Transition from hypothyroidism to Graves' disease, development of thyroid eye disease, progression to optic neuropathy after inpatient pulse therapy, and long-term administration of outpatient pulse therapy: a case report with review of literature.

A 55-year-old woman transitioned from hypothyroidism to Graves' disease (GD) and then developed thyroid eye disease (TED) with proptosis and diplopia. After three cycles of daily methylprednisolone pulse therapy, her condition progressed to dysthyroid optic neuropathy with decreased visual acuity in both eyes. Her clinical activity score (CAS) was 7 points. Orbital magnetic resonance imaging (MRI) showed that the enlarged extraocular muscles were compressing the optic nerve in the area of the cones. Although her visual acuity recovered during two further cycles of daily pulse therapy, disease activity persisted for 4 years. TED exacerbated five times. Each time, the patient received weekly pulse therapy with no adverse reactions until her ophthalmopathy was relieved. The total cumulative dose of methylprednisolone was 59.5 g. Thyroid-stimulating antibody (TSAb) was positive from the time of hypothyroidism onset and became strongly positive with the onset of GD and the progress of TED. In addition, MRI was useful for the evaluation of the pathophysiology of ophthalmopathy. This case report suggests that careful monitoring by both endocrinologists and ophthalmologists using CAS, ophthalmological assessments, TSAb measurement, and orbital MRI are useful for making treatment decisions for TED.

Role of a new bioassay for thyroid-stimulating antibodies (aequorin TSAb) in Graves' ophthalmopathy.

Graves' ophthalmopathy (GO) is characterized by an autoimmune reaction against thyrotropin (TSH) receptors and is diagnosed by TSH receptor antibody (TRAb). A novel assay for thyroid-stimulating antibody (TSAb) was recently introduced using a frozen Chinese hamster ovary cell line expressing TSH receptors, cyclic adenosine monophosphate (cAMP)-gated calcium channel, and aequorin (aequorin TSAb). The aim of this study was to evaluate the role of aequorin TSAb in GO. We studied 136 Japanese patients with GO (22 euthyroid and 8 hypothyroid GO patients) at our hospital. TRAbs were estimated by first generation TRAb (TRAb 1st), second generation TRAb (hTRAb 2nd), conventional porcine TSAb, and the new aequorin TSAb assays. Aequorin TSAb, porcine TSAb, TRAb 1st, and hTRAb 2nd were positive in 125/136 (92%), 110/136 (81%), 81/130 (62%), and 93/114 (82%) patients, respectively. In patients with hyperthyroid GO, they were positive in 98/106 (98%), 96/106 (91%), 78/101 (77%), and 84/93 (90%) patients, respectively. In patients with euthyroid GO, they were positive in 19/22 (86%), 9/22 (41%), 1/21 (5%), and 6/17 (35%) patients, respectively. Aequorin TSAb levels were significantly related to TRAb 1st (r = 0.4172, p < 0.0001), hTRAb 2nd (r = 0.2592, p < 0.0001), and porcine TSAb (r = 0.4665, p < 0.0001). Clinical activity score (CAS) was significantly greater in patients with high titers of aequorin TSAb than in those with low titers. Aequorin TSAb levels were significantly related to the signal intensity ratio of the enlarged eye muscle and proptosis evaluated by MRI before steroid pulse therapy. Aequorin TSAb assay was more sensitive than the conventional assays, especially in euthyroid GO.

Immunoglobulin G4-positive staining of orbital lesions in thyroid eye disease: Report of two cases.

We report two cases with immunoglobulin G4 (IgG4)-positive staining of orbital lesions and thyroid eye disease (TED). Case 1 was a 63-year-old male with right upper eyelid swelling due to right lacrimal gland enlargement. Case 2 was a 49-year-old male with bilateral proptosis due to multiple orbital masses. Both the biopsied right lacrimal gland in Case 1 and the orbital masses on both sides in Case 2 showed infiltration of immunoglobulin-G4-positive plasma cells.

Enzyme-linked immunosorbent assay of 3 Screen Islet Cell Autoantibody in patients with autoimmune thyroid disease.

