Patients' Persistent Symptoms, Clinician Demographics, and Geo-Economic Factors Are Associated with Choice of Therapy for Hypothyroidism by European Thyroid Specialists: The "THESIS" Collaboration.

Background: Hypothyroidism is common, however, aspects of its treatment remain controversial. Our survey aimed at documenting treatment choices of European thyroid specialists and exploring how patients' persistent symptoms, clinician demographics, and geo-economic factors relate to treatment choices. Methods: Seventeen thousand two hundred forty-seven thyroid specialists from 28 countries were invited to participate in an online questionnaire survey. The survey included respondent demographic data and treatment choices for hypothyroid patients with persistent symptoms. Geo-economic data for each country were included in the analyses. Results: The response rate was 32.9% (6058 respondents out of 17,247 invitees). Levothyroxine (LT4) was the initial treatment preferred by the majority (98.3%). Persistent symptoms despite normal serum thyrotropin (TSH) while receiving LT4 treatment were reported to affect up to 10.0% of patients by 75.4% of respondents, while 28.4% reported an increasing such trend in the past 5 years. The principal explanations offered for patients' persistent symptoms were psychosocial factors (77.1%), comorbidities (69.2%), and unrealistic patient expectations (61.0%). Combination treatment with LT4+liothyronine (LT3) was chosen by 40.0% of respondents for patients who complained of persistent symptoms despite a normal TSH. This option was selected more frequently by female thyroid specialists, with high-volume practice, working in countries with high gross national income per capita. Conclusions: The perception of patients' dissatisfaction reported by physicians seems lower than that described by hypothyroid patients in previous surveys. LT4+LT3 treatment is used frequently by thyroid specialists in Europe for persistent hypothyroid-like symptoms even if they generally attribute such symptoms to nonendocrine causes and despite the evidence of nonsuperiority of the combined over the LT4 therapy. Pressure by dissatisfied patients on their physicians for LT3-containing treatments is a likely explanation. The association of the therapeutic choices with the clinician demographic characteristics and geo-economic factors in Europe is a novel information and requires further investigation.

Serum afamin and its implications in adult growth hormone deficiency: a prospective GH-withdrawal study.

Introduction: Adult growth hormone deficiency (AGHD) is associated with a high prevalence of metabolic syndrome (MS), which contributes to the unfavorable cardiovascular risk profile in these patients. Insulin like growth factor-1 (IGF-1) is a widely used biomarker, however it does not always reflect the cardiometabolic risk and has a poor relationship with clinical efficacy endpoints. Consequently, there is an unmet need for biomarkers to monitor responses to GH-replacement. Afamin is a hormone-like glycoprotein, expressed in the liver. Higher afamin levels are strongly associated with MS and insulin resistance (IR). Although both MS and IR are very common in AGHD, afamin has not been investigated in these patients. Purpose: To investigate afamin as a potential biomarker in patients with AGHD. Materials and methods: Participants included 20 AGHD patients (11 GH-substituted and 9 GH-unsubstituted) and 37 healthy controls. Subjects underwent routine laboratory examinations, anthropometric measurements, body composition analysis using multi-frequency bioelectrical impedance analysis (InBody720) and measurement of serum afamin concentrations. In GH-substituted subjects, GH-substitution was withdrawn for 2 months. Measurements were carried out right before GH-withdrawal, at the end of the 2-month withdrawal period, and 1 month after reinstituting GH-replacement therapy (GHRT). Results: GH-unsubstituted patients demonstrated higher afamin levels compared to controls (p=0.03). Afamin positively correlated with skeletal muscle mass, bone mineral content, total body water, extracellular- and intracellular water content, insulin (all, p<0.01), HOMA-IR (p=0.01) and C-peptide (p=0.03) levels in AGHD but not in healthy controls. In GH-substituted patients 2-month of GH-withdrawal caused significant changes in body composition, including decreased fat-free mass, skeletal muscle mass, total body water, and intracellular water content (all, p<0.01); but these changes almost fully recovered 1 month after reinstituting GHRT. Unexpectedly, afamin levels decreased after GH-withdrawal (p=0.03) and increased with reinstitution (p<0.01). Changes of afamin levels during GH-withdrawal positively correlated with changes of HOMA-IR (r=0.80; p<0.01) and changes of insulin (r=0.71; p=0.02). Conclusion: Higher afamin levels in unsubstituted AGHD patients might indicate severe metabolic dysregulation. Significant changes accompanying GH-withdrawal and reinstitution, along with strong correlations with measures of IR, suggest that afamin could be a promising biomarker to monitor GHRT-associated changes of insulin sensitivity.

