of GG genotype, a significant association of 49A/G and CT60 polymorphism existed only for Graves' disease. In the 49A/G polymorphism, the frequency of GG genotype was significantly higher (p = 0.0408) compared with controls; the frequency of the CT60 polymorphism was significantly higher as well (p = 0.0213). The frequencies of AA and AG genotypes in control subjects did not significantly differ from frequencies in AITD patients for both polymorphisms. Our results may therefore lend support to the hypothesis that humoral autoimmunity is correlated with 49A/G and CT60 polymorphisms of the CTLA-4 gene.

The influence of the exon 1 polymorphism of the cytotoxic T lymphocyte antigen 4 gene on thyroid antibody production in patients with newly diagnosed Graves' disease.

Increasing evidence supports the genetic susceptibility for thyroid antibody (TAb) production in patients with autoimmune thyroid disease, and recently, it has been shown that the cytotoxic T lymphocyte antigen 4 (CTLA-4) gene is most likely a major TAb susceptibility gene. To assess the relationship between exon 1 CTLA-4 gene polymorphism and TAb production, we genotyped 67 patients with newly diagnosed Graves' disease. Free thyroid hormones and TAb were measured, including thyroglobulin antibodies (TgAb), thyroid peroxidase antibodies (TPOAb), and thyroid-stimulating antibodies (TSAb). AA genotype was found in 25 patients, AG genotype in 34 patients, and GG genotype in 8 patients. G allele carrying genotypes showed significantly higher frequency of positive TPOAb (p < 0.005) and TgAb (p < 0.05) compared to AA genotype. Furthermore, the median values of TPOAb were significantly higher in the group with G allele (p < 0.002). However, the median values of TgAb and TSAb did not differ significantly between both groups and similarly, CTLA-4 genotype showed no association with serum free thyroxine (T(4)) and Graves' ophthalmopathy. In conclusion, our findings suggest that G allele carrying genotype of the CTLA-4 gene influences higher production of TPOAb and TgAb, and therefore, support the hypothesis that CTLA-4 gene plays a major role in TAb production.