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Chen-Hua Liu,1–3 Jia-Horng Kao1–3 1Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 2Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; 3Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan Abstract: Asia is endemic for hepatitis C virus (HCV) infection, which is the leading cause of cirrhosis, hepatic decompensation, hepatocellular carcinoma , and liver transplantation worldwide. HCV has six major genotypes and each HCV genotype has its specific geographic distribution. HCV genotypes 1, 2, 3, and 6 are common in Asia. The aim of HCV treatment is to eradicate the virus by effective therapeutic agents; viral clearance is durable after long-term post-treatment follow-up. In most Asian countries, peginterferon alfa (PEG-IFN α) in combination with ribavirin remains the standard of care, and the overall sustained viral response (SVR) rate in Asian HCV patients is higher than that in Western patients. The differences are most significant in patients with HCV genotype 1 (HCV-1) infection, which is attributed to the higher frequency of IFN-responsive or favorable interleukin-28B (IL-28B) genotype in Asian populations than in other ethnic populations. In addition, the introduction of response-guided therapy, where the optimized treatment duration is based on the early viral kinetics during the first 12 weeks of treatment, increases the SVR rate. Recently, telaprevir or boceprevir-based triple therapy was found to further improve the SVR rate in treated and untreated HCV-1 patients and has become the new standard of care in Western and some Asian countries. Many novel direct-acting antiviral agents, either in combination with PEG-IFN α plus ribavirin or used as IFN-free regimens are under active investigation. At the time of this writing, simeprevir and sofosbuvir have been approved in the US. Because the SVR rates in Asian HCV patients receiving PEG-IFN α plus ribavirin therapy are high, health care providers should judiciously determine the clinical usefulness of these novel agents on the basis of treatment duration, anticipated viral responses, patient tolerance, financial burdens, and drug accessibility. Keywords: PEG-IFN α, HCV, SVR, RGT, IL28B

Background. It is unclear whether hepatitis B e antigen (HBeAg) seroconversion induced by nucleos(t)ide analogues (NUC) has a prognosis that is similar to that of spontaneous HBeAg seroconversion. Methods. A total of 148 noncirrhotic NUC-induced HBeAg seroconverters were consecutively enrolled. A historical control of 407 noncirrhotic spontaneous HBeAg seroconverters was also recruited. We compared the rates of HBeAg seroreversion and HBV reactivation between these 2 cohorts. Results. There were 1652.8 and 465.2 person-years of follow-up for spontaneous and NUC-induced HBeAg seroconverters, respectively. Compared with NUC-induced seroconverters, spontaneous seroconverters were younger when achieving HBeAg seroconversion. We thus compared these 2 cohorts according to their age at HBeAg seroconversion. In patients achieving HBeAg seroconversion before 30 years of age, NUC-induced seroconverters had a higher 2-year HBeAg seroreversion rate than spontaneous seroconverters (12.0% vs 2.9%; P = .004) and were at a higher risk of HBV reactivation (hazard ratio, 4.6; 95% confidence interval, 1.5-14.4). Using multivariate analysis, NUC-induced HBeAg seroconversion remained a risk factor of both endpoints in young HBeAg seroconverters. Conclusion. NUC-induced HBeAg seroconverters may not have durable response after stopping therapy. For patients achieving HBeAg seroconversion before 30 years of age, the risk of HBeAg seroreversion and HBV reactivation is higher in NUC-induced seroconverters than spontaneous HBeAg seroconverters. [ABSTRACT FROM AUTHOR]

Objectives: To develop a non-invasive MRI method for evaluation of liver fibrosis, with histological analysis as the reference standard.Methods: The study protocol was approved by the Institutional Review Board for Human Studies of our hospital, and written informed consent was obtained from all subjects. Seventy-nine subjects who received dynamic contrast-enhanced MRI (DCE-MRI) with Gd-EOB-DTPA were divided into three subgroups according to Metavir score: no fibrosis (n = 30), mild fibrosis (n = 34), and advanced fibrosis (n = 15). The DCE-MRI parameters were measured using two models: (1) dual-input single-compartment model for arterial blood flow (F (a)), portal venous blood flow, total liver blood flow, arterial fraction (ART), distribution volume, and mean transit time; and (2) curve analysis model for Peak, Slope, and AUC. Statistical analysis was performed with Student's t-test and the nonparametric Kruskal-Wallis test.Results: Slope and AUC were two best perfusion parameters to predict the severity of liver fibrosis (>F2 vs. ≦F2). Four significantly different variables were found between non-fibrotic versus mild-fibrotic subgroups: F (a), ART, Slope, and AUC; the best predictor for mild fibrosis was F (a) (AUROC:0.701).Conclusions: DCE-MRI with Gd-EOB-DTPA is a noninvasive imaging, by which multiple perfusion parameters can be measured to evaluate the severity of liver fibrosis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Chronic use of morphine causes rewarding effects and behavioral sensitization, which may lead to the development