A Case in Which HLA-DR4 is Involved in the Development of Complex Immune-Related Endocrinological Adverse Events following Combination Therapy with Nivolumab and Ipilimumab.

Immune checkpoint inhibitors (ICIs) have become a focal point in cancer immunotherapy, though their utilization is also linked to the occurrence of diverse immune-related adverse events (irAEs). Herein, we present details of a 42-year-old woman diagnosed with a malignant vaginal melanoma who underwent ICI therapy with the combination of nivolumab and ipilimumab. Approximately two months after initiating therapy, the patient manifested destructive thyroiditis and fulminant type 1 diabetes mellitus, thus necessitating intensive insulin therapy. Following the onset of adrenocorticotropic hormone deficiency, frequent hypoglycemic episodes prompted the initiation of replacement therapy with hydrocortisone. Human leukocyte antigen (HLA)-DNA typing revealed the presence of HLA-DRB1∗04 : 05 and DQB1∗04 : 01. HLA-DR4 has been suggested to be associated with the development of multiple endocrine irAEs. This is the first reported case of three endocrine irAEs occurring within a short period, in which the presence of HLA-DR4 may have contributed to the pathogenesis.

Prolonged Hypokalemia Following Metyrapone Treatment for Primary Bilateral Macronodular Adrenal Cortical Disease.

Surgical treatment is generally the standard therapeutic regimen used for primary bilateral macronodular adrenal cortical disease (PBMACD). However, in cases for which surgery is difficult or in which there is mild cortisol hypersecretion, metyrapone treatment can be selected. Although hypokalemia has been occasionally noted following metyrapone administration for Cushing syndrome associated with an adrenal adenoma, all such cases have been reported to be transient. Hypokalemia induced by metyrapone treatment is thought to occur due to excessive suppression of cortisol secretion, resulting in overproduction of adrenocorticotropic hormone from the pituitary gland, ultimately leading to excessive production of 11-deoxycorticosterone (DOC) in the adrenal cortex. A 52-year-old man diagnosed with PBMACD and started on metyrapone treatment subsequently presented with persistent hypokalemia. Interestingly, following initiation of metyrapone, blood test findings indicated marginal changes in serum cortisol, adrenocorticotropic hormone, and dehydroepiandrosterone sulfate levels, even when DOC levels were already markedly elevated. In addition to the effects of metyrapone, the present findings suggest a unique DOC synthesis regulatory mechanism involved in the pathogenesis of PBMACD.

Nocturnal Hypertension and Left Ventricular Diastolic Dysfunction in Patients With Diabetes With the Absence of Heart Failure: Prospective Cohort HSCAA Study.

BACKGROUND: Diabetes is an important risk factor for heart failure (HF) and is associated with left ventricular (LV) diastolic dysfunction. However, diabetic comorbid conditions, such as nocturnal hypertension, as predictors of diastolic dysfunction are not known in the absence of an HF period. The present study was conducted as the longitudinal examination of the predictive value of nocturnal hypertension profiles on the progression of LV diastolic dysfunction in patients with and without diabetes without HF. METHODS: The subjects (154 diabetes and 268 nondiabetes) in the absence of HF were followed for 36.8±18.2 months. The relationships among the patterns of nocturnal hypertension and the outcome of LV diastolic dysfunction, defined as an increase in E/e'>14, were investigated in the patients with and without diabetes. RESULTS: The interaction effect of the diabetes status and the patterns of nocturnal hypertension on the hazard rate of the occurrence of E/e'>14 was statistically significant (P=0.017). Kaplan-Meier analysis results revealed that patients with diabetes with nondipper (P=0.021 versus dipper) and riser (P=0.006 versus dipper) had a greater risk for a diastolic dysfunction event. Furthermore, multivariable Cox proportional hazards analysis revealed that nondipper (hazard ratio, 4.56 [95% CI, 1.49-13.96]; P=0.007) and riser (hazard ratio, 3.89 [95% CI, 1.31-11.57]; P=0.014) patterns were associated with elevated risk of the outcome of LV diastolic dysfunction. In contrast, no similar significant associations were found in patients without diabetes. CONCLUSIONS: During the absence of HF periods, nocturnal hypertension is an important predictor for the progression of LV diastolic dysfunction in patients with diabetes.

