Arterial hypertension represents a major global health concern; more than one fourth of the population is affected by high blood pressure. Albeit the underlying cause of the disease remains unclear in the vast majority of the cases, ~10% are of secondary origin. Endocrine disorders are common illnesses and some of them may lead to elevated blood pressure, among which thyroid diseases are of high prevalence and often overlooked, especially in mild cases. Overt and subclinical hyper- and hypothyroidism can both lead to (mostly mild) hypertension; however, the underlying mechanisms are only partially understood. The results of clinical studies are often controversial. During the past decades, some genetic mutations in the hypothalamus-pituitary-thyroid axis with cardiovascular consequences were revealed. Atherosclerotic changes resulting from lipid abnormalities due to thyroid dysfunction also affect the vasculature and can cause elevated blood pressure. The review gives a synopsis of our knowledge how thyroid hormone metabolism and functional thyroid diseases affect the cardiovascular system, their negative impact and causative role in the development of hypertension.

Impaired cytokine balance has been observed in tears of GO patients. Secretion of IL-6 into tears might be a useful indicator of disease activity in GO.

Corticosteriod treatment is associated with a decline in DTPA uptake in a fraction of GO patients. GO patients with a DTPA uptake above 12.28 MBq/cm(3) are more likely to have a favorable response to corticosteroid therapy while patients with lower values are less likely to have this potentially favorable response. An elevated DTPA uptake may identify patients who are most likely to benefit from immunosuppressive treatment.

The aim of this investigations was to study the effectiveness of anti-CD20 antibody therapy in Graves' orbitopathy (GO) resistant to glucocorticoids. Five patients were entered in the study. The protocol required no improvement of orbital status after a recent course of glucocorticoids. Activity of GO was confirmed by three independent techniques: clinical activity score (CAS), (99m)Tc-labeled diethylene triamine pentaacetic acid ((99m)Tc DTPA) single photon emission computed tomography and magnetic resonance imaging. Rituximab (RTX) was given as weekly infusions of 375 mg/m(2) body surface area for four weeks. The mean follow-up period was 67 (range 58-81) months. Improvement of GO has been observed in all patients: CAS before therapy was 6.5 ± 1.7 and decreased to 3.4 ± 1.6 by one month (p < 0.05) and remained unchanged (3.2 ± 1.7) at 12 months. No further CAS change, in either direction, was detected during the yearly follow-up visits. The mean DTPA uptake before therapy was 16.52 ± 4.51 MBq/cm(3) and decreased to 11.97 ± 2.36 MBq/cm(3) at one year (p < 0.002). The mean of T2 relaxation times before and one year after therapy were 96.91 ± 17.61 ms and 84.29 ± 9.41 ms, respectively (p < 0.001). The mean serum TSH receptor antibody (TRAb) levels before therapy, at the one month and one year control visits were 7.4 ± 3.4 U/L, 5.6 ± 4.5 U/L and 1.7 ± 1.5 U/L, respectively (p < 0.004). No correlation between changes of TRAb and activity parameters has been found. Anti-CD20 treatment seems to influence positively the clinical course of GO, and this effect seems to be stable for five years. To our knowledge, this is the longest published follow-up of RTX treatment in GO.

Abstract:Objective: The aim of this study was to investigate aortic stiffness and left ventricular systolic and diastolic function in patients with differentiated thyroid cancer (DTC) on thyroxin (L-T4) therapy and after L-T4 withdrawal in order to assess the cardiovascular impact of long-term subclinical hyperthyroidism and short-term overt hypothyroidism. Design: Twenty four patients who had had total thyroidectomy and radioiodine ablation for differentiated thyroid cancer were studied on two occasions: on TSH suppressive L-T4 therapy (sTSH 0.24±0.11 mU/L), and four weeks after L-T4 withdrawal (sTSH 89.82±29.36 mU/L). Echocardiography was performed and thyroid function, serum thyroglobulin, lipid parameters, homocystine, C-reactive protein, fibrinogen and von Willebrandt factor activity (vWF) were measured. Twenty two healthy volunteers matched for age and sex served as euthyroid controls. Results: Aortic stiffness was increased both in hypothyroidism (6.04±2.88 cm2/dyn/103, p< 0.05) and subclinical hyperthyroidism (9.27±4.81 cm2/dyn/103, p<0.05) vs. controls (3.92±1.84 cm2/dyn/103). Subclinical hyperthyroidism had a more marked effect (p<0.05). LV dimensions and ejection fractions were similar before and after L-T4 withdrawal. The E'/A' was higher in euthyroid controls (1.34±1.02) as compared to both subclinical hyperthyroidism (1.0±0.14, p<0.05) and overt hypothyroidism (1.13±0.98, p<0.05). Change of aortic stiffness correlated with change of free-thyroxine (fT4), vWF and fibrinogen levels in a positive manner. Conclusion: Long-term thyrotropin-suppression therapy has continuous adverse effects on the arterial wall. The degree of TSH suppression in patients with DTC should be kept at the possible minimum, based on individually determined potential benefits and risks of treatment, especially in patients with cardiovascular comorbidities. Dear Professor Bartalena,We would like to thank you for the suggestions which have contributed to the improvement of our paper entitled "Aortic stiffness and left ventricular function in patients with differentiated thyroid cancer", JENI-D-14-00120 .We have corrected the manuscript and we hope that you will find it worth publishing in the Journal of Endocrinological Investigation.We provide a detailed point-by-point response to each of the referees' concerns, describing exactly how we responded to each point and where you can find the amendment in the revised manuscript.Thank you very much for your patience and kind help. •How many time elapsed from thyroidectomy/RAI ablation and the current tests?20±12,6 months elapsed before the start of this study. This information has been added to page 4, line 47.•What was the thyroglobulin serum level at the time of aortic examination? In other words, were all the patients without evidence of persistent/recurrent disease (also by the biochemical point of view)? / Did the Authors evaluate the level of serum anti-Tg antibodies?The first off-T4 Tg measurrment was at least 6 months after RAI in parallel with anti-Tg antibody. Four of twenty...

