Estimating Triglyceride Levels Using Total Cholesterol, Low-Density Lipoprotein Cholesterol, and High-Density Lipoprotein Cholesterol Levels: A Cross-Sectional Study.

Objective: Triglyceride (TG) levels are affected by food intake, and the cutoff values for nonfasting TG levels vary. This study aimed to calculate fasting TG levels based on total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels. Methods: Multiple regression analysis was performed to determine estimated triglyceride (eTG) levels using data from 39,971 participants divided into six groups based on non-high-density lipoprotein cholesterol (nHDL-C) levels (<100, <130, <160, <190, <220, and ≥220 mg/dL). Results: Provided that fasting TG and eTG levels ≥150 mg/dL were positive and those <150 mg/dL were negative, the three groups (nHDL-C levels <100, <130, and <160 mg/dL) consisting of 28,616 participants had a false-positive rate of <5%. The coefficient and constant terms in the formula for the eTG in groups with nHDL-C levels <100, <130, and <160 mg/dL were as follows: constant terms, 12.193, 0.741, and -7.157; coefficients of LDL-C, -3.999, -4.409, and -5.145; coefficients of HDL-C, -3.869, -4.555, and -5.215; and coefficients of TC, 3.984, 4.547, and 5.231, respectively. The adjusted coefficients of determination were 0.547, 0.593, and 0.678, respectively (P < 0.001, P < 0.001, and P < 0.001, respectively). Conclusion: Fasting TG levels can be calculated from TC, LDL-C, and HDL-C levels when nHDL-C levels are <160 mg/dL. Using nonfasting TG and eTG levels as indicators of hypertriglyceridemia might eliminate the need for venous sampling after overnight fasting.

Clinical significance of thyroglobulin antibodies and thyroid peroxidase antibodies in Graves' disease: a cross-sectional study.

PURPOSE: The significance of thyroglobulin antibodies (TgAbs) and thyroid peroxidase antibodies (TPOAbs) in Graves' disease (GD) remains unclear. Therefore, this study aimed to clarify the clinical significance of TgAbs and TPOAbs in GD. METHODS: A total of 442 patients with GD were recruited and divided into four groups based on TgAb and TPOAb positivity. Their clinical parameters and the characteristics of the groups were compared. Cox proportional hazard regression analysis was performed to assess risk factors for GD remission. RESULTS: The free triiodothyronine (FT3) level was significantly higher in groups positive for TgAbs and TPOAbs than in the other groups. The FT3 to free thyroxine (FT4) (FT3/FT4) ratio was significantly higher and thyrotropin-stimulating hormone (TSH) receptor antibodies (TRAbs) were significantly lower in the TgAb+/TPOAb- group. Time to FT4 recovery was significantly shorter for groups negative for TPOAbs, whereas time to TSH recovery was significantly longer for groups positive for TPOAbs. Cox proportional hazard regression analysis revealed that TgAb positivity, prolonged treatment duration with antithyroid drugs, and Graves' ophthalmopathy treated with methylprednisolone were significantly associated with GD remission and that a smoking history, elevated FT3/FT4 ratio, and treatment with propylthiouracil hindered GD remission. CONCLUSION: The contributions of TgAbs and TPOAbs to GD pathogenesis differ. Patients positive for TgAbs develop GD with lower TRAb titers and undergo earlier remission than those negative for TgAbs. Patients positive for TPOAbs develop GD with high TRAb titers and need a long time to achieve remission.

Estimation of visceral fat area using criteria for metabolic syndrome: A cross-sectional study.

BACKGROUND AND AIMS: The aim of this study was to calculate the visceral fat area (VFA) based on the criteria for metabolic syndrome (MetS). METHODS: A multiple regression analysis was performed to determine the estimated VFA using data from Japanese participants (2315 men and 1684 women). Receiver operating characteristic curve (ROC) analyses were performed to determine the optimal estimated VFA cutoff for the diagnosis of central obesity. The cutoff was also applied to a second cohort to validate the model. RESULTS: The estimated VFA was calculated using the MetS criteria, age, and body mass index (adjusted coefficient of determination = 0.682 for men and 0.726 for women). The area under the ROC curve for waist circumference, VFA, and estimated VFA were 0.669, 0.741, and 0.749, respectively, for men and 0.711, 0.787, and 0.803, respectively, for women. The optimal cutoffs for estimated VFA were 128.1 cm2 for men and 82.2 cm2 for women. Multivariate logistic regression for heart disease revealed that estimated VFA, rather than waist circumference, was associated with a high risk of heart disease. CONCLUSION: The estimated VFA is a better index of central obesity than waist circumference and VFA for the diagnosis of MetS.

