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...
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.
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.
Chronic subclinical hyperthyroidism was associated with improved endothelial function and lipid profile, while haemostatic and inflammatory parameters were impaired. The two opposite mechanisms may well compensate for each other at the level of the vessel wall.
PURPOSE. Hyaluronan (HA) overproduction by orbital fibroblasts (OFs) is a major factor in the pathogenesis of Graves' orbitopathy (GO). 4-methylumbelliferone (4-MU) is an inhibitor of HA synthesis in different cell types in vitro and has beneficial effects in animal models of autoimmune diseases. METHODS. HA production and mRNA expression of HA synthases (HAS1, HAS2, and HAS3) and hyaluronidases (HYAL1 and HYAL2) were measured in the presence and absence of 4-MU in unstimulated and transforming growth factor-β-stimulated fibroblasts from GO orbital (n = 4), non-GO orbital (n = 4), and dermal origin (n = 4). RESULTS. The 4-MU treatment (1 mM) for 24 hours resulted in an average 87% reduction (P < 0.001) of HA synthesis, decreased the expression of the dominant HAS isoform (HAS2) by 80% (P < 0.0001), and increased the HYAL2 expression by 2.5-fold (P < 0.001) in control OFs, GO OFs, and dermal fibroblasts (DFs) regardless of the origin of the cells. The proliferation rate of all studied cell lines was reduced to an average 16% by 4-MU (P < 0.0001) without any effects on cell viability. HA production stimulated by transforming growth factor-β was decreased by 4-MU via inhibition of stimulated HAS1 expression in addition to the observed effects of 4-MU in unstimulated cases. Characteristics of HA synthesis inhibition by 4-MU did not differ in OFs compared with DFs. CONCLUSIONS. 4-MU has been found to inhibit the HA synthesis and the proliferation rate in OFs in vitro, adding it to the list of putative therapeutic agents in a disease the cure of which is largely unresolved.
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