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.

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.

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.

Graves' ophthalmopathy: epidemiology and natural history.

Graves' ophthalmopathy (GO) is an autoimmune disorder of the orbit that is clinically relevant in 25-50% of patients with Graves' disease and 2% of patients with chronic thyroiditis. The age-adjusted annual incidence of clinically relevant GO is 16 per 100,000 population in women and 2.9 in men. At the onset of ophthalmopathy, 80-90% of patients have hyperthyroidism, with the rest having euthyroidism or hypothyroidism. The natural history of GO consists of two phases: an active inflammatory phase and a static phase. Anti-inflammatory therapy is indicated for the first phase of GO. Approximately 5% of patients experience late reactivation of GO. Asians appear to have less severe manifestations, with milder orbital edema, proptosis and muscle restriction. Genetic, anatomic and environmental factors influence the development of GO. Aging, thyroid dysfunction, thyroid stimulating hormone (TSH) receptor antibodies, smoking and radioiodine treatment for hyperthyroidism also influence the development and course of GO.

Hypophosphatemic osteomalacia due to drug-induced Fanconi's syndrome associated with adefovir dipivoxil treatment for hepatitis B.

We herein present the case of a 58-year-old Japanese man with Fanconi's syndrome with a 13-month history of bone pain in his ribs, hips, knees and ankles. He had been receiving low-dose adefovir dipivoxil (ADV) for the treatment of lamivudine-resistant chronic hepatitis B virus infection for eight years and subsequently developed severe hypophosphatemia and proximal renal tubule dysfunction. Magnetic resonance imaging showed multiple insufficiency fractures in the ribs, ileum, tibia and calcaneus. Whole-body bone scintigraphy demonstrated increased uptake in those areas. Following dose reduction of ADV and the administration of treatment with calcitriol and phosphates, the patient's serum phosphate level increased and his clinical symptoms improved. Physicians prescribing ADV should carefully monitor the renal function and serum phosphate level.

The difference in relationship between 18F-FDG uptake and clinicopathological factors on thyroid, esophageal, and lung cancers.

OBJECTIVES: The aim of this study was to reveal the differences in clinicopathological factors affecting maximum standardized uptake value (SUVmax) between esophageal squamous cell carcinoma (ESCC), non-small-cell lung cancer (NSCLC), and papillary thyroid cancer (PTC). METHODS: This study consisted of 119 patients with ESCC (n=43), PTC (n=40), or NSCLC (n=36). We investigated the correlations between SUVmax and clinicopathological factors by using Spearman's correlation coefficient and the Kruskal-Wallis test. Multiple regression analysis was used to investigate which clinicopathological factors significantly affected SUVmax in each cancer type. RESULTS: The SUVmax correlated with glucose transporter-1 (GLUT-1) expression in NSCLC (r=0.536, P=0.007) and ESCC (r=0.597, P<0.001) but not in PTC. The SUVmax correlated with Ki-67 expression in NSCLC (r=0.381, P=0.022) and PTC (r=0.374, P=0.017) but not in ESCC. A high SUVmax was correlated with a higher pathological T stage (p-T stage) in NSCLC (r=0.536) and ESCC (r=0.597, both P<0.001) but not in PTC. An elevated SUVmax was significantly associated with pathological lymph node status (p-N) in NSCLC, but not in ESCC and PTC. In multiple regression analysis, p-T stage and GLUT-1 expression were statistically significant factors in ESCC, and p-T stage was a statistically significant factor in NSCLC. In PTC, Ki-67 showed a statistically significant association with SUVmax. CONCLUSION: SUVmax in NSCLC depended on the tumor invasion area; SUVmax in ESCC depended on tumor depth and GLUT-1 expression; and SUVmax in PTC might be associated with cell proliferation. The biological factors affecting SUVmax differ according to tumor type.

[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.

Relation between (99m)Tc-tetrofosmin thyroid scintigraphy and mitogen-activated protein kinase in papillary thyroid cancer patients.

