Masahiro Sogabe

Background and Aim: Fibrosis determines the prognosis of metabolic dysfunction–associated steatotic liver disease (MASLD) and metabolic dysfunction and alcohol‐associated liver disease (MetALD). However, how changes in alcohol consumption affect fibrosis progression in MASLD and MetALD remains unclear. We aimed to evaluate the longitudinal association between changes in alcohol intake and fibrosis risk scores (FRS) in patients with MASLD and MetALD. Methods: In this retrospective observational cohort study, 2198 patients with MASLD and 644 with MetALD underwent three health check‐ups, each conducted at least 1 year apart. Associations between changes in alcohol intake and the worsening FRS were assessed using Cox proportional hazards models. Results: FRS were higher in patients with MetALD than in those with MASLD. Among men with MASLD, changes in alcohol intake were not associated with worsening FRS; however, women with MASLD who increased alcohol consumption experienced worsening FRS. In patients with MetALD, including men with MetALD consuming 280–419.9 g/week of alcohol, reducing alcohol intake was associated with a lower risk of worsening FRS than that in individuals who maintained the same consumption level. Conclusions: The influence of changes in alcohol intake on FRS varied by sex and disease type. Although fibrosis risk scores were more advanced in patients with MetALD than in those with MASLD, reducing alcohol consumption was associated with a lower risk of further worsening FRS in patients with MetALD. These findings highlight the importance of considering both sex and changes in alcohol consumption when evaluating fibrosis risk in patients with MASLD or MetALD.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer. Recent studies indicated that cancer‐associated adipocytes (CAAs) play crucial roles in tumor progression; however, the precise mechanism remains unknown. Here, we analyzed specific exosomal microRNAs (miRNA) signatures derived from pancreatic CAAs to investigate their role in cancer progression.Methods: CAAs were generated by co‐culturing human adipocytes with human pancreatic cancer cells, and exosomes were isolated from the CAA‐conditioned medium (CAA‐CM). Small RNA‐seq analysis was used to identify differentially expressed miRNAs in these exosomes. The effects of miRNAs on cell proliferation, migration/invasion, and drug sensitivity were examined. Luciferase reporter assays, real‐time polymerase chain reaction, and western blotting were performed to investigate the molecular mechanisms of the miRNAs. The clinical relevance of the miRNAs was investigated using publicly available data and our cohort of patients with PDAC.Results: miR‐199a‐3p expression was significantly increased in CAA‐CM‐derived exosomes. CAA‐derived exosomes transferred miR‐199a‐3p to pancreatic cancer cells. Transfection with miR‐199a‐3p increased the proliferation, invasion, migration, and drug resistance of pancreatic cancer cells by downregulating SOCS7, increasing STAT3 phosphorylation, and upregulating SAA1 expression. High tissue miR‐199a‐3p expression is correlated with poor prognosis in patients with PDAC. Liquid biopsies revealed that exosomal miR‐199a‐3p could accurately differentiate patients with PDAC from healthy controls. Multivariate survival analysis indicated that miR‐199a is an independent prognostic factor for PDAC.Conclusion: miR‐199a‐3p in CAA‐derived exosomes contributes to the malignant transformation of pancreatic cancer via the SOCS7/STAT3/SAA1 pathway, suggesting its potential as a biomarker and therapeutic target for PDAC.

