Diagnostic criteria, clinical features, and incidence of thyroid storm based on nationwide surveys.

BACKGROUND: Thyroid storm (TS) is life threatening. Its incidence is poorly defined, few series are available, and population-based diagnostic criteria have not been established. We surveyed TS in Japan, defined its characteristics, and formulated diagnostic criteria, FINAL-CRITERIA1 and FINAL-CRITERIA2, for two grades of TS, TS1, and TS2 respectively. METHODS: We first developed diagnostic criteria based on 99 patients in the literature and 7 of our patients (LIT-CRITERIA1 for TS1 and LIT-CRITERIA2 for TS2). Thyrotoxicosis was a prerequisite for TS1 and TS2 as well as for combinations of the central nervous system manifestations, fever, tachycardia, congestive heart failure (CHF), and gastrointestinal (GI)/hepatic disturbances. We then conducted initial and follow-up surveys from 2004 through 2008, targeting all hospitals in Japan, with an eight-layered random extraction selection process to obtain and verify information on patients who met LIT-CRITERIA1 and LIT-CRITERIA2. RESULTS: We identified 282 patients with TS1 and 74 patients with TS2. Based on these data and information from the Ministry of Health, Labor, and Welfare of Japan, we estimated the incidence of TS in hospitalized patients in Japan to be 0.20 per 100,000 per year. Serum-free thyroxine and free triiodothyroine concentrations were similar among patients with TS in the literature, Japanese patients with TS1 or TS2, and a group of patients with thyrotoxicosis without TS (Tox-NoTS). The mortality rate was 11.0% in TS1, 9.5% in TS2, and 0% in Tox-NoTS patients. Multiple organ failure was the most common cause of death in TS1 and TS2, followed by CHF, respiratory failure, arrhythmia, disseminated intravascular coagulation, GI perforation, hypoxic brain syndrome, and sepsis. Glasgow Coma Scale results and blood urea nitrogen (BUN) were associated with irreversible damages in 22 survivors. The only change in our final diagnostic criteria for TS as compared with our initial criteria related to serum bilirubin concentration >3 mg/dL. CONCLUSIONS: TS is still a life-threatening disorder with more than 10% mortality in Japan. We present newly formulated diagnostic criteria for TS and clarify its clinical features, prognosis, and incidence based on nationwide surveys in Japan. This information will help diagnose TS and in understanding the factors contributing to mortality and irreversible complications.

The ratio of the blood urea nitrogen/creatinine index in patients with acute renal failure is decreased due to dextran or mannitol.

Acute renal failure (ARF) induced by dextran or mannitol is a lethal adverse effect, and hemodialysis or plasma exchange is recommended to avoid fatal ARF. This report describes 2 cases of ARF; one caused by dextran and the other by mannitol. Both showed decreases in the blood urea nitrogen (BUN)/creatinine ratios after the administration of these reagents. They immediately recovered to the level of creatinine on admission after the administration of these reagents was stopped, without hemodialysis or plasma exchange. Decreases in the BUN/creatinine ratio might be a useful index for the diagnosis of ARF is caused by these reagents.

Association of an A/C single nucleotide polymorphism in programmed cell death-ligand 1 gene with Graves' disease in Japanese patients.

OBJECTIVE: Programmed cell death-1 (PD-1) and its ligands (PD-L1 and PD-L2) inhibit T-cell proliferation and activation. This inhibition down-regulates the immune responses. The association of a PD-L1 polymorphism with Graves' disease (GD) was studied. DESIGN: The association of an A/C polymorphism at position 8923 in PD-L1 intron 4 with GD was studied. PATIENTS: The study included 327 GD patients and 192 controls, of which 252 GD patients were followed over 5-10 years. MEASUREMENTS: PD-L1 intron 4 position 8923 A/C polymorphism was typed using the PCR-restriction fragment length polymorphism method. RESULTS: The A/C genotype frequencies were significantly different between GD patients and controls. The A/C and C/C frequencies were higher in GD patients than in controls. The A/A frequencies were lower in GD patients than in controls. C-allele frequency was higher in GD patients than in controls. A total of 252 GD patients were followed over 5-10 years; 200 had discontinued antithyroid drugs (ATD) while 52 continued to take ATD. Of these 200, 176 continued to be in remission and 24 had relapsed into hyperthyroidism. Significant differences in the duration of positive TBII, positive thyroid-stimulating antibodies, and ATD treatment were noted between the patients in remission and those that had relapsed. Significant differences in the A- and C-allele frequencies were noted between the two. The C-allele frequency was higher in GD patients who did not achieve remission than in those who achieved remission. CONCLUSION: An A/C polymorphism at position 8923 in PD-L1 is associated with GD. The PD-L1 polymorphism plays a role in GD development. GD patients with the C allele at position 8923 in PD-L1 gene had difficulty in achieving remission.

