Search

Little is known about how blood free amino acids (FAAs) change in metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to identify the imbalance of FAAs in MASLD and explore its correction as a potential therapeutic target. We analyzed plasma FAAs data from 23,036 individuals with steatosis information from a biobank in Japan, and 310 patients with MASLD were enrolled. According to diagnostic criteria for steatotic liver disease (SLD) or cardiometabolic criteria (CC), we divided the subjects into five groups: MASLD, metabolic dysfunction and alcohol-associated liver disease (MetALD), CC-SLD-, CC + SLD-, and CC-SLD + . Twenty FAAs were compared among these groups and among MASLD patients with pathological information. Among the 20 FAAs, the levels of 16 FAAs increased in CC + SLD- according to the number of matches with CC items associated with insulin resistance (IR). Steatosis enhanced most of these changes but serine (Ser) and threonine (Thr) were unaffected. Glycine (Gly), Ser and Thr were significantly decreased in patients according to steatosis grade. We investigated the association between these FAAs imbalances and pathogenesis using MASLD mouse models. In mice fed a high-fat, fructose, and cholesterol (FFC) diet, metabolomics and RNA sequencing analyses indicated that abnormality in Gly, Ser, and Thr metabolism in the liver was associated with mitochondrial dysfunction and enhanced glycolysis via pyruvate. High-Gly, Ser, and Thr diet ameliorated pathogenesis of MASLD in leptin-deficient mice. Most FAAs increase due to cardiometabolic abnormalities, particularly IR. However, interventions targeting the metabolism of Gly, Ser, and Thr have the potential to improve MASLD., Competing Interests: Declarations. Conflicts of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Background and Objective: Durvalumab plus tremelimumab (Durva/Treme) has recently been approved as a first-line or later-line treatment for patients with unresectable hepatocellular carcinoma (u-HCC) in Japan. We assessed the real-world outcomes of Durva/Treme for u-HCC, with a focus on treatment efficacy and safety., Methods: We retrospectively evaluated 22 patients with u-HCC treated with Durva/Treme at Iwate Medical University during the period from 2023 to 2024, with a comparison of the clinical outcomes between patients who received Durva/Treme as first-line and later-line treatments. We further evaluated changes in the modified albumin-bilirubin (mALBI) grade during treatment., Results: There were 10 patients in the first-line group and 12 patients in the later-line treatment group. During the follow-up with a median duration of 7.6 months, the median progression-free survival (first-line versus later-line: 4.7 months versus 2.9 months, p = 0.85), the objective response rate (0.0% versus 16.7%, p = 0.48), the disease control rate (60.0% versus 58.4%, p = 1.00), and the incidence of any adverse event (50.0% versus 75.0%, p = 0.38) were not statistically different between the two groups. The changes in the mALBI scores were not statistically significant (p = 0.75)., Conclusions: Durva/Treme may be effective and safe for patients with u-HCC, even in patients who receive Durva/Treme as a later-line treatment., Competing Interests: Declarations. Funding and conflict of interest: The authors declare no conflicts of interest or financial support associated with this study. Ethics approval: This study was approved by local ethics committee of Iwate Medical University (approval no.: MH2022-145, approval date: 25 April 2023). The patients provided their written informed consent prior to treatment, in accordance with the ethical standards of the 2013 Declaration of Helsinki and its subsequent amendments. Consent to participate: All participants provided written informed consent before participation. Consent for publication: Not applicable. Code availability: Not applicable. Availability of data and material: The data presented in this study are available upon request from the corresponding author. Author contributions: Y.F. designed the study and wrote the manuscript; H.K., K.K., and T.M. corrected the manuscript; Y.F. and T.A. created the database system; T.A., T.N., I.N., A.I., T.W., K.Y., H.S., A.S., K.E., Y.Y., T.O., K.K., K.S., and A.M. treated the patients; and H.K. and T.M. supervised the study. All authors discussed the results and contributed to the final manuscript. All the authors have read and agreed to the published version of the manuscript., (© 2024. The Author(s).)

Aim: An accurate assessment of the general condition of patients with hepatocellular carcinoma (HCC) is essential. We evaluated the impact of grip strength (GS) and Eastern Cooperative Oncology Group Performance Status (ECOG-PS) on the clinical outcomes of patients with unresectable HCC (u-HCC) treated with atezolizumab plus bevacizumab., Methods: This observational cohort study analyzed 89 patients with u-HCC treated with atezolizumab plus bevacizumab between October, 2020 and October, 2023. A Cox proportional hazards model and Kaplan-Meier curve were used to identify the prognostic factors associated with survival outcomes., Results: There were 33 patients who had low GS and 16 had an ECOG-PS ≥1. The frequency of patients with low GS increased as the ECOG-PS score increased. The overall survival of the normal GS group was significantly higher than that of the low GS group (p < 0.01). There was no significant difference in progression-free survival between the normal GS group and low-GS group (p = 0.28). Among the patients in the ECOG-PS 0 groups, the overall survival in the normal GS group was significantly higher than that in the low GS group (p < 0.01). A multivariate analysis revealed that modified albumin-bilirubin 2b (HR 2.24; 95% confidence interval [CI] 1.06-4.73), α-fetoprotein ≥100 ng/mL (HR 2.35; 95% CI 1.20-4.58), and low GS (HR 2.87; 95% CI 1.31-6.27) were independently associated with a poor overall survival., Conclusions: The present study demonstrated that GS is a sensitive marker for detecting a subclinical decline in the general condition and is therefore a potential predictor of the outcome of u-HCC patients treated with atezolizumab plus bevacizumab., (© 2024 Japan Society of Hepatology.)

Background: Subharmonic-aided pressure estimation (SHAPE) is a technique for determining changes in ambient pressure. We aimed to analyze a novel SHAPE integrated into ultrasound diagnostic equipment to predict patients with liver cirrhosis at high risk of esophagogastric varices (EV)., Methods: This prospective study included 111 patients with liver cirrhosis diagnosed between 2020 and 2023. We obtained liver stiffness measurements (LSM) and spleen stiffness measurements (SSM) using shear wave elastography and hepatic vein-portal vein (HV-PV) gradient using the SHAPE method. The EV risk was determined either as null, low, or high by esophagoscopy and Child-Pugh stage., Results: HV-PV gradient increased concordantly with the increase in EV risk (- 7.0 dB in null-risk, - 4.4 dB in low-risk, and - 2.0 dB in high-risk) with statistically significant difference among any two groups. The most appropriate cut-off value of the HV-PV gradient was - 3.5 dB, and sensitivity, specificity, and positive and negative predictive values were 80.0%, 89.0%, 80.0%, and 88.0%, respectively. The areas under the curve values for predicting the high-risk EV were 0.920, 0.843, and 0.824 for the HV-PV gradient, LSM, and SSM, respectively., Conclusions: The novel SHAPE system demonstrated high accuracy in identifying patients with liver cirrhosis at a high risk of EV., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest. Ethical approval: The Iwate Medical University Institutional Review Board approved all protocols of this study (approval number: MH2019-102). Informed consent: All patients provided written informed consent before the study, which was conducted according to the principles of the Declaration of Helsinki., (© 2024. The Author(s).)