Characteristics of specialists treating hypothyroid patients: the "THESIS" collaborative.

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 33·0%). The mean age was 49 years, and 65·0% were female. The proportion of female respondents was lowest in Northern (45·6%) and highest in Eastern Europe (77·2%) (p <0·001). Respondent work volume, university affiliation and private practice differed significantly between countries (p<0·001). Age and GNI per capita were correlated inversely with the proportion of female respondents (p<0·01). GNI per capita was inversely related to the proportion of respondents working exclusively in private practice (p<0·011) and the proportion of respondents who treated >100 patients annually (p<0·01). 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.

[Unfavourable cardiovascular consequences of adult growth hormone deficiency]. / A felnottkori növekedésihormon-hiány szív- és érrendszeri szövodményei.

The growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis plays a crucial role in maintaining the normal function of the cardiovascular system. Results of the last decades demonstrated that GH-IGF-1 takes part in regulating peripheral resistance and contributes to preserving physiological cardiac mass and left ventricular function. Vasculoprotective functions of the GH-IGF-1 axis are believed to counteract atherosclerosis. Unlike in childhood, when GH-deficiency results in growth retardation, GH deficiency does not cause specific symptoms in adults. Adult growth hormone deficiency (AGHD) is characterized by a clustering of cardiometabolic risk factors resulting in a clinical picture similar to the metabolic syndrome. Besides visceral obesity, dyslipidemia and insulin resistance, novel cardiovascular risk factors, such as chronic low-grade inflammation, oxidative stress and prothrombotic state have also been reported in AGHD and may contribute to the increased cardiometabolic risk. Based on a growing body of evidence, long-term GH-replacement improves lipid profile significantly and has a favorable impact on body composition, endothelial function, left ventricular mass as well as the novel, non-traditional cardiometabolic risk factors. Increased mortality associated with the disease is now considered to be multicausal and as such cannot be solely attributed to the GH-deficiency. The etiology of GH-deficiency, treatment of the underlying pathology as well as the inadequate treatment of coexisting hormonal deficiencies might also be responsible for the increased mortality. Nevertheless, in hypopituitarism, adequate replacement therapy including GH-substitution may result in a mortality that is comparable to the general population. Orv Hetil. 2023; 164(41): 1616-1627.

Advanced glycation end products and their soluble receptor (sRAGE) in patients with Hashimoto's thyroiditis on levothyroxine substitution.

Background: Advanced glycation end products (AGEs) are heterogenous group of irreversible chemical moieties originated from non-enzymatic glycation and oxidation of proteins, nucleic acids, and lipids. The engagement of AGEs with their chief cellular receptor (RAGE) activates a myriad of signaling pathways contributing to the progression of chronic diseases like autoimmune thyroiditis, type 2 diabetes mellitus and its complications. Soluble RAGE (sRAGE) prevents AGE-RAGE interaction in a competitive manner. Objective: We investigated the association between serum AGE, sRAGE and thyroid function in 73 Hashimoto thyroiditis patients (HT) on levothyroxine substitution, and in 83 age, BMI and gender-matched healthy controls. Methods: The serum AGEs levels were determined by autofluorescence on a multi-mode microplate reader, and the serum sRAGE levels by ELISA method. Results: Mean AGE level was lower (10.71 vs 11.45 AU/µg protein; p=0.046), while mean sRAGE level was higher (923 vs 755 pg/mL; p<0.0005) in the serum of HT patients than the controls. AGE correlated with age, while sRAGE correlated negatively with BMI in both groups. We found negative correlation between AGE and fT3 levels (r=-0.32; p=0.006) and sRAGE and TSH levels (r=-0.27; p=0.022) in HT patients, while we failed to find association between AGE, sRAGE and parameters of thyroid function in the control group. Median AGE/sRAGE ratio was lower in HT patients than in controls (2.4, IQR 1.9 - 3.1 vs 3.3, IQR 2.3 - 4.1 AU/pg; p < 0.001). In HT patients, the AGE/sRAGE ratio correlated positively with BMI and correlated negatively with fT3. Conclusion: According to our results in HT patients lower TSH and higher fT3 levels within the reference range is accompanied by a favorable AGE/RAGE balance. Further investigations are needed to confirm these results.

