Takemi Akahane

Aim: Although steatotic liver disease (SLD) has been associated with chronic kidney disease (CKD), it remains unclear whether CKD‐related outcomes are driven by hepatic steatosis itself or by accompanying cardiometabolic abnormalities. We investigated the relative contribution of hepatic steatosis and cardiometabolic risk factors to CKD‐related outcomes using a large Japanese health screening cohort. Methods: In total, 30,648 SLD and 76,182 non‐SLD participants enrolled in the MIRACLE‐J cohort across 13 centers in Japan between 2014 and 2018 were analyzed. CKD‐related outcomes were defined as reduced estimated glomerular filtration rate (eGFR< 60 mL/min/1.73 m ² ) and proteinuria. Multivariable logistic regression and trend analyses were performed to identify factors associated with these outcomes. Results: Compared with non‐SLD participants, those with SLD exhibited a higher burden of cardiometabolic abnormalities. Type 2 diabetes mellitus, obesity, and hyperuricemia were independently associated with proteinuria, whereas advanced age (≥ 65 years), low alcohol intake, and hyperuricemia were strongly associated with reduced eGFR. After multivariable adjustment, SLD showed an inverse association with CKD‐related outcomes. In both SLD and non‐SLD populations, the prevalence of CKD‐related outcomes increased stepwise with a higher number of cardiometabolic risk factors. Incorporation of hyperuricemia significantly improved model fit for reduced eGFR (Δ−2 log likelihood = 119.4, p < 0.001) and modestly improved model fit for proteinuria ( p = 0.002). Conclusions: CKD‐related outcomes were more strongly associated with the burden of cardiometabolic abnormalities than with hepatic steatosis itself, and these associations were consistent in individuals with and without SLD. Hyperuricemia provided incremental value for renal risk stratification within this cardiometabolic framework, underscoring the importance of comprehensive metabolic risk assessment beyond liver fat status.

Background: The outbreak of COVID-19 in 2019 led governments worldwide to introduce various public health measures, which included restrictions on travel and public gatherings, effectively reducing the spread of the virus and associated mortality rates. In Japan, nonlegally binding restrictions on outings effectively curbed infections, as in other countries. However, the restrictions impacted lifestyles, including reduced physical activity, increased frailty, and overeating issues, beyond the effect of preventing the spread of infection. Various factors such as personality, age, and cultural norms influenced outing behavior during the pandemic, which varied by activity type. Objective: To elucidate the association between personality traits and changes in outing behaviors during the COVID-19 pandemic, as well as to clarify age-specific differences in outing behaviors, focusing on different types of outings. Methods: A cross-sectional survey was conducted using a web-based questionnaire in January 2021, when Japan announced its second emergency declaration during the pandemic. Overall, 1236 participants were recruited, with an equal number of participants for each gender and 10-year age group. The survey included questions regarding changes in the frequency of three types of outings—medical institution visits, eating out, and traveling—in addition to participants’ personality traits, such as sociability and morality. Multinomial logistic regression analysis was performed to analyze the association between personality traits and changes in different outing behaviors. Stratified analysis by age group was also performed. Results: The findings revealed that 790 participants reported no change in medical institution visits, although the frequency of eating out and traveling decreased during the pandemic. Regarding an age-wise comparison, a higher percentage of older people reported no change in medical institution visits but reported a decrease in eating out and traveling than younger people. Multinomial logistic regression analysis stratified by age showed that sociable people were more likely to report a decrease in the frequency of medical institution visits and an increase in the frequency of eating out (odds ratio [OR] 1.92, 95% CI 1.36‐2.71, P<.001; OR 2.57, 95% CI 1.19‐5.54, P=.016, respectively), and participants with a strong sense of responsibility were more likely to report a decrease in the frequency of traveling (OR 1.76, 95% CI 1.14‐2.72, P=.011) among younger adults. Among older adults, strongly responsible individuals were less likely to eating out frequently (OR 2.56, 95% CI 1.12‐5.82, P=.026). Conclusions: We examined various behavioral changes observed during the pandemic for different types of outings and their associations with personality traits, as well as differences between age groups. The findings could help promote an understanding of how to effectively communicate and engage in appropriate behaviors in public health emergency settings.

