Effect of Advanced Glycation End Products on Human Thyroglobulin's Antigenicity as Identified by the Use of Sera from Patients with Hashimoto's Thyroiditis and Gestational Diabetes Mellitus

Advanced glycation end products (AGEs) are formed on proteins after exposure to high concentrations of glucose and modify protein's immunogenicity. Herein, we investigated whether the modification of thyroglobulin (Tg) by AGEs influences its antigenicity and immunogenicity. Human Tg was incubated in vitro with increasing concentrations of D-glucose-6-phosphate in order to produce Tgs with different AGE content (AGE-Tg). Native Tg and AGE-Tgs were used in ELISA to assess the serum antibody reactivity of two patient groups, pregnant women with gestational diabetes (GDM), and patients with Hashimoto's thyroiditis (HT). We produced in vitro AGE-Tg with low and high AGE content, 13 and 49 AGE units/mg Tg, respectively. All HT patients' sera presented the same antibody reactivity profile against native Tg and AGE-Tgs, indicating that the modification of Tg by AGEs did not alter its antigenicity. Similarly, the GDM patients' sera did not discriminate among the two forms of Tg, native or artificially glycated, suggesting that the modification of Tg by AGEs might not alter its immunogenicity. The modification of Tg by AGEs has no obvious effect on neither its antigenicity nor, most likely, its immunogenicity. It seems that other Tg modifications might account for the production of aTgAbs in patients with GDM

Characteristics of specialists treating hypothyroid patients: the “THESIS” collaborative

Copyright \ua9 2023 Žarković, Attanasio, Nagy, Negro, Papini, Perros, Cohen, Akarsu, Alevizaki, Ayvaz, Bednarczuk, Berta, Bodor, Borissova, Boyanov, Buffet, Burlacu, Ćirić, D\uedez, Dobnig, Fadeyev, Field, Fliers, Fr\uf8lich, F\ufchrer, Galofr\ue9, Hakala, Jiskra, Kopp, Krebs, Kršek, Kužma, Lantz, Laz\ufarov\ue1, Leenhardt, Luchytskiy, McGowan, Melo, Metso, Moran, Morgunova, Mykola, Beleslin, Niculescu, Perić, Planck, Poiana, Puga, Robenshtok, Rosselet, Ruchala, Riis, Shepelkevich, Unuane, Vardarli, Visser, Vrionidou, Younes, Yurenya and Heged\ufcs.Introduction: Thyroid specialists influence how hypothyroid patients are treated, including patients managed in primary care. Given that physician characteristics influence patient care, this study aimed to explore thyroid specialist profiles and associations with geo-economic factors. Methods: Thyroid specialists from 28 countries were invited to respond to a questionnaire, Treatment of Hypothyroidism in Europe by Specialists: an International Survey (THESIS). Geographic regions were defined according to the United Nations Statistics Division. The national economic status was estimated using World Bank data on the gross national income per capita (GNI per capita). Results: 5,695 valid responses were received (response rate 33\ub70%). The mean age was 49 years, and 65\ub70% were female. The proportion of female respondents was lowest in Northern (45\ub76%) and highest in Eastern Europe (77\ub72%) (p <0\ub7001). Respondent work volume, university affiliation and private practice differed significantly between countries (p<0\ub7001). Age and GNI per capita were correlated inversely with the proportion of female respondents (p<0\ub701). GNI per capita was inversely related to the proportion of respondents working exclusively in private practice (p<0\ub7011) and the proportion of respondents who treated >100 patients annually (p<0\ub701). Discussion: THESIS has demonstrated differences in characteristics of thyroid specialists at national and regional levels, strongly associated with GNI per capita. Hypothyroid patients in middle-income countries are more likely to encounter female thyroid specialists working in private practice, with a high workload, compared to high-income countries. Whether these differences influence the quality of care and patient satisfaction is unknown, but merits further study

Levothyroxine Monotherapy Cannot Guarantee Euthyroidism in All Athyreotic Patients

CONTEXT: Levothyroxine monotherapy is the treatment of choice for hypothyroid patients because peripheral T4 to T3 conversion is believed to account for the overall tissue requirement for thyroid hormones. However, there are indirect evidences that this may not be the case in all patients. OBJECTIVE: To evaluate in a large series of athyreotic patients whether levothyroxine monotherapy can normalize serum thyroid hormones and thyroid-pituitary feedback. DESIGN: Retrospective study. SETTING: Academic hospital. PATIENTS: 1,811 athyreotic patients with normal TSH levels under levothyroxine monotherapy and 3,875 euthyroid controls. MEASUREMENTS: TSH, FT4 and FT3 concentrations by immunoassays. RESULTS: FT4 levels were significantly higher and FT3 levels were significantly lower (p<0.001 in both cases) in levothyroxine-treated athyreotic patients than in matched euthyroid controls. Among the levothyroxine-treated patients 15.2% had lower serum FT3 and 7.2% had higher serum FT4 compared to euthyroid controls. A wide range of FT3/FT4 ratios indicated a major heterogeneity in the peripheral T3 production capacity in different individuals. The correlation between thyroid hormones and serum TSH levels indicated an abnormal feedback mechanism in levothyroxine-treated patients. CONCLUSIONS: Athyreotic patients have a highly heterogeneous T3 production capacity from orally administered levothyroxine. More than 20% of these patients, despite normal TSH levels, do not maintain FT3 or FT4 values in the reference range, reflecting the inadequacy of peripheral deiodination to compensate for the absent T3 secretion. The long-term effects of chronic tissue exposure to abnormal T3/T4 ratio are unknown but a sensitive marker of target organ response to thyroid hormones (serum TSH) suggests that this condition causes an abnormal pituitary response. A more physiological treatment than levothyroxine monotherapy may be required in some hypothyroid patients