Clinical Aspects of Genetic and Non-Genetic Cardiovascular Risk Factors in Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is the most common monogenic metabolic disorder characterized by considerably elevated low-density lipoprotein cholesterol (LDL-C) levels leading to enhanced atherogenesis, early cardiovascular disease (CVD), and premature death. However, the wide phenotypic heterogeneity in FH makes the cardiovascular risk prediction challenging in clinical practice to determine optimal therapeutic strategy. Beyond the lifetime LDL-C vascular accumulation, other genetic and non-genetic risk factors might exacerbate CVD development. Besides the most frequent variants of three genes (LDL-R, APOB, and PCSK9) in some proband variants of other genes implicated in lipid metabolism and atherogenesis are responsible for FH phenotype. Furthermore, non-genetic factors, including traditional cardiovascular risk factors, metabolic and endocrine disorders might also worsen risk profile. Although some were extensively studied previously, others, such as common endocrine disorders including thyroid disorders or polycystic ovary syndrome are not widely evaluated in FH. In this review, we summarize the most important genetic and non-genetic factors that might affect the risk prediction and therapeutic strategy in FH through the eyes of clinicians focusing on disorders that might not be in the center of FH research. The review highlights the complexity of FH care and the need of an interdisciplinary attitude to find the best therapeutic approach in FH patients.

Non-surgical orbital decompression using diuresis in dysthyroid optic neuropathy: a case report.

Introduction: Dysthyroid optic neuropathy (DON) is a rare, severe form of thyroid eye disease, in which decreased visual acuity is accompanied by characteristic MRI findings. The treatment of DON has always been a challenge. Case presentation: In a patient in whom visual acuity deteriorated on the left eye, mannitol 20% 200 mL followed by furosemide 40 mg 6 h later, administered daily, were initiated on the day of admission. Visual function by ophthalmology methods, and orbital compartment volumes and water content by MRI were followed. Intravenous diuretics resulted in an immediate therapeutic response. Visual acuity improved from 20/50 to 20/25 after 2 days of treatment. MRI revealed decreasing water content of both the muscle and connective tissue compartments without any volume changes. Subsequently, corticosteroids and orbital irradiation were started. Orbital decompression surgery was not required. Discussion/conclusion: Edematous swelling of orbital tissues is an established contributor of local pressure increase in thyroid eye disease. Diuretics reduce orbital pressure and, if confirmed by others, may be useful additions to the standard of care in sight-threatening DON.

Use of thyroid hormones in hypothyroid and euthyroid patients: A THESIS questionnaire survey of Hungarian physicians / Pajzsmirigyhormon-kezelési szokások Magyarországon: A THESIS kérdoíves felmérés eredményei