Excessive daytime napping independently associated with decreased insulin sensitivity in cross-sectional study - Hyogo Sleep Cardio-Autonomic Atherosclerosis cohort study.

Background: Although excessive daytime napping has been shown to be involved in diabetes occurrence, its impact on insulin secretion and sensitivity has not been elucidated. It is speculated that excessive napping disrupts the sleep-wake rhythm and increases sympathetic nerve activity during the day, resulting in decreased insulin sensitivity, which may be a mechanism leading to development of diabetes. We previously conducted a cross-sectional study that showed an association of autonomic dysfunction with decreased insulin sensitivity, though involvement of autonomic function in the association between napping and insulin sensitivity remained unclear. Furthermore, the effects of napping used to supplement to short nighttime sleep on insulin secretion and sensitivity are also unknown. In the present cross-sectional study, we examined the relationships of daytime nap duration and autonomic function with insulin secretion and sensitivity in 436 subjects enrolled in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA) Cohort Study who underwent a 75-g oral glucose tolerance test (75-g OGTT), after excluding those already diagnosed with diabetes. Methods: Daytime nap duration was objectively measured using actigraphy, with the subjects divided into the short (≤1 hour) and long (>1 hour) nap groups. Insulin secretion and sensitivity were determined using 75-g OGTT findings. Standard deviation of normal to normal R-R interval (SDNN), a measure of autonomic function, was also determined based on heart rate variability. Subgroup analysis was performed for the associations of napping with insulin secretion and sensitivity, with the results stratified by nighttime sleep duration of less or greater than six hours. Results: Subjects in the long nap group exhibited lower insulin sensitivity parameters (QUICKI: ß=-0.135, p<0.01; Matsuda index: ß=-0.119, p<0.05) independent of other clinical factors. In contrast, no associations with insulin secretion were found in either group. Furthermore, the association of long nap duration with insulin sensitivity was not confounded by SDNN. Specific subgroup analyses revealed more prominent associations of long nap habit with lower insulin sensitivity in subjects with a short nighttime sleep time (ß=-0.137, p<0.05). Conclusion: Long daytime nap duration may be a potential risk factor for decreased insulin sensitivity.

Sleep Apnea and Physical Movement During Sleep, But Not Sleep Duration, Are Independently Associated With Progression of Left Ventricular Diastolic Dysfunction: Prospective Hyogo Sleep Cardio-Autonomic Atherosclerosis Cohort Study.

Background Although co-occurrence of sleep disorder with heart failure is known, it is not clear whether that condition is a cause or consequence of heart failure. The present study was conducted as a longitudinal examination of the predictive value of sleep parameters on progression of left ventricular diastolic dysfunction. Methods and Results Four-hundred fifty-two subjects were followed for a mean of 34.7 months. An outcome of diastolic dysfunction was defined as increase in early inflow velocity/early diastolic tissue velocity >14. Sleep apnea-hypopnea index, minimal oxygen saturation, sleep duration, and activity index (physical movement during sleep time, a potential parameter of poor sleep quality) were determined using apnomonitor and actigraphy findings, while heart rate variability was measured with a 24-hour active tracer device. Sixty-six of the patients developed diastolic dysfunction during the follow-up period, with a median time of 25 months. Kaplan-Meier analysis results revealed that those with sleep apnea classified as moderate (apnea-hypopnea index 15 to <30, P<0.01 versus none) or severe (apnea-hypopnea index ≥30, P<0.01 versus none), and with a high activity index (Q3 or Q4, P<0.01 versus Q1), but not short sleep duration (P=0.27) had a significantly greater risk for a diastolic dysfunction event. Results of multivariable Cox proportional hazards regression analysis indicated that moderate to severe sleep apnea after a follow-up period of 3 years (hazard ratio [HR], 9.26 [95% CI, 1.89-45.26], P<0.01) and high activity index (HR, 1.85 [95% CI, 1.01-3.39], P=0.04) were significantly and independently associated with future diastolic dysfunction. Moreover, significant association of high activity index with the outcome was not confounded by either minimal oxygen saturation or heart rate variability. Conclusions Sleep apnea and physical movement during sleep, but not sleep duration and autonomic nervous dysfunction, are independent important predictors for progression of left ventricular diastolic dysfunction.