Modulation of 11β-hydroxysteroid dehydrogenase as a strategy to reduce vascular inflammation

Atherosclerosis is a chronic inflammatory disease in which initial vascular damage leads to extensive macrophage and lymphocyte infiltration. Although acutely glucocorticoids suppress inflammation, chronic glucocorticoid excess worsens atherosclerosis, possibly by exacerbating systemic cardiovascular risk factors. However, glucocorticoid action within the lesion may reduce neointimal proliferation and inflammation. Glucocorticoid levels within cells do not necessarily reflect circulating levels due to pre-receptor metabolism by 11β-hydroxysteroid dehydrogenases (11β-HSDs). 11β-HSD2 converts active glucocorticoids into inert 11-keto forms. 11β-HSD1 catalyses the reverse reaction, regenerating active glucocorticoids. 11β-HSD2-deficiency/ inhibition causes hypertension, whereas deficiency/ inhibition of 11β-HSD1 generates a cardioprotective lipid profile and improves glycemic control. Importantly, 11β-HSD1-deficiency/ inhibition is atheroprotective, whereas 11β-HSD2-deficiency accelerates atherosclerosis. These effects are largely independent of systemic risk factors, reflecting modulation of glucocorticoid action and inflammation within the vasculature. Here, we consider whether evidence linking the 11β-HSDs to vascular inflammation suggests these isozymes are potential therapeutic targets in vascular injury and atherosclerosis

Multiple endocrine neoplasias: Advances and challenges for the future

Several important advances have been made over the last 2 years, since the last international workshop on multiple endocrine neoplasias (MENs) that was held in Marseilles, France (MEN2006). The series of articles that are included in this issue summarize the most important of these advances as they were presented in Delphi, Greece, during the 11th International Workshop on MENs, September 25-27, 2008 (MEN2008). This editorial summarizes some of these advances: the identification of the AIP, and the PDE11A and PDE8B genes by genome-wide association (GWA) studies as predisposing genes for pituitary and adrenal tumours, respectively, the discovery of p27 mutations in a new form of MEN similar to MEN type 1 (MEN 1) that is now known as MEN 4, the molecular investigations of Carney triad (CT), a disorder that associates paragangliomas (PGLs), gastrointestinal stromal tumour (GISTs), and pulmonary chondromas (PCH) with pheochromocytomas and adrenocortical adenomas and other lesions, and the molecular elucidation of the association of GISTs with paragangliomas (Carney-Stratakis syndrome) that is now known to be because of SDHB, SDHC, and SDHD mutations. Molecular investigations in Carney complex (another MEN also described by Dr. Carney, who during the meeting, along with Dr. Charles E. (&apos;Gene&apos;) Jackson was honoured for his life-long and many contributions to the field) have also revealed the role of cyclic AMP signalling in tumorigenesis. As our knowledge of the molecular causes of MENs increases, the challenge is to translate these discoveries in better treatments for our patients. Indeed, new advances in the preventive diagnosis and molecular treatment of MEN 1 and MEN 2, respectively, continued unabated, and an update on this front was also presented at MEN2008 and is included in this issue. © 2009 Blackwell Publishing Ltd

TSH may not be a good marker for adequate thyroid hormone replacement therapy

The objective of this study was to evaluate parameters of thyroid function and indices of peripheral thyroid hormone action (such as SHBG) in patients whose hypothyroidism was considered well controlled under current criteria. Eighty-five patients with T4-treated hypothyroidism, 28 of whom had athyria, were compared with 114 normal individuals with the same TSH levels. T3 levels were significantly lower in hypothyroidism although mean T4 and fT4 levels were significantly higher. Furthermore, mean SHBG levels were significantly lower in hypothyroidism independently of age. The difference remained when stricter criteria for adequate treatment were applied (TSH &lt; 2.5 mu U/ml). Significant negative correlations were found between logTSH and T3. The slopes of the regression lines of T3 to TSH were significantly different in the control group and the hypothyroid group: thus, for the same TSH levels, T3 levels were lower in the hypothyroid group. We conclude that patients with T4-treated hypothyroidism have lower T3 levels, lower T3/T4 ratio and lower SHBG than normal individuals with the same TSH, perhaps indicating relative tissue hypothyroidism in the liver. TSH levels used to monitor substitution, mostly regulated by intracellular T3 in the pituitary, may not be such a good indicator of adequate thyroid hormone action in all tissues. The co-administration of T3 may prove more effective in this respect, provided novel suitable preparations are developed. Until this is accomplished, substitution in hypothyroidism should aim at low normal TSH, to ensure normal T3 levels