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A G4-immunglobulinnal társult betegség az elmúlt években került az érdeklődés középpontjába. A kórképre jellemző az érintett szervek gyulladásával járó állapot, gyakran daganat gyanúját keltő makroszkópos megjelenés, emelkedett immunglobulin-G4-szint, szövettani vizsgálat során immunglobulin-G4-pozitív plazmasejtes beszűrődés, fibrosis, obliterativ phlebitis és típusos esetben kortikoszteroidra adott gyors terápiás válasz. A betegség változatos szervi manifesztációt mutathat, gyakori az exokrin mirigyek érintettsége. Az endokrin szervek közül a pajzsmirigyben és az agyalapi mirigyben jelenhetnek meg a tünetek. A G4-immunglobulinnal társult hypophysitis kritériumrendszerét 2011-ben fogalmazták meg. A G4-immunglobulinnal társult pajzsmirigybetegség évekig kizárólag a Riedel-thyreoiditist jelentette, majd néhány évvel ezelőtt változott az ezzel kapcsolatos szemlélet. A 2021-ben megjelent kritériumrendszer alapján a Hashimoto-thyreoiditisben és Graves–Basedow-kórban szenvedő betegek egy része is a G4-immunglobulinnal társult pajzsmirigybetegség kategóriájába sorolható. Az irodalmi adatokat alapul véve a G4-immunglobulinnal társult endokrin betegségek azonosítása, a pontos diagnózis felállítása a beteg kezelését módosíthatja, a betegség lefolyását meghatározhatja. A G4-immunglobulinnal társult endokrin kórképben szenvedő betegek esetében egyéb szervi manifesztációkat is keresni kell, és a betegek élethosszig tartó immunológiai követése indokolt. Orv Hetil. 2022; 163(30): 1175–1180.

Immunoglobulin G4-related disease has become the focus of interest in recent years. The disease is characterized by inflammation of the organs involved, often with a macroscopic appearance suggestive of a tumor, elevated immuno-globulin G4 levels, immunoglobulin G4-positive plasma cell infiltration on histological examination, fibrosis, oblit-erative phlebitis, and typically a rapid therapeutic response to corticosteroids. The disease can show a variety of organ manifestations, with frequent involvement of exocrine glands. Among the endocrine organs, symptoms may appear in the thyroid gland and the pituitary gland. The criteria for immunoglobulin G4-related hypophysitis were formu-lated in 2011. Until a few years ago, a condition formerly known as Riedel's thyroiditis was identified as immuno-globulin G4-related thyroiditis. Based on the criteria system for immunoglobulin G4-related thyroid diseases pub-lished in 2021, some patients with Hashimoto's thyroiditis and Graves' disease can also be classified as immunoglobulin G4-related thyroid disease. The identification of immunoglobulin G4-related endocrine diseases and the establishment of an accurate diagnosis can modify the treatment of the patient and determine the course of the disease. Other organ manifestations should be sought in patients with immunoglobulin G4-related endocrine disease and lifelong immunological follow-up is warranted.A G4-immunglobulinnal társult betegség az elmúlt években került az érdeklődés középpontjába. A kórképre jellemző az érintett szervek gyulladásával járó állapot, gyakran daganat gyanúját keltő makroszkópos megjelenés, emelkedett immunglobulin-G4-szint, szövettani vizsgálat során immunglobulin-G4-pozitív plazmasejtes beszűrődés, fibrosis, obliterativ phlebitis és típusos esetben kortikoszteroidra adott gyors terápiás válasz. A betegség változatos szervi manifesztációt mutathat, gyakori az exokrin mirigyek érintettsége. Az endokrin szervek közül a pajzsmirigyben és az agyalapi mirigyben jelenhetnek meg a tünetek. A G4-immunglobulinnal társult hypophysitis kritériumrendszerét 2011-ben fogalmazták meg. A G4-immunglobulinnal társult pajzsmirigybetegség évekig kizárólag a Riedel-thyreoiditist jelentette, majd néhány évvel ezelőtt változott az ezzel kapcsolatos szemlélet. A 2021-ben megjelent kritériumrendszer alapján a Hashimoto-thyreoiditisben és Graves–Basedow-kórban szenvedő betegek egy része is a G4-immunglobulinnal társult pajzsmirigybetegség kategóriájába sorolható. Az irodalmi adatokat alapul véve a G4-immunglobulinnal társult endokrin betegségek azonosítása, a pontos diagnózis felállítása a beteg kezelését módosíthatja, a betegség lefolyását meghatározhatja. A G4-immunglobulinnal társult endokrin kórképben szenvedő betegek esetében egyéb szervi manifesztációkat is keresni kell, és a betegek élethosszig tartó immunológiai követése indokolt. Orv Hetil. 2022; 163(30): 1175–1180.

