Use of levothyroxine for euthyroid, thyroid antibody positive women with infertility: Analyses of aggregate data from a survey of European thyroid specialists (Treatment of Hypothyroidism in Europe by Specialists: An International Survey).

OBJECTIVES: The use of levothyroxine (LT4) treatment aiming to improve fertility in euthyroid women with positive thyroid peroxidase antibodies (TPOAb) is not supported by the available evidence. The aim of the study was to document the use of LT4 by European thyroid specialists in such patients. DESIGN: The data presented derive from Treatment of Hypothyroidism in Europe by Specialists, an International Survey (THESIS), a questionnaire conducted between 2019 and 2021 to document the management of hypothyroidism by European thyroid specialists. Here, we report the aggregate results on the use of LT4 in infertile, euthyroid women with positive TPOAb. RESULTS: A total of 2316/5406 (42.8%) respondents stated that LT4 may be indicated in TPOAb positive euthyroid women with infertility. The proportion of those replying positively to this question varied widely across different countries (median 39.4, range 22.9%-83.7%). In multivariate analyses males (OR: 0.8; CI: 0.7-0.9) and respondents >60 years (OR: 0.7; 0.6-0.8) were the least inclined to consider LT4 for this indication. Conversely, respondents managing many thyroid patients ("weekly" [OR: 1.4; CI: 1.0-1.9], "daily" [OR: 1.8; CI: 1.3-2.4]) and practicing in Eastern Europe (OR: 1.5; CI: 1.3-1.9) were most likely to consider LT4. CONCLUSIONS: A remarkably high number of respondents surveyed between 2019 and 2021, would consider LT4 treatment in TPOAb positive euthyroid women with infertility. This view varied widely across countries and correlated with sex, age and workload, potentially influencing patient management. These results raise concerns about potential risks of overtreatment.

Glucocorticoids Directly Affect Hyaluronan Production of Orbital Fibroblasts; A Potential Pleiotropic Effect in Graves' Orbitopathy.

Orbital connective tissue expansion is a hallmark of Graves' orbitopathy (GO). In moderate-to-severe active GO, glucocorticoids (GC) are the first line of treatment. Here we show that hydrocortisone (HC), prednisolone (P), methylprednisolone (MP), and dexamethasone (DEX) inhibit the hyaluronan (HA) production of orbital (OF) and dermal (DF) fibroblasts. HA production of GO OFs (n = 4), NON-GO OFs (n = 4) and DFs (n = 4) was measured by ELISA. mRNA expression of enzymes of HA metabolism and fibroblast proliferation was examined by RT-PCR and BrdU incorporation, respectively. After 24 h of GC treatment (1µM) HA production decreased by an average of 67.9 ± 3.11% (p < 0.0001) in all cell cultures. HAS2, HAS3 and HYAL1 expression in OFs also decreased (p = 0.009, p = 0.0005 and p = 0.015, respectively). Ten ng/mL PDGF-BB increased HA production and fibroblast proliferation in all cell lines (p < 0.0001); GC treatment remained effective and reduced HA production under PDGF-BB-stimulated conditions (p < 0.0001). MP and DEX reduced (p < 0.001, p = 0.002, respectively) PDGF-BB-induced HAS2 expression in OFs. MP and DEX treatment decreased PDGF-BB stimulated HAS3 expression (p = 0.035 and p = 0.029, respectively). None of the GCs tested reduced the PDGF-BB stimulated proliferation rate. Our results confirm that GCs directly reduce the HA production of OFs, which may contribute to the beneficial effect of GCs in GO.

Thyroglobulin level at week 16 of pregnancy is superior to urinary iodine concentration in revealing preconceptual and first trimester iodine supply.

Pregnant women are prone to iodine deficiency due to the increased need for iodine during gestation. Progress has recently occurred in establishing serum thyroglobulin (Tg) as an iodine status biomarker, but there is no accepted reference range for iodine sufficiency during pregnancy. An observational study was conducted in 164 pregnant women. At week 16 of gestation urinary iodine concentration (UIC), serum Tg, and thyroid functions were measured, and information on the type of iodine supplementation and smoking were recorded. The parameters of those who started iodine supplementation (≥150 µg/day) at least 4 weeks before pregnancy (n = 27), who started at the detection of pregnancy (n = 51), and who had no iodine supplementation (n = 74) were compared. Sufficient iodine supply was found in the studied population based on median UIC (162 µg/L). Iodine supplementation ≥150 µg/day resulted in higher median UIC regardless of its duration (nonusers: 130 µg/L vs. prepregnancy iodine starters: 240 µg/L, and pregnancy iodine starters: 205 µg/L, p < .001, and p = .023, respectively). Median Tg value of pregnancy starters was identical to that of nonusers (14.5 vs. 14.6 µg/L), whereas prepregnancy starters had lower median Tg (9.1 µg/L, p = .018). Serum Tg concentration at week 16 of pregnancy showed negative relationship (p = .010) with duration of iodine supplementation and positive relationship (p = .008) with smoking, a known interfering factor of iodine metabolism, by multiple regression analysis. Serum Tg at week 16 of pregnancy may be a promising biomarker of preconceptual and first trimester maternal iodine status, the critical early phase of foetal brain development.

