Deciphering metabolic dysfunction-associated steatotic liver disease: insights from predictive modeling and clustering analysis.

BACKGROUND AND AIM: New nomenclature of steatotic liver disease (SLD) including metabolic dysfunction-associated SLD (MASLD), MASLD and increased alcohol intake (MetALD), and alcohol-associated liver disease (ALD) has recently been proposed. We investigated clustering analyses to decipher the complex landscape of SLD pathologies including the former nomenclature of nonalcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD). METHODS: Japanese individuals who received annual health checkups including abdominal ultrasonography (n = 15 788, men/women: 10 250/5538, mean age: 49 years) were recruited. RESULTS: The numbers of individuals with SLD, MASLD, MetALD, ALD, NAFLD, and MAFLD were 5603 (35.5%), 4227 (26.8%), 795 (5.0%), 324 (2.1%), 3982 (25.8%), and 4946 (31.3%), respectively. Clustering analyses using t-distributed stochastic neighbor embedding and K-means to visually represent interconnections in SLDs uncovered five cluster formations. MASLD and NAFLD mainly shared three clusters including (i) low alcohol intake with relatively low-grade obesity; (ii) obesity with dyslipidemia; and (iii) dysfunction of glucose metabolism. Both MetALD and ALD displayed one distinct cluster intertwined with alcohol consumption. MAFLD widely shared all of the five clusters. In machine learning-based analyses using algorithms of random forest and extreme gradient boosting and receiver operating characteristic curve analyses, fatty liver index (FLI), calculated by body mass index, waist circumference, and levels of γ-glutamyl transferase and triglycerides, was selected as a useful feature for SLDs. CONCLUSIONS: The new nomenclature of SLDs is useful for obtaining a better understanding of liver pathologies and for providing valuable insights into predictive factors and the dynamic interplay of diseases. FLI may be a noninvasive predictive marker for detection of SLDs.

[False-Positive ¹²³I-Metaiodobenzylguanidine Scan in a Patient with Adrenocortical Cancer].

A 59-year-old woman presented with a left adrenal tumor 4 cm in diameter. The ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy showed apparent accumulation in the left adrenal tumor. However, the patient had no sign or symptoms suggesting pheochromocytoma. No biochemical evidence of catecholamine excess was noticed. Computed tomography (CT) revealed relatively strong enhancement in the arterial phase, which persisted until the portal phase. The computed tomography (CT) and magnetic resonance imaging showed 2 liver nodule suspected to be metastatic tumors. No ¹²³I-MIBG accumulation was seen in these nodules. CT also showed thyroid nodules with calcification, which suggested papillary thyroid cancer. Based on the findings, open left adrenalectomy, partial hepatectomy and segmentectomy were performed under the clinical diagnosis of pheochromocytoma and metastatic liver tumors. Histopathological diagnosis was adrenocortical cancer. There was only lymphocyte infiltration in the liver nodules. Postoperative recovery was uneventful, and the patient underwent partial thyroidectomy 6 months later. The pathological diagnosis was papillary thyroid cancer. She has been without recurrence or metastases for 18 months after adrenalectomy. We found only 6 cases of MIBG scintigraphy-positive adrenocortical cancer in the literature. The mechanisms for MIBG uptake in adrenocortical cancer are discussed with a review of the literature.

[Two Cases of Penoscrotal Strangulation].

Case 1 (42-year-old man) : The patient was examined for penoscrotal swelling that had continued for 1 month. An annular erosive skin ulcer was observed at the penoscrotal base, with distal swelling. Asking the patient about the history of his condition was difficult due to a history of mental illness. We suspected his symptoms were due to an embedded foreign object. As computed tomography indicated the presence of a subcutaneous foreign object, surgery was performed to remove it. A rubber band was found wrapped twice around the area. After releasing the strangulation, penoscrotal swelling improved. Case 2 (72-year-old man) : Penoscrotal swelling appeared after having an automobile tow hook attached to the penoscrotal base for 2 weeks. The patient was examined at the emergency room because he could not remove it on his own. A rescue squad was called, and they cut the strangulating object with an electric saw. After releasing the strangulation, penoscrotal swelling improved. Although we experienced 2 cases of penoscrotal strangulation involving strangulating objects with different characteristics, improvement was achieved in both by releasing the strangulation. The cases of penoscrotal strangulation reported in Japan with known strangulation type are reviewed.