Absztrakt: A szerzők egy multiplex endokrin neoplasia-2A (MEN2A) szindrómában szenvedő beteg esetét ismertetik, akinél 55 éves korban hasi panaszok miatti részletes kivizsgálás részeként derült fény kétoldali mellékvese-térfoglalásra és pajzsmirigygöbre. Az utóbbi miatt végzett thyreoidectomia szövettani lelete medullaris pajzsmirigy-carcinomát igazolt. A mellékvese-térfoglalások hormon- és képalkotó vizsgálatok alapján bilaterális phaeochromocytomának bizonyultak. Tünetmentes primer hyperparathyreosisra is fény derült. Laparoszkópos adrenalectomia és mellékpajzsmirigy-adenoma eltávolítása történt. A beteg pozitív családi anamnézise és a klinikai kép alapján felmerülő MEN2A-szindrómát genetikai vizsgálattal bizonyítottuk. Az elsőfokú rokonok szűrése során a beteg 25 éves lánygyermeke génhordozónak bizonyult, nála preventív thyreoidectomiára került sor, és a szövettan többgócú medullaris carcinomát igazolt. Az eset kapcsán a szerzők áttekintik a MEN2A-szindróma klinikai jellemzőit, és hangsúlyozzák a genetikai vizsgálat és a családszűrés fontosságát. Orv Hetil. 2020; 161(2): 75–79.

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.Absztrakt: A szerzők egy multiplex endokrin neoplasia-2A (MEN2A) szindrómában szenvedő beteg esetét ismertetik, akinél 55 éves korban hasi panaszok miatti részletes kivizsgálás részeként derült fény kétoldali mellékvese-térfoglalásra és pajzsmirigygöbre. Az utóbbi miatt végzett thyreoidectomia szövettani lelete medullaris pajzsmirigy-carcinomát igazolt. A mellékvese-térfoglalások hormon- és képalkotó vizsgálatok alapján bilaterális phaeochromocytomának bizonyultak. Tünetmentes primer hyperparathyreosisra is fény derült. Laparoszkópos adrenalectomia és mellékpajzsmirigy-adenoma eltávolítása történt. A beteg pozitív családi anamnézise és a klinikai kép alapján felmerülő MEN2A-szindrómát genetikai vizsgálattal bizonyítottuk. Az elsőfokú rokonok szűrése során a beteg 25 éves lánygyermeke génhordozónak bizonyult, nála preventív thyreoidectomiára került sor, és a szövettan többgócú medullaris carcinomát igazolt. Az eset kapcsán a szerzők áttekintik a MEN2A-szindróma klinikai jellemzőit, és hangsúlyozzák a genetikai vizsgálat és a családszűrés fontosságát. Orv Hetil. 2020; 161(2): 75–79.

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.

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.

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 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.

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.Az endokrin orbitopathia a Graves-kór leggyakoribb extrathyreoidalis manifesztációja. A súlyos – látást veszélyeztető – esetek kezelése a mai napig nem megoldott probléma. A szerzők a közleményben a nemzetközi ajánlásokban is szereplő, elfogadott kezelési módok bemutatása mellett az elmúlt évtizedek terápiás próbálkozásait, a közelmúlt új kezelési lehetőségeit, valamint saját klinikai tapasztalataikat foglalják össze. Kiemelik, hogy az endokrin orbitopathia kezelésében a biológiai terápiák közül elsősorban az anti-CD20 antitesttel végzett terápiával kedvező irodalmi adatok állnak rendelkezésre. A szelén enyhe esetekben egyértelműen pozitív hatású. További, nagyobb esetszámú prospektív vizsgálatok szükségesek a biológiai terápiák alkalmazhatóságáról endokrin orbitopathiában. Orv. Hetil., 2014, 155(33), 1295–1300.