Critical Amino Acid Variants in HLA-DRB1 and -DQB1 Allotypes in the Development of Classical Type 1 Diabetes and Latent Autoimmune Diabetes in Adults in the Japanese Population.

The effects of amino acid variants encoded by the human leukocyte antigen (HLA) class II on the development of classical type 1 diabetes (T1D) and latent autoimmune diabetes in adults (LADA) have not been fully elucidated. We retrospectively investigated the HLA-DRB1 and -DQB1 genes of 72 patients with classical T1D and 102 patients with LADA in the Japanese population and compared the frequencies of HLA-DRB1 and -DQB1 alleles between these patients and the Japanese populations previously reported by another institution. We also performed a blind association analysis with all amino acid positions in classical T1D and LADA, and compared the associations of HLA-DRB1 and -DQB1 amino acid positions in classical T1D and LADA. The frequency of DRß-Phe-13 was significantly higher and those of DRß-Arg-13 and DQß-Gly-70 were significantly lower in patients with classical T1D and LADA than in controls. The frequencies of DRß-His-13 and DQß-Glu-70 were significantly higher in classical T1D patients than in controls. The frequency of DRß-Ser-13 was significantly lower and that of DQß-Arg-70 was significantly higher in LADA patients than in controls. HLA-DRß1 position 13 and HLA-DQß1 position 70 could be critical amino acid positions in the development of classical T1D and LADA.

Critical amino acid variants in HLA-DRB1 allotypes in the development of Graves' disease and Hashimoto's thyroiditis in the Japanese population.

The effects of amino acid variants encoded by human leukocyte antigen (HLA) class II on the development of Graves' disease (GD) and Hashimoto's thyroiditis (HT) have not been fully elucidated. We investigated the HLA-DRB1 genes of 243 GD patients and 82 HT patients in the Japanese population and compared the frequencies of HLA-DRB1 alleles and HLA-DRB1 amino acid variants between these patients and the Japanese populations previously reported by another institution. The frequencies of HLA-DRB1*04:05 and -DRB1*14:03 alleles were significantly higher and those of HLA-DRB1*01:01 and -DRB1*15:02 alleles were lower in GD patients than in controls. The frequencies of HLA-DRB1*08:03 and -DRB1*09:01 alleles were significantly higher and that of the HLA-DRB1*13:02 allele was lower in HT patients than in controls. A blind association analysis with all amino acid positions identified DRß9 and DRß31 for GD and DRß9, DRß13, and DRß21 for HT. The frequency of Glu-9 was significantly higher and that of Cys-9 was lower in GD patients than in controls. The frequencies of Lys-9 and Phe-13 were significantly higher in HT patients than in controls. DRß9 and DRß13 could be critical amino acid positions in the development of GD and HT.

Association of Autoimmune Thyroid Disease with Anti-GAD Antibody ELISA Test Positivity and Risk for Insulin Deficiency in Slowly Progressive Type 1 Diabetes.

The presence of antiglutamic acid decarboxylase antibody (GADA) is required for the diagnosis of slowly progressive type 1 diabetes (SPT1D). We examined the factors influencing GADA determination by radioimmunoassay (GADA-RIA) and by enzyme-linked immunosorbent assay (GADA-ELISA). Sixty patients with SPT1D and 154 patients with type 2 diabetes were examined by both GADA-RIA and GADA-ELISA and for the presence of autoimmune thyroid disease (AITD). We compared the clinical characteristics of these patients based on the positivity or negativity of GADA-RIA and GADA-ELISA, and the existence or nonexistence of AITD. Thirty of 60 (50.0%) GADA-RIA-positive patients were GADA-ELISA negative, whereas none of the 154 GADA-RIA-negative patients were GADA-ELISA positive. Concomitant AITD was significantly less in patients with GADA-RIA and without GADA-ELISA and was significantly more in patients with GADA-RIA and GADA-ELISA. In GADA-RIA-positive patients, there was no significant difference in the GADA-RIA titer among the GADA-ELISA-negative patients with and without AITD, and the GADA-ELISA-positive patients without AITD; whereas the frequency of insulin deficiency was significantly higher in the patients with AITD and/or GADA-ELISA than in those without AITD and GADA-ELISA. Examination of GADA-ELISA and AITD in GADA-RIA-positive patients might be useful in predicting insulin deficiency in these patients.

