Incidence and risk factors for Graves' orbitopathy in patients who underwent anti-inflammatory and immunosuppressive treatment during medical treatment for Graves' disease: investigation of 1,553 cases with newly diagnosed Graves' disease and proposal of a predictive score.

Appropriate administration of anti-inflammatory and immunosuppressive treatment (AIIST) is important for patients with Graves' orbitopathy (GO). This study aimed to clarify the incidence and risk factors for GO treated with AIIST and propose a predictive score, among newly diagnosed Graves' disease (GD) patients in Japan. A total of 1,553 GD patients who were newly diagnosed during the year 2011 were investigated. AIIST included local and/or systemic glucocorticoid administration and retrobulbar irradiation. A multivariable Cox proportional hazards model was used to investigate the risk factors for GO underwent AIIST during medical treatment, including at diagnosis, of GD. Then, a GO score was created by summing each point assigned to risk factors based on their coefficient obtained in the Cox model. AIIST was administered to 107 patients (6.9%). The risk factors and hazard ratios for GO underwent AIIST were: age (per 10 years), 1.32 (95% confidence interval: 1.16-1.50), p < 0.0001; TSH binding inhibitory immunoglobulin (TBII) (per 10 IU/L), 1.33 (1.15-1.54), p = 0.0001; and thyroglobulin antibody (TgAb) negativity, 2.98 (1.96-4.59), p < 0.0001. The GO score, ranging from 0 to 8 points, showed moderate performance (area under the curve: 0.71, cut-off value: 5 points, sensitivity: 0.76, specificity: 0.59, positive predictive value: 0.12, negative predictive value: 0.97). AIIST was performed for patients with active manifestations of GO in 6.9% of newly diagnosed GD patients. The risk factors for GO underwent AIIST were higher age, higher TBII, and TgAb negativity. The GO score based on these factors may be useful in managing GO.

Establishment of reference intervals for fT3, fT4, and TSH levels in Japanese children and adolescents.

The present study aimed to establish new reference intervals (RIs) for serum free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH) levels in Japanese children and adolescents aged 4 to 19 years. A total of 2,036 (1,611 girls, 425 boys) participants were included over a 17-year period; they all tested negative for antithyroid antibodies (TgAb, TPOAb) and were found to have no abnormalities on ultrasonography. RIs were determined by nonparametric methods. The results showed that serum fT3 was significantly higher in the 4-15-year-olds than in the 19-year-olds. The serum fT4 was significantly higher in the 4-10-year-olds than in the 19-year-olds. The serum TSH was significantly higher in the 4-12-year-olds than in the 19-year-olds. All of them gradually decreased with age to approximate the adult levels. The upper limit of TSH was lower in those aged 13 to 19 years than in adults. The differences were examined by sex. The serum fT3 was significantly higher in boys than in girls between the ages of 11 and 19 years. The serum fT4 was significantly higher in boys than in girls between the ages of 16 and 19 years. There did not seem to be any sex difference in those under 10 years of age. In conclusion, serum fT3, fT4, and TSH levels in children and adolescents differ from those in adults. It is important to evaluate thyroid function using the new RIs that are appropriate for chronological age.

Radioiodine uptake after monotherapy with potassium iodide in patients with Graves' disease.

The effect of potassium iodide (KI) on radioiodine uptake (RAIU) before radioisotope therapy in Graves' disease (GD) patients was investigated. A total of 82 patients who had been treated with KI monotherapy before 24-hour RAIU (24 h RAIU) were evaluated and 354 of those who had been treated with thiamazole (MMI) monotherapy were extracted from the 1,130 GD patients who were identified as having had appropriate iodine restriction based on urinary iodine excretion. Urinary iodine excretion (UIE) <200 µg/day was confirmed in all subjects. Propensity score-matching was performed to identify the difference in 24 h RAIU between the KI group and the MMI group. In addition, multiple regression analysis was performed to evaluate related to 24 h RAIU. Propensity score-matching resulted in 57 matched patients in each group. After matching, 24 h RAIU was still significantly lower in the KI group than in the MMI group (median 53% (interquartile range 47-61%) vs. 63% (56-66%); p = 0.001). In addition, KI monotherapy was weakly negatively correlated with 24 h RAIU, whereas the female sex and FT3 were very weakly positively correlated on multiple regression analysis. The results suggest that KI monotherapy likely suppressed 24 h RAIU more than MMI monotherapy in GD patients with appropriate iodine restriction, given the difference in the mechanism of hormone suppression.