BACKGROUND: In recent years, the emergence of multiplex technology that can simultaneously measure multiple anti-islet autoantibodies has become particularly valuable for the staging and early diagnosis of immune-mediated type 1 diabetes (T1D). While it has been established that 20%-30% of T1D patients suffer from autoimmune thyroid disease (AITD), there is limited available data regarding the presence of anti-islet autoantibodies in AITD patients. Among commercially available anti-islet autoantibodies, glutamic acid decarboxylase 65 autoantibodies (GADAs) are often the first marker measured in general clinical practice. AIM: To investigate the frequency of anti-islet autoantibodies in AITD patients. METHODS: Our study involved four hundred ninety-five AITD patients, categorized into three distinct groups: AITD with T1D (n = 18), AITD with phenotypic type 2 diabetes (T2D) (n = 81), and AITD without diabetes (n = 396), and the enzyme-linked immunosorbent assay (ELISA) was employed to determine the frequencies of 3 Screen Islet Cell Autoantibody (3 Screen ICA), GADA, insulinoma-associated antigen-2 autoantibodies (IA-2As), and zinc transporter 8 autoantibodies (ZnT8As) within these groups. RESULTS: The frequency of 3 Screen ICA in AITD patients with T1D, T2D, and those without diabetes were 88.9%, 6.2%, and 5.1%, respectively, with no significant difference seen between the latter two groups. Notably, the frequency of 3 Screen ICA was 11.1% higher in AITD patients with T1D, 1.3% higher in AITD patients with T2D, and 1.1% higher in AITD patients without diabetes compared to GADA, respectively. Furthermore, 12.5%, 20.0%, and 20.0% of the 3 Screen ICA-positive patients were negative for GADA. Additionally, 1.3% of the AITD patients who tested negative for 3 Screen ICA in both the AITD with T2D and non-diabetic AITD groups were found to be positive for individual autoantibodies. Among the 3 Screen ICA-positive patients, there was a significantly higher proportion of individuals with multiple autoantibodies in AITD patients with T1D compared to those without diabetes (37.5% vs 5.0%, P < 0.05). However, this proportion was similar to that in AITD patients with T2D (20.0%). Nevertheless, there was no significant difference in 3 Screen ICA titers between AITD patients with T1D and those without diabetes (436.8 ± 66.4 vs 308.1 ± 66.4 index). Additionally, no significant difference in 3 Screen ICA titers was observed between Graves' disease and Hashimoto's thyroiditis in any of the groups. CONCLUSION: Our findings reveal that some AITD patients without diabetes exhibit 3 Screen ICA titers comparable to those in AITD patients with T1D. Thus, 3 Screen ICA outperforms GADA in identifying latent anti-islet autoantibody-positive individuals among AITD patients.

[Management of Graves' ophthalmopathy by using orbital magnetic resonance imaging].

Orbital magnetic resonance imaging (MRI) can visualize the inflamed lesions of Graves' ophthalmopathy(GO). Parasagittal, transverse and coronal sections of T1-weighted, T2-weighted and short inversion time inversion recovery(STIR) images correlate clinical manifestations with the location of the inflamed lesions. In addition, the measurement of T2 relaxation time or signal intensity ratio of the enlarged muscles in T2-weighted fat suppression images or STIR images provide a precise quantitative evaluation of disease activity and may predict the outcome of immunosuppressive therapy for GO. Thus, MRI is useful for decision-making regarding immunosuppressive therapy and prompt surgery for GO. Therefore, we recommend MRI as a useful tool for the management of GO in specialized clinics.

Development of type 1 diabetes in a patient treated with anti-interleukin-6 receptor antibody for rheumatoid arthritis.