Xanthine oxidoreductase activity is correlated with hepatic steatosis.

The enzyme xanthine oxidoreductase (XOR) catalyzes the synthesis of uric acid (UA) from hypoxanthine and xanthine, which are products of purine metabolism starting from ribose-5-phosphate. Several studies suggested a relationship between hyperuricemia and hepatic steatosis; however, few previous studies have directly examined the relationship between XOR activity and hepatic steatosis. A total of 223 subjects with one or more cardiovascular risk factors were enrolled. The liver-to-spleen (L/S) ratio on computed tomography and the hepatic steatosis index (HSI) were used to assess hepatic steatosis. We used a newly developed highly sensitive assay based on [13C2, 15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry to measure plasma XOR activity. Subjects with the L/S ratio of < 1.1 and the HSI of < 36 had increased XOR activity and serum UA levels. Independent of insulin resistance and serum UA levels, multivariate logistic regression analysis revealed that plasma XOR activity was associated with the risk of hepatic steatosis as assessed by the L/S ratio and HSI. According to the findings of this study, plasma XOR activity is associated with hepatic steatosis independent of insulin resistance and serum UA levels.

Sleep quality, autonomic dysfunction and renal function in diabetic patients with pre-CKD phase.

Diabetes has been established as a strong risk factor for chronic kidney disease (CKD). Sleep apnea, poor sleep quality (PSQ), and autonomic imbalance are also considered to be potential risk factors for decline in renal function, though no known study has examined their integrated predictive value in diabetic and non-diabetic patients without CKD. The present cohort consisted of 754 serial patients (diabetes; n = 231, non-diabetes; n = 523) without CKD registered in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA) study. Patients underwent examinations to determine respiratory event index and objective sleep quality using actigraphy, as well as heart rate variability (HRV). Renal outcome was defined as a decline in estimated glomerular filtration rate to less than 60 ml/min/1.73 m2 for more than 3 months. Kaplan-Meier analysis showed that diabetic patients with PSQ or low HRV, but not sleep apnea, had a significantly increased risk for renal outcome. Furthermore, Cox proportional hazards analysis revealed that PSQ was significantly associated with elevated risk of renal outcome (HR: 2.57; 95% CI: 1.01-6.53, p = 0.045) independent of sleep apnea and classical risk factors. Low HRV tended to be, but not significantly (p = 0.065), associated with the outcome. In non-diabetic patients, PSQ was also significantly and independently associated with renal outcome, whereas sleep apnea and low HRV were not. In conclusion, PSQ and low HRV appear to be important predictors of decline in renal function in diabetic patients without CKD.

Associations of sleep quality, sleep apnea and autonomic function with insulin secretion and sensitivity: HSCAA study.

RATIONALE AND PURPOSE: Although sleep disorders are shown to be involved in occurrence of diabetes, impacts of several quantitative parameters related to sleep on insulin secretion and sensitivity is yet to be elucidated. We cross-sectionally examined relationships among quantitative sleep quality, sleep apnea, and autonomic function with insulin secretion and sensitivity in 399 patients without previous diagnosed diabetes who underwent 75-g oral glucose tolerance test (75gOGTT). METHOD: Poor sleep quality (PSQ) was defined as an activity index ≥50 by actigraphy. Sleep apnea was measured by apnomonitor, while standard deviation of all normal-to-normal R-R intervals (SDNN) was measured by active tracer. Parameters of insulin secretion and sensitivity were measured by 75gOGTT. RESULTS: Patients with PSQ exhibited significantly lower insulinogenic index (r = 0.155, p < 0.01), a parameter of insulin secretion, with the association independent of other clinical factors including apnea and SDNN (ß = -0.156, p < 0.01). In contrast, presence of sleep apnea (r = -0.143, p < 0.05) and the lower SDNN (r = -0.150, p < 0.01) were significantly and inversely associated with BIGTT-S, an insulin sensitivity parameter, with the association of SDNN with BIGTT-S remaining significant even after adjustments for PSQ and sleep apnea (ß = -0.111, p < 0.05). CONCLUSION: Poor sleep quality is an independent predictor of pancreatic ß-cell function, which could be involved in occurrence of type 2 diabetes.