Incidence of and Risk Factors for Neonatal Hypothyroidism Among Women with Graves' Disease Treated with Antithyroid Drugs Until Delivery.

Background: The incidence of neonatal hypothyroidism among newborns born to mothers with Graves' disease (GD) who continued antithyroid drug (ATD) treatment until delivery has never been reported. Objective: Our primary objective was to investigate the incidence of neonatal hypothyroidism among newborns born to mothers with GD who were treated with ATD until delivery. Our secondary objective was to identify the cutoff ATD daily doses for neonatal hypothyroidism risk, based on maternal thyrotropin (TSH) receptor antibody (TRAb) levels. Methods: We conducted a retrospective cohort study. We included 305 pregnant women with GD who were treated with an ATD until delivery (63 treated with methimazole [MMI] and 242 treated with propylthiouracil [PTU]). Umbilical cord TSH, free thyroxine (fT4), and TRAb levels were measured at delivery, and we investigated the respective relationships between neonatal hypothyroidism at delivery and maternal fT4 levels, TRAb levels, and daily ATD doses during pregnancy. Neonatal hypothyroidism was diagnosed when the umbilical cord fT4 level was below the lower limit of the reference range. Results: The incidence of neonatal hypothyroidism at delivery was 19.0% ([confidence interval, CI, 11.2-30.4]; 12/63) in the MMI group and 12.8% ([CI, 9.2-17.6]; 31/242) in the PTU group. Neonatal goiter was observed in one neonate in the PTU group, and two infants in the PTU group required levothyroxine treatment. The daily ATD dose in the third trimester was the strongest predictor of neonatal hypothyroidism at delivery; the cutoff MMI dose was 10 mg/day, and the cutoff PTU dose was 150 mg/day. When the maternal TRAb level in the third trimester was above three times the upper limit of the normal range, the cutoff MMI dose was 20 mg/day, and the cutoff PTU dose was 150 mg/day. Conclusions: Maternal fT4 and TRAb levels were higher in the neonatal hypothyroid group, which suggested prolonged GD activity. Careful follow-up is necessary when maternal GD remains active and the ATD dose to control maternal thyrotoxicosis cannot be reduced.

Diagnosis and Treatment Course of Insulinoma Presenting as Hypoglycemia Unawareness Using a Factory-Calibrated Continuous Glucose Monitoring System.

BACKGROUND Insulinoma presenting only with postprandial hypoglycemia is difficult to diagnose. Repeated episodes of hypoglycemia can lead to "hypoglycemia unawareness", which can be even more dangerous and requires early detection and treatment. CASE REPORT We report the case of a 35-year-old man with an insulinoma presenting as postprandial hypoglycemia who was treated with diazoxide and monitored using a factory-calibrated continuous glucose monitoring (CGM) system until surgery. When the patient initially presented with hypoglycemia, relative hyperinsulinemia was present. There were no obvious abnormal findings on imaging examination. Hypoglycemia was not repeated on endocrinological examination, even while fasting. Four months later, asymptomatic postprandial hypoglycemia of 48 mg/dL was incidentally detected. Although none of the conventional 3 indicators of relative hyperinsulinemia were met, an insulinoma was suspected based on the results of a fasting test. Computed tomography and magnetic resonance imaging showed a mass in the pancreatic uncinate process, and selective intra-arterial calcium infusion revealed high insulin levels in the same area, leading to a diagnosis of insulinoma. The patient was treated medically with diazoxide, using a factory-calibrated CGM system until surgery. Subsequently, pancreatic mass enucleation was performed, and pathological examination confirmed the diagnosis. After surgery, the hypoglycemia resolved, and the blood glucose level remained within a range of 100 to 180 mg/dL, without the use of diazoxide. CONCLUSIONS A factory-calibrated CGM system is useful for evaluating the course of medical treatment, monitoring hypoglycemic episodes during the diagnostic period, detecting unconscious hypoglycemia, monitoring the response to medical treatment, and treating insulinoma after surgery.

eHealth Delivery of Educational Content Using Selected Visual Methods to Improve Health Literacy on Lifestyle-Related Diseases: Literature Review.