Background: This study aimed to determine the number of patients with positive HCV RNA results who were eligible to receive direct-acting antiviral (DAA) therapy at Nara Medical University and to identify effective screening methods in this population. Methods: Between June 2021 and May 2024, the RNA detection status of HCV antibody-positive cases, including RNA detection rates (RNA detection number/antibody positive number) and positive rates (RNA positive number/RNA detection number), were evaluated. Results: Among the 866 patients who underwent anti-HCV testing, HCV RNA was assessed in 29.2% (n = 253, including department of Gastroenterology; n = 57, other departments n = 196). Among the 253 (29.2%) patients, 26 (45.6 ％ ) and 16 (8.2%), patients from the Gastroenterology and other departments, respectively, tested positive for HCV-RNA. The remaining 70.8% (n = 613) (41 cases in the department of Gastroenterology and 572 cases in the others). Based on the RNA positivity rate of the facilities, 613 (70.8%) tested for HCV antibody, will include 66 potential RNA patients included 19 patients (45.6 ％ ) in Gastroenterology and 47 patients (8.2 ％ ) in the other departments. Conclusions : Overall, 66 patients will potentially remain HCV RNA positive. Simultaneous evaluation of HCV antibodies and HCV RNA can efficiently identify patients with chronic HCV infection who are eligible for DAA therapy.

Covert hepatic encephalopathy (CHE) can worsen the quality of life and prognosis of patients with cirrhosis. We analyzed the risk factors of CHE and identified patients at high risk for overt hepatic encephalopathy (HE) who would benefit from therapeutic interventions. We included 145 patients without a history of or treatment for overt HE. Patients were divided into the CHE and no-CHE groups (n = 91 and 54, respectively). CHE had a score above the age-based cutoff value of one of the neuropsychological tests, such as the Stroop and number connection tests. CHE prevalence was 62.8% (n = 91). Compared with the no-CHE group, the CHE group had significantly lower serum zinc and albumin levels. Multiple logistic regression analysis identified serum zinc levels at a cutoff value of 74 µg/dL. Subclinical zinc deficiency showed a diagnostic performance of 55.6% sensitivity and 81.5% specificity for CHE. Blood ammonia levels and liver functional reserves were not predictive of CHE. Compared with patients with zinc levels < 74 µg/dL (n = 102), those with ≥74 µg/dL (n = 43) had significantly lower CHE prevalence and better hepatic functional reserve. Subclinical zinc deficiency was associated with CHE occurrence in patients with cirrhosis without a history of or treatment for overt HE. Measurement of zinc levels facilitates early detection of CHE by neuropsychological testing.

Aim: This study aimed to determine the predictive ability of the histological stage (HS) compared with biochemical response to ursodeoxycholic acid (UDCA) (BR) on developing complications in patients with primary biliary cholangitis (PBC). Methods: Overall, 226 patients with asymptomatic PBC treated with UDCA were enrolled. Pathological staging was conducted based on the Scheuer and Nakanuma classifications, which were graded for liver fibrosis (fibrosis) and bile duct loss (BDL). BR was evaluated according to the Nara criteria, Paris II criteria, and Barcelona criteria. PBC complications included pruritus, esophageal varices, ascites, and jaundice. Results: The cumulative complication rates (CCRs) of the four patient groups (early disease/responder [group A], early disease/non‐responder [group B], advanced disease/responder [group C], and advanced disease/non‐responder [group D]) were estimated by combining the HS according to the Scheuer and Nakanuma classifications and BR based on three UDCA response criteria. The CCRs for the Scheuer classification/Paris II criteria, Scheuer classification/Barcelona criteria, Nakanuma classification/Nara criteria, Nakanuma classification/Paris II criteria, Nakanuma classification/Barcelona criteria, fibrosis/Barcelona criteria, and BDL/Paris II criteria were significantly higher in group C than in group A. The CCRs for the Scheuer classification/Nara criteria, Scheuer classification/Barcelona criteria, Nakanuma classification/Nara criteria, Nakanuma classification/Barcelona criteria, fibrosis/Nara criteria, fibrosis/Paris II criteria, and fibrosis/Barcelona criteria were significantly higher in group D than in group B. An advanced Nakanuma stage was independently associated with developing complications in patients with PBC. Conclusions: The CCR increases with HS progression regardless of BR. HS is linked to a higher risk of developing complications than BR in patients with PBC.