Interleukin-6 is a pleiotropic cytokine that plays a pathogenic role in type 1 diabetes. Therefore, anti-interleukin-6 receptor antibody, tocilizumab, used for the treatment of rheumatoid arthritis, is considered a candidate for immune intervention in type 1 diabetes. Here, we report the case of a 73-year-old woman (HLA-DR9-DQ3 homozygote) with well-controlled rheumatoid arthritis who developed type 1 diabetes while receiving tocilizumab treatment. At 57 years-of-age, the patient was diagnosed with rheumatoid arthritis, for which she underwent tocilizumab therapy that enabled complete suppression of her joint inflammation. A total of 17 months after starting tocilizumab therapy, she noticed polydipsia, polyuria, general fatigue and weight reduction (-2 kg/month), and was diagnosed with type 1 diabetes with diabetic ketoacidosis based on an arterial pH of 7.26, serum ketone body of 7,437 µmol/L, blood glucose level of 925 mg/dL, glycated hemoglobin of 13.2% and the presence of anti-islet autoantibodies. This case report shows valuable insight regarding the effect of anti-interleukin-6 receptor antibody therapy on type 1 diabetes prevention.

Graves' Disease after Adrenalectomy for Cushing's Syndrome.

A 44-year-old woman presented with a 3-month history of back pain, gait disturbance, and insomnia. She had moon face and central obesity but no goiter. Cushing's syndrome due to left adrenal adenoma was diagnosed. She also had low triiodothyronine syndrome and central hypothyroidism. Treatment involved adrenalectomy followed by 30 mg/day of hydrocortisone. Inappropriate secretion of thyroid-stimulating hormone occurred postoperatively. She developed Graves' disease nine months postoperatively and was treated with methimazole. Excess glucocorticoids followed by their withdrawal may influence the hypothalamic-pituitary-thyroid axis and immune system. Therefore, a careful evaluation of the thyroid function and antibodies is important after surgery for Cushing's syndrome.

Efficacy of omarigliptin, once-weekly dipeptidyl peptidase-4 inhibitor, in patients with type 2 diabetes.

BACKGROUND: Omarigliptin is one of several once-weekly dipeptidyl peptidase-4 inhibitors (DPP-4is). Despite the high frequency of switching from various daily DPP-4is to omarigliptin in actual clinical practice, data regarding its efficacy in patients with type 2 diabetes (T2D) after switching are limited. AIM: To analyze the efficacy of omarigliptin in Japanese patients with T2D who had previously received treatment with other glucose-lowering agents. METHODS: Forty-nine T2D patients treated for the first time with omarigliptin were recruited retrospectively and divided into four groups defined as either add-on or switched from daily DPP-4is: switched from linagliptin, switched from sitagliptin, and switched from vildagliptin. During a 3-mo follow-up, the clinical parameters among these groups were assessed and compared, with the impact of the switch on glycemic variability as measured by continuous glucose monitoring also being evaluated in the switched groups. RESULTS: Hemoglobin A1c levels saw a significant decrease of -0.32% ± 0.41% in the add-on group (P = 0.002). However, the other groups' variables depended on the pre-switch daily DPP-4i: switched from linagliptin, -0.05% ± 0.22%; switched from sitagliptin, -0.17% ± 0.33%; and switched from vildagliptin, 0.45% ± 0.42%, which saw significant worsening (P = 0.0007). Multivariate logistic regression analysis revealed that switching from vildagliptin to omarigliptin was independently associated with worsening glycemic control (P = 0.0013). The mean and standard deviation of sensor glucose value, the mean amplitude of glycemic excursions, and the mean of daily difference significantly improved when switching the patient from either linagliptin or sitagliptin to omarigliptin. However, in patients switched from vildagliptin, not only did the glucose variability indices see no improvements, the mean of daily difference even underwent significant worsening. CONCLUSION: Administering omarigliptin as add-on therapy or switching to it from sitagliptin and linagliptin, but not vildagliptin, improves glycemic control and thus should help in decision making when selecting DPP-4is for T2D patients.

Clinical characteristics of thyroid abnormalities induced by sunitinib treatment in Japanese patients with renal cell carcinoma.