Subclinical decrease in cardiac autonomic and diastolic function in patients with metabolic disorders: HSCAA study.

Heart failure due to decreased diastolic function, HFpEF, is a growing health concern with rising prevalence. We examined subclinical cardiac autonomic and diastolic functions in 605 patients with metabolic diseases classified as pre-heart failure. Presence of glucose intolerance or diabetes, or visceral adiposity was significantly associated with reduced cardiac autonomic and diastolic functions. Higher autonomic functions were significantly associated with a parameter of better cardiac diastolic function (E/A) (SDNN: r = 0.306, p < 0.01; HF: r = 0.341, p < 0.01), with the association independent of diabetes, body mass index, visceral adiposity and insulin resistance index. Thus, reduced autonomic function may be a potential predictor for decreased cardiac diastolic functions in metabolic disorders.

Hypokalemia associated with pseudo-Cushing's syndrome and magnesium deficiency induced by chronic alcohol abuse.

Hypokalemia and hypomagnesemia are frequently observed in patients with chronic alcoholism. However, the involvement of deranged cortisol regulation in patients with those conditions has not been reported. A 63-year-old Japanese male with chronic alcoholism was referred to the Department of Diabetes, Endocrinology and Metabolism for examination and treatment of hypokalemic periodic paralysis. Laboratory findings showed hypokalemia (2.3 mmol/l), as well as a high level of urinary excretion of potassium and hypomagnesemia (1.2 mg/dl), whereas urinary excretion of magnesium was undetectable. Potassium infusion treatment recovered that level in serum to 4.1 mmol/l, though it decreased to 2.2 mmol/l following discontinuation. A dexamethasone suppression test and urinary cortisol level showed corticotropin-dependent hypercortisolemia. However, gadolinium-enhanced MRI revealed no evidence of pituitary adenoma. The patient recovered from hypokalemia following an administration of magnesium in addition to potassium, which was accompanied by potassium over-excretion improvement. After being discharged, serum potassium level was maintained within a normal range with only magnesium infusion treatment. Furthermore, alcohol intake was reduced from 160 to 20 g/day and an endocrinological re-examination after that restriction showed normal cortisol regulation. The patient was diagnosed with pseudo-Cushing's syndrome induced by alcohol abuse. Serum potassium level was maintained within a normal range even after discontinuation of magnesium supplementation. Our findings in this case indicate that pseudo-Cushing's syndrome in conjunction with hypomagnesemia may be involved in development of hypokalemia in patients with chronic alcoholism.

Low sleep quality is associated with progression of arterial stiffness in patients with cardiovascular risk factors: HSCAA study.

BACKGROUND AND AIMS: Improvement in sleep quality is considered to be a viable target for prevention and treatment of cardiovascular diseases. To gain insight into its underlying mechanisms, we evaluated the significance of objectively measured sleep quality in patients with regard to progression of arterial stiffness over a 3-year follow-up period. METHODS: This prospective cohort study included 306 serial patients registered in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA) study. In addition to classical cardiovascular risk factors (body mass index, current smoking, past history of cardiovascular disease, dyslipidemia, diabetes mellitus), the participants were examined for ambulatory blood pressure (BP), apnea-hypopnea index (AHI), standard deviation of the NN (RR) interval (SDNN) for heart rate variability (HRV), and objective sleep quality using actigraphy findings. Brachial-ankle pulse wave velocity (baPWV) was measured at both baseline and follow-up (36.6 ±â€¯6.8 months) as a parameter of arterial stiffness. RESULTS: Increases in PWV (%) were greater (p = 0.03) in the low sleep quality (LSQ) group (5.75 ±â€¯1.15%) as compared to the normal sleep quality group (2.69 ±â€¯0.85%). Patients with the greatest increase (≥20%) from baseline exhibited a significantly (p < 0.05) larger percentage of LSQ (75% vs. 49.6%) as compared to those without PWV progression (<0%), with the association still significant (odds ratio 3.62, 95% confidence interval 1.04-12.55, p = 0.04) even after adjustment for other clinical risk factors. For all subjects, univariate logistic regression analyses showed that diabetes and LSQ were significantly associated with the greatest increase of PWV. Comparisons of characteristics among specific subgroups showed more prominent associations of LSQ with the greatest increase of PWV in patients with greater age, dyslipidemia, and higher AHI. CONCLUSIONS: LSQ was associated with progression of arterial stiffness over a 3-year period, independent of cardiovascular risk factors such as BP, AHI, and HRV.

