Thiamazole Therapy Research Articles

The level of blood neutrophils primary reactive oxygen species production in Graves’ disease patients undergoing conservative therapy with thiamazole.

Background. Conservative therapy with thiamazole in Graves’ disease helps to reduce the level of oxidative stress by restoring euthyroidism and the total reactive antioxidant potential of plasma. However, until now, in patients with Graves’ disease, the radical-producing ability of neutrophils remains unexplored at the initial stage of free radical conversion at different durations of drug-induced euthyroidism, which seems significant in revealing the mechanisms of disease recurrence. The aim is to study the level of production of primary reactive oxygen species in peripheral blood neutrophils depending on the duration of drug — induced euthyroidism in patients with Graves’ disease. Materials and methods. A single-center, prospective, controlled study was conducted with the participation of patients with laboratory-confirmed Graves’ disease. Subgroups of patients with Graves’ disease were formed depending on the duration of achieved drug-induced euthyroidism with continuous conservative therapy with thiamazole. The level of ROS production in peripheral blood neutrophils was determined by chemiluminescence. The assessment of spontaneous and zymosan-induced chemiluminescence was carried out for 90 minutes on a 36-channel chemiluminescence analyzer BLM-3607 (Medbiotech LLC, Krasnoyarsk). Results. The study included 102 Graves’ disease women with an average age of 47.54 ± 15.47 years. Of these, 75 (73.5 %) with relapse and 27 (26.47 %) with newly diagnosed disease. The total synthesis of (S) primary ROS increased statistically significantly relative to the control values in the examined patients with a duration of the euthyroid state of 5–8 and 9–12 months. It was found that in patients with Graves’ disease with stable drug-induced euthyroidism for 5–8 and 9–12 months, the S index of zymosan-induced lucigenin-dependent chemiluminescence of neutrophils increased statistically significantly, respectively, by 10.7 and 7.4 times relative to the control values. Conclusion. The restoration and maintenance of drug-induced euthyroidism for more than 12 months against the background of conservative thiamazole therapy in patients with Graves’ disease reduces the load of systemic oxidative stress on the immune system. However, the high total production of primary ROS in neutrophils of patients with Graves’ disease in a state of drug-induced euthyroidism with conservative thiamazole therapy may play a significant role in disconnecting the functioning of the NADPH oxidase complex and determine the functional capabilities of neutrophils in case of disease recurrence.

Autosomal Dominant Hypocalcemia Due to a GNA11 Variant: The First Case in Japan

Abstract Background: Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and hyperphosphatemia due to hypoparathyroidism. ADH type 1 is caused by gain-of-function variants in CASR gene coding the calcium-sensing receptor. Recently, ADH type 2 caused by gain-of-function variants in GNA11 gene coding G-protein subunit α11 has been recognized. Case: A 32-year-old female patient visited our hospital because she suffered from hyperhidrosis, exertional dyspnea, and palpitations. She had a past medical history of paroxysmal kinesigenic dyskinesia confirmed by genetic analysis of PRRT2. Although her sister has unspecified epilepsy, no members of her kindred have episodes of tetany. Her height was 155.7 cm and weight was 64.1 kg. She had goiter with tremor and tachycardia and was diagnosed as Graves’ disease (fT3 >32.55 pg/mL, fT4 >7.77 ng/dL, TSH <0.005 µIU/mL, and TRAb 36.9 IU/L). Thiamazole therapy ameliorated her hyperthyroidism, while serum calcium level was low (7.5 mg/dL) and serum phosphate level was slight high (5.1 mg/dL). Hypoparathyroidism was confirmed because intact-PTH was relatively low (20 pg/mL) under the hypocalcemia. Her episode of tetany that she could not sit on her heels from childhood and her basal ganglia calcification in head CT scan suggest the long disease duration. Germline whole exome sequence detected a rare variant in GNA11 gene; c.1023C>A resulted in p.Phe341Leu. There were no relevant pathogenic variants in other candidate genes such as CASR, PTH, and GCM2. Treatment with 2 µg/day of alfacalcidol and 1200 mg/day of calcium aspartate could not normalize serum calcium level (7.0 mg/dL) and serum phosphate level (5.3 mg/dL) even after 1 year. Conclusions: The pathogenicity of the variant, p.Phe341Leu, in GNA11 gene was previously confirmed [1]. ADH type 2 is extremely rare as our literature review found only four previous reports; 17 patients in 5 families [1–4]. Phenotypes of the present case are mild and skeletal growth is normal. Meanwhile, we are having difficulty in management of her hypocalcemia, even though Graves’ disease might affect her bone metabolism. Optimal therapy for ADH type 2 needs further investigation.