Background: Steatotic liver disease, characterized by a combination of metabolic dysfunction, alcohol use, or specific etiologies, is a leading cause of chronic liver disease. However, the role of metabolic dysfunction in chronic liver disease with harmful alcohol use remains unclear. This study aimed to investigate factors associated with hepatic steatosis and fibrosis in patients with harmful alcohol use., Methods: Over a 2-year period, we registered patients with harmful alcohol use, defined by an Alcohol Use Disorders Identification Test score of 8 or higher. We retrospectively analyzed background information, blood test results, ultrasound-guided attenuation parameter (attenuation coefficient), and liver stiffness measurement. Hepatic steatosis was defined as attenuation coefficient ≥0.65 dB/cm/MHz, and fibrosis as liver stiffness measurement ≥7.5 kPa., Results: The study included 131 patients (82% men, median age 59 years). Linear regression analysis revealed significant associations with attenuation coefficient for body mass index ≥23 (0.08, p < 0.0001) and age (-0.002, p = 0.002). Liver stiffness measurement was associated with body mass index ≥23 (2.52, p = 0.001), aspartate aminotransferase (0.02, p = 0.0189), gamma-glutamyl transpeptidase (0.008, p < 0.0001), platelet count (-0.02, p = 0.001), and prothrombin international normalized ratio (26.40, p < 0.0001). Among the four groups classified by the presence or absence of steatosis and fibrosis, patients with fibrosis, but without steatosis, demonstrated the lowest liver reserve. In contrast, patients with both steatosis and fibrosis showed higher aspartate aminotransferase and gamma-glutamyl transpeptidase levels., Conclusions: Body mass index is associated with both hepatic steatosis and fibrosis in patients with harmful alcohol use., (© 2024 Japan Society of Hepatology.)

Aim: This study aimed to compare the effects of the molecular targeted drugs, sorafenib and lenvatinib, on the survival, invasion, and angiogenesis of hepatocellular carcinoma cells. Additionally, we investigated the involvement of transforming growth factor beta (TGF-β) signaling in their molecular mechanisms., Methods: To investigate the effects of sorafenib and lenvatinib, we conducted cell viability, invasion, and angiogenesis assays, as well as western blotting analyses., Results: In human hepatocellular carcinoma cells (HepG2), sorafenib demonstrated potent inhibitory effects on cell proliferation, but induced cell invasion similar to TGF-β. In contrast, lenvatinib showed weaker cytotoxicity compared with sorafenib, but suppressed cell invasion induced by TGF-β. The actions of these two molecular targeted drugs were suggested to involve the regulation of the TGFβR2/ERK pathway. Moreover, in human umbilical vein endothelial cells, Sorafenib showed weaker cytotoxicity and enhanced the effects of TGF-β on angiogenesis. Conversely, lenvatinib showed potent cytotoxic abilities and suppressed angiogenesis induced by TGF-β. The actions of these two molecular targeted drugs were suggested to involve the regulation of the crosstalk between TGF-β signaling and vascular endothelial growth factor signaling., Conclusions: Our findings indicate that both sorafenib and lenvatinib possess anticancer abilities by inducing the cytotoxicity of hepatocellular carcinoma cells. Furthermore, they show opposing effects on TGF-β-induced cell invasion and angiogenesis, thereby enhancing the understanding of the multifaceted functions of molecular targeted drugs in treating hepatocellular carcinoma., (© 2024 Japan Society of Hepatology.)

Acute liver failure (ALF) induces increased energy expenditure and disrupts the metabolism of essential nutrients. Hepatic encephalopathy is a complication of ALF with a poor prognosis and mainly involves the metabolic disturbance of amino acids in its pathogenesis. In this review, we discuss the nutritional management for ALF in consideration of the pathophysiology of ALF with respect to the impairment of hepatocyte function. It is known that enteral nutrition is recommended for patients with ALF, while parenteral nutrition is recommended for patients who cannot tolerate enteral nutrition. As ALF leads to a hypermetabolic state, the energy intake is recommended to cover 1.3 times the resting energy expenditure. Because of the high risk of hypoglycemia associated with disturbances in glucose metabolism, substantial glucose intake is recommended. Along with the deterioration of glucose metabolism, protein metabolism is also disrupted. As patients with ALF have increased systemic protein catabolism together with decreased protein synthesis, appropriate amounts of amino acids or protein under monitoring serum ammonia levels are recommended. In conclusion, nutritional management based on the understanding of nutritional pathophysiology is a pivotal therapeutic approach for patients with ALF. The approach should be individualized in the acute phase, the recovery phase, and the pretransplant phase., (© 2024 The Author(s). Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Background and Aim: The study aims to determine the prognostic impact of obesity, sarcopenic obesity, and dynapenic obesity in patients with chronic liver disease., Methods: This retrospective observational study enrolled patients with chronic hepatitis (n = 746) and liver cirrhosis (n = 434) without hepatocellular carcinoma at entry. The patients were evaluated for sarcopenia and obesity between April 2016 and April 2022. Obesity was defined as a body mass index of ≥ 25 kg/m 2 . Sarcopenic obesity was defined as low skeletal muscle mass (pre-sarcopenia) with obesity and dynapenic obesity was defined as low muscle strength (dynapenia) with obesity. The effects of obesity on survival were evaluated retrospectively., Results: The mean observation period was 2.5 years. Obesity, sarcopenic obesity, and dynapenic obesity were found in 271 (45.5%), 17 (2.9%), and 21 (3.5%) men, and 261 (44.7%), 59 (10.1%), and 53 (9.1%) women, respectively. A multivariate Cox proportional hazards model revealed that Child-Pugh class, dynapenia (hazard ratio [HR] 3.89), elderly (≥ 65 years old) (HR 2.11), and obesity (HR 0.58) were independently associated with overall survival (OS). However, neither sarcopenic nor dynapenic obesity were associated with OS. In patients with cirrhosis, the OS of the obese group was significantly higher than that of the non-obese group. The effect of obesity on OS was significant in elderly patients, but not in younger patients., Conclusions: Sarcopenic and dynapenic obesity seem unrelated to the prognosis of patients with chronic liver disease. Obesity has a positive effect on the prognosis of elderly patients with cirrhosis., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Spontaneous reactivation of the Hepatitis B virus (HBV) is rare in individuals with previously resolved infections. This report presents the case of a 71 year-old Japanese woman who experienced HBV reactivation without any prior immunosuppressive therapy or chemotherapy. Before the onset of liver injury, the patient was negative for hepatitis B surface antigen (HBsAg) but positive for hepatitis B surface antibody. She subsequently developed liver injury, with the reappearance of HBsAg and HBV DNA. The patient was successfully treated with tenofovir alafenamide, and prednisolone. Full-genome sequencing of HBV revealed subgenotype B1 without hepatitis B e-negative mutations in the precore and core promoter regions and 12 amino acid alterations in the pre-S1/S, P, and X genes. Notably, the S gene mutations D144A and K160N, which alter the antigenicity of HBsAg and potentially contribute to its reactivation, were identified. This case emphasizes the importance of vigilance for spontaneous reactivation of resolved HBV, highlighting the need for comprehensive genomic analysis to understand the associated virological intricacies., (© 2024. Japanese Society of Gastroenterology.)