Plasma brain-derived neurotrophic factor concentration is a predictor of chronic kidney disease in patients with cardiovascular risk factors - Hyogo Sleep Cardio-Autonomic Atherosclerosis study.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been shown to have protective effects against cardiovascular diseases and death through neural and non-neural pathways via tropomyosin-related kinase B signaling. However, it is not known whether plasma BDNF concentration is a predictor of chronic kidney disease (CKD). DESIGN: This study was conducted as a prospective cohort study as part of the Hyogo Sleep Cardio-Autonomic Atherosclerosis. METHODS: We measured plasma BDNF concentration in 324 patients without CKD, defined as an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73m2, and with cardiovascular risk factors. As potential confounders, sleep condition, nocturnal hypertension, and autonomic function were quantitatively examined. The patients were followed for a median 37 months (range 2-59 months) and occurrence of CKD was noted. RESULTS: Plasma BDNF concentration was significantly and independently associated with CKD development, which occurred in 38 patients (11.7%). Kaplan-Meier analysis revealed that patients with reduced plasma BDNF concentration exhibited a significantly (p = 0.029) greater number of CKD events as compared to those with a higher concentration. Moreover, comparisons of key subgroups showed that the risk of CKD in association with low plasma BDNF concentration was more prominent in patients with a greater reduction of nocturnal systolic blood pressure, better movement index, higher standard deviations of the NN(RR) interval or average NN(RR) interval for each 5-minute period, and without past cardiovascular disease events, smoking habit, or albuminuria. CONCLUSIONS: Plasma BDNF concentration is an independent predictor for development of CKD in patients with cardiovascular risk factors.

Nonpharmacological Management of Gout and Hyperuricemia: Hints for Better Lifestyle.

We reviewed lifestyle factors that influence serum uric acid levels and risk of gout flare, and how to improve their deleterious effects. Since obesity increases uric acid and weight gain increases gout risk, weight reduction by daily exercise and limiting intake of excess calories is recommended. However, strenuous exercise, which causes adenine nucleotide degradation; starvation, which decreases uric acid excretion; and dehydration may raise the level of uric acid in serum and trigger gout. Increased intake of purine-rich foods, such as meat and seafood, raise the level of uric acid in serum and is associated with increased risk of gout, whereas dairy products, especially low-fat types, are associated with a lower risk of gout. Also, heavy alcohol drinking raises the uric acid level and increases the risk of gout through adenine nucleotide degradation and lactate production. Sweet fruits and soft drinks containing fructose should be moderated, since fructose may raise uric acid and increase gout risk through uric acid production and/or decreased excretion. On the other hand, the Mediterranean diet is recommended for gout patients, since it may also help prevent hyperuricemia. Furthermore, coffee and vitamin C supplementation could be considered as preventive measures, as those can lower serum uric acid levels as well as the risk of gout.

Plasma leptin concentration is associated with fatigue severity in patients with cardiovascular risk factors - HSCAA study.

Fatigue induced by complex dysfunctions of the central nervous system is frequently complained by patients with cardiovascular risk factors. Although leptin is considered to regulate the central nervous system, there are no reports regarding its association with fatigue in those patients. This cross-sectional study included 347 patients with cardiovascular risk factors. Fatigue score and plasma leptin concentration were measured. In addition, abdominal fat accumulation, systemic inflammation, sleep condition, and functions of hypothalamus-pituitary axis and autonomic system were estimated. Plasma leptin concentration (natural logarithm transformed) was significantly and positively (r=0.222, p<0.001) associated with fatigue score, and significantly (p<0.001) higher in the moderately-fatigued group (2.32±0.75ng/ml, mean±SD, n=52) than in the normally-fatigued group (1.85±1.02ng/ml, mean±SD, n=295). Multiple logistic regression analysis showed that plasma leptin concentration was significantly and independently associated with a moderately-fatigued condition independent of other factors, including age, gender, presence of diabetes, hypertension, dyslipidemia, alcohol consumption habit, urinary free cortisol, serum high-sensitive CRP concentration, visceral and subcutaneous fat area, apnea/hypopnea index, sleep efficiency, and heart rate variability. Hyperleptinemia may contribute to fatigue severity in patients with cardiovascular risk factors.