A case of severe jaundice caused by thiamazole therapy

S 21 ANNUAL CONFERENCE—2013 D LI industrial applications, on liver carcinogenesis still remain elusive. Aims: To study the role of isocyanate in liver carcinogenesis. Methods: Experiments were performed on the cultured human liver epithelial cell line to ascertain the possible molecular risks associated with isocyanate exposure using Nsuccinimidyl N-methylcarbamate, a chemical entity that mimics the effects of methyl isocyanatein vitro. Qualitative and quantitative assessment of phosphorylation states of ATM, H2AX, ATR and p53, put forth the kinetics of DNA damage. Analyses of apoptosis in treated cells and inflammatory cytokines secreted in culture supernatant were done through annexin-V FITC/PI assay and cytometric bead array respectively. Cytogenetic studies along with inter simple sequence repeat PCR were done in control and treated cells to check for the possible precariousness at the chromosomal and microsatellite levels of the genome. Results: An increasing trend of all the DNA damage responsive parameters along with the apoptotic index were displayed in treated cells. Isocyanate exposed cells secreted an elevated levels of inflammatory cytokines in the culture supernatant. Cytogenetic analysis and inter simple sequence repeat PCR revealed varied chromosomal anomalies with greater instability at the microsatellite level. Conclusion: To conclude, these findings demonstrate that human liver epithelial milieu could confront with molecular risks due to isocyanate exposure attributing to defective DNA repair pathway along with de-regulated cell cycle and genomic instability which may accelerate the development of HCC. Corresponding author. Kewal Krishan Maudar. E-mail: maudarji@yahoo.com A CASE OF SEVERE JAUNDICE CAUSED BY THIAMAZOLE THERAPY Maria Sergeevna Zharkova, Marina Trofimovich Maevskaya, Elena Nikolaevna Shirokova, Tatjana Petrovna Nekrasova, Marina Victorovna Ivashkin Hepatology Department, University Clinical Hospital N 2, First Moscow State Medical University, Moscow, Russia Objective:Hepatotoxicity is a rare serious adverse reaction to antithyroid agents. It occurs with a frequency of 0.1– 0.2% of treated patients. Here we describe a case of severe jaundice with expected poor prognosis in a Thiamazoletreated patient with thyrotoxicosis. Case report: A 48-year-old woman with thyrotoxicosis developed jaundice after two weeks of Thiamazole therapy (40 mg/day). Viral hepatitis and mechanical biliary obstruction were excluded. Drug-induced liver injury had S38 been suspected. Despite drug discontinuation, weakness, skin itching, weight loss intensified. She was hospitalized to our clinic six weeks after disease onset. There were significant jaundice and visible traces after scratching; tachycardia. Liver and spleen were not palpable. Laboratory analyses showed elevation of ALT> AST (5-6 times higher ULN), total bilirubin (36 times higher ULN) due to both fractions, hypoalbuminemia (2.6 g/dl). Tests for autoantibodies were negative. Serum thyroid-stimulating hormone level was less than 0.01 uIU/ml (N: 0.4–4), free thyroxine two times higher ULN. Liver biopsy revealed parenchymatous and canalicularbilirubinostasis, necrosis of some hepatocytes. We diagnosed: Thiamazole-induced hepatitis. Hepatic failure: jaundice, hypoalbuminemia, thyrotoxicosis. In spite of drug withdrawal and administration of Ademethionine, UDCA, plazmapheresis, we observed a very slow regression of jaundice. Prednisolone prescription led to a rapid full patient's recovery with normalization of all biochemical markers during a month. The patient passed later radioactive iodine ablation of the thyroid gland. Discussion: Here we observed a mixed (dose-dependent and idiosyncratic) liver injury. There was an untypical form of hepatotoxicity hepatocellular damage with jaundice, without increase in laboratory markers of cholestasis, what makes the uniqueness of this clinical case. Conclusion: Severe jaundice is a rare adverse effect of antithyroid drugs’ therapy. The liver injury is usually reversible after drug withdrawal but in some cases can require Prednizolone administration. Physicians should keep in mind such a rare adverse reaction of antithyroid drugs. Corresponding Author. Maria Sergeevna Zharkova. E-mail: zharkovamaria@mail.ru HCV INFECTION IN THE HIV PATIENT IN ORAN ALGERIA Nadjet Allab Mouffok, Fatima Bensadoun, Ahmed Kouiad Belkadi