Prothrombin time (PT) is a key parameter for assessing the severity of liver disease. We present the case of a 37-year-old woman with severe acute liver injury due to autoimmune hepatitis. Although prednisolone drastically improved her hepatocyte function, her PT did not recover to the reference range. A review of her medical records revealed that the patient had normal transaminase levels and prolonged PT 2 years previously. Further examinations of her coagulopathy revealed that she had low factor VII activity, suggesting a diagnosis of factor VII deficiency. Our experience suggests that altered coagulopathy should be considered in cases of liver injury with an extraordinary PT.

Aim: There are few data regarding the safety and effectiveness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with intractable hepatobiliary diseases. We conducted a multicenter, questionnaire-based, cross-sectional study to determine the safety and effectiveness of the SARS-CoV-2 vaccines in Japanese patients with intractable hepatobiliary disease., Methods: Patients aged ≥18 years with autoimmune hepatitis (AIH), primary biliary cholangitis, primary sclerosing cholangitis, Budd-Chiari syndrome, idiopathic portal hypertension, and extrahepatic portal vein obstruction at each center were consecutively invited to join the study. Participants were asked to complete a questionnaire regarding their characteristics, vaccination status, post-vaccination adverse effects, and SARS-CoV-2 infection. Additionally, liver disease status, treatment regimens, and liver function test values pre- and post-vaccination were collected., Results: The survey was conducted from September 2021 to May 2022, and 528 patients (220 AIH, 251 primary biliary cholangitis, 6 AIH- primary biliary cholangitis/primary sclerosing cholangitis overlap, 39 primary sclerosing cholangitis, 4 Budd-Chiari syndrome, 5 idiopathic portal hypertension, and 3 extrahepatic portal vein obstruction) participated in the study. Post-vaccination adverse effects were comparable to those observed in the general population. Post-vaccination liver injuries classified as grade 1 or higher were observed in 83 cases (16%), whereas grades 2 and 3 were observed in only six cases (1.1%); AIH-like liver injury requiring treatment was not observed. Overall, 12 patients (2.3%) were infected with SARS-CoV-2, and only one patient was infected 6 months after the second vaccination., Conclusion: SARS-CoV-2 vaccines demonstrated satisfactory safety and effectiveness in Japanese patients with intractable hepatobiliary diseases., (© 2024 Japan Society of Hepatology.)

Aim: Acute pancreatitis is a complication of acute liver failure (ALF). This study aimed to investigate the prevalence of and clinical features associated with acute pancreatitis in patients with ALF., Methods: We retrospectively analyzed a cohort of ALF patients without hepatic encephalopathy diagnosed during a period 2011-2018, and compared clinical features between patients with acute pancreatitis and those without. Acute pancreatitis was diagnosed according to the Acute Pancreatitis Clinical Practice Guidelines 2021. A multivariate analysis was carried out to identify factors associated with acute pancreatitis., Results: There were 83 ALF patients without hepatic encephalopathy (34 men; 11 deaths; 6 liver transplants; median age, 63 years). Acute pancreatitis occurred in nine patients (10.8%). The median time duration from ALF to the onset of acute pancreatitis was 8 days. The survival rate was lower in patients with than those without acute pancreatitis (22% vs. 86%). The model for end-stage liver disease score (hazard ratio 1.10, 95% confidence interval 1.03-1.18) was found to be a significant factor associated with acute pancreatitis, whereas triglyceride, age, and sex were not., Conclusions: A high model for end-stage liver disease score may be a marker to stratify patients with ALF at a risk of acute pancreatitis., (© 2024 Japan Society of Hepatology.)

Aim: The diagnosis of drug-induced liver injury (DILI) is challenging. We modified the revised electronic version of the Roussel Uclaf Causality Assessment Method (RUCAM) for the diagnosis of DILI (RECAM), the scoring system developed in US and Spanish cohorts in 2022, and developed RECAM-J 2023 to align with the clinical practice in Japan. In the current study, we introduce RECAM-J 2023 and verify its performance in the context of Japanese patients with DILI., Methods: After translation of RECAM into Japanese, modifications were made to develop RECAM-J 2023 without any alteration to the scores. To examine the validity and performance of RECAM-J 2023, clinical information on DILI and non-DILI cases in Japan were retrospectively collected. The diagnosis of DILI was made by expert's decision. Then we scored each case using RECAM-J 2023, and calculated area under curve (AUC) values for identification for DILI., Results: We collected data from 538 DILI and 128 non-DILI cases. The sum of highly probable (HP) and probable (PR) cases categorized by RECAM-J 2023 were only 206 (38%) in DILI cases. As the primary cause of low scores was the deduction with missing hepatitis virus markers, which is unlikely to be an issue in prospective applications, we rescored without these deductions. At this time, the sum of HP and PR was raised to 421 (78%). The AUCs of RECAM-J 2023 without deductions were 0.70 and 0.88 for identifying at least HP, and at least PR, respectively., Conclusion: RECAM-J 2023, when prospectively used without any missing hepatitis virus markers, provides acceptable performance for identifying at least PR DILI cases in Japanese daily clinical practice., (© 2024 Japan Society of Hepatology.)

Purpose: To clarify the relationships between the changes in hepatokines and weight loss, and between these changes and the metabolic effects, and the roles played by these changes, after laparoscopic sleeve gastrectomy (LSG)., Methods: We recruited 25 Japanese patients with severe obesity, who underwent LSG. We measured two hepatokines: selenoprotein P (SeP) and leukocyte cell-derived chemotaxin 2 (LECT2), at the baseline, and then 6 months and 1 year after LSG. Finally, we compared the changes in the hepatokines with the parameters of type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH)., Results: Changes in LECT2 were correlated with the percentage of total weight loss (ρ = - 0.499, P = 0.024) and the decrease in total fat area (ρ = 0.559, P = 0.003). The changes in SeP were correlated with those in hemoglobin A1c (ρ = 0.526, P = 0.043) and the insulinogenic index (ρ = 0.638, P = 0.010) in T2D patients. In patients with NASH, the LECT2 levels were correlated with liver steatosis (ρ = 0.601)., Conclusions: SeP levels decrease in association with HbA1c reduction, whereas LECT2 levels are associated with reductions in fat mass and NASH scores after LSG. Hepatokines may be involved in the pathology of obesity and its complications., (© 2023. The Author(s).)