[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.

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.

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.

[A rare cause of kidney injury: vitamin D3 intoxication]. / A vesekárosodás ritka oka: D3-vitamin-intoxikáció.

The beneficial effects of vitamin D3 treatment are known, and its side effects are documented. In connection with the case presentation, we would like to sum up the dangers of excessive vitamin D supplementation, and to draw attention to the shortcomings experienced in everyday medical practice. We discuss the tests required to create a diagnosis of vitamin D intoxication, the differential diagnosis, and present the possible treatment strategies. A 57-year-old female patient was admitted to hospital in November 2020 due to complaints of nausea, vomiting, diarrhea and general weakness. Upon admission, laboratory tests confirmed new-onset kidney damage (eGFR 38 mL/min/1.73 m2), calcium metabolism was not checked. During non-invasive investigations, urinary sediment results showed leukocyturia and non-nephrotic proteinuria, but no clear underlying cause was found. Nephrology consultation suggested acute tubular injury, kidney biopsy was performed, immune serology and serum protein electrophoresis tests were ordered. Despite conservative treatment, her kidney function deteriorated further (eGFR 32 mL/d/1.73 m2). The patient arrived at our department in December 2020 with histological results in progress. Laboratory tests taken on arrival confirmed severe hypercalcemia (tCa 3.22 mmol/L, iCa 1.74 mmol/L), and kidney function was stable (eGFR 33 mL/p/1.73 m2). Intact parathyroid hormone level was below the normal range (0.54 pmol/L), 25-OH-vitamin D level was extremely high (1106.2 nmol/L). The patient then admitted that in October 2020, she received a course of "megadose" parenteral vitamin D, but she could not recall the exact dosage nor wanted to mention the department administering the treatment. We diagnosed vitamin D intoxication. Intravenous saline, furosemide and calcitonin treatment was started. The result of the treatment: serum calcium level normalized (2.52 mmol/L), and kidney functions improved (eGFR 54 mL/p/1.73 m2). Vitamin D treatment was stopped. The patients' serum tCa and vitamin D levels normalized by February 2021, and her kidney functions improved (tCa 2.54 mmol/L, 25-OH-vitamin D 125.0 ng/mL, eGFR 72 mL/p/1.73 m2). Kidney biopsy confirmed the presence of acute tubular necrosis. Granulomatous diseases and multiple myeloma were excluded. The symptoms of vitamin D intoxication are non-specific and varied, each case presents a differential diagnostic challenge. Orv Hetil. 2023; 164(47): 1871-1876.

[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.

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.

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.

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.

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.

Novel cytochrome P450-2D6 promoter sequence variations in hepatitis C positive and negative subjects.

INTRODUCTION: CYP2D6 is a liver enzyme that metabolizes more that 25% of drugs and thus may play a pivotal role in drug-drug interactions. The promoter sequences of cytochrome P450 2D6 (CYP2D6) gene could impact metabolic activity. METHODS: We analyzed genetic variations in the promoter sequence of CYP2D6 gene for 71 hepatitis C negative and 15 hepatitis C positive subjects. RESULTS: We found two novel genetic variants -1822A→G; -1740C→T, only in two patients with hepatitis C. Also, two linked new promoter sequence variations at -2060 G→A and -2053 T→G nucleotide positions that present in both hepatitis C negative and positive subjects are identified. The -2060 and -2053 variations are confirmed to be in linkage disequilibrium. The individuals with -2060A/A, and -2053G/G variation appeared to be associated with significantly lower levels of liver CYP2D6 mRNA. Analysis of CYP2D6 enzymatic activity in *1/*1 (wild type) subjects revealed that hepatitis C positive subjects expressed about 2.6-fold lower activity (24.0 ± 1.5 vs. 62.6 ± 3.7 pmol/min/mg; p = 0.0061) relative to hepatitis C negative. CONCLUSION: These data suggest that promoter variations -1822A→G and -1740C→T are present only in hepatitis C infected subjects. Hepatitis C positive individuals were associated with a lower liver CYP2D6 enzyme activity.

EU-TIRADS-Based Omission of Fine-Needle Aspiration and Cytology from Thyroid Nodules Overlooks a Substantial Number of Follicular Thyroid Cancers.