Thyroglobulin Autoantibodies Are Associated with Refractoriness to Antithyroid Drug Treatment for Graves' Disease.

Objective The recurrence rate associated with antithyroid drug (ATD) treatment for Graves' disease (GD) is high compared with that for radioiodine therapy or surgery. It is important to identify patients in whom remission is unlikely, so that they are not given treatment that is destined to fail. The objective of this study was thus to evaluate factors influencing the prognosis of GD patients treated with ATDs. Patients One hundred and sixty-one patients were divided into two groups: 100 patients who could not discontinue ATDs for eight years or more (refractory group) and 61 patients who achieved remission within eight years after starting ATD treatment (nonrefractory group). The groups were compared in terms of age, thyroid function and thyroid-related autoantibodies at diagnosis, and the durations to the recovery of thyroid function and thyroid-related autoantibodies. Results The baseline levels of free triiodothyronine (T3), free thyroxine (T4), thyroid-stimulating antibodies (TSAbs) and thyroid-stimulating hormone (TSH) receptor antibodies (TRAbs) were high, and the age at diagnosis and the baseline level of thyroglobulin autoantibodies (TgAbs) were low in the refractory group compared with those in the nonrefractory group. The durations to the recovery of TSH, free T4, TRAb and TSAb levels were longer in the refractory group than in the nonrefractory group. No significant difference was observed with regard to thyroid peroxidase autoantibodies. Conclusion We compared the clinical features of these two groups in order to identify factors influencing the prognosis of GD patients treated with ATDs. A low baseline level of TgAbs is associated with the refractoriness of GD to ATD treatment.

Effect of human leukocyte antigen class II genes on Hashimoto's thyroiditis requiring replacement therapy with levothyroxine in the Japanese population.

Contribution of the human leukocyte antigen (HLA) subtype to Hashimoto's thyroiditis (HT) that requires replacement therapy with levothyroxine remains unclear in the Japanese population. The frequencies of HLA DR-DQ haplotypes were compared between patients with HT requiring levothyroxine replacement therapy and the control individuals. We studied 82 patients with HT requiring levothyroxine replacement therapy. The frequencies of DRB1*08:03-DQB1*06:01 and DRB1*09:01-DQB1*03:03 haplotypes were significantly higher in HT patients, whereas those of DRB1*13:02-DQB1*06:04 and DRB1*15:01-DQB1*06:02 haplotypes were significantly lower in these patients than in the controls. Deduced from known linkage disequilibria, DRB1*13:02-DQB1*06:04 and DRB1*15:01-DQB1*06:02 haplotypes share the same DQA1*01:02 allele. Since DQB1*06:02 and DQB1*06:04 molecules differ in the beta chain by 7 residues, these DQB1 genes are very similar. The DQA1*01:02-DQB1*06 (DQB1*06:02 or DQB1*06:04) haplotype might play a pivotal role in the resistance to HT.

The age of onset of diabetes and glutamic acid decarboxylase titer measured long after diagnosis are associated with the clinical stage of slow-onset type 1 diabetes.

AIMS: Diabetes mellitus is divided into 3 clinical stages: not insulin requiring, insulin requiring for control, and insulin requiring for survival. We investigated the clinical characteristics of patients with slow-onset type 1 diabetes (T1D) to examine which clinical factors influence the clinical stage. METHODS: One hundred fifty patients with slow-onset T1D were divided into 3 groups based on disease stage, and clinical features were compared among these groups. The patients were also divided into 4 groups based on the age of onset and the glutamic acid decarboxylase antibody (GAD-Ab) titer, which was measured long after diagnosis (mean, 9.2 years). The frequencies of the 3 stages were compared among these 4 groups. RESULTS: The age of onset and the log (GAD-Ab) titer differed significantly among the 3 stages. The number of patients not requiring insulin was significantly higher and the number of those requiring insulin for survival was significantly lower in the group in which the age of onset was ≥50 and the log (GAD-Ab) titer <0.6, while the opposite pattern was observed in the group in which the age of onset was <50 and the log(GAD-Ab) titer ≥0.6. CONCLUSIONS: Our results suggest that the combination of the age of onset and GAD-Ab titer measured long after diagnosis might predict the clinical stage of slow-onset T1D.