Background: The branched-chain amino acids (BCAAs) to tyrosine (Tyr) ratio (BTR) test is used to evaluate the progression of chronic liver disease (CLD). However, the differences across sex, age, body mass index (BMI) and etiologies are still unclear., Methods: We retrospectively reviewed data from 2,529 CLD cases with free amino acids (FAAs) in peripheral blood from four hospitals and 16,421 general adults with FAAs data from a biobank database. In total, 1,326 patients with CLD (covering seven etiologies) and 8,086 healthy controls (HCs) were analyzed after exclusion criteria. We investigated the change of BTR in HCs by sex, age and BMI and then compared these to patients divided by modified ALBI (mALBI) grade after propensity score matching., Results: BTR is significantly higher in males than females regardless of age or BMI and decreases with aging in HCs. In 20 types of FAAs, 7 FAAs including BCAAs were significantly decreased, and 11 FAAs including Tyr were significantly increased by mALBI grade in total CLD. The decreasing timings of BTR were at mALBI grade 2b in all CLD etiologies compared to HCs, however in chronic hepatitis C (CHC), chronic hepatitis B (CHB) and alcoholic liver disease (ALD), BTR started to decrease at 2a. There was a positive correlation between BCAAs and albumin among parameters in BTR and mALBI. The correlation coefficients in PBC, ALD and MASLD were higher than those of other etiologies., Conclusions: BTR varies by sex and age even among healthy adults, and decreasing process and timing of BTR during disease progression is different among CLD etiologies., (© 2024. Japanese Society of Gastroenterology.)

The HIMALAYA trial is the first chemotherapeutic trial to demonstrate the efficacy of combined immune checkpoint inhibitors (ICIs) for unresectable hepatocellular carcinoma (u-HCC). The STRIDE regimen used in this trial consists of a cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor and programmed cell death ligand 1 (PD-L1) inhibitor. Herein, we report two cases of ICI-colitis that occurred immediately after the initiation of the STRIDE regimen for u-HCC. A 73-year-old man and 75-year-old man with u-HCC were treated with the STRIDE regimen. Both patients developed grade 3 diarrhea (Common Terminology Criteria for Adverse Events, ver. 5.0) within 10 days of treatment initiation. Colonoscopy revealed aphthous erosions and erythema extending from the terminal ileum to the rectum in one case, while the other showed aphthous ulcers in the terminal ileum and shallow ulcers in the colorectum. Histopathological examination of a biopsy specimen revealed epithelial cell apoptosis and neutrophil infiltration bodies, consistent with ICI-colitis. Prednisolone (0.5 mg/kg) was effective in both patients. Our experience suggests the need for both careful monitoring and early endoscopic examination of ICI colitis in patients with unresectable HCC treated with the STRIDE regimen., (© 2024. Japanese Society of Gastroenterology.)

Nonalcoholic fatty liver disease (NAFLD) develops as a result of unhealthy lifestyle but improves with laparoscopic sleeve gastrectomy (LSG). The transforming growth factor (TGF)-β signaling pathway reportedly contributes to liver fibrosis, mainly in animal experiments. The aim of the present study was to evaluate changes in serum proteins before and after LSG by proteomic analysis and to investigate their association with NAFLD. This study enrolled 36 severely obese patients who underwent LSG at our hospital from January 2020 to April 2022. As a pilot study, proteomic analysis was conducted on six patients using serum collected before and at 6 months after LSG, and significantly fluctuating proteins were extracted. Subsequently, verification by enzyme-linked immunosorbent assay (ELISA) using collected serum was performed on the remaining 30 patients. The mean weight of enrolled patients was 118.5 kg. Proteomic analysis identified 1,912 proteins, many of which were related to the TGF-β signaling pathway. Among these proteins, we focused on five TGF-β-related proteins: asporin, EMILIN-1, platelet factor-4, serglycin, and thrombospondin-1. Verification by ELISA revealed that asporin (p = 0.006) and thrombospondin-1 (p = 0.043) levels significantly fluctuated before and after LSG. Univariate analysis with a linear regression model showed that aspartate aminotransferase (p = 0.045), asporin (p = 0.011), and thrombospondin-1 (p = 0.022) levels were significantly associated with postoperative liver fibrosis. On multivariate analysis, asporin was an independent prognostic factor for postoperative liver fibrosis (95% confidence interval: 0.114-1.291, p = 0.002). TGF-β-related proteins dramatically fluctuated before and after LSG and were correlated with NAFLD pathogenesis. Asporin may be a useful prognostic marker of liver fibrosis in NAFLD after LSG.

Aim: Hepatitis E virus (HEV) causes subclinical or acute self-limiting hepatitis. We surveyed the current seroprevalence and incidence of HEV infection among the general population in Iwate Prefecture, Japan, where the endemic infection is presumed to be low., Methods: Between 2014 and 2016, we recruited individuals from Iwate Prefecture, Japan, who visited a general medical work-up program. Serum anti-HEV antibody and HEV RNA were measured twice, with an interval of 2 years. Anti-HEV antibody was measured with enzyme-linked immunosorbent assay and HEV RNA with reverse transcription-polymerase chain reaction., Results: Study participants comprised 1284 Japanese (650 men and 634 women) with age ranging 20-89 years. A total of 90 participants were found to be positive for anti-HEV immunoglobulin G on the first visit, with a prevalence of 7.0% (95% confidence interval [CI] 5.6%-8.4%). Seroprevalence was higher in men than in women (10.1% vs. 3.7%, p < 0.001), and in those aged in their 50s-80s than in those aged in their 20s-40s (p = 0.006). Positive seroconversion indicating new HEV infection was found in seven of 1194 seronegative participants (0.59%; 95% CI 0.15%-1.0%), indicating the incidence of HEV infection to be 272 per 100 000 person-years (95% CI 109-561)., Conclusions: Our observations suggest that the incidence of HEV infection is high and that it is a leading cause of hepatitis virus infection in Iwate Prefecture, Japan., (© 2023 Japan Society of Hepatology.)

Background Because of the global increase in the incidence of nonalcoholic fatty liver disease, the development of noninvasive, widely available, and highly accurate methods for assessing hepatic steatosis is necessary. Purpose To evaluate the performance of models with different combinations of quantitative US parameters for their ability to predict at least 5% steatosis in patients with chronic liver disease (CLD) as defined using MRI proton density fat fraction (PDFF). Materials and Methods Patients with CLD were enrolled in this prospective multicenter study between February 2020 and April 2021. Integrated backscatter coefficient (IBSC), signal-to-noise ratio (SNR), and US-guided attenuation parameter (UGAP) were measured in all participants. Participant MRI PDFF value was used to define at least 5% steatosis. Four models based on different combinations of US parameters were created: model 1 (UGAP alone), model 2 (UGAP with IBSC), model 3 (UGAP with SNR), and model 4 (UGAP with IBSC and SNR). Diagnostic performance of all models was assessed using area under the receiver operating characteristic curve (AUC). The model was internally validated using 1000 bootstrap samples. Results A total of 582 participants were included in this study (median age, 64 years; IQR, 52-72 years; 274 female participants). There were 364 participants in the steatosis group and 218 in the nonsteatosis group. The AUC values for steatosis diagnosis in models 1-4 were 0.92, 0.93, 0.95, and 0.96, respectively. The C-indexes of models adjusted by the bootstrap method were 0.92, 0.93, 0.95, and 0.96, respectively. Compared with other models, models 3 and 4 demonstrated improved discrimination of at least 5% steatosis ( P < .01). Conclusion A model built using the quantitative US parameters UGAP, IBSC, and SNR could accurately discriminate at least 5% steatosis in patients with CLD. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Han in this issue.