More than 80% of traumatic brain injury (TBI) patients suffer from mild TBI (mTBI). However, even mTBI carries the risk of late pituitary dysfunction. A predictive biomarker at the time of injury that could identify patients who subsequently may develop permanent pituitary dysfunction would help to direct patients toward endocrine care. We enrolled 508 TBI patients (406 with mTBI) into our study. Blood samples were collected for identification of predictive biomarkers of late pituitary dysfunction at the time of admission. Follow-up blood samples were collected between 6 and 12 months after the TBI and were evaluated for pituitary function. Of the 406 mTBI patients, 76 were available for follow-up. Pre-existing mild pituitary dysfunction was found for 15 patients based on hormone levels at the time of injury. Of the remaining 61 patients, 10 have shown deficiency in at least one pituitary hormone: 4 had growth hormone deficiency, 3 gonadotropin, 2 thyrotropin, and 1 patient combined gonadotropin and thyrotropin deficiency. Hence, newly developed pituitary hormone deficiency was found in 16% of mTBI patients. Neither the cause of mTBI nor its complications were predictive of late pituitary dysfunction. Of the hemostasis parameters studied, lower plasminogen activator inhibitor type 1 (PAI-1) level at the time of injury was found to be predictive for the development of late pituitary dysfunction; sensitivity, specificity, and positive and negative predictive values were 80%, 67%, 32%, and 94%, respectively. Even mTBI carries a substantial risk of endocrine consequences. Serum PAI-1 level at the time of TBI may serve as a predictive biomarker of late pituitary dysfunction in mTBI patients.

In Graves' ophthalmopathy (GO), only patients with immunologically active disease respond to immunosuppressive therapy. Previous studies and theoretical considerations suggest that elevated orbital (99m)Tc-diethylenetriamine-pentaacetic-acid (DTPA) single photon emission computed tomography (SPECT) reflects inflammatory disease activity. We studied whether corticosteroid treatment causes a substantial decrease in DTPA uptake in GO, a result consistent with successful immunosuppressive treatment of GO and referred to as a favorable treatment outcome.One hundred fourteen orbits in 57 patients with active GO (CASor= 4) were entered into the study. All patients received corticosteroid treatment. Orbital DTPA uptakes were numerically quantified for the entire orbit as well as the anterior and posterior segments separately. DTPA SPECT was performed before, and 2 to 9 months after the initiation of immunosuppressive treatment. The normal range for DTPA uptake was established in 34 orbits of 17 patients who were being worked up for Raynaud's phenomenon and had no thyroid disease.The mean DTPA uptake of the 114 orbits of GO patients was higher prior to corticosteroid therapy than after this treatment (11.03 +/- 4.26 MBq/cm(3) and 9.84 +/- 3.51 MBq/cm(3), respectively, p0.001) but a substantial decline in DTPA uptake was seen in only 39.5% of GO patients. The positive predictive value of an initial DTPA12.28 MBq/cm(3) for a substantial decline in DTPA uptake (favorable treatment outcome) was 76%, while a negative predictive value of a pretreatment DTPAor=12.28 MBq/cm(3) was 78%.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.

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.

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. Orv. Hetil., 2016, 157(8), 310–315.

The aim of this study was to investigate aortic stiffness and left ventricular (LV) systolic and diastolic function in patients with differentiated thyroid cancer (DTC) on thyroxine (L-T4) therapy and after L-T4 withdrawal to assess the cardiovascular impact of long-term subclinical hyperthyroidism and short-term overt hypothyroidism. 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 4 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 Willebrand factor activity (vWF) were measured. Twenty-two healthy volunteers matched for age and sex served as euthyroid controls. Aortic stiffness was increased both in hypothyroidism (6.04 ± 2.88 cm2/dyn/103, p