PURPOSE: The aim of this study was to investigate the relation between (99m)Tc-tetrofosmin uptake and extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) expression in papillary thyroid cancer patients. MATERIALS AND METHODS: Our study population consisted of 14 patients. The histopathological findings for all patients were confirmed by surgery. Patients were administ 740 MBq of (99m)Tc-tetrofosmin. The tumor/background (T/B) ratios in regions of interest (ROIs) were measured at 10 min, 1 h, and 3 h to determine the uptake by papillary cancer. Immunohistopathological staining was performed, and the expression of phospho-ERK MAPK in papillary cancer was investigated. The relation between the expression of phospho-ERK MAPK and the T/B ratio was examined using the Mann-Whitney U-test. RESULTS: (99m)Tc-tetrofosmin uptake was positive in all patients. There was a statistically significant relation between the T/B ratio (at 3 h) and the expression of phospho-ERK MAPK but not with the T/B ratio at 10 min or 1 h: T/B ratio at 10 min (P = 0.32), at 1 h (P = 0.62), and at 3 h (P = 0.0072). CONCLUSION: Our results suggest that the relation between (99m)Tc-tetrofosmin uptake (3 h T/B ratio) may lead us to assume cell proliferation of papillary cancer.

Relationship between clinicopathological factors and fluorine-18-fluorodeoxyglucose uptake in patients with papillary thyroid cancer.

OBJECTIVE: To examine the relationship between clinicopathological factors and fluorine-18-fluorodeoxyglucose (F-FDG) uptake in patients with papillary thyroid cancer (PTC). MATERIALS AND METHODS: Fifty-four patients were included in this study.F-FDG positron emission tomography was performed before surgery. Immunohistochemistry of glucose transporter (GLUT) was performed using postoperative histopathological specimens. We investigated the relationship between maximum standardized uptake value (SUVmax) and GLUT-1, GLUT-3, and GLUT-4 expression/SUVmax and prognostic risk factors {tumor size, age, sex, extrathyroidal extension, and lymph node metastasis [ly (+)]}. RESULTS: GLUT-3 and GLUT-4 expressions significantly correlated with SUVmax (GLUT-3: r=0.38, P=0.008; GLUT-4: r=0.46, P=0.001), but GLUT-1 did not (r=0.21, P=0.147). The tumor size correlated with SUVmax (r=0.5, P<0.001), but GLUT-1, GLUT-3, and GLUT-4 did not (GLUT-1: r=0.006, P=0.681; GLUT-3: r=0.05, P=0.705; GLUT-4: r=-0.17, P=0.217). Both SUVmax and GLUT-4 expressions were statistically significant with ly (+) (SUVmax: P=0.012; GLUT-4: P=0.018), but GLUT-1 and GLUT-3 expressions were not (GLUT-1: P=0.165; GLUT-3: P=0.499). There was no significant difference between other clinicopathological factors and SUVmax or any GLUT expressions. CONCLUSION: F-FDG uptake in PTC may be determined by GLUT-3 and GLUT-4 expressions and may be related to tumor size and lymph node metastasis of PTC. F-FDG uptake may reflect tumor progression of PTC.

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.

Graves' ophthalmopathy and tongue cancer complicated by peg-interferon α-2b and ribavirin therapy for chronic hepatitis C: A case report and review of the literature.

Hepatitis C virus (HCV) infection induces not only chronic liver disease, but also extrahepatic manifestations such as thyroid disease and oral cancer. Thyroid dysfunction is also a complication known to be associated with interferon (IFN) therapy for HCV infection. We report on a 69-year-old Japanese man who developed Graves' ophthalmopathy and tongue cancer (malignant transformation of leukoplakia) while receiving peg-interferon (Peg-IFN) α-2b and ribavirin (RBV) treatment for chronic hepatitis C. This patient had no history of thyroid disease before the combination therapy, but did have bilateral leukoplakia of the tongue. The leukoplakia lesions did not change until 20 weeks after the start of the combination therapy, and ophthalmopathy was not diagnosed until 47 weeks later. As ophthalmopathy is considered to be a severe adverse event induced by Peg-IFN α-2b plus RBV, therapy was discontinued after 47 weeks. The patient received a partial glossectomy to remove the malignant neoplasm as well as extraocular muscle surgery for the ophthalmopathy, and was treated with an antithyroid agent and steroids. In conclusion, it is necessary to clinically examine organs other than the liver in patients with HCV infection.