of craving for morphine. A number of studies indicate that the NMDA receptors may be involved in these effects, especially the NR2B-containing NMDA receptors. It is also well recognized that the nucleus accumbens (NAc) and the ventral tegmental area (VTA) are involved in drug addiction, including morphine addiction. AIMS: In this study, we further investigate the role of the NR2B subunit of NMDA receptors at NAc or VTA in morphine rewarding effects and behavioral sensitization. METHODS AND RESULTS: The siRNA against the NR2B subunit of NMDA receptors was locally injected to decrease the expression of NR2B at NAc or posterior VTA in male Sprague-Dawley (S.D.) rats in the present study. The rats were then treated with morphine chronically. A conditioned place preference (CPP) test was used to examine the rewarding effect, and locomotor activity was measured to determine the behavioral sensitization induced by chronic morphine treatment. Results showed that morphine-induced rewarding behavior but not behavioral sensitization was abolished when the NR2B subunit of NMDA receptors at the NAc were significantly decreased. The dopamine turnover rate was not altered by the decrease of NR2B subunit at NAc. CONCLUSION: These findings suggest that the NR2B subunit of NMDA receptors at the NAc is involved in morphine-induced rewarding effect and may not be through directly interacting with dopamine neurons. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, affecting >30% of the global population. Metabolic dysregulation, particularly insulin resistance and its subsequent manifestation as type 2 diabetes mellitus, serves as the fundamental pathogenesis of metabolic liver disease. Clinical evidence of the recent nomenclature evolution is accumulating. The interaction and impacts are bidirectional between MASLD and diabetes in terms of disease course, risk, and prognosis. Therefore, there is an urgent need to highlight the multifaceted links between MASLD and diabetes for both hepatologists and diabetologists. The surveillance strategy, risk stratification of management, and current therapeutic achievements of metabolic liver disease remain the major pillars in a clinical care setting. Therefore, the Taiwan Association for the Study of the Liver (TASL), Taiwanese Association of Diabetes Educators, and Diabetes Association of the Republic of China (Taiwan) collaboratively completed the first guidance in patients with diabetes and MASLD, which provides practical recommendations for patient care., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Aims: Metabolic associated fatty liver disease (MAFLD) was proposed to replace "non-alcoholic fatty liver disease (NAFLD) with new diagnostic criteria." The group meeting these two diagnostic criteria is called "Overlapping Fatty Liver Disease (FLD)." Its clinical characteristics remain unknown., Methods: This study included participants from the Taiwan Bio-Bank database, where NAFLD was defined as hepatic steatosis in liver ultrasound, with exclusion of other known chronic liver diseases. MAFLD was defined as the presence of hepatic steatosis plus metabolic dysfunction, defined as having any of following three criteria: overweight/obesity, type 2 diabetes mellitus (DM), or ≥2 metabolic risk abnormalities in lean/normal weight subjects. According to these two diagnostic criteria, three groups were identified: "overlapping FLD", "NAFLD alone", and "MAFLD alone." NAFLD fibrosis score (NFS) >0.675 was defined as advanced liver fibrosis., Results: Eight thousand thirty-eight NAFLD participants (age 55.86 ± 10.12; males 41.07%) were included in the final analysis. Of them, "overlapping FLD" was diagnosed in 7377 (91.8%) and "NAFLD alone" in 661 (8.2%) participants. "Overlapping FLD" patients were older and had a higher percentage of male, worse metabolic profiles, higher NFS, and the percentage of carotid plaques was higher than those with "NAFLD alone." Multivariate analysis showed age, hypertension, DM, and BMI were positively associated with advanced liver fibrosis in "overlapping FLD" patients., Conclusions: "Overlapping FLD" is better for liver research due to identifying a high-risk population among NAFLD patients. NAFLD definition introduces the heterogeneity through "NAFLD alone" group and MAFLD criteria overcome this limitation., (© 2024 The Author(s). JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background & Aims: Data are limited on the risk of de novo hepatocellular carcinoma (HCC) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) after achieving sustained virologic response (SVR 12 ) using direct-acting antivirals (DAAs) for hepatitis C virus (HCV)., Methods: 1598 eligible patients received biannual alpha-fetoprotein (AFP) and liver imaging surveillance to detect de novo HCC beyond achieving SVR 12 . MASLD was defined as presence of controlled attenuation parameter (CAP) ≥ 248 dB/m and ≥ one cardiometabolic risk factor (CMRF). Cumulative HCC incidence was compared between patients with/without MASLD. We built univariable and multivariable Cox proportional hazards models to evaluate factors associated with HCC. Sensitivity analysis was performed using the Fine-Gray subdistribution hazards model. Additionally, we evaluated the mediation effect of MASLD on CMRFs and of CMRFs on MASLD for HCC using mediation analysis with bootstrapping., Results: The incidence rate of HCC was 1.44 per 100 person-years of follow-up (PYFU) [95% confidence interval (CI): 1.19-1.74]. Patients with MASLD had a higher cumulative HCC incidence than those without MASLD (log-rank test, p < 0.001). Multivariable Cox regression analysis revealed that in addition to age, sex, LSM, platelet count, and AFP, MASLD (adjusted hazard ratio (aHR): 2.07 [95% CI:1.36-3.16], p < 0.001) was independently associated with HCC. This finding was confirmed by the Fine-Gray model, which showed a subdistribution HR (sHR) of 2.07 (95% CI: 1.34-3.19, p < 0.001) for MASLD. MASLD significantly mediated CMRFs for HCC development., Conclusion: After achieving SVR 12 , patients with MASLD exhibited an increased HCC risk compared to those without MASLD. Vigilant HCC surveillance and control of CMRFs to mitigate the effect MASLD on HCC remain crucial for this population., Impact and Implications: The risk of de novo HCC among patients with MASLD, a novel nomenclature of steatotic liver disease (SLD), after the attaining of SVR 12 using DAAs remains to be confirmed. In this study recruiting 1598 patients in Taiwan, individuals with MASLD exhibited approximately a two-fold increased risk of de novo HCC, compared to those without MASLD after achieving SVR 12 . MASLD significantly mediated CMRFs for HCC development. Our findings underscore the critical importance of pharmacological interventions and proactive lifestyle modifications to control CMRFs in patients with MASLD, as well as the need for vigilant HCC surveillance to ensure favorable outcomes following HCV eradication., Competing Interests: Declaration of Competing Interest All authors declare no competing interests., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Hepatitis B virus (HBV)-specific T cell response is a major host immune response to control the virus. However, it is still unclear how it affects long-term outcomes of chronic hepatitis B patients, especially those who stop nucleos(t)ide analogue (NA) therapy. We aimed to explore whether the HBV-specific T cell response at the end of treatment (EOT) was associated with clinical outcomes., Methods: In a prospective cohort study, 51 HBeAg-negative patients who discontinued NA therapy were enrolled., Results: In a mean follow-up of 25.3 months, 25 patients developed clinical relapse. We found that a stronger hepatitis B core (HBc)-specific T cell response at EOT was associated with a lower risk of clinical relapse. Compared to the low-response group, the high-response group had a lower risk of clinical relapse with hazard ratio of 0.21 (95% CI: 0.05-0.88). The high HBc-specific T cell response was associated with reduced surge of HBV DNA and HBcrAg during the first year of follow-up. The T cell response at EOT was comparable between different NA treatments. Notably, the overall HBV-specific T cell response could be partially restored along with clinical relapse; however, such reinvigorated T cell response was not associated with HBsAg seroclearance., Conclusions: A higher HBc-specific T cell response at EOT was associated with lower risk of clinical relapse and reduced surge of HBV DNA and HBcrAg levels off NA therapy., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Background: Steatotic liver disease (SLD) is an emerging liver disease that has been associated with an increased risk for hepatocellular carcinoma (HCC). The impact of concurrent SLD on the prognosis of HCC remains unknown. This study investigates how concurrent SLD affects the outcomes of patients with HCC undergoing curative radiofrequency ablation (RFA) therapy., Methods: A retrospective analysis of patients with early-stage HCC receiving curative RFA at a tertiary medical center was conducted. Laboratory data and HCC characteristics were recorded and analyzed by a Cox proportional hazards regression model to predict recurrence and all-cause mortality after RFA., Results: A total of 598 patients with HCC were included between 2005 and 2015, with 139 and 459 classified in SLD and non-SLD groups, respectively. The SLD group exhibited a significantly better liver reserve and a lower cumulative incidence of HCC recurrence and liver-related and all-cause mortality after a median follow-up of 51 months. After adjusting for metabolic dysfunction, liver reserve, and HCC characteristics, the presence of SLD reduced all-cause mortality (adjusted hazard ratio [aHR], 0.67; 95% confidence interval [CI], 0.45-0.996; p = .048), which was supported by inverse probability weighting analysis (aHR, 0.65; 95% CI, 0.42-1.00; p = .049). Poor liver functional reserve (high albumin-bilirubin grades) increased all-cause mortality dose dependently. Barcelona Clinic Liver Cancer staging and a higher Fibrosis-4 index were predictors for HCC recurrence, whereas SLD was not., Conclusions: Among patients with HCC undergoing curative RFA, those with concurrent SLD had a lower risk of all-cause mortality compared to those with poor liver functional reserve., Plain Language Summary: The present research demonstrated that patients with both liver cancer and steatotic liver disease who received curative radiofrequency ablation for liver cancer survived longer compared to those without steatotic liver disease. Maintaining good liver function is an important prognostic factor for survival., (© 2024 American Cancer Society.)