Introduction: The aim is to clarify the hepatitis C virus (HCV) status of hemodialysis (HD) patients and patient management after HCV elimination., Methods: Questionnaire survey was conducted in Iwate prefecture, Japan from 2016 to 2021., Results: Patients underwent HD was 2944, including 132 anti-HCV antibody-positive patients, with 91 HCV RNA-positive patients. Of the 91 HCV RNA-positive patients, 51 received antiviral treatment. Sustained virological response (SVR) rate was 94%. The patients treated with direct antiviral agents had significantly lower mortality rate than the untreated patients, and no liver-related deaths occurred in patients who achieved SVR or in HCV RNA-negative patients. The HCV RNA-positive prevalence was finally 0.79%. Approximately 40% of the facilities had dedicated beds and dialysis-related items for patients who achieved an SVR., Conclusion: To eliminate HCV in HD facilities, it is necessary to promote HCV RNA testing for anti-HCV antibody-positive patients and to provide antiviral treatment for HCV RNA-positive patients. Additionally, collaboration among hepatologists and HD specialists are essential., (© 2023 The Authors. Therapeutic Apheresis and Dialysis published by John Wiley & Sons Australia, Ltd on behalf of International Society for Apheresis and Japanese Society for Apheresis.)

Aim: We aimed to establish a method that will identify patients at a high risk for progressive phenotype of fatty liver., Methods: Patients with fatty liver who underwent liver biopsy between July 2008 and November 2019 were included as cohort 1, and those who underwent abdominal ultrasound screening examination by general physicians between August 2020 and May 2022 served as cohort 2. According to the definition of metabolic dysfunction-associated fatty liver (MAFLD), the subjects were classified by body mass index of ≥23, diabetes mellitus, and coexistence of two or more metabolic risk items. The progressive phenotype of MAFLD is defined by significant fibrosis complicated with either nonalcoholic fatty liver disease activity score ≥4 (BpMAFLD) or steatosis grade ≥2 by ultrasound examination (UpMAFLD)., Results: One hundred sixty-eight patients and 233 patients were enrolled in cohorts 1 and 2, respectively. In cohort 1, the prevalence of BpMAFLD was 0% in patients without a complicating factor (n = 10), 13% in those with one complicating factor (n = 67), 32% in those with two (n = 73), and 44% in those with all three complicating factors (n = 36). A logistic regression analysis revealed that factors in the MAFLD definition were significantly associated with BpMAFLD. In cohort 2, a criterion of two or more positive MAFLD definitions was found to have a 97.4% negative predictive value for the diagnosis of UpMAFLD., Conclusion: Patients with two or more complicating factors in the MAFLD definition should have further evaluation for liver fibrosis., (© 2023 Japan Society of Hepatology.)

Many arthropods harbour bacterial symbionts, which are maintained by vertical and/or horizontal transmission. Spiroplasma is one of the most well-known symbionts of ticks and other arthropods. It is still unclear how Spiroplasma infections have spread in tick populations despite its high prevalence in some tick species. In this study, Ixodes ovatus, which has been reported to harbour Spiroplasma ixodetis at high frequencies, was examined for its vertical transmission potential under experimental conditions. Next, two isolates of tick-derived Spiroplasma, S. ixodetis and Spiroplasma mirum, were experimentally inoculated into Spiroplasma-free Haemaphysalis longicornis colonies and the presence of Spiroplasma in their eggs and larvae was tested. Our experimental data confirmed that S. ixodetis was transmitted to eggs and larvae in a vertical manner in the original host I. ovatus. In the second experiment, there was no significant difference in engorged weight, egg weight, and hatching rate between Spiroplasma-inoculated and control H. longicornis groups. This suggested that Spiroplasma infection does not affect tick reproduction. Spiroplasma DNA was only detected in the eggs and larvae derived from some individuals of S. ixodetis-inoculated groups. This has demonstrated the potential of horizontal transmission between different tick species. These findings may help understand the transmission dynamics of Spiroplasma in nature and its adaptation mechanism to host arthropod species., (© 2023. Springer Nature Limited.)

Background and Aims: Acute liver injury (ALI) due to autoimmune hepatitis (AIH) can be treated by immunosuppression. In contrast, idiosyncratic drug-induced liver injury (DILI) had a poor prognosis. DILI thus needs to be distinguished from non-DILI., Methods: Twenty-nine patients with DILI and 77 with non-DILI (42 of AIH and 35 with undetermined cause) diagnosed during 2005-2017 comprised the derivation cohort. 110 patients with ALI due to either AIH, DILI, or obscure causes at 6 liver centers during 2010-2015 were the validation cohort. Revised international AIH group scores (IAIHGs) and the Roussel-Uclaf Causality Assessment Method (RUCAM) were modified to calculate results using medical interviews and laboratory data without chronological changes. Diagnostic accuracy for the distinction of DILI and non-DILI was evaluated by receiver operating characteristic analysis and results were expressed as the area under the curve (AUC). This study received institutional institutional review board approval (MH2020-205)., Results: The AUCs of modified IAIHGs and RUCAM scores for the diagnosis of DILI were 0.96 and 1.00 when cut-off values were set at 3 for the modified RUCAM and 5 for the modified IAIHGs in the derivation cohort. In the validation cohort, the AUCs of modified IAIHGs and RUCAM scores for the diagnosis of DILI were 0.95 and 0.97, respectively. The accuracy of the combination of the modified scores was 81% (89/110)., Conclusion: Modified diagnostic scores based on detailed medical interviews and routine laboratory data can distinguish DILI from non-DILI in patients with ALI., (© 2023 The Authors.)

Sarcopenia is a common complication in patients with chronic liver disease (CLD); however, the progression of sarcopenia over the course of CLD is unclear. The present study therefore determined the natural course of the progression of sarcopenia in patients with CLD and the effect of liver cirrhosis (LC) on this progression. This observational study analyzed patients with chronic hepatitis (CH) (n = 536) and LC (n = 320) who underwent evaluations of the grip strength and skeletal muscle mass of the arms, trunk, and legs for sarcopenia between 2016 and 2021. A bioelectrical impedance analysis was used to evaluate skeletal muscle mass. The annual rate of change (%/year) in two tests were compared between patients with CH and LC. The annual rates of change in grip strength and skeletal muscle of arms, trunk, and legs of patients with CH and LC were - 0.84% vs. - 2.93%, - 0.54% vs. - 1.71%, - 0.43% vs. - 1.02%, and - 0.76% vs. - 1.70% for men and - 0.12% vs. - 1.71%, - 0.66% vs. - 1.71%, - 0.49% vs. - 1.31%, and - 0.76% vs. - 1.54% for women, respectively. The progression of sarcopenia was greater in LC patients than in CH patients and that the decrease in grip strength was most prominent in the progression of sarcopenia in patients with LC., (© 2023. The Author(s).)