BACKGROUND: The classification of nodules by Thyroid Imaging Reporting and Data Systems (TIRADS) is important in guiding management. Whether sensitivity in identifying thyroid cancers varies with thyroid cancer phenotype remains unclarified. METHODS: The ultrasound (US) characteristics of nodules of 26,908 nodular goiter patients were recorded. Fine-needle aspiration cytology (FNA) was performed in all nodules >1 cm irrespective of US findings (n = 25,025) and in nodules between 5 mm and 10 mm with suspicious US characteristics (n = 1,883). Of the 3281 operated cases, 221, 30, and 23 were papillary (PTC), follicular (FTC), and medullary (MTC) cancers, respectively. The US-based indication of FNA, as defined by EU-TIRADS scores, combined with lesion size, was calculated. This study design is unique in avoiding the common selection bias when TIRADS' sensitivity is tested in a cohort selected for FNA and surgery based on the same US characteristics on which TIRADS is based. RESULTS: The EU-TIRADS score influences decision of FNA in the 10-20 mm range. In such nodules (n = 118), the number of suspicious features (marked hypoechogenicity, microcalcifications, irregular shape, and irregular border) per lesion was lower in FTC (0.7 ± 0.6) than in PTC (1.7 ± 1.0) or MTC (1.8 ± 0.7; p < 0.02), resulting in EU-TIRADS scores of 4.1 ± 0.6, 4.8 ± 0.3, and 4.9 ± 0.2, respectively (p < 0.01). The EU-TIRADS-based FNA indication rate was lower in FTC (55.5%) compared to PTC (85.0%) and MTC (88.9%) (p=0.02). CONCLUSIONS: EU-TIRADS-defined suspicious US features are less common in FTC than in PTC and MTC. Therefore, a substantial number of FTCs in the 10-20 mm range escape surgery.

Case Report: Medullary Thyroid Cancer Workup Initiated by Unexpectedly High Procalcitonin Level-Endocrine Training Saves Life in the COVID-19 Unit.

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel coronavirus that has caused a worldwide pandemic. The majority of medullary thyroid cancers present as a thyroid nodule. At the time of diagnosis, cervical lymph nodes and distant metastases are frequently detected. Case Report: Here, we present a case of a 46-year-old man with coronavirus disease (COVID) pneumonia, who had persistently high serum procalcitonin levels despite normal C-reactive protein levels. The attending infectologist happened to be a colleague who spent some time, as part of her internal medicine rotation, in the Endocrine Ward and recalled that medullary thyroid cancer might be the cause. This led to the timely workup and treatment of the medullary cancer.

Lower educational status interferes with maternal iodine intake during both pregnancy and lactation.

OBJECTIVE: To investigate factors affecting conscious iodine intake among pregnant and lactating women in a rural area in Hungary. METHODS: Pregnant women were studied and followed during lactation. Urinary and breast milk iodine concentration (UIC and MIC) were measured by inductively coupled plasma mass spectrometry. Potential interfering factors, including age, educational status and smoking were assessed. RESULTS: During pregnancy and lactation, mild iodine deficiency was observed; median UIC were 66 and 49 µg/L, respectively. Educational status was found to be a strong determinant of both iodine nutrition and smoking status during pregnancy (P < 0.01 and P < 0.001) and lactation (P < 0.001 and P < 0.01). While smoking and non-smoking lactating mothers had similar concentrations of urinary iodine (median UIC: 47 and 51 µg/L, P = 0.95), the breast milk of smoking mothers contained less iodine (median MIC: 150 and 203 µg/L, P = 0.03). CONCLUSIONS: Both low iodine intake and smoking contribute to the higher risk of iodine deficiency in women with lower educational status. In smokers, MIC is often low in spite of normal UIC, presumably due to the iodine transport blocking effect of the cigarette smoke towards breast milk; normal UIC may be misinterpreted as sufficient iodine supply towards the child. Antenatal health promotion strategies should focus on young women with lower educational status, even in regions where sufficient iodine intake has been achieved in non-pregnant adults.

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.

[Development and clinical success of novel soft drugs]. / Új lágy gyógyszerek kifejlesztése és klinikai sikere.

Retrometabolic drug design combines the structure-activity and structure-metabolism relationships, allowing the effective separation of drug action and side effects. This combination results in significant improvement of the therapeutic index. The main aim is not only to study the metabolism but to build into the drug molecule the desired metabolic route, in addition to the therapeutic activity. There are two basically different approaches to achieve this aim. Both use designed-in metabolism. The 1. chemical drug-targeting systems (CDS) and 2. soft drug, both control the drug targeting and action by strategically designed metabolism. In the case of the soft drugs, we want to rely on hydrolytic enzymes, avoiding the oxidative processes. In the present work, we focus on the clinical successes of the soft drugs designed in our laboratories. In order to show the difference, we briefly present a brain-targeted delivery system, where the originally inactive molecular construct undergoes sequential metabolism to allow specific concentration of the active drug in the brain. Among the soft drugs first we present the highly successful soft corticosteroids. Loteprednol etabonate has been used worldwide for over twenty years, and its use is constantly growing. In addition to the dramatically improved therapeutic index, the specific, serious ophthalmic side effects (elevation of intraocular pressure; glaucoma and cataract formation) were completely eliminated. Similarly designed second generation of soft corticosteroids are also presented, where the soft pharmacophore is structurally unexpected. The most recent soft drug design involves anticholinergics. Sofpironium bromide, a highly effective molecule but without the typical anticholinergic side effects, was first developed to treat hyperhidrosis, an unmet need. Phase III clinical studies were successfully completed and its marketing approval is pending. Since the soft drug design principles, methods and rules are general and specific in nature, a computerized expert system was also developed. Orv Hetil. 2020; 161(10): 363-373.