Secretion of cytokines and expression of cytokine receptors have been reported in the orbital connective tissue in Graves' orbitopathy (GO). Lacrimal glands are putative autoimmune targets, and changes in tear film and ocular surface have also been described. Our aim was to characterize the cytokine profile of tears in patients with Graves' disease (GD) with and without orbitopathy.Tear samples were collected from 54 eyes of GO patients (age 43.4±15.2 years), 18 eyes of GD patients (age 46.8±11.7 years), and 24 control eyes (age 38.6±13.8 years). Patients underwent ophthalmological examination including Clinical Activity Score (CAS). The level of interleukin (IL)-1β, IL-6, IL-13, IL-17A, IL-18, tumor necrosis factor (TNF)-α, and RANTES (regulated upon activation, normal T-cell expressed, and secreted) as well as plasminogen activator inhibitor-1 (PAI-1) were measured by multiplex bead array and release values were calculated.The release of IL-1β, IL-6, IL-13, IL-17A, IL-18, TNF-α, and RANTES were significantly higher in GO patients compared to controls (p0.05). There was a 2.5-fold increase of IL-6 release. No significant differences were found in cytokine release between the GO and GD groups. In the GO group, significant positive correlation was found between CAS and the release of IL-6 and PAI-1 into tears (r=0.27, p0.05 and r=0.24, p0.05, respectively). PAI-1 release was significantly higher in GO than in GD patients and was increased in both the GD and GO groups compared to controls.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.

Although macrovascular complications are typical for type 2 diabetes mellitus (T2DM), cerebral microvascular damage develops both in type 1 diabetes mellitus (T1DM) and T2DM. Color Doppler ultrasound is widely used for the examination of large- and medium-sized arteries, whereas SPECT and MRI are capable of identifying disturbances in the circulation of microvessels. Former studies using semiquantitative methods showed reduced reactivity and reserve capacity of cerebral vessels in both T1DM and T2DM patients. Our aim was to investigate whether there was any difference in the effects of the 2 types of diabetes mellitus on the global or regional cerebral blood flow, influenced by microvascular damage.In our study, the circulation and reserve capacity of cerebral arteries was examined using (99m)Tc-hexamethylpropylene amine oxime SPECT. A total of 17 individuals with T1DM and 43 individuals with T2DM were involved in the study.Both basal and acetazolamide-challenged brain circulation were significantly lower in T2DM patients than in T1DM patients. We did not find a significant difference in the reserve capacity. However, the circulation of the frontal and occipital lobes changed differently in the 2 groups. The ratio of the circulation of the frontal and occipital lobes was significantly reduced both in basal and in acetazolamide-stimulated states in T2DM patients, independently of age (P0.0005 and P0.017), showing a greater relative decrease in the circulation of the frontal lobe in T2DM patients.There was a significant association between basal brain circulation and age, body mass index, and high-density lipoprotein (HDL), whereas acetazolamide-stimulated circulation showed a significant association with serum triglyceride and HDL.

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

Background Symptomatic paroxysmal hypertension without significantly elevated catecholamine concentrations and with no evidence of an underlying adrenal tumor is known as pseudopheochromocytoma. Methods We describe the case of a female patient with paroxysmal hypertensive crises accompanied by headache, vertigo, tachycardia, nausea and altered mental status. Previously, she was treated for a longer period with alprazolam due to panic disorder. Causes of secondary hypertension were excluded. Neurological triggers (intracranial tumor, cerebral vascular lesions, hemorrhage, and epilepsy) could not be detected. Results Setting of the diagnosis of pseudopheochromocytoma treatment was initiated with alpha- and beta-blockers resulting in reduced frequency of symptoms. Alprazolam was restarted at a daily dose of 1 mg. The patient’s clinical condition improved rapidly and the dosage of alpha- and beta-blockers could be decreased. Conclusions We conclude that the withdrawal of an anxiolytic therapeutic regimen may generate sympathetic overdrive resulting in life-threatening paroxysmal malignant hypertension and secondary encephalopathy. We emphasize that pseudopheochromocytoma can be diagnosed only after exclusion of the secondary causes of hypertension. We highlight the importance of a psychopharmacological approach to this clinical entity.