Sunitinib is a multi-targeted tyrosine kinase inhibitor that is effective for advanced renal cell carcinoma. However, sunitinib often causes hypothyroidism. In this study, we report eight cases with thyroid dysfunction that occurred during sunitinib treatment for advanced renal cell carcinoma. In seven cases, mild hypothyroidism developed early in the first treatment cycle, and recovered spontaneously. Transient hyperthyroidism was observed during the second or third treatment cycles and was preceded by a rapid increase in thyroglobulin levels. (99m)Tc scintigraphy in the hyperthyroid state showed decreased thyroidal uptake of (99m)TcO(4)(-), suggesting destructive thyroiditis. Hypothyroidism subsequently developed, requiring levothyroxine replacement therapy. Ultrasonography showed a hypoechogenic pattern of the parenchyma and decreased intrathyroidal blood flow. The thyroid glands ultimately became atrophic, which may progress to permanent hypothyroidism. These findings suggest that sunitinib-induced hypothyroidism may occur frequently and may be a consequence of thyroiditis with transient thyrotoxicosis. The marked decrease in thyroid size due to reduced capillary blood flow induced by VEGF receptor inhibition may cause delayed and/or permanent hypothyroidism. Therefore, thyroid function should be monitored in all patients treated with sunitinib.

Characterization of patients with diabetes who were incidentally found to be glutamic acid decarboxylase autoantibody-positive by bridging-type enzyme-linked immunosorbent assay.

This study aimed to characterize diabetic patients incidentally found to be positive for glutamic acid decarboxylase autoantibodies (GADA) in general practice. Using bridging-type enzyme-linked immunosorbent assay, we screened 1,040 patients with phenotypic type 2 diabetes for GADA, finding 25 (2.4%) to be positive. However, on retesting, with a median interval of 19 days, 44% of GADA-positive patients turned negative (Disappearing Group). The mean age at diabetes onset was significantly higher (P < 0.05) and GADA titers at first determination were significantly lower (P < 0.001) in the Disappearing Group compared with the Persistent Positive Group. On initial screening, all patients in the Disappearing Group had GADA titers of <6.5 U/mL. The current study showed that a portion of phenotypic type 2 diabetic patients incidentally identified as GADA-positive were falsely positive, and that to avoid the misclassification, remeasurement of GADA is essential in cases showing very low titers.

Diabetes mellitus exacerbates citrin deficiency via glucose toxicity.

AIMS: Citrin is an aspartate/glutamate carrier that composes the malate-aspartate reduced nicotinamide adenine dinucleotide (NADH) shuttle in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD), failure to thrive and dyslipidemia (FTTDCD) and adult-onset type II citrullinemia (CTLN2). Hepatic glycolysis is essentially impaired in citrin deficiency and a low-carbohydrate diet was recommended. The lethal effect of infusion of glycerol- and fructose-containing osmotic agents was reported in these patients. Hyperalimentation was also reported to exacerbate CTLN2; however, glucose toxicity was unclear in citrin deficiency. METHODS: We studied two CTLN2 patients complicated with type 2 diabetes mellitus (DM), Case 1 presented with hyperammonemic encephalopathy accompanied with DM, while Case 2 presented with hyperammonemic encephalopathy relapse upon the onset of DM after several years' remission following supplementation with medium-chain triglycerides (MCT) and adherence to a low-carbohydrate diet. RESULTS: Insulin therapy with MCT supplementation and a low-carbohydrate diet improved hyperammonemia and liver function in Case 1. Additional insulin therapy improved hyperammonemia in Case 2. CONCLUSION: Glucose is not toxic for citrin deficiency in normoglycemia because glucose uptake and metabolism by hepatocytes are limited in normoglycemia. However, glucose becomes toxic during persistent hyperglycemia and antidiabetic therapy is indispensable for CTLN2 patients with DM.

A High-Fat/High-Sucrose Diet Induces WNT4 Expression in Mouse Pancreatic ß-cells.