Aims Diabetic dyslipidaemia with decreased high‐density lipoprotein‐cholesterol (HDL‐C) concentration plays a key role in enhanced atherosclerosis. The antioxidant effect of HDL is due to the influence of human paraoxonase 1 (PON1) and several authors have described decreased activity of this enzyme in Type 2 diabetics and subjects with metabolic syndrome. The goal of this study was to examine the effect of daily ciprofibrate on serum PON1 and lipoprotein concentrations in patients with metabolic syndrome. Methods Fifty‐one patients with metabolic syndrome were enrolled into the study. We examined the effect of 100 mg day−1 ciprofibrate treatment on lipid concentrations, oxidized low‐density lipoprotein (LDL), PON1 concentrations and activity. We also investigated the calculated size of LDL‐cholesterol (LDL‐C). Results During the 3‐month study, it was observed that following treatment with ciprofibrate, the serum triglyceride concentration decreased significantly (from 2.76 ± 0.9 mmol l−1 to 2.27 ± 1.6 mmol l−1; −18%; P < 0.001), while HDL‐C increased significantly (from 0.95 ± 0.2 mmol l−1 to 1.2 ± 0.3 mmol l−1; 26%; P < 0.001). The oxidatively modified LDL‐C concentration decreased significantly (from 137 ± 19 U l−1 to 117 ± 20 U l−1; P < 0.001), while HDL‐associated apolipoprotein A1 significantly increased (from 1.35 ± 0.2 g l−1 to 1.75 ± 0.3 g l−1; P < 0.001). The LDL‐C/LDL‐apoB ratio, which reflects the size of LDL, increased significantly (from 0.96 ± 0.05 to 1.05 ± 0.06; P < 0.05). Serum PON1 activity was significantly elevated (from 108 ± 34 U l−1 to 129 ± 31 U l−1; P < 0.05), while standardized values for HDL‐C remained significantly unchanged (PON1/HDL‐C) (from 114 ± 21 to 107 ± 20; NS). Conclusion Three months of treatment with ciprofibrate favourably affected the lipid profile, increased LDL resistance to oxidation and improved antioxidant status by increasing serum paraoxonase activity in these patients.

Purpose Multiple endocrine neoplasia type 1 is a rare tumor syndrome caused by germline mutations of MEN1 gene. Phenotype varies widely, and no definitive correlation with the genotype has been observed. Mutation-negative patients with MEN1-associated tumors represent phenocopies. By comparing mutation-positive and mutation-negative patients, we aimed to identify phenotype features predictive for a positive genetic test and to evaluate the role of MEN1 mutations in phenotype modulation. Methods Mutation screeening of MEN1 gene by Sanger sequencing and assessment of clinical data of 189 consecutively enrolled probands and relatives were performed at our national and European Reference Center. Multiple ligation probe amplification analysis of MEN1 gene and Sanger sequencing of CDKN1B were carried out in clinically suspicious but MEN1 -negative cases. Results Twenty-seven probands and twenty family members carried MEN1 mutations. Five mutations have not been described earlier. Pronouncedly high number of phenocopies (>70%) was observed. Clinical suspicion of MEN1 syndrome emerged at significantly earlier age in MEN1 -positive compared to MEN1 -negative probands. Gastroenteropancreatic neuroendocrine tumors developed significantly earlier and more frequently in carriers compared to non-carriers. Probands with high-impact (frameshift, nonsense, large deletions) mutations, predicted to affect menin function significantly, developed GEP-NETs more frequently compared to low-impact (inframe and missense) mutation carriers. Conclusions MEN1 phenocopy is common and represents a significant confounder for the genetic testing. GEP-NET under 30 years best predicted a MEN1 mutation. The present study thus confirmed a previous proposal and suggested that GEP-NET under 30 years should be considered as a part of the indication criteria for MEN1 mutational analysis.

During the course of Graves’ orbitopathy (GO), orbital fibroblasts are exposed to factors that lead to proliferation and extracellular matrix (ECM) overproduction. Increased levels of tissue plasminogen activator inhibitor type 1 (PAI-1 (SERPINE1)) might promote the accumulation of ECM components. PAI-1 expression is regulated by cell density and various cytokines and growth factors including transforming growth factorβ(TGF-β). We examined the effects of increasing cell densities and TGF-β on orbital fibroblasts obtained from GO patients and controls. Responses were evaluated by the measurement of proliferation, PAI-1 expression, and ECM production. There was an inverse correlation between cell density and the per cell production of PAI-1. GO orbital, normal orbital, and dermal fibroblasts behaved similarly in this respect. Proliferation rate also declined with increasing cell densities. Hyaluronan (HA) production was constant throughout the cell densities tested in all cell lines. In both GO and normal orbital fibroblasts, but not in dermal fibroblasts, TGF-β stimulated PAI-1 production in a cell density-dependent manner, reaching up to a five-fold increase above baseline. This has been accompanied by increased HA secretion and pericellular HA levels at high cell densities. Increasing cell density is a negative regulator of proliferation and PAI-1 secretion both in normal and GO orbital fibroblasts; these negative regulatory effects are partially reversed in the presence of TGF-β. Cell density-dependent regulation of PAI-1 expression in the orbit, together with the local cytokine environment, may have a regulatory role in the turnover of the orbital ECM and may contribute to the expansion of orbital soft tissue in GO.