Plasma leptin level is associated with cardiac autonomic dysfunction in patients with type 2 diabetes: HSCAA study.

BACKGROUND: It has been shown that visceral fat accumulation is associated with autonomic dysfunction, though the precise mechanism remains unclear. A recent basic study found that leptin can directly modulate autonomic function through the dorsomedial hypothalamus in relation to obesity. Here, we investigated the mutual relationships among plasma leptin, visceral fat accumulation, and cardiac autonomic dysfunction in patients with type 2 diabetes. METHODS: This cross-sectional study included 100 diabetic patients, and 100 age- and gender-matched non-diabetic patients with cardiovascular risk factors. Plasma leptin and soluble leptin receptor levels, visceral fat area (VFA), and heart rate variability (HRV) were determined in addition to classical cardiovascular risk factors. RESULTS: In the type 2 diabetic patients, VFA was significantly (p < 0.05) and inversely associated with HRV parameters (SDNN: r = -0.243; SDANN5: r = -0.238), while the plasma level of leptin, but not soluble leptin receptor, was also significantly (p < 0.05) and inversely associated with HRV parameters (SDNN: r = -0.243; SDANN5: r = -0.231). Multiple regression analysis showed that plasma leptin was significantly associated with SDNN and SDANN5 independent of other factors, including age, gender, presence of hypertension and dyslipidemia, duration of diabetes, HbA1c, and eGFR. Furthermore, the relationship of leptin with SDNN and SDANN5 (ß = -0.279 and -0.254, respectively) remained significant (p < 0.05) after adjustment for VFA. In patients without diabetes, no significant associations were observed between leptin and any of the HRV parameters. CONCLUSIONS: Hyperleptinemia may be involved in cardiac autonomic dysfunction in patients with type 2 diabetes and visceral obesity.

Sleep, cardiac autonomic function, and carotid atherosclerosis in patients with cardiovascular risks: HSCAA study.

OBJECTIVES: Behavioral and psychosocial factors have been gaining increased attention in regard to cardiovascular diseases. We evaluated sleep conditions, cardiac autonomic function, and carotid atherosclerosis in subjects who participated in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA) Study. METHODS: This cross-sectional study included 330 serial patients registered in the HSCAA study who were free from past cardiovascular diseases, and prescribing α- or ß-blockers. In addition to clinical background and classical cardiovascular risk factors, sleep efficiency, apnea hypopnea index (AHI), awake physical activity, heart rate variability (HRV), carotid intima-media thickness (IMT), presence of plaque and plaque score were determined. RESULTS: Sleep efficiency (r = -0.183) and all HRV parameters (SDNN: r = -0.202; rMSSD: r = -0.234; pNN50: r = -0.277) were significantly (p < 0.01) and negatively associated with IMT, while AHI (r = 0.220, p < 0.001) was positively associated with IMT. Similarly, sleep efficiency (r = -0.129), HRV parameters (SDNN: r = -0.170; rMSSD: r = -0.217; pNN50: r = -0.260) and AHI (r = 0.184) were also significantly (p < 0.05) associated with plaque scores. Multivariate logistic regression analyses showed that rMSSD, but not sleep efficiency or AHI, was significantly associated with carotid plaque (OR 0.74, 95% CI 0.56-0.98, p = 0.037), independent of classical risk factors. The association of rMSSD with carotid plaque remained significant even after adjustment for sleep efficiency or AHI. A comparison of risk factors in specific subgroups showed that the association of lower HRV with carotid plaque was more prominent in patients with cardiovascular risk factors including male gender, hypertension, dyslipidemia and diabetes mellitus. CONCLUSION: Cardiac autonomic nervous dysfunction was independently associated with carotid atherosclerosis, independent of sleep condition. Moreover, that association was more prominent in specific subgroups with cardiovascular risk factors.