The prevalence of nonalcoholic steatohepatitis (NASH) in severely obese Japanese patients is extremely high. However, there are currently no methods other than liver biopsy to assess hepatic steatosis and fibrosis. The purpose of this study was to comprehensively analyze changes in fatty acid (FA) and serum-free fatty acid (FFA) metabolism in severely obese Japanese patients to determine whether these could be surrogate markers. In this study, we enrolled 20 Japanese patients who underwent laparoscopic sleeve gastrectomy (LSG) for severe obesity and intraoperative liver biopsy. Serum FFAs were analyzed with liquid chromatography-mass spectrometry, and FAs in liver tissue were assessed using matrix-assisted laser desorption/ionization-imaging mass spectrometry to determine FAs that may be indicative of a positive NASH diagnosis. All patients showed significant weight loss and metabolic improvement following LSG. Regarding weight loss and metabolic improvement indices, 23 FFAs showed significant correlations with the baseline data. Narrowing down the phospholipids to commonly detected FAs detected in liver tissue, PC(18:1e&#95;20:4) was significantly changed in the NASH group, suggesting that it could be used as a surrogate marker for NASH diagnosis. The results suggest that specific postoperative changes in blood phospholipids could be used as surrogate markers for NASH treatment.

Non-alcoholic fatty liver disease (NAFLD), the hepatic phenotype of metabolic syndrome, has been identified as a major health concern as the number of cirrhosis and deaths associated with NAFLD is expected to increase. Although fructose intake has been considered to be a progressive factor in the pathophysiology of NAFLD, it remains unclear how fructose contributes to hepatocellular damage during lipotoxicity. In the present study, we aimed to analyze the hepatotoxicity of fructose in steatosis. Fructose effects on lipotoxicity were evaluated in HepG2 cells, primary mouse hepatocytes, and in mice fed a high-fat diet with or without sucrose (HFDS/HFD). Oleate induced caspase 3-independent cell death in HepG2 cells and primary mouse hepatocytes cultured in fructose-supplemented medium, and induced cleavage of caspase-1 in primary mouse hepatocytes. In addition, the number of cells stained positive for reactive oxygen species (ROS) was significantly increased, and N-acetyl cysteine was found to inhibit ROS production and cell death. Cell death was confirmed to be through necrotic cell death, and phosphorylation of mixed lineage kinase domain-like (MLKL) protein was observed. Taken together, hepatocyte cytotoxicity was due to excess fructose with oleate-induced ROS-mediated necroptosis. HFDS mice showed progressive hepatic fibrosis and inflammation and a higher NAS score than HFD mice or mice fed a control diet. The expression of hemoxygenase-1, phosphorylation of MLKL, cleavage of caspase1, and apoptosis were significantly increased in the livers of mice fed a HFDS. Overall, excess fructose intake induces necroptosis through the production of ROS and enhances the toxicity of oleatic cytotoxicity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: Myostatin has been assumed to be involved in the development of sarcopenia in patients with chronic liver disease, but the effect of hepatitis C virus (HCV) elimination on myostatin is unclear. The aim of this study was to assess the effect of a sustained virologic response at 24 wk (SVR24) after direct-acting antiviral (DAA) therapy on serum myostatin levels in patients infected with HCV., Methods: In this single-center retrospective study based on data collected from a university hospital, we analyzed patients infected with HCV who were treated with DAA between 2014 and 2017. We compared the serum myostatin level before and after DAA treatment and evaluated the correlation between myostatin and laboratory data., Results: In the 91 participants, the median myostatin level at the start of DAA and after achieving an SVR24 were 3042 (924-10177) and 3349 (498-7963) pg/mL, respectively. There was no significant difference in the myostatin level between the start of DAA treatment and after achieving an SVR24 (P = 0.79). The serum myostatin levels were significantly higher in men than in women and in patients with cirrhosis than in patients with chronic hepatitis both at the start of DAA and after achieving an SVR24. Serum myostatin levels showed a significant positive correlation with the skeletal muscle index and liver fibrosis markers (e.g., type Ⅳ collagen 7S, aspartate aminotransferase-platelet ratio index score, and fibrosis-4 index)., Conclusions: Viral eradication by DAA treatment did not decrease the serum myostatin level in patients infected with HCV., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare no conflict of interest.

Ticks are the second most important vector capable of transmitting diseases affecting the health of both humans and animals. Amblyomma testudinarium Koch 1844 (Acari: Ixodidae), is a hard tick species having a wide geographic distribution in Asia. In this study, we analyzed the composition of A. testudinarium whole mitogenomes from various geographical regions in Japan and investigated the population structure, demographic patterns, and phylogeographic relationship with other ixodid species. In addition, we characterized a potentially novel tick species closely related to A. testudinarium from Myanmar. Phylogeographic inference and evolutionary dynamics based on the 15 mitochondrial coding genes supported that A. testudinarium population in Japan is resolved into a star-like haplogroup and suggested a distinct population structure of A. testudinarium from Amami island in Kyushu region. Correlation analysis using Mantel test statistics showed that no significant correlation was observed between the genetic and geographic distances calculated between the A. testudinarium population from different localities in Japan. Finally, demographic analyses, including mismatch analysis and Tajima's D test, suggested a possibility of recent population expansion occurred within Japanese haplogroup after a bottleneck event. Although A. testudinarium has been considered widespread and common in East and Southeast Asia, the current study suggested that potentially several cryptic Amblyomma spp. closely related to A. testudinarium are present in Asia., Competing Interests: The authors have no competing interests to declare., (© 2022 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

Aim: Hepatic encephalopathy (HE) development is crucial in liver transplantation for patients with acute liver injury (ALI) and failure (ALF); to predict HE development, the Japan Hepatic Encephalopathy Prediction (JHEP) model, calculated using age, etiology, prothrombin time (PT), and total bilirubin, was established in 2004, and a referral system to the liver center was implemented using the JHEP model from April 2004., Methods: The JHEP model's ability to predict HE development in 460 consecutive patients with ALI between April 2004 and January 2021 using data from the referral system was evaluated, and the JHEP model was revised., Results: During the observation period, 7.8% patients developed HE. There was no difference in the proportion of HE development among the etiologies. In the Hosmer-Lemeshow test for HE development prediction, the JHEP model, revised JHEP (rJHEP) model, which was calculated without etiology data, and the modified JHEP model, which used the PT international ratio instead of PT in the rJHEP model, were good fitting models. Upon 30% random sampling from the total patients 60 times, the receiver operating curve analysis of both JHEP and rJHEP models for HE development was performed in all the datasets. The area under the curve of the JHEP model was subtracted from that of the rJHEP model (95% confidential interval, 0.000516-0.01793)., Conclusions: The referral system using the JHEP model reduced the difference in the risk for HE development among each etiology; the rJHEP model had a better prediction ability for HE development than the JHEP model., (© 2022 Japan Society of Hepatology.)