Background: Chronic hepatitis C (CHC) increases the risk of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). This nationwide cohort study assessed the effectiveness of viral eradication of CHC., Methods: The Taiwanese chronic hepatitis C cohort and Taiwan hepatitis C virus (HCV) registry are nationwide HCV registry cohorts incorporating data from 23 and 53 hospitals in Taiwan, respectively. This study included 27,577 individuals from these cohorts that were given a diagnosis of CHC and with data linked to the Taiwan National Health Insurance Research Database. Patients received either pegylated interferon and ribavirin or direct-acting antiviral agent therapy for > 4 weeks for new-onset LC and liver-related events., Results: Among the 27,577 analyzed patients, 25,461 (92.3%) achieved sustained virologic response (SVR). The mean follow-up duration was 51.2 ± 48.4 months, totaling 118,567 person-years. In the multivariable Cox proportional hazard analysis, the hazard ratio (HR) for incident HCC was 1.39 (95% confidence interval [CI]: 1.00-1.95, p = 0.052) among noncirrhotic patients without SVR compared with those with SVR and 1.82 (95% CI 1.34-2.48) among cirrhotic patients without SVR. The HR for liver-related events, including HCC and decompensated LC, was 1.70 (95% CI 1.30-2.24) among cirrhotic patients without SVR. Patients with SVR had a lower 10-year cumulative incidence of new-onset HCC than those without SVR did (21.7 vs. 38.7% in patients with LC, p < 0.001; 6.0 vs. 18.4% in patients without LC, p < 0.001)., Conclusion: HCV eradication reduced the incidence of HCC in patients with and without LC and reduced the incidence of liver-related events in patients with LC., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectves: Among immunosuppressants, rituximab is most strongly associated with the risk of hepatitis B virus (HBV) reactivation in chronic HBV individuals. Current guidelines recommending antiviral prophylaxis for these patients on rituximab are predominantly based on studies in oncology. However, limited data existed for the precise risk of HBV flares, effectiveness and optimal duration of antiviral prophylaxis in rituximab-treated rheumatic patients, whose immune status and treatment regimen differ significantly from those of oncology patients. Therefore, we aimed to assess the incidence and clinical outcome of HBV reactivation in HBsAg-positive patients receiving rituximab for various autoimmune diseases who discontinue the antiviral agents., Methods: A retrospective analysis was performed on 95 hepatitis B surface antigen (HBsAg)-positive patients treated with rituximab for autoimmune diseases in a single centre in Taiwan. HBV related hepatitis, defined as alanine aminotransferase (ALT) more than 3 times of baseline level and concurrent HBV reactivation, after anti-viral discontinuation, was the primary endpoint. Factors associated with HBV hepatitis flare and off-antiviral hepatitis flare were also analysed., Results: With nucleos(t)ide analogues (NA) prophylaxis, no hepatitis flares occurred. However, without prophylaxis, 59% had flare (24.5 per 100 person-years) and 8% experienced liver decompensation. Concurrent steroid use was a dose-dependent risk factor for flare. After NA discontinuation, rituximab "retreatment" led to flares in 75% of cases and liver decompensation in 63% of patients. Stopping NAs within one-year post-rituximab, even without further rituximab treatment, resulted in a 38% flare rate., Conclusions: This study offers the direct evidence for the necessity of universal antiviral prophylaxis in rheumatic patients with chronic HBV receiving rituximab. After NA discontinuation, rituximab "retreatment" led to even higher flare rate and worse outcome. Patients who completed rituximab treatment should also keep antiviral agents for at least one more year to prevent hepatitis flare.

Background and Aim: Rituximab therapy is associated with a high risk of hepatitis B virus (HBV) reactivation. We aimed to assess whether the risk of reactivation differed among various underlying diseases and between hepatitis B surface antigen (HBsAg) carriers and patients with resolved HBV infection., Methods: We retrospectively analyzed patients with chronic or resolved HBV infection who received rituximab without prophylactic anti-HBV therapy at a tertiary medical center. The risks of HBV reactivation, hepatitis, and hepatic decompensation were compared between the patients with hematologic and rheumatic diseases., Results: There were 78 patients with hematologic diseases and 39 patients with rheumatic diseases included. Among them, 43 (59%) HBsAg-positive patients and 24 (55%) patients with resolved HBV infection experienced HBV reactivation at a median of 14.6 months after rituximab therapy. After rituximab treatment, the 1-year HBV reactivation rate among patients with hematologic and rheumatic diseases was 29% and 45% in HBsAg-positive patients, respectively, while the rates were 38% and 17% in patients with resolved HBV infection. The reactivation risk continued to increase even 2 years after rituximab therapy and was comparable between hematologic and rheumatic patients. A higher baseline HBV DNA level (≥20 IU/mL vs <20 IU/mL) was an independent predictor for HBV reactivation (adjusted hazard ratio [aHR]: 10.9, 95% confidence interval [CI]: 1.1-107) and HBV-associated hepatitis (aHR: 14.8, 95% CI: 1.4-158)., Conclusions: Rituximab therapy is associated with a 50-64% risk of HBV reactivation regardless of underlying diseases and HBsAg status. HBV DNA levels should be assessed before initiating rituximab., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background/aims: Hepatitis C virus (HCV) eradication using antiviral agents augments the metabolic profile. Changes in glycated hemoglobin (HbA1c) levels in chronic hepatitis C patients who receive glecaprevir/pibrentasvir (GLE/PIB) remain elusive., Methods: Data from 2417 patients treated with GLE/PIB from the Taiwan HCV Registry were analyzed, and pretreatment HbA1c levels were compared with 3-months after the-end-of treatment levels. A sustained virological response (SVR) was defined as undetectable HCV RNA at 12 weeks after the end of treatment. A significant change in HbA1c level was defined as the 75th percentile of the change in the HbA1c level before and after treatment (decrement >0.2%)., Results: Serum HbA1c levels decreased significantly (6.0 vs 5.9%, P < 0.001). Post-treatment HbA1c levels decreased in all subgroups, except