Effect of human leukocyte antigen class II genes on insulin deficiency in slow-onset type 1 diabetes in the Japanese population.

The aim of this study is to determine the contribution of human leukocyte antigen (HLA) class II genes to insulin deficiency in slow-onset type 1 diabetes (T1D). Our results suggest that the susceptibility conferred by HLA subtypes to slow-onset T1D differs between insulin-deficient patients and non-insulin-deficient patients.

Effect of human leukocyte antigen class II genes on acute-onset and slow-onset type 1 diabetes in the Japanese population.

The contribution of the human leukocyte antigen (HLA) subtype to slow-onset type 1 diabetes (T1D), which includes latent autoimmune diabetes in adults (LADA), remains unclear in the Japanese population. We compared the frequencies of HLA DR-DQ haplotypes and genotypes of 72 acute-onset T1D patients, 100 slow-onset T1D patients, and 292 control subjects. The frequencies of DRB1*0405-DQB1*0401 (DR4) and DRB1*1302-DQB1*0604 (DR13) haplotypes were significantly higher in acute-onset patients, whereas that of the DRB1*1502-DQB1*0601 haplotype was significantly lower than those in slow-onset diabetes patients and controls. In contrast, DRB1*0802-DQB1*0302 (DR8) and DRB1*0901-DQB1*0303 (DR9) haplotypes were significantly more frequent, and the DRB1*1501-DQB1*0602 haplotype was extremely rare, in acute-onset patients and slow-onset diabetes patients. Genotype analysis revealed that DR4/9, DR4/13, and DR9/13 in acute-onset patients indicated high odds ratios (6.81, 12.0, and 15.6, respectively), whereas DR4/8 was significantly more frequent in slow-onset diabetes patients, but not in acute-onset patients. Our study demonstrated for the first time that the DR8 haplotype confers susceptibility to slow-onset T1D in the Japanese population. Moreover, there potentially are hierarchies for predisposing haplotypes, namely, DR13 > DR4 > DR9 > DR8 and for protective haplotypes, namely, DRB1*1501-DQB1*0602 > DRB1*1502-DQB1*0601.

The human leukocyte antigen class II gene has different contributions to autoimmune type 1 diabetes with or without autoimmune thyroid disease in the Japanese population.

AIM: Type 1 diabetes (T1D) is associated with autoimmune thyroid disease (AITD). The human leukocyte antigen (HLA) has been extensively studied in these diseases. We aimed to clarify the contribution of AITD on the susceptibility and resistance of the HLA subtype to autoimmune T1D in the Japanese population. METHODS: The frequency of the HLA DR-DQ haplotype was compared between 56 autoimmune T1D patients with AITD and 71 autoimmune T1D patients without AITD, and control subjects. RESULTS: The frequencies of DRB1 0405-DQB1 0401, DRB1 0802-DQB1 0302, and DRB1 0901-DQB1 0303 haplotypes were significantly higher in T1D patients with AITD than in control subjects. The frequencies of DRB1 0101-DQB1 0501, DRB1 0901-DQB1 0303, and DRB1 1302-DQB1 0604 haplotypes were significantly higher in T1D patients without AITD than in control subjects. The frequencies of DRB1 1101-DQB1 0301 and DRB1 1501-DQB1 0602 haplotypes were significantly lower in T1D patients with or without AITD than in control subjects. CONCLUSIONS: Our results suggest that the susceptibility of the HLA subtype to autoimmune T1D differs between T1D with AITD and T1D without AITD, whereas there is no difference between the two groups with regard to HLA subtypes that confer protection against autoimmune T1D.

Reevaluation of human leukocyte antigen DR-DQ haplotype and genotype in type 1 diabetes in the Japanese population.

AIM: This study aims at clarifying the human leukocyte antigen haplotypes and genotypes conferring susceptibility or resistance to type 1 diabetes in the Japanese population. METHODS: The frequencies of human leukocyte antigen DR-DQ haplotypes and genotypes were compared between 83 type 1 diabetic patients, except for fulminant type 1 diabetes, and control subjects in the Japanese population. The patients were divided by onset age into four groups (ages 5-14, 15-29, 30-49, and 50-71 years); the haplotype frequency was compared between each group. RESULTS: The frequencies of DRB1*0405-DQB1*0401 (DR4), DRB1*0802-DQB1*0302 (DR8), DRB1*0901-DQB1*0303 (DR9), and DRB1*1302-DQB1* 0604 (DR13) haplotypes were significantly higher in the patients than in the control subjects. The frequencies of DRB1* 1501-DQB1*0602 and DRB1*1502-DQB1*0601 haplotypes were significantly lower in the patients than in the controls. The frequencies of DR4/8, DR4/13, DR9/9, and DR9/13 genotypes were significantly higher in the patients than in the control subjects. The DR13 haplotype was the most frequent haplotype in the age group 30-49 years, whereas the other haplotypes but DR13 were the most frequent in the other age groups. CONCLUSION: DR4, DR8, DR9, and DR13 haplotypes confer susceptibility to type 1 diabetes in Japanese patients.