Practitioners routinely perform intraoperative liver biopsies during laparoscopic sleeve gastrectomy (LSG) to evaluate nonalcoholic fatty liver disease (NAFLD). In some patients, hepatocyte ballooning, inflammation, and fibrosis without steatosis are observed, even in the absence of other etiologies. We call this finding indeterminable nonalcoholic steatohepatitis (Ind-NASH). In this study, we clarified the prevalence, as well as histopathological and clinical features, of Ind-NASH through intraoperative liver biopsy in Japanese patients presenting with severe obesity. We enrolled 63 patients who had undergone LSG and intraoperative liver biopsy. In patients diagnosed with histopathological NASH, we performed protocol liver biopsies at 6 and 12 months after LSG. We statistically analyzed these histopathological findings and clinical parameters and found the prevalence rate of Ind-NASH discovered through intraoperative biopsy to be 15.9%. Protocol liver biopsy also revealed that Ind-NASH was an intermediate condition between NASH and normal liver. The clinical features of patients with Ind-NASH are a higher body weight compared to NASH (134.9 kg vs. 114.7 kg; p = 0.0245), stronger insulin resistance compared to nonalcoholic fatty liver (homeostasis model assessment-insulin resistance: 7.1 vs. 4.9; p = 0.0188), and mild liver dysfunction compared to NASH. Patients with Ind-NASH observed positive weight-loss effects from a preoperative diet compared to the postoperative course (percentage total weight loss: 32.0% vs. 26.7%; p < 0.0001). Patients with Ind-NASH may also be good candidates for metabolic surgery owing to their good treatment response; therefore, efforts should be made by specialists in the near future to deeply discuss and define Ind-NASH.

The liver has a remarkable regenerative capacity with different modes of regeneration according to the type and extent of an injury. It has been reported that mature hepatocytes could transdifferentiate into a cholangiocyte phenotype. Sry HMG box protein 9 (SOX9) is one of the earliest biliary markers that regulate bile duct development. We have found that SOX9-positive biphenotypic hepatocytes appear in severe acute liver injury patients' liver specimens accompanied by an elevation in plasma interleukin-8 levels. In vitro assays revealed that interleukin-8 homologs induce the expression of SOX9 in mature mouse hepatocytes. Here, we describe the methods used to detect SOX9-positive hepatocytes in human liver specimens and to induce SOX9-positive hepatocytes in mature mouse hepatocytes., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Primary biliary cholangitis (PBC) is considered to be caused by the interaction between genetic background and environmental triggers. Previous case-control studies have indicated the associations of environmental factors (tobacco smoking, a history of urinary tract infection, and hair dye) use with PBC. Therefore, we conducted a multicenter case-control study to identify the environmental factors associated with the development of PBC in Japan., Methods: From 21 participating centers in Japan, we prospectively enrolled 548 patients with PBC (male/female = 78/470, median age 66), and 548 age- and sex-matched controls. These participants completed a questionnaire comprising 121 items with respect to demographic, anthropometric, socioeconomic features, lifestyle, medical/familial history, and reproductive history in female individuals. The association was determined using conditional multivariate logistic regression analysis., Results: The identified factors were vault toilet at home in childhood [odds ratio (OR), 1.63; 95% confidence interval (CI), 1.01-2.62], unpaved roads around the house in childhood (OR, 1.43; 95% CI, 1.07-1.92), ever smoking (OR, 1.70; 95% CI, 1.28-2.25), and hair dye use (OR, 1.57; 95% CI, 1.15-2.14) in the model for lifestyle factors, and a history of any type of autoimmune disease (OR, 8.74; 95% CI, 3.99-19.13), a history of Cesarean section (OR, 0.20; 95% CI, 0.077-0.53), and presence of PBC in first-degree relatives (OR, 21.1; 95% CI, 6.52-68.0) in the model for medical and familial factors., Conclusions: These results suggest that poor environmental hygiene in childhood (vault toilets and unpaved roads) and chronic exposure to chemicals (smoking and hair dye use) are likely to be risk factors for the development of PBC in Japan., (© 2021. Japanese Society of Gastroenterology.)

A 78-year-old woman who was diagnosed with acute liver failure due to an undetermined cause presented with liver atrophy. Coagulopathy was normalized at 35 days of hospitalization, although atrophy in the liver persisted. During the observation period, alpha-fetoprotein (AFP) bi-modally increased at 36 and 377 days. Around the second peak of AFP, the liver volume was regained within the normal range. Fucosylated AFP was found at the first peak but not at the second peak. Cytokines/chemokines were simultaneously evaluated, and the results were evaluated using PANTHER ( http://www.pantherdb.org/ ). Although transaminase and prothrombin time were within the normal range, cytokines/chemokines associated with angiogenesis and inflammation increased prior to the second peak of AFP. Our study suggests that the first peak of AFP occurs in response to acute insult, while the second peak may be associated with the resolution of liver fibrosis. The present case provides new insights into the mechanism of AFP elevation., (© 2021. Japanese Society of Gastroenterology.)

Introduction: Ammonia is a key component in the pathogenesis of hepatic encephalopathy. Branched-chain amino acids (BCAA) have been reported to improve the symptoms of HE induced by hyperammonemia; however, we recently reported that ammonia increases intracellular levels of BCAA and exerts toxic effects on astrocytes., Objectives: This follow-up study was designed to confirm the direct effects of BCAA on human astrocytes and clarify their underlying mechanisms using metabolome analysis and evaluation of associated signaling., Methods: We performed cytotoxicity and cell proliferation tests on astrocytes following BCAA treatment with and without ammonium chloride (NH 4 Cl) and then compared the results with the effects of BCAA on hepatocytes and neurons. Subsequently, we used metabolomic analysis to investigate intracellular metabolite levels in astrocytes with and without BCAA treatment., Results: The astrocytes showed increased leakage of intracellular lactate dehydrogenase and reduced proliferation rate upon BCAA treatment. Interestingly, our analysis showed a BCAA-induced impairment of intracellular glycolysis/glyconeogenesis as well as amino acid and butyric acid metabolism. Furthermore, BCAA treatment was found to cause decreased levels of Glut-1 and phosphorylated GSK-3 β and mTOR in astrocytes., Conclusions: Although further investigations of the effect of BCAA on human astrocytes with hyperammonemia are needed, our work demonstrates that BCAA supplementation has direct negative effects on astrocyte survival and intracellular metabolism., Competing Interests: All authors declare no conflict of interest., (Copyright © 2021 Ting Wang et al.)