in non-SVR patients (5.7 vs 5.7%, P = 0.79). Compared to patients without significant HbA1c improvement (decrement >0.2%), those with HbA1c improvement were older (60.2 vs 58.6 years, P < 0.001), had higher serum creatinine levels (1.9 vs 1.6 mg/dL, P < 0.001), triglycerides (129.8 vs 106.2 mg/dL, P < 0.001), fasting glucose (135.8 vs 104.0 mg/dL, P < 0.001), and pretreatment HbA1c (7.1 vs 5.7%, P < 0.001) and had a higher proportion of male sex (57.9% vs 50.9%, P = 0.003), diabetes (84.3 vs 16.8%, P < 0.001), more advanced stages of chronic kidney disease (CKD) (15.7 vs 11.1 %, P < 0.001), anti-diabetic medication use (47.3 vs 16.4%, P < 0.001) and fatty liver (49.6 vs 38.3 %, P < 0.001). Multivariate analysis revealed that the factors associated with significant HbA1c improvement were age (odds ratio [OR]/95% confidence intervals [CI]: 1.01/1.00-1.02, P = 0.01), HbA1c level (OR/CI: 2.83/2.48-3.24, P < 0.001) and advanced CKD stages (OR/CI: 1.16/1.05-1.28, P = 0.004). If the HbA1c variable was not considered, the factors associated with significant HbA1c improvement included alanine aminotransferase level (OR/CI, 1.002/1.000-1.004, P = 0.01), fasting glucose level (OR/CI: 1.010/1.006-1.013, P < 0.001), and diabetes (OR/CI: 3.35/2.52-4.45, P < 0.001)., Conclusions: The HbA1c levels improved shortly after HCV eradication using GLE/PIB. The improvement in glycemic control can be generalized to all subpopulations, particularly in patients with a higher baseline HbA1c level or diabetes., Competing Interests: Declaration of competing interest Ming-Lung Yu. Research support from Abbvie, Abbott, BMS, Gilead, Merck and Roche. Consultant for Abbvie, Abbott, Ascletis, BMS, Gilead, J&J, Merck, Novartis, Pharmaessential and Roche. Speaker for Abbvie, Abbott, Ascletis, BMS, Gilead, Merck, Pharmaessential and Roche. Chung-Feng Huang. Speaker for Abbvie, BMS, Gilead, Merck, and Roche., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Pre-treatment host and viral factors may affect serum ferritin levels in patients with hepatitis C virus (HCV) infection. We delineated pre-treatment factors associated with hyperferritinemia in these patients. 1682 eligible patients underwent pre-treatment assessment for serum ferritin and various host/viral factors. Univariate and multivariate logistic regression analyses were conducted to evaluate factors associated with hyperferritinemia. Multivariate logistic regression analyses revealed that age > 50 years (adjusted odds ratio [OR]: 1.38 (95% confidence interval [CI] 1.09-1.74), p = 0.008), fibrosis stage ≥ F3 (adjusted OR: 1.36 (95% CI 1.04-1.77), p = 0.02), fibrosis index based on four parameters (FIB-4) > 3.25 (adjusted OR: 1.46 (95% CI 1.11-1.92), p = 0.01), presence of metabolic dysfunction-associated steatotic liver disease (MASLD) (adjusted OR: 1.43 (95% CI 1.21-1.76), p = 0.001), and alanine transaminase (ALT) > 2 folds upper limit of normal (ULN) (adjusted OR: 2.87 (95% CI 2.20-3.75), p < 0.001) were associated hyperferritinemia. The log 10 value of HBV or HCV viral load was not associated with the log 10 value of ferritin level (Spearman's rank correlation coefficient: - 0.025, p = 0.81 and 0.002, p = 0.92). In conclusion, host factors, rather than viral factors, are associated with hyperferritinemia in patients with HCV., (© 2024. The Author(s).)

Background/purpose: Lymphoepithelioma-like cholangiocarcinoma (LELCC) is a rare variant of intrahepatic cholangiocarcinoma (ICC). We aim to analyze the differences in the clinical and radiological features of LELCC and ICC., Methods: Between January 2003 and December 2019, a total of 21 patients diagnosed with LELCC were retrospectively enrolled, and 84 patients with ICC were selected through propensity score matching by sex, age, and initial cancer stage. The clinical characteristics, pathological findings, and radiological features were analyzed. The differences in overall survival (OS) between LELCC and ICC were evaluated using the Kaplan-Meier method., Results: The serum carbohydrate antigen 19-9 (CA 19-9) level was higher in the ICC group than in the LELCC group (77.9 vs 30.0 U/mL, p = 0.004). Non-rim arterial phase hyperenhancement (47.1% vs 13.7%, p = 0.005) and portovenous washout (35.3% vs 4.1%, p = 0.001) were more frequently observed in the LELCC group than in the ICC group. Intrahepatic duct dilatation was a distinct feature of the ICC group. The 5-year OS rates in the LELCC and ICC groups were 69.3% and 58.2%, respectively (p = 0.047). The 5-year OS of patients with stages I and II LELCC between ICC were not significantly different (90.0% vs 83.4%, p = 0.464). However, the 5-year OS of patients with stages III and IV LELCC was more favorable than that of patients with ICC (29.2% vs 23.0%, p = 0.017)., Conclusions: LELCC had a favorable outcome and several different clinicoradiological features compared with ICC., Competing Interests: Declaration of competing interest Nothing to report., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Introduction: Pharmacotherapy against hepatitis C virus (HCV) infection has tremendously improved since the advent of interferon (IFN)-free direct-acting antivirals (DAAs). Additionally, fixed-dose pangenotypic DAAs, which are safe, potent, easy for use, and can cover a wide spectrum of patients, have been recommended by professional guidelines for DAA-naïve and DAA-experienced patients with HCV., Areas Covered: We review the pharmacokinetics, pharmacodynamics, and potential drug-drug interactions (DDIs) of fixed-dose pangenotypic DAA regimens, including glecaprevir/pibrentasvir (GLE/PIB), sofosbuvir/velpatasvir (SOF/VEL), and sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX). Additionally, we summarize the efficacy and safety of these regimens in clinical trials as well as real-world studies for treating different populations. Lastly, we discuss unmet medical needs in managing HCV in the era of fixed-dose pangenotypic DAAs., Expert Opinion: Protease inhibitors (PIs), including GLE and VOX, are prone to have more frequent DDIs, compared to the non-structural (NS) 5A and 5B inhibitors. These regimens are generally well tolerated and can be applied to different populations, except for the contraindicated use of PI-containing DAA regimens in decompensated cirrhosis. Using the first-line GLE/PIB and SOF/VEL can eradicate HCV in more than 95% of DAA-naïve patients across different populations. The viral cure usually exceeds 95% when using the rescue SOF/VEL/VOX regimen for prior DAA failures.