Concerted Catalysis by Adjacent Palladium and Gold in Alloy Nanoparticles for the Versatile and Practical [2+2+2] Cycloaddition of Alkynes.

A Pd-Au alloy efficiently catalyzed the [2+2+2] cycloaddition of substituted alkynes. Whereas monometallic Pd and Au catalysts were totally ineffective, Pd-Au alloy nanoparticle catalysts with a low Pd/Au molar ratio showed high activity to give the corresponding polysubstituted arenes in high yields. A variety of substituted alkynes participated in various modes of cycloaddition under Pd-Au alloy catalysis. The Pd-Au alloy catalysts exhibited high air tolerance and reusability.

Calculated Small Dense Low-Density Lipoprotein Cholesterol Level is A Predominant Predictor for New Onset of Ischemic Heart Disease.

AIM: A high level of directly measured small dense low-density lipoprotein cholesterol (sdLDL-C) is a strong risk factor for ischemic heart disease (IHD). However, it remains unclear whether estimated sdLDL-C level is a predictor for IHD. We investigated the associations of new onset of IHD with levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides (TG), LDL-C and calculated sdLDL-C by Sampson's equation. METHODS: After exclusion of subjects with IHD or those with TG ≥ 800 mg/dL, a total of 18,176 subjects (men/women: 11,712/6,464, mean age: 46 years) were recruited among 28,990 Japanese individuals who received annual health checkups. RESULTS: During the 10-year follow-up period, 456 men (3.9%) and 121 women (1.9%) newly developed IHD. Multivariable Cox proportional hazard analyses after adjustment of age, sex, obesity, smoking habit, family history of IHD, estimated glomerular filtration rate, hypertension and diabetes mellitus at baseline showed that the hazard ratio (HR) (1.38 [95% confidence interval: 1.03-1.85]) for new onset of IHD in subjects with the 4th quartile (Q4) of sdLDL-C (≥ 42 mg/dL) was significantly higher than that in subjects with the 1st quartile (Q1) (≤ 24 mg/dL) as the reference, though the adjusted HRs in subjects with Q2-Q4 of TC, HDL-C, non-HDL-C, LDL-C and TG were comparable with those in subjects with Q1 of the respective lipid fractions. The adjusted HR with a restricted cubic spline increased with a higher level of calculated sdLDL-C as a continuous value at baseline. CONCLUSIONS: sdLDL-C level calculated by Sampson's equation is a predominant predictor for the development of IHD in a general Japanese population.

A high level of thyroid-stimulating hormone is a risk factor for the development of chronic kidney disease in men: a 10-year cohort study.

Hypothyroidism has been reported to be associated with chronic kidney disease (CKD). However, the impact of thyroid-stimulating hormone (TSH) on new onset of CKD and its gender dependence remain undetermined. We investigated the association of serum TSH level and the development of CKD defined by estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or positive for urine protein in 28,990 Japanese subjects who received annual health examinations. After excluding subjects with no data for serum TSH, urinalysis and eGFR and those with CKD at baseline, a total of 10,392 subjects (men/women: 6802/3590, mean age: 48 years) were recruited. During a 10-year follow-up, 1185 men (6.7%) and 578 women (2.9%) newly developed CKD. Multivariable Cox proportional hazard models after adjustment of age, body mass index, smoking habit, hypertension, diabetes mellitus, dyslipidemia, ischemic heart disease and eGFR (≥ 90 mL/min/1.73 m2) showed that the hazard ratio (HR) for the development of CKD in the high TSH (> 4.2 mU/L) group was significantly higher than that in the low TSH (≤ 4.2 mU/L) group in men (HR [95% confidence interval]: 1.41 [1.09-1.83]) but not in women (1.08 [0.77-1.51]). There was a significant interaction between sex and the category of TSH level for the development of CKD (p = 0.02). The adjusted HR with a restricted cubic spline increased with a higher level of TSH in men but not in women. In conclusion, a high level of TSH is associated with an increased risk for the development of CKD in men but not in women.