Rapid Progression of Graves' Ophthalmopathy Despite the Administration of Thiamazole

A 42-year-old female with body weight loss, finger tremors and ocular discomfort was diagnosed with Graves' disease complicated with ophthalmopathy. Thiamazole therapy rapidly improved her hyperthyroidism. However, she was admitted to our hospital because her eye symptoms acutely deteriorated over a period of two weeks. She had ocular immotility, exposure keratitis, conjunctival edema, severe proptosis and visual impairment with a high titer of serum thyroid-stimulating antibody (TSAb). Methylprednisolone pulse therapy at a dose of 500 mg/day improved her eye symptoms. Although the mechanism of the progression of Graves' ophthalmopathy has not yet been elucidated, special attention should be paid to the occurrence of ophthalmopathy even after the initiation of thiamazole therapy.

Successful treatment of thyrotoxicosis is accompanied by a decrease in serum sclerostin levels

Sclerostin, a product of a SOST gene, is a protein expressed by osteocytes that inhibits osteoblastic bone formation. Several hormones, including PTH and glucocorticosteroids, have been suggested to be possible regulators of sclerostin production. The influence of thyroid hormones on sclerostin synthesis has not been investigated, so far. The aim of the study was to evaluate sclerostin concentrations in patients before and after treatment of thyrotoxicosis.Patients and methodsThe study involved 15 patients (4 men), mean age 51.8±15.3 years, mean BMI value - 24.7±3.5, with thyrotoxicosis due to Graves’ disease or toxic multinodular goitre. Serum sclerostin was measured by immunoassay at diagnosis of thyrotoxicosis and after 6–10 weeks of treatment with thiamazole. The data were analysed by means of simple descriptive statistics of location and dispersion and Mann–Whitney U test for pairs of results, before and after thiamazole therapy. Association between variables was evaluated with use of Spearman`s correlation coefficient.ResultsThere was a significant decrease in free T3 (FT3) and free T4 (FT4) concentrations (from 8.74±4.79 pg/ml to 3.54±2.40 pg/ml, and from 4.48±2.21 ng/ml to 1.02±1.07 ng/ml, respectively, p<0.001). This was accompanied by a marked decrease of serum sclerostin levels from 55.46±20.90 pmol/l to 35.73±15.70 pmol/l, p<0.0015). Interestingly, enough, sclerostin levels did not correlate with serum FT3 or FT4 concentrations.ConclusionsRestoration of a euthyroid state in patients with thyrotoxicosis results in a significant decrease in serum sclerostin concentrations. The above mentioned phenomenon may reflect lowering of bone metabolism, but a possible direct influence of thyroid hormones on SOST gene needs to be investigated.