Summary: Background: The relationships between alcohol consumption, cardiometabolic factors, and liver fibrosis in patients with metabolic dysfunction‐associated steatotic liver disease and those with metabolic dysfunction and alcohol‐associated liver disease remain unclear.Aims: To investigate the longitudinal associations among alcohol consumption, cardiometabolic factors, and liver fibrosis in patients with these two liver diseases.Methods: This observational cohort study included 1866 patients with metabolic dysfunction‐associated steatotic liver disease and 521 patients with metabolic dysfunction and alcohol‐associated liver disease who underwent > two health checkups over >2 years. The associations of both liver diseases with worsening non‐invasive liver fibrosis scores were assessed using the Cox regression analysis.Results: Both liver diseases independently worsened liver fibrosis in both sexes. However, the hazard ratio for worsening liver fibrosis in females was significantly higher with metabolic dysfunction and alcohol‐associated liver disease than with metabolic dysfunction‐associated steatotic liver disease. Worsening liver fibrosis was not associated with alcohol consumption. Among males with metabolic dysfunction‐associated steatotic liver disease, the hazard ratio for worsening liver fibrosis was significantly higher in those with multiple cardiometabolic factors compared to those with a single cardiometabolic factor.Conclusions: Although both metabolic steatotic liver disease and metabolic alcohol‐associated liver disease were correlated with liver fibrosis progression in both sexes, the impact of alcohol consumption and cardiometabolic factors on fibrosis progression differed by sex. Cardiometabolic factors may have a stronger impact on liver fibrosis than alcohol consumption in males with metabolic dysfunction‐associated steatotic liver disease.

Background: The influence of alcohol intake on metabolic dysfunction‐associated fatty liver disease (MAFLD) development and remission remains unclear; thus, we aimed to investigate their longitudinal associations.Methods: This observational cohort study included 6349 patients who underwent more than two health check‐ups over >2 years between April 2013 and March 2021. Generalized estimation equations were used to analyse the longitudinal associations between changes in alcohol intake and MAFLD according to repeated measures at baseline and the most recent stage.Results: The MAFLD development and remission rates were 20.4 and 5.1 and 9.1 and 4.7% in men and women, respectively. Although alcohol consumption was not a significant factor for MAFLD development, consuming 0.1–69.9 g/week (odds ratio [OR]: 0.672, 95% confidence interval [CI]: 0.469–0.964, p < .05) and ≥280 g/week were significant factors for MAFLD development in males (OR: 1.796, 95% CI: 1.009–3.196, p < .05) and females (OR: 16.74, 95% CI: 3.877–72.24, p < .001). Regardless of quantity and frequency, alcohol consumption was not a significant factor for MAFLD remission. Several noninvasive liver fibrosis scores were significantly associated with alcohol intake quantity and frequency in males with MAFLD development and remission (p < .05). The nonalcoholic fatty liver disease fibrosis score differed significantly between males with and without reduced alcohol intake (p < .05) who showed MAFLD remission.Conclusions: Although the influence of alcohol intake on MAFLD development and remission differed, alcohol consumption was not beneficial for MAFLD remission in either sex. Alcohol intake reduction or cessation is recommended to prevent liver fibrosis, even in those who achieve MAFLD remission.

Background and Aim: Although erosive esophagitis (EE) is associated with fatty liver and metabolic dysregulation, the association between EE and metabolic dysfunction‐associated steatotic liver disease (MASLD) remains unclear. Thus, this study aimed to investigate the longitudinal association between MASLD and EE.Methods: We included 1578 patients without EE at baseline who underwent more than two health checkups over 2 years. Generalized estimation equations were used to analyze associations between MASLD and EE according to repeated measures at baseline and most recent stages.Results: EE development rates in men and women were 14.5% and 7.2%, respectively. After adjusting for lifestyle habits, the odds ratios of MASLD for EE development in men and women were 1.907 (95% confidence interval [CI]: 1.289–2.832, P < 0.005) and 1.483 (95% CI: 0.783–2.811, P = 0.227), respectively. In the subgroup analysis, after adjusting for lifestyle habits, among men and women aged ≥50 years with more than three MASLD components, the odds ratios for EE development were 2.408 (95% CI: 1.505–3.855, P < 0.001) and 2.148 (95% CI: 1.093–4.221, P < 0.05), respectively. After adjusting for various factors, the significant risk factors for EE development were different between men and women.Conclusion: The influence of MASLD and other factors on EE development differed by sex and age. Particularly, patients aged ≥50 years with MASLD and with an increased number of MASLD components should be considered at increased risk for EE.