Tirzepatide ameliorates eating behaviors regardless of prior exposure to glucagon-like peptide receptor agonists in Japanese patients with type 2 diabetes mellitus.

AIMS: To investigate effects of tirzepatide, a dual receptor agonist for glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1), on eating behaviors. METHODS: Eating behaviors were evaluated by using a validated questionnaire survey in 33 Japanese patients with type 2 diabetes mellitus (T2DM) (mean age: 51.8 years) who were treated with tirzepatide (2.5 mg/week for 4 weeks and then 5.0 mg/week) for 6 months (M). RESULTS: Treatment with tirzepatide significantly decreased median hemoglobin A1c (HbA1c) (baseline/3 M/6 M: 7.3 %/6.0 %/5.8 %), mean body weight (BW) (baseline/3 M/6 M: 87.7 kg/82.0 kg/79.6 kg) and mean relative score of eating behaviors (baseline/3 M/6 M: 57.0/50.7/45.9). In the GLP-1 receptor agonist (GLP-1RA) naïve group (n = 20, men/women: 13/7), HbA1c and BW were continuously decreased up to 6 M. Changes in eating behaviors were mainly observed in the first 3 M. In the GLP-1RA non-naïve group (n = 13, men/women: 8/5), reductions in HbA1c and BW were predominant in the first 3 M, and changes in eating behaviors were observed up to 6 M. There were no significant correlations of changes in scores of eating behaviors with changes in glycemic control or those in BW. CONCLUSIONS: Tirzepatide ameliorates eating behaviors as well as glycemic management and obesity in Japanese patients with T2DM, and the patterns of improvement are partially dependent on prior exposure to GLP-1RAs.

Validation of Estimated Small Dense Low-Density Lipoprotein Cholesterol Concentration in a Japanese General Population.

AIM: A high level of directly measured small dense low-density lipoprotein cholesterol (sdLDL-C) is a strong risk factor for atherosclerotic cardiovascular disease. A method for estimating sdLDL-C by using Sampson's equation that includes levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), non-HDL-C and triglycerides (TG) has recently been proposed. We investigated the validation and exploration of estimated sdLDL-C level. METHODS: The associations between measured and estimated sdLDL-C levels were investigated in 605 Japanese subjects (men/women: 280/325; mean age: 65±15 years) who received annual health check-ups in the Tanno-Sobetsu Study, a population-based cohort. RESULTS: Estimated sdLDL-C level was highly correlated with measured sdLDL-C level in all subjects (R2=0.701), nondiabetic subjects without any medication (n=254, R2=0.686) and subjects with diabetes mellitus (n=128, R2=0.721). Multivariable regression analysis showed that levels of non-HDL-C, TG and γ-glutamyl transpeptidase (γGTP) were independent predictors of measured sdLDL-C level. In a stratification of the LDL window, all of the subjects with a combination of high non-HDL-C (≥ 170 mg/dL) and high TG (≥ 150 mg/dL) had high levels of measured and estimated sdLDL-C (≥ 35 mg/dL). Furthermore, machine learning-based estimation of sdLDL-C level by artificial intelligence software, Prediction One, was substantially improved by using components of Sampson's equation (R2=0.803) and by using those components with the addition of γGTP and deletion of TC (R2=0.929). CONCLUSIONS: sdLDL-C level estimated by Sampson's equation can be used instead of measured sdLDL-C level in general practice. By building multiple machine learning models of artificial intelligence, a more accurate and practical estimation of sdLDL-C level might be possible.

Metabolic dysfunction-associated fatty liver disease is associated with an increase in systolic blood pressure over time: linear mixed-effects model analyses.