BACKGROUND: Lifestyle-related diseases, such as stroke, heart disease, and diabetes, are examples of noncommunicable diseases. Noncommunicable diseases are now the leading cause of death in the world, and their major causes are lifestyle related. The number of eHealth interventions is increasing, which is expected to improve individuals' health literacy on lifestyle-related diseases. OBJECTIVE: This literature review aims to identify existing literature published in the past decade on eHealth interventions aimed at improving health literacy on lifestyle-related diseases among the general population using selected visual methods, such as educational videos, films, and movies. METHODS: A systematic literature search of the PubMed database was conducted in April 2019 for papers written in English and published from April 2, 2009, through April 2, 2019. A total of 538 papers were identified and screened in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram. Finally, 23 papers were included in this review. RESULTS: The 23 papers were characterized according to study characteristics (author and year of publication, study design and region where the study was conducted, study objective, service platform, target disease and participant age, research period, outcomes, and research method); the playback time of the educational videos, films, and movies; and the evaluation of the study's impacts on health literacy. A total of 7 studies compared results using statistical methods. Of these, 5 studies reported significant positive effects of the intervention on health literacy and health-related measures (eg, physical activity, body weight). Although most of the studies included educational content aimed at improving health literacy, only 7 studies measured health literacy. In addition, only 5 studies assessed literacy using health literacy measurement tools. CONCLUSIONS: This review found that the provision of educational content was satisfactory in most eHealth studies using selected visual methods, such as videos, films, and movies. These findings suggest that eHealth interventions influence people's health behaviors and that the need for this intervention is expected to increase. Despite the need to develop eHealth interventions, standardized measurement tools to evaluate health literacy are lacking. Further research is required to clarify acceptable health literacy measurements.

Using mHealth to Provide Mobile App Users With Visualization of Health Checkup Data and Educational Videos on Lifestyle-Related Diseases: Methodological Framework for Content Development.

BACKGROUND: The number of people with lifestyle-related diseases continues to increase worldwide. Improving lifestyle behavior with health literacy may be the key to address lifestyle-related diseases. The delivery of educational videos using mobile health (mHealth) services can replace the conventional way of educating individuals, and visualization can replace the provision of health checkup data. OBJECTIVE: This paper aimed to describe the development of educational content for MIRAMED, a mobile app aimed at improving users' lifestyle behaviors and health literacy for lifestyle-related diseases. METHODS: All videos were based on a single unified framework to provide users with a consistent flow of information. The framework was later turned into a storyboard. The final video contents were created based on this storyboard and further discussions with leading experts and specialist physicians on effective communication with app users about lifestyle-related diseases. RESULTS: The app uses visualization of personal health checkup data and educational videos on lifestyle-related diseases based on the current health guidelines, scientific evidence, and expert opinions of leading specialist physicians in the respective fields. A total of 8 videos were created for specific lifestyle-related diseases affecting 8 organs: (1) brain-cerebrovascular disorder, (2) eyes-diabetic retinopathy, (3) lungs-chronic obstructive pulmonary disease, (4) heart-ischemic heart disease, (5) liver-fatty liver, (6) kidneys-chronic kidney disease (diabetic kidney disease), (7) blood vessels-peripheral arterial disease, and (8) nerves-diabetic neuropathy. CONCLUSIONS: Providing enhanced mHealth education using novel digital technologies to visualize conventional health checkup data and lifestyle-related diseases is an innovative strategy. Future studies to evaluate the efficacy of the developed content are planned.

The association of repeatedly measured low-density lipoprotein cholesterol and all-cause mortality and cardiovascular disease in dyslipidemic patients: A longitudinal study.