Background and Aim: The influence of metabolic dysfunction‐associated fatty liver disease on gallstone development remains unclear. We aimed to investigate the longitudinal association between metabolic dysfunction‐associated fatty liver disease and gallstone development in both men and women.Methods: This observational cohort study included 5398 patients without gallstones who underwent > 2 health check‐ups between April 1, 2014, and March 31, 2020. A generalized estimation equation model was used to analyze the association between metabolic dysfunction‐associated fatty liver disease and gallstone development according to repeated measures at baseline and most recent stage.Results: After adjustment, the odds ratios of metabolic dysfunction‐associated fatty liver disease for gallstone development in men and women were 3.019 (95% confidence interval [CI]: 1.901–4.794) and 2.201 (95% CI: 1.321–3.667), respectively. Among patients aged ≥ 50 years, the odds ratio for gallstone development was significantly enhanced with increasing metabolic dysfunction‐associated fatty liver disease component numbers in both sexes; however, no significance was observed in those aged < 50 years. Other significant risk factors for gallstone development were age (odds ratio: 1.093, 95% CI: 1.060–1.126) and waist circumference (odds ratio: 1.048, 95% CI: 1.018–1.079) in men and age (odds ratio: 1.035, 95% CI: 1.003–1.067) and current smoking (odd ratio: 5.465, 95% CI: 1.881–15.88) in women.Conclusion: Although the risk factors for gallstone development differed between sexes, metabolic dysfunction‐associated fatty liver disease was common. Paying attention to an increase in the number of metabolic dysfunction‐associated fatty liver disease components in patients aged ≥ 50 years is important for gallstone prevention.

The prevalence of nonalcoholic fatty liver disease (NAFLD) in the non-obese population has increased and NAFLD is not always recognized in individuals with metabolic syndrome (MS). The risk of cirrhosis is higher in patients having NAFLD with elevated alanine aminotransferase (ALT) levels than in those having NAFLD with normal ALT levels. To measure the differences in clinical factors associated with NAFLD having elevation of ALT among subjects with Non-MS, Pre-MS, and MS, and to measure differences in metabolites between MS subjects with and without NAFLD having elevation of ALT. Among 7,054 persons undergoing health check-ups, we included 3,025 subjects who met the selection criteria. We measured differences in clinical factors for NAFLD having elevation of ALT among subjects with Non-MS, Pre-MS, and MS, and compared metabolites between subjects with and without NAFLD having elevation of ALT in 32 subjects with MS. The prevalence of NAFLD and NAFLD having elevation of ALT was significantly progressively greater in subjects with Non-MS, Pre-MS, and MS (p p <0.05). Although NAFLD having elevation of ALT is important for development of NAFLD, differences in factors associated with NAFLD having elevation of ALT at various stages of MS should be considered. Additionally, several metabolites may play roles in the identification of risk for NAFLD in individuals with MS.

Esophagogastroduodenoscopy (EGD) provides an indispensable and unambiguous inspection allowing the discovery upper gastrointestinal lesions. However, many patients are anxious about undergoing EGD. Few studies have investigated the influence on patients’ vital signs and tolerance during EGD using subjective and objective assessments. This study was a prospective randomized controlled study that investigated the influence of audio and visual distraction on EGD. We randomly divided 289 subjects who underwent EGD into 4 groups (control group, audio group, visual group, combination group) and examined their vital signs, heart rate variability (HRV), psychological items, and acceptance of distraction. Pulse rate (PR) at post-distraction and post-EGD in the 3 distraction groups were significantly lower than those of control group (p < 0.001 and p < 0.01, respectively). Blood pressure (BP) during and post-EGD was significantly higher than that at pre-EGD in control group (p < 0.05), but no significant elevation of BP was observed during the latter half of EGD and post-EGD in the 3 distraction groups. BP at post-distraction improved significantly compared to pre-distraction in the 3 distraction groups (p < 0.05). There was a significant difference in the low-frequency (LF) power/ high-frequency (HF) power at post-distraction and post-EGD among the 4 groups (p < 0.001 and p < 0.001, respectively). The LF power/HF power at post-distraction and post-EGD in the 3 distraction groups was significantly lower than that in control group (p < 0.05). Several items of profile of mood states (POMS) and the impression of EGD at post-distraction improved significantly compared to those at pre-distraction among the 3 distraction groups (p < 0.05). Visual analog scale (VAS) of willingness for the next use of distraction in the 3 distraction groups was excellent because VAS was more than 70. Distractions effectively improved psychological factors, vital signs and some of HRV at pre and post-EGD. Distractions may suppress BP elevation during the latter half of EGD and lead to stability of HRV on EGD. This prospective trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000029637. Registered on 20 October 2017.