Metabolic dysfunction-associated fatty liver disease (MAFLD), a new feature of fatty liver (FL) disease that is defined as FL with overweight/obesity, type 2 diabetes mellitus or metabolic dysregulation, has been reported to be associated with the development of diabetes mellitus, chronic kidney disease and cardiovascular disease. However, the association between MAFLD and hypertension remains unclear. We investigated the association between MAFLD and systolic blood pressure (SBP) over a 10-year period in 28,990 Japanese subjects who received annual health examinations. After exclusion of subjects without data for SBP and abdominal ultrasonography at baseline, a total of 17,021 subjects (men/women: 10,973/6048; mean age: 49 years) were recruited. Linear mixed-effects model analyses using diagnoses of FL, nonalcoholic fatty liver disease (NAFLD) or MAFLD and age, sex, SBP, use of anti-hypertensive drugs, levels of uric acid and estimated glomerular filtration rate, family history of hypertension and habits of current smoking and alcohol drinking at baseline as well as the duration of the observation period and the interaction between each covariate and the duration of the observation period showed that the significant association of change in SBP over time with diagnosis of MAFLD (estimate: 0.223 mmHg/year, P < 0.001) was greater than that with diagnoses of FL (estimate: 0.196 mmHg/year, P < 0.001) and NAFLD (estimate: 0.203 mmHg/year, P < 0.001). Furthermore, the rate of increase in SBP over time was higher in subjects with MAFLD than in subjects without FL and subjects with FL who had no MAFLD. In conclusion, MAFLD is significantly associated with an increase in SBP over time. The presence of metabolic dysfunction-associated fatty liver disease (MAFLD) is significantly associated with an increase in systolic blood pressure over time.

3D culture induction of adipogenic differentiation in 3T3-L1 preadipocytes exhibits adipocyte-specific molecular expression patterns and metabolic functions.

Adipose tissues are closely related to physiological functions and pathological conditions in most organs. Although differentiated 3T3-L1 preadipocytes have been used for in vitro adipose studies, the difference in cellular characteristics of adipogenic differentiation in two-dimensional (2D) culture and three-dimensional (3D) culture remain unclear. In this study, we evaluated gene expression patterns using RNA sequencing and metabolic functions using an extracellular flux analyzer in 3T3-L1 preadipocytes with and without adipogenic induction in 2D culture and 3D culture. In 2D culture, 565 up-regulated genes and 391 down-regulated genes were identified as differentially expressed genes (DEGs) by adipogenic induction of 3T3-L1 preadipocytes, whereas only 69 up-regulated genes and 59 down-regulated genes were identified as DEGs in 3D culture. Ingenuity Pathway Analysis (IPA) revealed that genes associated with lipid metabolism were identified as 2 out of the top 3 causal networks related to diseases and function in 3D spheroids, whereas only one network related to lipid metabolism was identified within the top 9 of these causal networks in the 2D planar cells, suggesting that adipogenic induction in the 3D culture condition exhibits a more adipocyte-specific gene expression pattern in 3T3-L1 preadipocytes. Real-time metabolic analysis revealed that the metabolic capacity shifted from glycolysis to mitochondrial respiration in differentiated 3T3-L1 cells in the 3D culture condition but not in those in the 2D cultured condition, suggesting that adipogenic differentiation in 3D culture induces a metabolic phenotype of well-differentiated adipocytes. Consistently, expression levels of mitochondria-encoded genes including mt-Nd6, mt-Cytb, and mt-Co1 were significantly increased by adipogenic induction of 3T3-L1 preadipocytes in 3D culture compared with those in 2D culture. Taken together, the findings suggest that induction of adipogenesis in 3D culture provides a more adipocyte-specific gene expression pattern and enhances mitochondrial respiration, resulting in more adipocyte-like cellular properties.

An increase in calculated small dense low-density lipoprotein cholesterol predicts new onset of hypertension in a Japanese cohort.