Aims/Introduction: Several lines of evidence suggest that dysregulation of the WNT signaling pathway is involved in the pathogenesis of type 2 diabetes. This study was performed to elucidate the effects of a high-fat/high-sucrose (HF/HS) diet on pancreatic islet functions in relation to modulation of WNT ligand expression in ß-cells. MATERIALS AND METHODS: Mice were fed either standard mouse chow or a HF/HS diet from 8 weeks of age. At 20 weeks of age, intraperitoneal glucose tolerance tests were performed in both groups of mice, followed by euthanasia and isolation of pancreatic islets. WNT-related gene expression in islets and MIN6 cells was measured by quantitative real-time RT-PCR. To explore the direct effects of WNT signals on pancreatic ß-cells, MIN6 cells were exposed to recombinant mouse WNT4 protein (rmWNT4) for 48 h, and glucose-induced insulin secretion was measured. Furthermore, Wnt4 siRNAs were transfected into MIN6 cells, and cell viability and insulin secretion were measured in control and Wnt4 siRNA-transfected MIN6 cells. RESULTS: Mice fed the HF/HS diet were heavier and their plasma glucose and insulin levels were higher compared with mice fed standard chow. Wnt4, Wnt5b, Ror1, and Ror2 expression was upregulated, while Fzd4, Fzd5, Fzd6, Lrp5, and Lrp6 expression was downregulated in the islets of mice fed the HF/HS diet. Wnt4 was the most abundantly expressed WNT ligand in ß-cells, and its expression was increased by the HF/HS diet. Although exposure to recombinant mouse WNT4 protein for 48 h did not alter glucose-induced insulin secretion, it was significantly reduced by knockdown of Wnt4 in MIN6 cells. CONCLUSIONS: We demonstrated that the HF/HS diet-induced increase of WNT4 signaling in ß-cells is involved in augmentation of glucose-induced insulin secretion and impaired ß-cell proliferation. These results strongly indicate an essential role of WNT4 in the regulation of ß-cell functions in mouse pancreatic islets.

Associations of protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene polymorphisms with susceptibility to Graves' disease in a Japanese population.

BACKGROUND: The polymorphism of the protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene, which encodes an important negative regulator of T cell activation, has been reported to be associated with susceptibility to Graves' disease (GD) in Caucasians. The objective of this study was to investigate whether PTPN22 gene polymorphisms confer susceptibility to GD and Graves' ophthalmopathy (GO) in a Japanese population. METHODS: We performed a case-control study of PTPN22 gene polymorphisms in Japanese GD patients (n = 414) and healthy control subjects with no antithyroid autoantibodies or family history of autoimmune disorders (n = 231). The G-1123C polymorphism (rs2488457) in the promoter region, Arg620Trp (C1858T) polymorphism (rs2476601) in exon 14, IMS-JST146695 polymorphism (rs3789607) in intron 19, and SNP37 (rs3789604) downstream of the PTPN22 gene were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism using restriction enzymes and direct PCR sequencing methods. RESULTS: None of the GD patients or control subjects had the 1858T allele of the PTPN22 gene polymorphism. The AA-genotype and A-allele frequencies of SNP37 were significantly higher in GD patients than in control subjects (A-allele frequency: p = 0.0085, odds ratio = 1.45). The genotype frequencies and allele frequencies of the G-1123C and IMS-JST146695 polymorphisms did not differ between GD patients and control subjects. The -1123G/1858C/JST146695T/SNP37C haplotype frequency was significantly lower in GD patients than in control subjects. There were no associations between PTPN22 gene polymorphisms and GO. CONCLUSIONS: The results suggest that SNP37 of the PTPN22 gene is associated with susceptibility to GD in a Japanese population. Further studies including functional analyses are required.

Cytotoxic T-lymphocyte associated antigen 4 gene polymorphisms and autoimmune thyroid disease: a meta-analysis.