BACKGROUND AND AIMS: This study aimed to evaluate the association between very low levels of low-density lipoprotein (LDL) cholesterol and subsequent clinical outcomes among dyslipidemic patients. METHODS: A retrospective longitudinal study was conducted at a large teaching hospital in Tokyo, Japan, from 2005 to 2018. We included all dyslipidemic adult patients who were followed up at the department of endocrinology. The primary outcome was all-cause mortality and the secondary outcome was cardiovascular disease. We compared the development of these outcomes according to LDL cholesterol categories through longitudinal analyses adjusting for potential confounders. RESULTS: We included total of 4485 dyslipidemic patients. The mean patient age (standard deviation) was 58.4 (12.2) years, and 2286 patients were men. During a median follow-up of 5.3 (interquartile range 2.2-9.6) years, 252 (5.7%) patients died (25[0.6%] were cardiovascular deaths) and 912 (20.3%) patients developed cardiovascular diseases. Multivariable longitudinal analyses showed that the very low LDL cholesterol group (<60 mg/dl) had significantly higher all-cause mortality than the normal LDL cholesterol group (100-140 mg/dl) (odds ratio[OR] 1.96, 95%confidence interval [CI]:1.22-3.16). Among high-risk patients for atherosclerotic cardiovascular disease (ASCVD), very low LDL cholesterol was significantly associated with increased all-cause mortality (OR 2.61, 95%CI: 1.12-6.10) but decreased incidence of cardiovascular disease (OR 0.47, 95%CI: 0.23-0.93). CONCLUSIONS: Very low LDL cholesterol is associated with increased all-cause mortality but not statistically associated with cardiovascular disease incidence among dyslipidemic patients, regardless of risk. When patients were stratified according to ASCVD risk, this association was more obvious among high-risk patients.

Development of malignancies and changes in time-dependent hemoglobin A1c among a nondiabetic population: longitudinal analysis.

BACKGROUND: The fluctuation of hemoglobin A1c (HbA1c) and changes in health habits over time was not considered in previous studies. The aim of this study was to evaluate the time-sequenced association between malignancy incidence and HbA1c with a longitudinal study design using repeated measurements of HbA1c. METHODS: A retrospective longitudinal study was conducted at a large teaching hospital in Tokyo, Japan, from 2005 to 2016. All participants who underwent voluntary health check-ups at the hospital were included. Our outcomes were the development of malignancy. We compared these outcomes using HbA1c categories. Longitudinal analyses were conducted with a mixed effects model in which time-dependent HbA1c measurements were applied to consider fluctuations in HbA1c levels, adjusted for covariates. RESULTS: A total of 77,385 nondiabetic participants were included in the study; the mean age was 44.7 and 49.4% of participants were male. During a median follow-up of 1588 (interquartile range 730-2946) days, 4506 (5.8%) participants developed malignancies. The relationship between future malignancies and HbA1c was U-shaped; both the lower HbA1c groups (OR 1.31, 95% CI 1.17-1.46 for < 5.0%) and the higher HbA1c group (OR 1.87, 95% CI 1.03-3.39 for ≥ 7.5%) had significantly higher odds ratios compared to the 5.5-5.9%. The lowest HbA1c was associated with higher odds of breast cancer (OR 1.5, 95% CI 1.21-1.86) and female genital cancer (OR 1.57, 95% CI 1.04-2.37). CONCLUSIONS: Our study found a U-shaped association between HbA1c and future malignancies among nondiabetic people but did not find additional risk at the prediabetic level. Low HbA1c may be associated with the incidence of breast cancer and female genital cancer.

Acquired hemophilia associated with autoimmune bullous diseases: a report of two cases and a review of the literature.

Acquired hemophilia (AHA) is a relatively rare and life-threatening disease caused by autoantibodies against factor VIII. Autoimmune bullous diseases (ABD) are also caused by autoantibodies against specific skin proteins. We herein report two cases of AHA associated with ABD. These coincidences are extremely rare, and only 14 documented cases have been reported previously. We further analyzed the properties of the autoantibodies in our patients. The epitopes were the A2 domain in patient 1, and both the A2 domain and the light chain in patient 2. Their isoforms were predominantly IgG4. Cross-reactivity could not be demonstrated. An accumulation of cases is required to unveil the pathogenesis of AHA.