A disorder of lipid metabolism is involved in cardiovascular diseases including hypertension. A high level of small dense low-density lipoprotein cholesterol (sdLDL-C) is a strong risk factor for atherosclerotic cardiovascular disease. However, the association between sdLDL-C and hypertension has not been fully investigated. We investigated the associations between the development of hypertension during a 10-year period and levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides (TG), and LDL-C and sdLDL-C calculated by using the Sampson equations in 28,990 Japanese subjects who received annual health examinations. After exclusion of subjects with missing data, those with hypertension, and those with TG ≥ 800 mg/dL at baseline, a total of 15,177 subjects (men/women: 9374/5803, mean age: 46 years) were recruited. During the 10-year period, 2379 men (25.4%) and 724 women (12.5%) had new onset of hypertension. Multivariable Cox proportional hazard model analyses showed that levels of HDL-C, non-HDL-C, TG and sdLDL-C, but not levels of TC and LDL-C, were independent risk factors for the development of hypertension after adjustment of age, sex, family history of hypertension, systolic blood pressure, obesity, current smoking habit, alcohol drinking habit, estimated glomerular filtration rate, diagnosis of diabetes mellitus and use of lipid-lowering drugs and that the adjusted risk of sdLDL-C (per 1-standard deviation) was highest (hazard ratio [95% confidence interval: 1.09 [1.05-1.13]). The addition of sdLDL-C to traditional risk factors for hypertension significantly improved the discriminatory capability, which was better than that of other lipid fractions. In conclusion, a high level of calculated sdLDL-C predicts the development of hypertension.

Coexistence of Metabolic Dysfunction-Associated Fatty Liver Disease and Chronic Kidney Disease Is a More Potent Risk Factor for Ischemic Heart Disease.

Background Metabolic dysfunction-associated fatty liver disease (MAFLD), defined as fatty liver with overweight/obesity, type 2 diabetes, or metabolic abnormalities, is a newly proposed disease. However, it remains unclear whether the coexistence of MAFLD and chronic kidney disease (CKD) is a more potent risk factor for ischemic heart disease (IHD). Methods and Results We investigated the risk of the combination of MAFLD and CKD for development of IHD during a 10-year follow-up period in 28 990 Japanese subjects who received annual health examinations. After exclusion of subjects without data for abdominal ultrasonography or with the presence of IHD at baseline, a total of 14 141 subjects (men/women: 9195/4946; mean age, 48 years) were recruited. During the 10-year period (mean, 6.9 years), 479 subjects (men/women, 397/82) had new onset of IHD. Kaplan-Meier survival curves showed significant differences in rates of the cumulative incidence of IHD in subjects with and those without MAFLD (n=4581) and CKD (n=990; stages 1/2/3/4-5, 198/398/375/19). Multivariable Cox proportional hazard model analyses showed that coexistence of MAFLD and CKD, but not MAFLD or CKD alone, was an independent predictor for development of IHD after adjustment for age, sex, current smoking habit, family history of IHD, overweight/obesity, diabetes, hypertension, and dyslipidemia (hazard ratio, 1.51 [95% CI, 1.02-2.22]). The addition of the combination of MAFLD and CKD to traditional risk factors for IHD significantly improved the discriminatory capability. Conclusions The coexistence of MAFLD and CKD predicts new onset of IHD better than does MAFLD or CKD alone.

Abdominal nonfunctional paraganglioma in which succinate dehydrogenase subunit B (SDHB) immunostaining was performed: a case report.

BACKGROUND: Abdominal nonfunctional paraganglioma is rare. Malignant potential of paraganglioma is assessed by Grading of Adrenal Pheochromocytoma and Paraganglioma score and genetic testing, but genetic testing is not common. We present a case of abdominal nonfunctional paraganglioma whose malignant potential was assessed by grading of adrenal pheochromocytoma and paraganglioma score and succinate dehydrogenase subunit B staining alternative to genetic testing. CASE PRESENTATION: A 39-year-old Japanese man had a right retroperitoneal tumor without symptoms. Uptake in the tumor was shown by 123I-meta-iodobenzylguanidine scintigraphy. There were no metastases. The results of biochemical workups including blood hormones and urinary metanephrines were normal. We performed retroperitoneoscopic surgery. The tumor was positive for chromogranin A staining but negative for tyrosine hydroxylase. On the basis of the preoperative biochemical workups and pathology results, we diagnosed the tumor as nonfunctional paraganglioma. The Grading of Adrenal Pheochromocytoma and Paraganglioma score classified the tumor as moderately differentiated. Furthermore, negative succinate dehydrogenase subunit B staining suggested the patient has the SDHx (SDHA, SDHB, SDHC and SDHD) mutation. CONCLUSION: Abdominal nonfunctional PGLs are associated with SDHB mutation, and SDHB staining should be performed as a screening.