CONTEXT: Cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) polymorphisms have been widely examined for their associations with autoimmune thyroid diseases [Graves' disease (GD) and Hashimoto thyroiditis (HT)], but their relative population effect remains unclear. OBJECTIVE: The aim was to generate large-scale evidence on whether the CTLA-4 polymorphisms (A49G and CT60) and haplotypes thereof increase the susceptibility to GD and/or HT. DESIGN, SETTING, AND PARTICIPANTS: Meta-analyses of group-level data were reviewed from 32 (11,019 subjects) and 12 (4,479) published and unpublished studies for the association of the A49G polymorphism with GD and HT, respectively (PubMed and HuGeNet search until July 2006). There were 15 (n = 7246) and six (n = 3086) studies available for the CT60 polymorphism, respectively. Meta-analyses of individual-level data from 10 (4906 subjects) and five (2386) collaborating teams for GD and HT, respectively, were also reviewed. MAIN OUTCOME MEASURES: Association of gene variants and haplotypes with GD and HT was measured. RESULTS: Group-level data suggested significant associations with GD and HT for both A49G [odds ratios 1.49 (P = 6 x 10(-14)) and 1.29 (P = 0.001) per G allele, respectively] and CT60 [1.45 (P = 2 x 10(-9)) and 1.64 (P = 0.003) per G allele, respectively]. Results were consistent between Asian and Caucasian descent subjects. Individual-level data showed that compared with the AA haplotype, the risk conferred by the GG haplotype was 1.49 (95% confidence interval 1.31,1.70) and 1.36 (95% confidence interval 1.16,1.59) for GD and HT, respectively. Data were consistent with a dose-response effect for the G allele of CT60. CONCLUSION: The CT60 polymorphism of CTLA-4 maps an important genetic determinant for the risk of both GD and HT across diverse populations.

Diffuse and diffuse-plus-focal uptake in the thyroid gland identified by using FDG-PET: prevalence of thyroid cancer and Hashimoto's thyroiditis.

OBJECTIVE: To investigate and evaluate the prevalence of incidental thyroid diffuse and diffuse-plus-focal fluorine-18 fluorodeoxyglucose (FDG) uptake in healthy subjects who underwent cancer screening on positron emission tomography (PET) scan, and also to evaluate the prevalence of thyroid cancer and Hashimoto's thyroiditis. METHODS: We carried out a retrospective review of 1626 subjects who underwent PET scanning at our institution. Diffuse uptake was defined as FDG uptake in the whole thyroid gland, whereas diffuse-plus-focal uptake was defined as a thyroid lesion with both diffuse uptake and focal FDG uptake. The maximum standardized uptake value of the thyroid lesions was recorded and reviewed. In each selected subject with positive thyroid FDG uptake, serum thyroid-stimulating hormone, thyroid hormone, and thyroid antibodies were measured. Fine needle aspiration cytology was performed on patients with a definite nodule using ultrasonography. RESULTS: Twenty-nine subjects (1.78%) were identified as having either diffuse FDG uptake (n = 25, 1.53%) or diffuse-plus-focal FDG uptake (n = 4, 0.24%). All subjects with diffuse FDG uptake were diagnosed as having Hashimoto's thyroiditis. In 1 of the 25 subjects with diffuse FDG uptake and two of the four with diffuse-plus-focal FDG uptake, histopathologic diagnosis showed papillary thyroid carcinoma associated with Hashimoto's thyroiditis. However, PET scan did not detect papillary carcinoma associated with Hashimoto's thyroiditis in one of the three subjects. CONCLUSIONS: Our results suggest that although diffuse FDG uptake usually indicates Hashimoto's thyroiditis, the risk of thyroid cancer must be recognized in both diffuse FDG uptake and diffuse-plus-focal FDG uptake on PET scan.

Lack of association of interleukin-18 gene polymorphisms with susceptibility of Japanese populations to Graves' disease or Graves' ophthalmopathy.

OBJECTIVE: To investigate whether polymorphisms of interleukin (IL)-18 gene confer susceptibility to Graves' disease (GD) and Graves' ophthalmopathy (GO). DESIGN: We performed a case control study on polymorphisms of IL-18 gene in Japanese patients with GD (n = 435), and healthy control subjects without antithyroid autoantibodies or family history of autoimmune disorders (n = 255). The C-4675G, C-607A, and G-137C polymorphisms in the promoter region and A105C (exon 5) polymorphism were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using restriction enzymes, sequence-specific PCR, and PCR-direct sequencing methods. RESULTS: None of the polymorphisms in the IL-18 gene were associated with development of Graves' disease. The CC genotype and C allele frequencies of IL-18 gene G-137C polymorphism tended to be greater in patients with ophthalmopathy than in patients without evident ophthalmopathy. However, the differences were not statistically significant. Although there were three major haplotypes, none of the haplotypes were statistically associated with susceptibility to GD or ophthalmopathy. CONCLUSIONS: These results suggest that IL-18 gene polymorphisms are not major genetic factors for susceptibility to GD in a Japanese population. Further studies with adequate sized data set in the subset analyses for GO are needed.