Purpose: The aim of this study was to examine the predictive scoring system of advanced liver fibrosis in severely obese Japanese patients., Methods: Seventy-two patients underwent laparoscopic sleeve gastrectomy and intraoperative liver biopsies. We classified these patients into two groups: Brunt stage ≥ 2 (advanced fibrosis) and 0/1 (none/mild fibrosis). A logistic regression analysis was performed to identify the predictors of advanced fibrosis., Results: Sixteen patients had advanced fibrosis, while 56 had no/mild fibrosis. The prevalence of type 2 diabetes mellitus (T2DM) in advanced fibrosis group was significantly higher than in none/mild fibrosis. An univariate analysis of the factors predicting advanced fibrosis showed significant differences in AST/ALT ratio, serum insulin levels, HOMA-IR, and type IV collagen 7S in the T2DM group. According to a multivariate analysis, type IV collagen 7S was an independent predictor and the cutoff value was 5.6 ng/mL. We created a flow chart; high risk (T2DM and type IV collagen 7S ≥ 5.6 ng/mL), moderate risk (T2DM and type IV collagen 7S < 5.6 ng/mL), and low risk (non-DM). For those at high risk, the sensitivity, specificity, positive predictive value, and negative predictive value were 56.2%, 94.4%, 75.0%, and 87.9%, respectively., Conclusion: This classification system has the potential to accurately categorize the risk of liver fibrosis., (© 2021. Springer Nature Singapore Pte Ltd.)

Nonalcoholic steatohepatitis (NASH) and glucose intolerance are associated with an increased risk of mortality in patients with severe obesity; however, whether histological findings of the liver are related to glucose intolerance in these patients remain unknown. Sixty-nine consecutive patients who underwent metabolic surgery between June 2008 and February 2020 were included; histological findings of the liver and laboratory data were analyzed. Twenty patients with biopsy-proven NASH were chronologically evaluated using sequential biopsies; data before metabolic surgery was considered as the baseline. Glucose intolerance-demonstrated by an increased area under the curve (AUC) for blood sugar (BS) during the 75-g oral glucose tolerance test-and increased homeostatic model assessment for insulin resistance (HOMA-IR) correlated with the grade of hepatocyte ballooning in patients. Patients with persistent ballooning at the follow-up biopsy had a higher HOMA-IR, high AUC for BS, and lower adiponectin level than those in patients in whom ballooning was eliminated, while there was no significant difference in body weight. We concluded that glucose intolerance was associated with the grade of hepatocyte ballooning; additionally, persistent hepatocyte ballooning sustained glucose intolerance, while elimination of hepatocyte ballooning improved the condition. Glucose intolerance may, thus, mediate balloon formation of the hepatocyte., (© 2021. The Author(s).)

Patients with severe acute liver injury (SLI) usually recover spontaneously. However, some SLI patients progress to acute liver failure with varying degrees of hepatic encephalopathy. Acute liver failure is associated with high mortality and can be substantially reduced by liver transplantation. Therefore, distinguishing SLI patients who might progress to acute liver failure and are at a risk of death is important when evaluating patients needing liver transplantation. The present study aimed to determine whether technetium-99m-diethylenetriaminepentaacetic acid galactosyl human serum albumin (Tc-99m GSA) scintigraphy can predict the prognosis of patients with SLI. This prospective observational study included 69 SLI patients. The accuracy of Tc-99m GSA for predicting death or liver transplantation for 6 months was assessed. Between the two groups of patients stratified based on the cut-off values from the receiver operating characteristic curves, 6-month transplant-free survival was compared. Sixteen (23.2%) patients died or underwent liver transplantation from admission (poor outcome). The hepatic accumulation index was calculated by dividing the radioactivity of the liver region of interest by that of the liver-plus-heart region of interest at 15 min (i.e., LHL15). The LHL15 in the 16 patients (0.686) was significantly lower than that in survivors (0.836; P < 0.0001). The optimal LHL15 cut-off for distinguishing poor outcome and survival was 0.737 with a sensitivity of 81.3%, specificity of 88.7%, and area under the curve of 0.907 (95% CI, 0.832-0.981). When patients were divided into two groups based on the LHL15 cut-off value, the 6-month transplant-free survival was significantly lower in patients with an LHL15 level ≤ 0.737. Tc-99m GSA scintigraphy may help predict the prognosis of patients with SLI.

Background and Aims: Acute liver failure (ALF) is a rare but dramatic clinical syndrome characterized by massive hepatic necrosis leading to multiorgan failure. It is difficult to predict the outcomes in patients with ALF using existing prognostic models. We aimed to analyze hepatic perfusion using contrast-enhanced ultrasound and Doppler ultrasound in patients with ALF and investigate its utility as a prognostic biomarker., Approach and Results: In this prospective observational study, 208 patients with acute liver injury/ALF were enrolled from 2015 to 2019. We evaluated 50 consecutive patients with ALF with Doppler ultrasound and contrast-enhanced ultrasound performed on admission. The cases were divided into the following two groups: survivors (recovered without surgical intervention) and nonsurvivors (died of ALF or underwent liver transplantation). The time to peak and peak intensity of hepatic artery, portal vein, hepatic vein, and liver parenchyma were calculated using the time-intensity curve analysis. The hepatic artery (HA) resistive index was calculated using the fast Fourier transform analysis of Doppler ultrasound. The time interval (TI) between the time to peak of HA and liver parenchyma (LP) was significantly shorter in the nonsurvivors than in the survivors (P < 0.0001). The area under the receiver operating curve values for TI (HA, LP), Japanese scoring system, HE prediction model, Model for End-Stage Liver Disease score, and King's College Hospital criteria for the prediction of poor prognosis were 0.953, 0.914, 0.861, 0.816, and 0.731, respectively. The most appropriate cutoff value of TI (HA, LP) was 6.897 seconds; the sensitivity, specificity, positive and negative predictive values were 94.4%, 90.6%, 85.0%, and 96.7%, respectively., Conclusions: TI (HA, LP) accurately predicts the outcome in patients with ALF and may be useful in clinical decision making., (© 2020 The Authors. HEPATOLOGY published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Ribosomal RNA genes have been widely used for the identification and phylogenetic analysis of various organisms, including parasitic protozoa. Here, we report nine near full-length Theileria orientalis 18S rRNA gene sequences from cattle from different areas of Myanmar. Phylogenetic analysis of the 18S rRNA genes revealed a considerably close genetic relationship among T. orientalis isolates from Australia, China, Japan, Korea, Myanmar, and Pakistan. We also obtained four Theileria velifera-like (Theileria cf. velifera) 18S rRNA gene sequences from two cattle and two water buffaloes from the northernmost area of Myanmar. The phylogenetic analysis of T. cf. velifera isolates from Myanmar along with T. velifera and T. cf. velifera isolates from African countries suggested an evolutionary lineage of greater complexity in T. velifera-related parasites. DNA alignment analysis indicated the presence of 51 and 55 nucleotide variation positions within the 18S rRNA genes from 15 T. orientalis and 11 T. velifera-related isolates, respectively. Alignment entropy analysis of the 18S rRNA sequences indicated that both T. orientalis and T. velifera-related isolates had three hyper variable regions, corresponding to V2, V4, and V7 regions in eukaryotes. The degree of variation was prominent in the V2 in T. orientalis and V4 in T. velifera-related isolates. The secondary structure analysis of the 18S rRNA predicted using minimum free energy algorism revealed that the structure of V4 region differed most significantly between T. orientalis and T. velifera. These results provide novel insights into common structures, variations and functions of small subunit rRNA in Theileria species., (Copyright © 2021 Elsevier B.V. All rights reserved.)