Imeglimin promotes glucose-stimulated insulin secretion in the pancreas in a glucose-dependent manner and inhibits gluconeogenesis in the liver. Meanwhile, imeglimin can improve mitochondrial function in hepatocytes. We used a nondiabetic metabolic dysfunction-associated steatohepatitis (MASH) model to examine the effects of imeglimin on MASH independent of its glucose-lowering action. Mice fed a choline-deficient high-fat diet (CDA-HFD) were orally administered imeglimin (100 and 200 mg/kg twice daily), and MASH pathophysiology was evaluated after 8 weeks. Moreover, an in vitro study investigated the effects of imeglimin on palmitic acid (PA)-stimulated lipid accumulation, apoptosis, and mitochondrial dysfunction in human hepatocytes. CDA-HFD-fed mice showed hepatic steatosis, inflammation, and fibrosis without hyperglycemia. Imeglimin reduced hepatic steatosis in response to increased expression of β-oxidation-related markers. Imeglimin reduced reactive oxygen species accumulation and increased mitochondrial biogenesis in CDA-HFD-fed mice. Consequently, imeglimin suppressed hepatocyte apoptosis and decreased macrophage infiltration with reduced proinflammatory cytokine expression, suppressing hepatic fibrosis development. PA-stimulated hepatocytes induced lipogenesis, inflammatory cytokine production, and apoptosis, which were significantly suppressed by imeglimin. In mitochondrial function, imeglimin improved PA-stimulated decrease in mitochondrial membrane potential, mitochondrial complexes activity, oxygen consumption rate, and mitochondrial biogenesis marker expression. In conclusion, imeglimin could contribute to prevention of MASH progression through suppressing de novo lipogenesis and enhancing fatty acid oxidation.

Aim: Esophagogastric varices (EGV) are a serious complication of hepatitis C virus (HCV)‐related liver cirrhosis (HCV‐LC). In most cases, portal hypertension improves after a sustained virologic response (SVR) is achieved with direct‐acting antiviral (DAA) treatment; however, in some cases, EGV exacerbation occurs after HCV elimination. We investigated whether von Willebrand factor (VWF) and a disintegrin‐like metalloproteinase with thrombospondin type‐1 motif 13 (ADAMTS13) can predict EGV progression with HCV‐LC after SVR achievement.Methods: This retrospective study enrolled 47 patients with HCV‐LC who achieved an SVR after DAA treatment. Eighteen patients experienced EGV progression after the SVR was achieved (EGV progression group). Twenty‐nine patients did not experience EGV progression after the SVR was achieved (non‐EGV progression group). Plasma VWF antigen levels and ADAMTS13 activity were measured the day before DAA treatment.Results: The EGV progression group had significantly higher plasma VWF antigen levels (p = 0.00331) and VWF‐to‐ADAMTS13 ratios (p = 0.000249) than the non‐EGV progression group. Multivariate logistic regression models found that a VWF‐to‐ADAMTS13 ratio >2.3 was the only risk factor for EGV progression after the SVR was achieved (hazard ratio [HR], 18.4; 95% confidence interval [CI], 3.08–109; p = 0.00138). During the observation period, patients with a VWF‐to‐ADAMTS13 ratio >2.3 had a significantly higher cumulative incidence of EGV progression after SVR achievement than patients with a VWF‐to‐ADAMTS13 ratio ≤2.3 (HR, 6.4; 95% CI, 1.78–22.96; p = 0.0044).Conclusions: The VWF‐to‐ADAMTS13 ratio before DAA treatment for HCV could predict EGV progression after SVR achievement.

