Hashimoto’s thyroiditis (HT) is the most prevalent autoimmune thyroid disorder. Intrathyroidal lymphocytic infiltration is followed by a gradual destruction of the thyroid gland which may lead to subclinical or overt hypothyroidism. Biochemical markers of the disease are thyroid peroxidase and/or thyroglobulin autoantibodies in the serum which are present with a higher prevalence in females than in males and increase with age. Although exact mechanisms of aetiology and pathogenesis of the disorder are not completely understood, a strong genetic susceptibility to the disease has been confirmed predominantly by family and twin studies. Several genes were shown to be associated with the disease occurrence, progression, and severity. Genes for human leukocyte antigen, cytotoxic T lymphocyte antigen-4, protein tyrosine phosphatase nonreceptor-type 22, thyroglobulin, vitamin D receptor, and cytokines are considered to be of utmost importance. Amongst endogenous factors for the disease development, the attention is focused predominantly on female sex, pregnancy with postpartum period and fetal microchimerism. Environmental factors influencing HT development are iodine intake, drugs, infections and different chemicals. Disturbed self-tolerance accompanied by the increased antigen presentation is a prerequisite for the HT occurrence, whereas proper interaction of thyroid cells, antigen presenting cells, and T cells are necessary for the initiation of thyroid autoimmunity. Secreted cytokines lead predominantly to T-helper type 1 (Th1) response as well as to Th 17 response which has only recently been implicated. Final outcome of HT is thyroid destruction which is mostly a consequence of the apoptotic processes combined with T-cell mediated cytotoxicity.

Early data suggest that US-guided HIFU ablation is an effective and safe procedure for treatment of benign solid thyroid nodules. Initial US echogenicity and vascularization influence the ablation outcome.

Thyroid disorders, especially Hashimoto's thyroiditis (HT), and polycystic ovary syndrome (PCOS) are closely associated, based on a number of studies showing a significantly higher prevalence of HT in women with PCOS than in controls. However, the mechanisms of this association are not as clear. Certainly, genetic susceptibility contributes an important part to the development of HT and PCOS. However, a common genetic background has not yet been established. Polymorphisms of the PCOS-related gene for fibrillin 3 (FBN3) could be involved in the pathogenesis of HT and PCOS. Fibrillins influence the activity of transforming growth factor beta (TGFb). Multifunctional TGFb is also a key regulator of immune tolerance by stimulating regulatory T cells (Tregs), which are known to inhibit excessive immune response. With lower TGFb and Treg levels, the autoimmune processes, well known in HT and assumed in PCOS, might develop. In fact, lower levels of TGFb1 were found in HT as well as in PCOS women carrying allele 8 of D19S884 in the FBN3 gene. Additionally, vitamin D deficiency was shown to decrease Tregs. Finally, high estrogen-to-progesterone ratio owing to anovulatory cycles in PCOS women could enhance the immune response. Harmful metabolic and reproductive effects were shown to be more pronounced in women with HT and PCOS when compared with women with HT alone or with controls. In conclusion, HT and PCOS are associated not only with respect to their prevalence, but also with regard to etiology and clinical consequences. However, a possible crosstalk of this association is yet to be elucidated.

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IntroductionFrom a series of radiolabelled cholecystokinin (CCK) and gastrin analogues, 111In-CP04 (111In-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) was selected for further translation as a diagnostic radiopharmaceutical towards a first-in-man study in patients with medullary thyroid carcinoma (MTC). A freeze-dried kit formulation for multicentre application has been developed. We herein report on biosafety, in vivo stability, biodistribution and dosimetry aspects of 111In-CP04 in animal models, essential for the regulatory approval of the clinical trial.Materials and methodsAcute and extended single dose toxicity of CP04 was tested in rodents, while the in vivo stability of 111In-CP04 was assessed by HPLC analysis of mouse blood samples. The biodistribution of 111In-CP04 prepared from a freeze-dried kit was studied in SCID mice bearing double A431-CCK2R(±) xenografts at 1, 4 and 24 h pi. Further 4-h animal groups were either additionally treated with the plasma expander gelofusine or injected with 111In-CP04 prepared by wet-labelling. Pharmacokinetics in healthy mice included the 30 min, 1, 4, 24, 48 and 72 h time points pi. Dosimetric calculations were based on extrapolation of mice data to humans adopting two scaling models.ResultsCP04 was well-tolerated by both mice and rats, with an LD50 > 178.5 μg/kg body weight for mice and a NOAEL (no-observed-adverse-effect-level) of 89 μg/kg body weight for rats. After labelling, 111In-CP04 remained >70% intact in peripheral mouse blood at 5 min pi. The uptake of 111In-CP04 prepared from the freeze-dried kit and by wet-labelling were comparable in the A431-CCK2R(+)-xenografts (9.24 ± 1.35%ID/g and 8.49 ± 0.39%ID/g, respectively; P > 0.05). Gelofusine-treated mice exhibited significantly reduced kidneys values (1.69 ± 0.15%ID/g vs. 5.55 ± 0.94%ID/g in controls, P < 0.001). Dosimetry data revealed very comparable effective tumour doses for the two scaling models applied, of 0.045 and 0.044 mSv/MBq.ConclusionThe present study has provided convincing toxicology, biodistribution and dosimetry data for prompt implementation of the freeze-dried kit formulation without or with gelofusine administration in a multicentre clinical trial in MTC patients.

PDRP-Slovenia proves to be a robust and reproducible functional imaging biomarker independent of patient population. It accurately differentiates PD patients from NCs and AP and correlates well with the clinical measure of PD progression.

AimTo 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.MethodsIn 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 1 000 000 inhabitants.ResultsIn 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).ConclusionsThe 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.