Background: Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) reduce the risk of hepatocellular carcinoma (HCC) in patients of hepatitis B. This study compared the difference between ETV and TDF on risk of HCC recurrence and mortality in patients with HBV-related HCC after curative intent treatment., Methods: Patients with HBV-related HCC who received HCC treatment (surgery or radiofrequency ablation [RFA]) and underwent long-term ETV or TDF therapy were retrospectively included. Baseline characteristics including age, sex, antiviral therapy, liver reserve, HCC stages, pathology reports and treatment modality were obtained. The risk of tumor recurrence, all-cause mortality, HCC-related mortality, and liver function were compared., Results: We identified 390 HBV-related HCC patients with curative intent treatment for HCC and treated with ETV (n = 328) or TDF (n = 62) between January 2011 and December 2020. The median age was 60 years, and 90.7% patients were males. After a median follow-up of 29 months, 186 patients developed recurrent HCC and 111 died. The baseline characteristics were comparable except more ALBI grade 3 patients in TDF group (76% vs. 48%, P < 0.001). Compared to ETV group, TDF users had lower all-cause mortality (adjusted hazard ratio [aHR]: 0.38, P = 0.003), and HCC-related mortality (aHR: 0.23, P = 0.005). Lower recurrence rate was noticed in TDF users after inverse probability of treatment weighting (IPTW). TDF users had improved ALBI grade and FIB-4 index compared with ETV groups., Conclusion: TDF therapy is associated with a reduced risk of HCC-related outcomes among patients with HBV-related HCC after curative intent treatment compared with ETV usage., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Longitudinal analysis of antibody responses following three-dose COVID-19 vaccination in patients with chronic liver disease (CLD) has been limited. From August 2021 to February 2023, sequential anti-SARS-CoV-2 spike IgG titers were determined in 45 patients with CLD who received two or three doses of COVID-19 vaccine. The geometric mean of anti-spike IgG at four weeks after the second and third doses were 1313.16 BAU/mL and 3042.29 BAU/mL, respectively, and it decreased significantly from four to 24 weeks after the second (1313.16 vs. 198.42 BAU/mL, p = 0.002) and the third (3042.29 vs. 636.71 BAU/mL, p < 0.001) dose. The anti-spike IgG titers in participants receiving prime-boost homologous mRNA vaccines (BNT162b2 or mRNA-1273) were comparable between participants with and those without significant liver fibrosis at each follow-up time point. This study demonstrated a notable decrease in anti-spike IgG after completion of the vaccination schedule in patients with CLD, highlighting the importance of additional booster doses., Competing Interests: Declaration of competing interest The authors have no conflict of interest., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Risk stratification for patients with a higher risk of hepatocellular carcinoma (HCC) is crucial. We aimed to investigate the role of the Fibrosis-4 (FIB-4) index in predicting chronic hepatitis C (CHC)-related HCC., Methods: A retrospective cohort study consecutively included treatment-naive CHC patients receiving longitudinal follow-up at the National Taiwan University Hospital from 1986 to 2014. The clinical data were collected and traced for HCC development. Multivariable Cox proportional hazard regression analysis was used to investigate the predictors for HCC., Results: A total of 1285 patients in the ERADICATE-C cohort were included. The median age was 54, 56% were females, and 933 had HCV viremia. There were 33%, 38%, and 29% of patients having FIB-4 index <1.45, 1.45-3.25, and ≥3.25, respectively. After a median of 9-year follow-up, 186 patients developed HCC. Multivariable analysis revealed that older age, AFP≥20 ng/mL, cirrhosis, and a higher FIB-4 index were independent predictors for HCC. Compared with patients with FIB-4 index <1.45, those with FIB-4 1.45-3.25 had a 5.51-fold risk (95% confidence interval [CI]: 2.65-11.46), and those with FIB-4 ≥ 3.25 had 7.45-fold risk (95% CI: 3.46-16.05) of HCC. In CHC patients without viremia, FIB-4 index 1.45-3.25 and FIB-4 ≥ 3.25 increased 6.78-fold and 16.77-fold risk of HCC, respectively, compared with those with FIB-4 < 1.45., Conclusion: The baseline FIB-4 index can stratify the risks of HCC in untreated CHC patients, even those without viremia. The FIB-4 index should thus be included in the management of CHC., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background and Aim: Understanding the dynamics of serum Mac-2 binding protein glycosylation isomer (M2BPGi) remains pivotal for hepatitis C virus (HCV) patients' post-sustained virologic response (SVR 12 ) through direct-acting antivirals (DAAs)., Methods: We