Impact of the COVID-19 Pandemic on Glycemic Control and Blood Pressure Control in Patients with Diabetes in Japan.

Objective In this study, we investigated whether and how the COVID-19 pandemic affected glycemic control and blood pressure (BP) control in patients with diabetes mellitus (DM). Methods DM patients whose HbA1c level was measured regularly before and after the declaration of a state of emergency were included in this study. Some patients were given questionnaires about changes in their lifestyle to determine the factors affecting glycemic control and BP control. Results The median HbA1c level of the 804 patients increased significantly from 6.8% before the state of emergency to 7.1% and 7.0% during and after the state of emergency, respectively. This was in contrast to the decrease one year earlier due to seasonal variations. In the 176 patients who responded to the questionnaire, the HbA1c level also increased significantly during and after the state of emergency. The worsening of glycemic control was more pronounced in the group that had achieved HbA1c of <7% before the state of emergency than in those with higher values. Unlike the rise in HbA1c, the BP did not rise during the state of emergency but did rise significantly afterwards. There was no marked decrease in HbA1c or BP after the state of emergency, even in patients who responded that they were much more careful with their diet, ate less, or exercised more. Conclusions The COVID-19 pandemic worsened glycemic control and BP control, even in patients who perceived no marked change in their diet or exercise, suggesting that more active lifestyle guidance is necessary for good treatment of DM patients.

Characteristics of patients with emergency attendance for severe hypoglycemia and hyperglycemia in a general hospital in Japan.

ABSTRACT: Despite advances in treatments for diabetes mellitus (DM), severe acute glycemic crises still occur. In this study, the characteristics of patients who were transported to an emergency department due to acute glycemic crises were investigated.We enrolled patients who were transported to our hospital by ambulance due to hypoglycemia or hyperglycemia during the period from January 2015 to December 2019. Initial glucose levels below 70 mg/dL and above 250 mg/dL were defined as hypoglycemia and hyperglycemia, respectively.In the 5-year period, 16,910 patients were transported to our hospital by ambulance. Of those patients, 87 patients (0.51%) were diagnosed with hypoglycemia, 26 patients (0.15%) were diagnosed with hyperglycemia and 1 patient was diagnosed with lactic acidosis. Compared to patients with hypoglycemia, blood urea nitrogen, serum potassium and hemoglobin levels were higher in patients with hyperglycemia. Systolic blood pressure was lower and pulse rate was higher in patients with hyperglycemia, possibly reflecting dehydration in hyperglycemia. Patients with hyperglycemia were younger (63 vs 70 years old, median), more likely to be hospitalized (92.3% vs 23.0%) with poorer prognosis (23.1% vs 4.6%) than those with hypoglycemia. In 64 DM patients with hypoglycemia, 34 patients were treated with insulin and 24 patients were treated with sulfonylurea or glinide, and their medication was often inappropriate. Excessive alcohol intake and malnutrition were the main causes of hypoglycemia in 23 non-DM patients. The main reasons for hyperglycemia were interrupted treatment, forgetting insulin injection and infection.To avoid acute glycemic crises, optimization of anti-DM therapy and education of patients are needed.

Synthesis of orthorhombic Mo-V-Sb oxide species by assembly of pentagonal Mo6O21 polyoxometalate building blocks.

Mix and match: The pentagonal [Mo(6)O(21)](n-) polyoxomolybdate building block assembles with other sources of Mo, V, and Sb ions to form an orthorhombic Mo-V-Sb oxide. The first single-crystal X-ray analysis of an orthorhombic Mo-V-based oxide, a promising catalyst for light alkane selective oxidation known as the "M1 phase", revealed the structure of the compound.