A case of cushing syndrome with both secondary hypothyroidism and hypercalcemia due to postoperative adrenal insufficiency.

A 48-year-old woman was referred to our hospital because of secondary hypothyroidism. Upon admission a left adrenal tumor was also detected using computed tomography. Laboratory data and adrenal scintigraphy were compatible with Cushing syndrome due to the left adrenocortical adenoma, although she showed no response to the TRH stimulation test. Hypercortisolism resulting in secondary hypothyroidism was diagnosed. After a left adrenalectomy, hydrocortisone administration was begun and the dose was reduced gradually. After discharge on the 23rd postoperative day, she began to suffer from anorexia. ACTH level remained low, and serum cortisol, free thyroxine and TSH levels were within the normal range. Since her condition became worse, she was re-admitted on the 107th postoperative day at which time serum calcium level was high (15.6 mg/dl). Both ACTH response to the CRH stimulation test and TSH response to the TRH stimulation test were restored to almost normal levels, but there was no response of cortisol to CRH stimulation test. We diagnosed that the hypercalcemia was due to adrenal insufficiency. Although the serum calcium level decreased to normal after hydrocortisone was increased (35 mg/day), secondary hypothyroidism recurred. It was suggested that sufficient glucocorticoids suppressed TSH secretion mainly at the pituitary level, which resulted in secondary (corticogenic) hypothyroidism. However, both postoperative glucocorticoid deficiency and adequate amounts of thyroxine due to the elimination of inhibition of TSH secretion by glucocorticoids might cause hypercalcemia possibly through increased bone reabsorption of calcium.

Maternal uniparental disomy for chromosome 14 with diabetes mellitus.

A 20-year-old Japanese man was admitted to our hospital because of thirst and weight loss. His fasting plasma glucose, glycated hemoglobin, and urinary C-peptide were 262 mg/dl, 13.6%, and 44.8 microg/day, respectively, and the autoimmune antibodies related to type 1 diabetes were negative. Chromosome analysis of his peripheral blood lymphocytes showed a mos45,XY,der(14;14)(q10;ql0)[129]/ 46,XY,+14, der(14;14)(q10;q10)[1] karyotype. His parents were karyotypically normal. Microsatellite marker analysis on chromosome 14 demonstrated mosaic maternal segmental isodisomy for 14q21-q24. Although the parents had normal glucose regulation, the patient who finally returned to impaired glucose tolerance and his mother both have a deficiency in early postprandial insulin secretion. Since obesity was mild (body mass index, 24.1 kg/m2) and he was relatively young for type 2 diabetes, we speculated that his isodisomy 14 may have been involved in the onset of diabetes mellitus in this patient.

Maternal isodisomy for 14q21-q24 in a man with diabetes mellitus.

We report a 20-year-old man with maternal uniparental disomy for chromosome 14 (UPD14) and maturity-onset diabetes mellitus (DM). He had pre- and postnatal growth retardation, developed DM at age 20 years without any autoimmune antibodies, and had a mosaic 45,XY,der(14;14)(q10;q10)[129]/46,XY,+14,der(14;14)(q10;q10)[1] karyotype. Allelotyping using microsatellite markers covering the entire 14q indicated segmental maternal isodisomy for 14q21-q24 and maternal heterodisomy of the remaining regions of the chromosome. It is thus tempting to speculate that the segmental isodisomy led to reduction to homozygosity for a mutant gene and thus caused his DM, although the possibility of coincidental occurrence of the two events cannot totally be ruled out. Fluorescence in situ hybridization (FISH) analysis using BAC clone probes revealed that the isodisomic segment did not overlap any known IDDM or NIDDM susceptibility loci on chromosome 14, suggesting a novel locus for a subset of DM at the isodisomic segment.