Acute-on-chronic liver failure due to thiamazole in a patient with hyperthyroidism and trilogy of Fallot: case report

BackgroundThiamazole is a widely used antithyroid agent that has been approved for the treatment of hyperthyroidism. Although thiamazole-induced hepatotoxicity is a main side effect, it may progress to liver failure in a very few cases.Case PresentationWe described a 24-year-old patient with hyperthyroidism and trilogy of Fallot, who developed liver failure due to thiamazole. Liver biopsy showed intrahepatic cholestasis, mild inflammatory infiltrates, as well as significant fibrosis, indicating both acute and chronic liver injuries. Although a series of potent therapies were given, the patient deceased due to severe liver decompensation.ConclusionsThis case suggests that thiamazole-induced hepatotoxicity in the setting of advanced fibrosis increases the risk of poor outcome. Regular liver function monitoring during thiamazole therapy is therefore important.

Cytokine Status, Thyroid Autoantibodies and Their Dynamic Changes During the Treatment of Graves' Disease

It has been found during the research that the changes of Th1 and Th2 marker cytokine content in Graves Disease are dynamic and are directly correlated not only with the severity of autoimmune thyrotoxicosis, but also with the method of treatment used and duration of Thiamazole therapy. The beginning of autoimmune thyrotoxicosis shows the largest amounts of both pro-inflammatory (IL-1a, IL-8, IFN-γ) and anti-inflammatory (IL-10) cytokines which are significantly reduced during Thiamazole therapy, with the exception of the cases of severe disease course. Thyroid resection does not result in immunologic remission either, which is confirmed by persisting high serum levels of IL-1a, IL-8, IFN-γ, IL-10 and TSH antibodies in the severe GBD group. Among the unfavorable prognostic factors for recurrent disease are high serum levels of TSH antibodies, IL-1a and IFN-γ during pre-surgery period.

Increased macrophage colony-stimulating factor levels in patients with Graves’ disease

Previous studies have found markedly elevated serum concentrations of proinflammatory cytokines in patients with Graves' disease (GD). We investigated the role of macrophage colony-stimulating factor (M-CSF) in GD. We assayed concentrations of M-CSF in sera from 32 patients with GD (25 untreated; 7 receiving thiamazole therapy). We also studied 32 age-matched healthy subjects as controls. Relationships between serum M-CSF and both thyroid state and serum lipids were examined. Moreover, to examine the effect of thyroid hormone alone on serum M-CSF, T3 was administered orally to normal subjects. Serum concentrations of M-CSF in GD patients who were hyperthyroid were significantly increased compared with GD patients who were euthyroid (P < 0.05) and control subjects (P < 0.0001). Serum M-CSF concentrations correlated closely with T3 levels in patients (r = 0.51, P < 0.005). Serial measurement of five individual patients revealed that serum concentrations of M-CSF were significantly decreased (P < 0.05), reaching normal control values upon attainment of euthyroidism. Furthermore, oral T3 administered to 15 volunteers for 7 days produced significant increases in serum levels of M-CSF (P < 0.05). The close correlation between serum M-CSF and serum thyroid hormone levels suggests that high circulating levels of thyroid hormones may directly or indirectly potentiate the production of M-CSF in patients with GD.

Activity of antioxidative enzymes and concentration of malondialdehyde as oxidative status markers in women with newly diagnosed Graves‑Basedow disease and after thiamazole therapy leading to euthyroidism