Aim: A nationwide survey in 2018 showed decreasing involvement of viral hepatitis and increasing involvement of nonviral liver diseases in the etiology of liver cirrhosis (LC) in Japan. An updated nationwide survey was undertaken in 2023.Methods: Cases of LC diagnosed between 2018 and 2021 were collected from 75 institutions, and the etiologies of LC were investigated. In addition, the data obtained were compared with the results of previous studies.Results: Among the 15 517 cases, alcohol‐related liver disease (ALD)‐associated LC was the most frequent cause (n = 5,487, 35.4%). Hepatitis C virus‐associated LC, nonalcoholic steatohepatitis (NASH)‐associated LC, and hepatitis B virus‐associated LC were ranked as second, third, and fourth, respectively. In comparison to the previous survey, the ratios of viral hepatitis‐associated LC decreased (HBV: from 11.5% to 8.1%; HCV: from 48.2% to 23.4%), while the ratios of ALD‐associated LC and NASH‐associated LC increased (from 19.9% to 35.4% and from 6.3% to 14.6%, respectively). Regarding cases of LC with hepatocellular carcinoma (n = 5906), HCV‐associated LC (1986 cases, 33.6%) was the most frequent cause. Alcohol‐related liver disease‐associated LC, NASH‐associated LC, and HBV‐associated LC were the second‐, third‐, and fourth‐ranked causes, respectively. In comparison to the previous survey, as the cause of hepatocellular carcinoma‐complicated LC, HCV‐associated LC decreased from 60.3% to 33.6%, while the ratios of ALD‐associated LC and NASH‐associated LC increased from 14.2% to 28.6% and from 4.2% to 14.0%, respectively.Conclusions: The major causes of LC in Japan are suggested to have been shifting from viral hepatitis to nonviral chronic liver diseases.

Lipopolysaccharides (LPSs) have been reported to be important factors in promoting the progression of hepatocellular carcinoma (HCC), but the corresponding molecular mechanisms remain to be elucidated. We hypothesize that epiregulin (EREG), an epidermal growth factor (EGF) family member derived from hepatic stellate cells (HSCs) and activated by LPS stimulation, is a crucial mediator of HCC progression with epidermal growth factor receptor (EGFR) expression in the tumor microenvironment. We used a mouse xenograft model of Huh7 cells mixed with half the number of LX-2 cells, with/without intraperitoneal LPS injection, to elucidate the role of EREG in LPS-induced HCC. In the mouse model, LPS administration significantly enlarged the size of xenografted tumors and elevated the expression of EREG in tumor tissues compared with those in negative controls. Moreover, CD34 immunostaining and the gene expressions of angiogenic markers by a reverse transcription polymerase chain reaction revealed higher vascularization, with increased interleukin-8 (IL-8) expression in the tumors of the mice group treated with LPS compared to those without LPS. Our data collectively suggested that EREG plays an important role in the cancer microenvironment under the influence of LPS to increase not only the tumor cell growth and migration/invasion of EGFR-positive HCC cells but also tumor neovascularization via IL-8 signaling.

Background: Liver cirrhosis leads to portal hypertension (PH) with capillarization of liver sinusoidal endothelial cells (LSECs), although drug treatment options for PH are currently limited. Sodium glucose transporter 2 inhibitors, which are antidiabetic agents, have been shown to improve endothelial dysfunction. We aimed to elucidate the effect of tofogliflozin on PH and liver fibrosis in a rat cirrhosis model. Methods: Male-F344/NSlc rats repeatedly received carbon tetrachloride (CCl₄) intraperitoneally to induce PH and liver cirrhosis alongside tofogliflozin (10 or 20 mg/kg). Portal hemodynamics and hepatic phenotypes were assessed after 14 weeks. An in vitro study investigated the effects of tofogliflozin on the crosstalk between LSEC and activated hepatic stellate cells (Ac-HSC), which are relevant to PH development. Results: Tofogliflozin prevented PH with attenuated intrahepatic vasoconstriction, sinusoidal capillarization, and remodeling independent of glycemic status in CCl₄-treated rats. Hepatic macrophage infiltration, proinflammatory response, and fibrogenesis were suppressed by treatment with tofogliflozin. In vitro assays showed that tofogliflozin suppressed Ac-HSC-stimulated capillarization and vasoconstriction in LSECs by enhancing the antioxidant capacity, as well as inhibited the capilliarized LSEC-stimulated contractive, profibrogenic, and proliferative activities of Ac-HSCs. Conclusions: Our study provides strong support for tofogliflozin in the prevention of liver cirrhosis-related PH.