Although many patients still have anxiety about upper gastrointestinal (GI) endoscopy, there have been few reports on the influence of distractions for a person who is going to undergo upper GI endoscopy soon. This study was a prospective randomized controlled study investigating the influence of distractions, such as auditive and visual distractions using subjective and objective assessments including autonomic nervous function prior to upper GI endoscopy. 206 subjects who underwent upper GI endoscopy as regular health check-ups were divided randomly into 4 groups prior to upper GI endoscopy; group 1 (control group), group 2 (auditive group), group 3 (visual group), and group 4 (combination group). We measured vital signs, autonomic nervous function, profile of mood state (POMS), and the impression for upper GI endoscopy pre- and post-distraction in the 4 groups. There was no significant difference in vital signs between 5 and 15 min after sitting in group 1, however, several vital signs in all distraction groups improved significantly after distraction (Pulse rate (P): p < 0.001 in group 4; blood pressure: p < 0.05 in group 2, 3, 4) and the rate of decrease in P and diastolic blood pressure was highest in group 4 (p < 0.001). Several scores of POMS and the impression for upper GI endoscopy post-distraction improved significantly compared to pre-distraction between distraction groups and the satisfaction for distraction was highest in group 4 (p < 0.01). Regarding autonomic nerve function, the low- frequency power/ high- frequency power ratio post-distraction was significantly lower than that pre-distraction in all distraction groups (p < 0.001). Although auditive distraction alone and visual distraction alone were effective, a combination distraction was more effective than any other distraction by subjective and objective assessments. These distractions, which were simple and safe, may play an assistive role in the stability of physical and psychological conditions prior to upper GI endoscopy. This trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000022801 . Registered on 10 July 2016.

Nonalcoholic fatty liver disease (NAFLD) is known to be strongly associated with obesity, visceral fat, metabolic syndrome (MS), lifestyle, and lifestyle-related diseases in both males and females. However, the prevalence of NAFLD, MS, and clinical backgrounds is different between males and females. We conducted a cross-sectional study to examine the differing influence of lifestyle-related factors and visceral fat on fatty liver (FL) with elevation of liver enzymes between males and females with MS. We enrolled 42,134 persons who underwent a regular health check-up, and after excluding subjects who fulfilled excluding criteria, the remaining subjects were 2,110 persons with MS. We examined the differing influence of lifestyle-related factors and visceral fat on FL with elevation of alanine aminotransferase (ALT) (ALT elevation was defined as ALT level of ≥31 IU/l in the present study). The odds rations for FL with ALT elevation were as follows: WC, 1.83 (95% confidence interval (CI) 1.36–2.46); dyslipidemia, 1.89 (95% CI 1.34–2.68); hemoglobin A1c, 1.36 (95% CI 1.00–1.85); visceral fat type MS (V-type MS), 5.78 (95% CI 4.29–7.80); and light drinker, 0.56 (95% CI 0.41–0.78) in males with MS and BMI, 2.18 (95% CI 1.43–3.33); WC, 1.85 (95% CI 1.27–2.70); diastolic blood pressure, 1.69 (95% CI 1.16–2.45); triglyceride, 2.22 (95% CI 1.56–3.17); impaired glucose tolerance, 1.66 (95% CI 1.11–2.47); and V-type MS, 3.83 (95% CI 2.57–5.70) in females with MS. The prevalence of FL with ALT elevation and ALT was significantly higher in V-type MS than in the subcutaneous fat type MS in both males and females with MS (P < 0.001). Although V-type MS and WC is a common significant predictor of an increased prevalence of FL with ALT elevation in both males and females with MS, gender, lifestyle-related factors, and MS type in individuals with MS should be considered for the development of FL with ALT elevation.