INTRODUCTION. Hyperthyroidism in the course of Graves-Basedow disease leads to intensification of oxidative processes and increased production of free oxygen radicals. It results in abnormal oxidative status of the organism. Aim of this work was to assess the dynamics of oxidative status changes in women with Graves-Basedow disease before and after treatment with thiamazole. Studies were carried out in 20 women with newly diagnosed hyperthyroidism in the course of Graves-Basedow disease and in 15 healthy women. Measurements of activity of antioxidant enzymes--superoxide dismutase (cytosolic copper/zinc isoform--Cu/ZnSOD, mitochondrial manganese isoform--MnSOD and extracellular copper/zinc isoform--EC-SOD) and glutathione peroxidase (GPx), as well as of malondialdehyde (MDA) concentration were performed twice, i.e. before the treatment and after 3-7 months of thiamazole therapy (euthyroidism). Before the treatment, higher MnSOD plasma activity and lower EC-SOD activity were observed in women with hyperthyroidism in comparison with the control group, whereas the erythrocyte Cu/ZnSOD activity did not differ between the groups. Besides, women with hyperthyroidism had higher GPx activity in red blood cells. In this group studies have demonstrated higher plasma MDA levels, without any differences between the groups in MDA levels in red blood cells. After thiamazole therapy no differences could be demonstrated in MnSOD, EC-SOD, Cu/ZnSOD and GPx activities and MDA level between the groups. Women with hyperthyroidism in the course of Graves-Basedow disease experience abnormal oxidative status of the organism, and induction of euthyroidism after therapy with thiamazole results in resolution of these abnormalities.

LYMPHOCYTES IN PERIPHERAL BLOOD AND THYROID TISSUE IN CHILDREN WITH GRAVES' DISEASE

OBJECTIVE: Our goal was to analyze interactions of lymphocytes in peripheral blood and thyroid tissue in children with Graves' disease (GD). METHODS: The prospective study concerned 15 children affected with GD and 15 healthy children. The levels of autoantibodies against thyrotropin receptor, thyroid peroxidase, and thyroglobulin were assayed. Monoclonal antibodies (Ortho Diagnostic Systems, Raritan, NJ) were used to define peripheral blood lymphocyte subsets and analyzed by using a flow cytometer. After thyroidectomy, thyroid specimens were stained with hematoxylin/eosin. T cells were detected by CD3+, CD4+, and CD8+ antibodies and the antigen-presenting dendritic cells with CD1a+ and CD35+ antibodies (DakoCytomation, Glostrup, Denmark). RESULTS: Before treatment, all children with GD had increased thyroid autoantibody levels, an increased percentage of CD4+ helper cells, and decreased levels of CD8+ suppressor/cytotoxic T cells, which resulted in an elevated CD4/CD8 ratio. The percentage of CD19+Cd5+ B cells was increased, although the total population of CD19+ B cells did not differ from that of the control group. The number of lymphocytes in the thyroid was decreased in 10 patients after long-term thiamazole treatment. In 5 patients with short-term therapy (&amp;lt;6 months after relapse of GD), the lymphocytes had formed lymphatic follicles: antigen-presenting dendritic cells CD1a+CD35+ in the germinal center and T-helper CD4+, T-suppressor CD8+, and B cells CD79+ on the edges. CONCLUSIONS: The primary defect of immunoregulation in GD consists of an increase of T-helper lymphocytes with a simultaneous decrease in the number of T-cytotoxic/suppressor cells. Thiamazole therapy probably leads to reduction of the lymphocyte amount in the thyroid.

Graves' disease—associated changes in the serum lysosomal glycosidases activity and the glycosaminoglycan content