compared areas under receiver operating characteristic curves (AUROCs) of M2BPGi, FIB-4, and APRI and assess M2BPGi cutoff levels in predicting fibrosis stages of ≥F3 and F4 utilizing transient elastography in 638 patients. Variations in M2BPGi levels from pretreatment to SVR 12 and their association with pretreatment alanine transaminase (ALT) levels and fibrosis stage were investigated., Results: The AUROCs of M2BPGi were comparable to FIB-4 in predicting ≥F3 (0.914 vs 0.902, P = 0.48) and F4 (0.947 vs 0.915, P = 0.05) but were superior to APRI in predicting ≥F3 (0.914 vs 0.851, P = 0.001) and F4 (0.947 vs 0.857, P < 0.001). Using M2BPGi cutoff values of 2.83 and 3.98, fibrosis stages of ≥F3 and F4 were confirmed with a positive likelihood ratio ≥10. The median M2BPGi change was -0.55. Patients with ALT levels ≥5 times ULN or ≥F3 demonstrated more pronounced median decreases in M2BPGi level compared to those with ALT levels 2-5 times ULN and <2 times ULN (-0.97 vs -0.68 and -0.44; P < 0.001) or with < F3 (-1.52 vs -0.44; P < 0.001)., Conclusions: Serum M2BPGi is a reliable marker for advanced hepatic fibrosis. Following viral clearance, there is a notable M2BPGi decrease, with the extent of reduction influenced by ALT levels and fibrosis stage., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objectives: Metabolic-associated fatty liver disease (MAFLD) was proposed in 2020 to replace the original term nonalcoholic fatty liver disease (NAFLD) with new diagnostic criteria. The disease risks of lean and overweight/obese MAFLD patients remain controversial., Materials and Methods: The participants from the Taiwan biobank cohort were included. Advanced liver fibrosis is defined as NAFLD fibrosis score (NFS) >0.675. We use carotid plaques of duplex ultrasounds to diagnose atherosclerosis., Results: A total of 20,058 participants (age 55.67 ± 10.32; males 37.6%) were included in the final analysis. Seven thousand eight hundred and forty-three (39.1%) participants were diagnosed with MAFLD. Of them, 965 (12.3%) were lean MAFLD patients. Among lean MAFLD patients, 25.6% were comorbid with diabetes mellitus (DM). Lean MAFLD patients were older and had higher percentages of females and DM than overweight/obese MAFLD patients. After propensity score matching for age and sex, they had lower levels of NFS but a higher percentage of carotid plaques. Among four subtypes of MAFLD including "lean with DM," "lean without DM," "overweight/obese with DM," and "overweight/obese without DM," logistic regression showed that "lean with DM" subjects had the highest risk of atherosclerosis and "overweight/obese with DM" subjects had the highest risk of advanced liver fibrosis in MAFLD patients., Conclusion: The population-based study revealed that lean MAFLD patients make up 12.3% of all MAFLD patients, and they have a higher proportion of coexisting diabetes. Among lean MAFLD patients concurrent with diabetes, they have the highest risk of atherosclerosis and should receive special attention clinically., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Tzu Chi Medical Journal.)

Background: Information on the dynamics of metabolic dysfunction-associated steatotic liver disease (MASLD) among hepatitis C virus patients achieving sustained virologic response (SVR 12 ) with direct-acting antivirals (DAAs) is limited., Methods: We enrolled 1512 eligible participants in this prospective study. MASLD was defined by a controlled attenuation parameter (CAP) of ≥248 dB/m utilizing vibration-controlled transient elastography in conjunction with presence of  ≥1 cardiometabolic risk factor. The distribution of MASLD and the changes in CAP were evaluated before treatment and at SVR 12 . Forward stepwise logistic regression analyses were performed to determine factors significantly associated with the regression or emergence of MASLD., Results: The prevalence of MASLD decreased from 45.0% before treatment to 36.1% at SVR 12 . Among 681 participants with MASLD before treatment, 144 (21%) exhibited MASLD regression at SVR 12 . Conversely, among 831 participants without MASLD before treatment, 9 (1.1%) developed MASLD at SVR 12 . Absence of type 2 diabetes (T2D) [odds ratio (OR): 1.73, 95% confidence interval (CI): 1.13-2.65, p = 0.011], age > 50 years (OR: 1.73, 95% CI: 1.11-2.68, p = 0.015), and alanine transaminase (ALT) ≤ 2 times the upper limit of normal (ULN) (OR: 1.56; 95% CI: 1.03-2.37, p = 0.035) were associated with the regression of MASLD. Presence of T2D was associated with the emergence of MASLD (OR: 5.83, 95% CI: 1.51-22.56, p = 0.011)., Conclusions: The prevalence of MASLD decreased after achieving SVR 12 with DAAs. Patients with pre-existing T2D showed a diminished probability of MASLD regression and a heightened risk of MASLD emergence post-SVR 12 ., (© 2024. Japanese Society of Gastroenterology.)