Influence of motorization and supermarket-proliferation on the prevalence of type 2 diabetes in the inhabitants of a small town on Okinawa, Japan.

BACKGROUND: Motorization and supermarket-proliferation affect lifestyles. About 15 years ago, Okinawans went to several shops on foot, but now they go to supermarkets by car. The influences of these changes on the prevalence of diabetes are uncertain. OBJECTIVE AND MEASUREMENTS: The influence of motorization and supermarket-proliferation on the prevalence of diabetes was studied in the inhabitants of a town on Okinawa, Japan. Measurements were composed of anthropometry and blood chemistry. Participants were asked where they buy food and daily necessities (several shops or a supermarket) and how they get there (by car or on foot). DESIGN: Serial cross-sectional. PARTICIPANTS: Inhabitants of the island of Okinawa were studied. RESULTS: In 1991, 24% went to several shops and 20% to a supermarket. However, in 2004, only 3.1% went to several shops and 83% to a supermarket. In 1991, 55% went to shopping places on foot and 38% by car. However, in 2004, only 14% went on foot and 76% by car. The prevalence of diabetes in Okinawa increased from 4.7% in 1991 to 8.4% in 2004. The prevalence of diabetes correlated positively with the percent of inhabitants going to supermarkets, and those going there by car. In 1991, the prevalence of type 2 diabetes was 4.7% in men and 4.6% in women; no difference was noted between men and women. In 2004, the prevalence of type 2 diabetes increased to 9.2% in men and to 7.5% in women. The increase in the prevalence of type 2 diabetes from 1991 to 2004 was higher in men than in women. CONCLUSIONS: About 15 years ago, Okinawans went to shops on foot, but now they go to supermarkets by car. The prevalence of diabetes is increasing. Motorization and supermarket-proliferation are associated with the increases of the prevalence of diabetes. The increase in diabetes prevalence was higher in men than in women.

False-positive 123I-metaiodobenzylguanidine (MIBG) scan in a patient with angiomyolipoma; positive MIBG scan does not necessarily indicate the presence of pheochromocytoma.

123I-Metaiodobenzylguanidine (123I-MIBG)-accumulation in angiomyolipoma (AML) is demonstrated. A 24-year-old Japanese woman presented with tumors in the right retroperitoneal space. The tumors, which accumulated 123I-MIBG, had been thought to be adrenal pheochromocytoma before surgery. They were removed, and were found to be AML. 123I-MIBG was accumulated in AML. 123I-MIBG-accumulation in AML led to a false-positive diagnosis of adrenal pheochromocytoma. Catecholamine levels had been normal. No chromaffin cells were found in the histological examination of the tumors. MIBG accumulation does not necessarily indicate the presence of pheochromocytoma.

CTLA-4 AT-repeat polymorphism reduces the inhibitory function of CTLA-4 in Graves' disease.