Összefoglaló. Bevezetés: A pajzsmirigy-alulmuködés gyakori betegség. Kezelésében a levotiroxin (LT4)-pótlás a szokásos eljárás, mely tabletta vagy gélkapszula formájában áll rendelkezésre Magyarországon. A nemzetközi trendeknek megfeleloen az esetek korai felismerése miatt már a kevésbé kifejezett hormonális eltérések idején elindul a kezelés. Az endokrinológusok hypothyreosiskezelési szokásaival kapcsolatban Magyarországon és Európában felmérés eddig nem történt. Célkituzés: A THESIS (Treatment of Hypothyroidism in Europe by Specialists: an International Survey) célja, hogy felmérjük az európai és közte jelen munkánkban a magyar endokrinológusok hypothyreosiskezelési szokásait és az LT4 esetleges alkalmazását pajzsmirigy-muködészavarral nem járó állapotokban. Módszer: A Magyar Endokrinológiai és Anyagcsere Társaság (MEAT) tagjainak e-mailben meghívót küldtünk az online kérdoíves vizsgálathoz. Eredmények: 165 magyar endokrinológus válaszai alapján végeztük az elemzést. A válaszadók többsége, 99,4%-uk elso kezelésként LT4-pótlást alkalmaz. Az LT4 + LT3 kombinációt elsosorban olyan betegeknél alkalmazzák, akik LT4 szedése mellett euthyreoid hormonértékek ellenére hypothyreosisra jellemzo tüneteket mutatnak (36,1%). Euthyreoid hormonértékek mellett, magas antitestszint és infertilitás esetén 60,3% megfontolná LT4 indítását, amit evidenciák jelenleg nem indokolnak. Számos kórállapot befolyásolja az LT4 felszívódását, ezekben az esetekben a magyar endokrinológusok 66,4%-a preferálja a lágy kapszula alkalmazását, jobb eredményt várva a gyógyszerformák közötti váltástól. Következtetés: A pajzsmirigy-alulmuködés kezelésében a magyar endokrinológusok elsodlegesen az LT4-et választják. Az LT4 + LT3 kombinált alkalmazását a pajzsmirigy-stimuláló hormon normális szintjének elérése után perzisztáló hypothyreosisos tünetek esetén fontolják meg. Az újabb gyógyszerformákat a többség preferálja, ha az LT4 hagyományos tablettás formájának alacsonyabb biohasznosulása várható. Orv Hetil. 2022; 163(12): 463-472. INTRODUCTION: Hypothyroidism has a high prevalence in the adult population. Levothyroxine (LT4) supplementation is considered to be the gold-standard treatment method. In Hungary, LT4 tablets and soft gel capsules are the available formulations. Similarly to the international trends, hypothyroidism is earlier recognised, leading to early LT4 supplementation. Up till now, there has been no survey on the treatment of hypothyroidism among Hungarian endocrinologists. OBJECTIVE: THESIS (Treatment of Hypothyroidism in Europe by Specialists: an International Survey) had been conducted to assess treatment preferences among European endocrinologists. Here we report the results on the use of thyroid hormones in hypothyroid patients and euthyroid individuals in Hungary. METHOD: An e-mail invitation to participate, containing the link to the online survey was sent to members of the Hungarian Society for Endocrinology and Metabolism. RESULTS: There were 165 responses with full demographics which were included in the analysis. By the majority (99.4%) of them, LT4 was the first treatment of choice. LT4 + LT3 combination was considered an option in patients with persistent symptoms despite biochemical euthyroidism while on LT4 (36,1%). In euthyroid individuals, 60.3% of the respondents would consider starting LT4 in euthyroid infertile women with high antibody levels, which is hardly supported by evidence. In the presence of comorbidities and interfering medications which may hinder LT4 absorption, 66.4% of Hungarian endocrinologist anticipate significant improvement after switching from tablets to soft gel capsules. CONCLUSION: The treatment of choice for hypothyroidism is LT4 in Hungary. Combination therapy with LT4 + LT3 was considered for patients with persistent symptoms. In the presence of diseases and interfering medications affecting bioavailability, a high number of Hungarian endocrinologists prefer the new LT4 formulation. The administration of LT4 in euthyroid conditions awaits explanation and calls for intensive discussions at local conferences and courses. Orv Hetil. 2022; 163(12): 463-472.

The 4G/5G Polymorphism of Plasminogen Activator Inhibitor Type 1 is a Predictor of Moderate-to-Severe Thyroid Eye Disease.

INTRODUCTION: Thyroid eye disease (TED) is an autoimmune disease of the orbits. Once developed, complete cure is rare. Plasminogen activator inhibitor type 1 (PAI-1) contributes to remodeling of connective tissue and has a central role in the pathogenesis of TED. We aimed to test if the 4G/5G polymorphism of PAI-1 is a predictor of the development of moderate-to-severe TED. METHODS: A total of 185 patients with Graves' disease, 87 of them with TED, 98 without TED, as well as 201 healthy controls, were studied. Genomic DNA was isolated from peripheral blood samples. The 4G/5G polymorphism of the PAI-1 gene was analyzed by allele-specific PCR, and the distribution of genotypes was calculated in each group. Plasma PAI-1 and thyroid hormone levels were measured by ELISA and ECLIA, respectively. RESULTS: The 4G/4G genotype was associated with the development of moderate-to-severe TED (OR = 2.54; 95% CI: 1.26-5.14; p < 0.01). The 4G/5G polymorphism of PAI-1 was not a predictor of plasma PAI-1 levels. CONCLUSION: The 4G/4G genotype of PAI-1 is a risk factor for the development of moderate-to-severe TED. Patients with Graves' disease who harbor this genotype may be candidates for special attention towards the development of TED.

Characteristics of Hyaluronan Synthesis Inhibition by 4-Methylumbelliferone in Orbital Fibroblasts.

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-ß-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-ß 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.

[Multiple endocrine neoplasia type 2A in a family]. / A multiplex endokrin neoplasia-2A szindrómáról egy család kapcsán.