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.

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.

Autoimmune hypophysitis treated with intravenous glucocorticoid therapy.

A 46-year-old man presented with frontal headache, a visual field defect and general fatigue. Magnetic resonance imaging (MRI) of the brain showed symmetrical enlargement of the pituitary gland and stalk due to the presence of a mass lesion extending toward the optic chiasm. Gadolinium injection further revealed homogeneous strong enhancement with involvement of the adjacent dura (dural tail). Basal plasma levels of ACTH, free thyroxine and gonadotropins were decreased, and 24-h urinary 17-OHCS excretion was reduced. An elevated anti-thyroglobulin antibody titer indicated the presence of autoimmune thyroiditis. Under the suspicion of autoimmune hypophysitis, 60 mg/day prednisolone sodium succinate was intravenously administered for two weeks followed by a decreasing dose of oral prednisolone. Clinical symptoms and pituitary dysfunction recovered during steroid treatment and MRI showed marked shrinkage of the pituitary mass. Early initiation of an intravenous dose of glucocorticoid followed by oral steroid administration therefore seems to be an efficient treatment for autoimmune hypophysitis even in patients with visual dysfunction.

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.

A C/T polymorphism in the 5' untranslated region of the CD40 gene is associated with later onset of Graves' disease in Japanese.

Graves' disease (GD) is an autoimmune disorder with genetic predisposition. CD40, which stimulates lymphocyte proliferation and differentiation, is an important immunomodulator and is expressed in the thyroid follicular cells as well as antigen-presenting cells. A single nucleotide polymorphism (SNP) at position -1 of the Kozak sequence of the CD40 gene has been reported to be associated with the development of GD. The aim of the present study was to investigate whether CD40 gene polymorphism confers susceptibility to GD in Japanese. CD40 gene polymorphisms were studied in Japanese GD patients (n = 324) and healthy control subjects without anti-thyroid autoantibodies or a family history of autoimmune disorders (n = 229). A C/T polymorphism at position -1 of the CD40 gene was measured using the polymerase chain reaction restriction fragment length polymorphism. There was no significant difference in allele or genotype frequency of the CD40 SNP between GD and control subjects. There was a significant decrease in the TT genotype frequency in the GD patients, who developed GD after 40 years old, than those under 40 year of age. These data suggest that the SNP of CD40 gene is associated with susceptibility to later onset of GD in Japanese.

Association of G-174C polymorphism of the interleukin-6 gene promoter with Graves' ophthalmopathy.

Interleukin-6 (IL-6) may play an important role in the pathogenesis of Graves' ophthalmopathy (GO). The aim of this study was to analyze the association of IL-6 gene promoter polymorphism, at position - 174 (G --> C, termed as G-174C), which may affect IL-6 production, with the development of GO. The G-174C polymorphism was determined in 279 Polish-Caucasian patients with Graves' disease (GD), of which 108 had clinically evident ophthalmopathy (NOSPECS class III or higher) and 186 healthy Polish adults. In patients with GD, the frequencies of the C allele (45 vs 42%; P = 0.35) and C/C genotype (20 vs 15%; P = 0.13) were not significantly different compared to controls. Subdividing patients with GD for the presence of eye disease revealed that the C allele (44 vs 45%; P = 0.76) and C/C genotype (20 vs 20%; P = 0.92) were equally distributed in patients with or without ophthalmopathy. There was also no association between the G-174C polymorphism and the severity of eye changes. Finally, IL-6 genotypes were not associated with laboratory findings (thyroid volume, serum IL-6 and thyroid autoantibodies levels) in patients with GD at diagnosis. Our results suggest that G-174C polymorphism of the IL-6 gene does not contribute to the development and severity of GO.