Background: This study was undertaken to elucidate the influence of Graves' hyperthyroidism upon the metabolism of proteoglycans (PGs), the extracellular matrix (ECM) components. We determined the serum activity of lysosomal hydrolases contributing to GAGs degradation ( N-acetyl-β- d-glucosaminidase, β- d-glucuronidase, β- d-galactosidase, α- d-mannosidase, β- d-xylosidase and α- l-fucosidase). An effect of Graves' hyperthyroidism on total serum GAGs content was also analysed. Methods: Blood samples were taken from 30 patients with newly diagnosed Graves' disease, prior to antithyroid treatment and after attainment of euthyroid state, as well as from 30 healthy individuals. Results: The activity of all investigated enzymes involved in GAGs degradation was found markedly increased in blood serum of patients with hyperthyroidism, except for α- d-mannosidase, which was not significantly modified. Antithyroid treatment with thiamazole resulted in normalization of the lysosomal glycosidases activity, so they no longer differed from the healthy subjects. The total glycosaminoglycans content in blood serum of patients with newly diagnosed untreated Graves' disease significantly increased compared to control group. Following thiamazole therapy total serum amount of GAGs decreased significantly, but was still markedly increased as compared to serum of healthy individuals. Conclusions: The obtained results indicate that Graves' hyperthyroidism is associated with extracellular matrix components' alterations. Furthermore, we suggest that general increase of the serum lysosomal glycosidases activity and serum GAG concentration may both result from the same reason, i.e. excessive reactive oxygen species formation in the course of hyperthyroidism due to Graves' disease.

Ovarian Ultrasound and Ovarian and Adrenal Hormones before and after Treatment for Hyperthyroidism

Objective: To relate thyroid, steroid and pituitary hormones to ovarian ultrasonographic findings in hyperthyroid patients before and during treatment. Study Design: Ultrasonography of the ovaries and serum hormone determination by immunoassay were performed before and during thiamazole therapy in 18 women of fertile age treated for hyperthyroidism at the Danderyd Hospital from 1996 to 1998. Results: When hyperthyreotic, the patients had elevated serum levels of sex hormone-binding globulin (SHBG) and subnormal values of cortisol, free testosterone (fT) and dehydroepiandrosterone (DHEA). In the euthyreotic state following treatment, endocrine variables were normalized. Patients with a short duration of the disease had higher pretreatment levels of free thyroxine (fT4), SHBG and testosterone and lower corticosteroid binding globulin (CBG) and cortisol levels compared to patients with a long duration of the disease. The pretreatment ultrasonographic picture was abnormal in 16 of 18 patients. Of the 8 patients who were examined by ultrasonography after 3 months of treatment, all but 1 showed a normal picture. Samples from patients showing an abnormal ultrasonographic picture had significantly higher fT4 and lower free testosterone (fT) values than samples from patients with a normal ultrasonographic picture. Conclusion: Ultrasonographic findings showing a multicystic/multifollicular picture, resembling polycystic ovaries (PCO), in hyperthyroidism may be related to direct effects of thyroid hormones on the ovaries and/or altered intraovarian androgen environment due to elevated SHBG levels. It is highly recommended to assess the thyroid status in patients with multicystic/multifollicular ovaries/PCO.

Long-term outcome of HTLV-I associated uveitis

O-35 Purpose: To elucidate long-term outcome of HTLV-I associated uveitis (HAU). Patients and Methods: We have long followed up (mean, 83 months; range, 12-253) a consecutive series of 70 ocular patients (44 men, 26 women) consisting of 46 cases with isolated HAU, 10 with HTLV-I associated myelopathy (HAM), and 14 with hyperthyroidism. Results: The mean age of onset was 42.8 years (range, 7-71). A single episode of mild to moderate acute uveal inflammation lasting a few weeks occurred in 43 (61.4%) cases, and multiple episodes in 27 (38.6%) with a mean interval of 16 months (range, 1 - 250 months) that affected the same eye, fellow eye, or both. Two cases developed HAM many years following onset of HAU, and 14 cases presented with ocular disease in close association with thiamazole therapy for endocrinological dysfunction. The majority of patients showed favorable visual outcome at the last examination, and only a few had suffered poor visual results due to retinochoroidal degeneration or steroid therapy-related cataract. Conclusions: HAU is usually isolated and affects a portion of otherwise unremarkable HTLV-I-infected individuals, but it may occur as part of HTLV-I associated syndromes. Although multiple episodic inflammations are fairly common, the clinical course of HAU is usually benign and its long-term outcome is favorable.