The authors present the case of a multiplex endocrine neoplasia type 2A (MEN2A). The 55-year-old woman underwent detailed examinations for abdominal complaints. Bilateral adrenal masses and thyroid nodular goiter were found. Based on metanephrine excretion and MIBG imaging, bilateral phaeochromocytomas were diagnosed. The thyroid nodules were confirmed by thyroidectomy as bilateral medullary thyroid carcinoma. Asymptomatic primary hyperparathyroidism was also detected. Laparoscopic adrenalectomy and parathyroid adenoma removal were performed. Based on family history and the characteristic clinical presentation, MEN2A syndrome was confirmed by genetic testing. During genetic screening of first-degree relatives, the patient's 25-year-old daughter was shown to be a gene carrier. Preventive thyroidectomy was performed and histology proved multifocal medullary thyroid cancer. In addition to the importance of genetic testing, the authors emphasize the guideline-based, but individualized approach to patients with suspected MEN2A syndrome. Orv Hetil. 2020; 161(2): 75-79.

Hypertension in Thyroid Disorders.

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.

Early Stage Graves' Disease is Uniformly Accompanied by Orbital Immune Activity even in Patients who Fail to Develop Orbithopathy during Follow-up.

PURPOSE: Graves' orbitopathy (GO) is a complication of Graves' disease (GD), the development of which cannot be predicted at the time of diagnosis of GD. Our aims were (i) to test if orbital 99mTc-labelled diethylenetriamine pentaacetic acid single-photon emission computer tomography (DTPA SPECT) can predict development of GO later during the course of the disease and (ii) to study whether orbital immune activity can be detected in GD patients who do not develop GO during follow-up. METHODS: Fifty-four orbits of 27 patients with newly diagnosed GD were entered into the case-control study. Individuals showing signs of GO at enrolment were excluded. During the two-year follow-up, eye signs were recorded every 3 months. Orbital DTPA uptakes on SPECT images were measured when entering the study and at the end of the follow-up period, or when clinical signs of GO developed, whichever occurred first. RESULTS: During the follow-up, 6 patients (22%) were diagnosed with GO. There was no significant difference between the initial DTPA uptakes of the patients with or without later developing GO (10.45±1.72 MBq/cm3 vs. 9.18±1.18 MBq/cm3 respectively). However, the DTPA uptakes of both GD groups (ie. with and without GO) were higher than that of the control group (7.45±1.36 MBq/cm3, p<0.05). CONCLUSIONS: We have shown that GD is accompanied by moderate orbital immune activity in GD patients without GO, irrespective of later development of GO. Why this orbital autoimmunity remains subclinical in the majority of the cases, and progresses into clinically detectable GO in others, remains unclear.

Cell density-dependent stimulation of PAI-1 and hyaluronan synthesis by TGF-ß in orbital fibroblasts.

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 factorß(TGF-ß). We examined the effects of increasing cell densities and TGF-ß 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-ß 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-ß. 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.

[Differential diagnosis of Graves' orbitopathy. Case report]. / Az endokrin orbitopathia differenciáldiagnosztikája.

Graves' orbitopathy is the extrathyroidal manifestation of Graves' disease, which is the most common cause of exophthalmos. As eye symptoms usually coincide with the development of thyrotoxicosis, the diagnosis of the disease is rarely difficult. The aim of the authors was to summarize the differential diagnosis of Graves' orbitopathy based on literature review and presentation of their own four problematic cases on this topic. They conclude that symptoms similar to endocrine orbitopathy are present in other disorders. Endocrinologists need to be aware of these other conditions to avoid treatment failures.

[Novel treatment opportunities in Graves' orbitopathy]. / Új lehetoségek az endokrin orbitopathia kezelésében.

Graves' orbitopathy is the most common extrathyroidal manifestation of Graves' disease. Up to now, curative treatment modalities for the most severe sight-threatening cases have not been developed. Here the authors summarize the treatment protocol of Graves' orbitopathy and review novel therapeutic options. They review the literature on this topic and present their own clinical experience. The authors point out that anti-CD20 antibody could positively influence the clinical course of Graves' orbitopathy. Selenium is efficient in mild cases. Further prospective investigations are warranted.

Rapid response to and long-term effectiveness of anti-CD20 antibody in conventional therapy resistant Graves' orbitopathy: A five-year follow-up study.

Abstract 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.