Graves' disease (GD) is thought to be an autoimmune disease with a strong genetic component. Candidate genes include human leukocyte antigen (HLA) class II genes and CTLA-4. The CTLA-4 gene has a variable length AT-repeat polymorphism in the 3'-untranslated region. We previously found that the AT-repeat of 104 bp or longer was associated with GD. In this study, we categorized patients with GD and normal controls (NC) by genotyping the CTLA-4 AT-repeat and investigated the function of CTLA-4. Peripheral blood mononuclear cells (PBMC) and DNA were prepared from adult Caucasians (NC = 34, GD = 37). Genotypes of the AT-repeat polymorphism were divided into three groups according to their alleles. We related the CTLA-4 polymorphism in each genotype to augmentation of T-cell proliferation induced by a soluble anti-CTLA-4 antibody during incubation with irradiated Epstein-Barr virus (EBV)-transformed B cells. Proliferation of T cells from subjects with the 86/86 bp (shorter) allele was less than T cells from patients with longer alleles. The length of the AT-repeat allele correlated inversely with augmentation of proliferation after CTLA-4 blockade in subjects with GD. The CTLA-4 AT-repeat polymorphism affects the inhibitory function of CTLA-4. The long AT-repeat allele is associated with reduced control of T-cell proliferation and thus contributes to the pathogenesis of GD.

Cytotoxic T-lymphocyte antigen-4 gene polymorphisms and human T-cell lymphotrophic virus-1 infection: their associations with Hashimoto's thyroiditis in Japanese patients.

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) decreases the immune response of T cells by inactivating the signal that occurs with interaction between CD28 on T cells and B7 on antigen-presenting cells. Gene polymorphisms involving CTLA-4 promoter (-318 C/T), exon 1 (49 A/G), and exon 4 (microsatellite (AT)n) have been linked to Hashimoto's thyroiditis (HT) and other autoimmune diseases. HT also has a reported association with human T-cell lymphotrophic virus-1 (HTLV-1) infection. We investigated the occurrence of CTLA-4 polymorphisms in Japanese patients with HT with and without anti-HTLV-1 antibodies (HTLV-1 Ab). DNA samples from 143 patients with HT and 199 controls were subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis using the restriction enzymes, Bbv 1, Tse 1, and Mse 1. In the HTLV-1 Ab-positive group the exon 1 G allele was more frequent in patients with HT than in controls (67% vs. 53%, p = 0.0377), and in HTLV-1 Ab-negative group it was also frequent in patients with HT than in controls (68% vs. 53%, p = 0.0041). Frequency of the G allele in HT with HTLV-1 Ab was comparable to those without HTLV-1 Ab. Frequency of polymorphism in the promoter did not differ between patients with HT and controls, nor between controls with and without HTLV-1 Ab. HTLV-1 infection is not associated with CTLA-4 polymorphisms in either HT or controls. HTLV-1 infection is not regulated by genetic factor such as CTLA-4, and may affect occurrence of HT as an independent purely environmental factor.

Remission of Graves' hyperthyroidism and A/G polymorphism at position 49 in exon 1 of cytotoxic T lymphocyte-associated molecule-4 gene.

We studied whether a patient with Graves' disease will go into remission during antithyroid drug (ATD) treatment. Remission of Graves' hyperthyroidism is predicted by a smooth decrease in TSH receptor antibody (TRAb) during ATD treatment. Cytotoxic T cell lymphocyte-associated molecule-4 (CTLA-4) may play an important role in the development of Graves' hyperthyroidism and in its remission. We studied A/G polymorphism at position 49 in exon 1 of the CTLA-4 gene in 144 Japanese Graves' patients. We intended to reveal the possible association of CTLA-4 gene polymorphism with the remission of Graves' hyperthyroidism. All patients with Graves' disease were treated with ATD. Thyroid-stimulating antibody and TSH binding inhibitory Ig were measured as TRAb. We analyzed CTLA-4 genotypes and alleles with PCR. We calculated the frequencies of CTLA-4 genotypes and alleles. A significant increase in the frequency of the G allele was seen in Graves' patients compared with controls (P = 0.0095). Graves' patients were divided into three groups (A, B, and C) according to time of TRAb disappearance after the start of ATD treatment. In group A patients TRAb had disappeared within 1 yr after the start of ATD treatment, in group B TRAb had disappeared between the beginning of the second year and the end of the fifth year of treatment, and in group C TRAb continued to be positive after 5 yr of ATD treatment. The frequencies of the GG genotype and the G allele were significantly higher in group C patients with persistently positive TRAb over 5 yr of ATD treatment than in the other groups (P < 0.0001). Group C patients did not have the AA genotype. The periods of time until remission were significantly shorter in the AA genotype. Graves' patients with the G allele need to continue ATD treatment for longer periods.