[Steroid therapy for Graves' ophthalmopathy].

Glucocorticoids are usually given for management of Graves' ophthalmopathy (GO) for their anti-inflammatory and immunosuppressive effects. The overall rate of favorable response for moderately severe and active GO is 77% in patients treated with methylprednisolone iv pulse therapy. When radioiodine therapy is indicated for hyperthyroidism in Graves' patients with high risk factors, the use of glucocorticoid with small doses and short periods is recommended to prevent the development or progression of GO. Cushingoid features, glucose intolerance, gastritis, hypertension, hepatitis, and depression are major adverse effects of glucocorticoids. Fatal liver failure after high dose of pulse therapy (9-12g) was observed in 0.8%. Limiting the cumulative dose to 4.5-6g, assessment of liver virus markers and monitoring liver function before, during and after i.v. treatment are warranted.

Interleukin-13 gene polymorphisms confer the susceptibility of Japanese populations to Graves' disease.

Graves' disease (GD) is an autoimmune disorder with genetic predisposition. IL-13 is an important mediator of antiinflammatory immune responses and is expressed in the thyroid and orbit. The aim of the present study was to investigate whether IL-13 gene polymorphisms are associated with the development of GD. IL-13 gene polymorphisms were studied in Japanese GD patients (n = 310) and healthy control subjects without antithyroid autoantibodies or a family history of autoimmune disorders (n = 244). A C/T polymorphism at position -1112 of the promoter region was measured using the direct sequencing method, and an Arg(130)Gln (G2044A) polymorphism in exon 4 was examined using the PCR-restriction fragment length polymorphism method. There was a significant decrease in -1112T allele frequency in GD patients compared with controls (16% vs. 23%; P = 0.0019). The frequency of the 2044A allele on exon 4 also appeared lower in GD patients compared with controls. Haplotype analysis showed a significant decrease in the -1112T/2044A haplotype in GD patients. There was no association between IL-13 gene polymorphisms and ophthalmopathy, severity, or serum IgE levels. In conclusion, IL-13 gene polymorphisms are associated with GD susceptibility in Japan.

Association of CD40 gene polymorphism (C-1T) with susceptibility and phenotype of Graves' disease.

OBJECTIVE: Recently, a functional polymorphism in the CD40 gene at position -1, C to T change (C-1T) has been identified and the C/C genotype has been reported to be associated with Graves' disease (GD). DESIGN: We performed a case-control, replication study on 556 patients with GD and 611 healthy subjects in a Polish population. Furthermore, we analyzed the distribution of CD40 genotypes in subgroups of patients with GD divided according to age of onset, gender, family history, tobacco smoking, ophthalmopathy, and genetic parameters (CTLA4 49G, PTPN22/LYP 1858T or HLA-DRB1*03 alleles). RESULTS: Although the frequency of C/C genotype was increased in GD compared to controls, the difference was not significant (60.5% versus 55.8%, p = 0.062, odds ratio [OR] = 1.21, 95% confidence interval [CI]: 0.96-1.53). Because our study was underpowered to detect such a modest association, we performed a meta-analysis with the data from previous studies. The combined OR for the C/C genotype as a risk factor for GD was 1.22 (95% CI: 1.08-1.38, p = 0.001). We failed to find an interaction between CD40 genotypes and other GD susceptibility alleles. No significant genotype-phenotype associations were found. CONCLUSIONS: Our results support the notion that CD40 C-1T polymorphism has a modest effect on genetic susceptibility to sporadic GD.