Background/aims: Chronic hepatitis C (CHC) patients who failed antiviral therapy are at increased risk for hepatocellular carcinoma (HCC). This study assessed the potential role of metformin and statins, medications for diabetes mellitus (DM) and hyperlipidemia (HLP), in reducing HCC risk among these patients., Methods: We included CHC patients from the T-COACH study who failed antiviral therapy. We tracked the onset of HCC 1.5 years post-therapy by linking to Taiwan's cancer registry data from 2003 to 2019. We accounted for death and liver transplantation as competing risks and employed Gray's cumulative incidence and Cox subdistribution hazards models to analyze HCC development., Results: Out of 2,779 patients, 480 (17.3%) developed HCC post-therapy. DM patients not using metformin had a 51% increased risk of HCC compared to non-DM patients, while HLP patients on statins had a 50% reduced risk compared to those without HLP. The 5-year HCC incidence was significantly higher for metformin non-users (16.5%) versus non-DM patients (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Statin use in HLP patients correlated with a lower HCC risk (3.8%) compared to non-HLP patients (12.5%; aSHR=0.50; P<0.001). Notably, the increased HCC risk associated with non-use of metformin was primarily seen in non-cirrhotic patients, whereas statins decreased HCC risk in both cirrhotic and non-cirrhotic patients., Conclusion: Metformin and statins may have a chemopreventive effect against HCC in CHC patients who failed antiviral therapy. These results support the need for personalized preventive strategies in managing HCC risk.

Introduction: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing among the chronic hepatitis B (CHB) population. This study aimed to explore the impact of metabolic dysfunction (MD) on cirrhosis and cirrhotic complication risks in CHB., Methods: Patients with CHB were consecutively recruited between 2006 and 2021. The presence of MD was based on the 5 cardiometabolic criteria specified in the MASLD definition. Patients were categorized into MD/non-MD groups based on these criteria., Results: Eleven thousand five hundred two treatment-naive noncirrhotic patients with CHB were included with a median follow-up of 5.3 years. Patients in the MD group (n = 7,314) were older and had lower hepatitis B virus DNA levels than non-MD patients (n = 4,188). After adjustment for clinical and viral factors, MD patients had significantly higher risks of cirrhosis (adjusted hazard ratio [aHR]: 1.82, 95% confidence interval [CI]: 1.40-2.37, P < 0.001) and cirrhotic complications (aHR: 1.30 per MD, 95% CI: 1.03-1.63, P = 0.025) in a dose-dependent manner. Furthermore, new-onset diabetes mellitus during the follow-up aggravated the risk of cirrhotic complications (aHR: 2.87, 95% CI: 1.34-6.11, P = 0.006). Hepatic steatosis was associated with lower risks of cirrhosis (aHR: 0.57 within 5 years, 95% CI: 0.44-0.74, P < 0.001) and cirrhotic complications (aHR: 0.45, 95% CI 0.23-0.88, P = 0.020). Among individuals with hepatic steatosis, patients with MASLD exhibited a higher cirrhosis risk than non-MD patients., Discussion: Concurrent and new-onset MDs increase the risks of cirrhosis and cirrhotic complications in patients with CHB, independent of hepatic steatosis. Proactively investigating metabolic comorbidities in CHB is critical to stratify the risk of liver disease progression., (Copyright © 2024 by The American College of Gastroenterology.)

Competing Interests: The authors have no conflicts to report.

Background and Aims: In 2023, a new nomenclature of "metabolic associated steatotic liver disease" (MASLD) has emerged by incorporating cardio-metabolic criteria to redefine "non-alcoholic fatty liver disease" (NAFLD). Among steatotic liver disease (SLD), those having no known causes and without any one of cardio-metabolic criteria are deemed to have cryptogenic SLD. This study aims to compare the liver and atherosclerotic risks between MASLD and cryptogenic SLD patients., Approach: We analyzed participants with liver ultrasound data from the Taiwan Bio-Bank cohort, excluding those with positive HBsAg, positive anti-HCV, or "frequent drinker". MASLD involves hepatic steatosis and any of five cardiometabolic risk factors, whereas cryptogenic SLD features hepatic steatosis without these risk factors. Liver fibrosis severity was assessed by using NAFLD fibrosis score (NFS), while atherosclerosis was determined by carotid plaques on duplex ultrasound., Results: Among 17,595 subjects (age 55.47 ± 10.41; males 31.8%), 7538 participants (42.8%) had SLD, comprising 96.5% of MASLD and 3.5% of cryptogenic SLD. Cryptogenic SLD patients are younger and had a lower percentage of male than those with MASLD. After propensity score matching for age and sex, patients with cryptogenic SLD exhibited milder glucose and lipid profiles, fewer carotid plaques, lower liver steatosis, inflammation, and fibrosis markers than those with MASLD., Conclusions: In this large population-based study, cryptogenic SLD, the excluded group, occupy only 3.5% in NAFLD patients. It has lower liver and atherosclerotic risks than MASLD, supporting its exclusion from NAFLD and justifying the rationale for the new disease name and diagnostic criteria of MASLD., (© 2024. Asian Pacific Association for the Study of the Liver.)

End-stage liver disease (ESLD) is a life-threatening clinical syndrome and when complicated with infection the mortality is markedly increased. In patients with ESLD, bacterial or fungal infection can induce or aggravate the occurrence or progression of liver decompensation. Consequently, infections are among the most common complications of disease deterioration. There is an overwhelming need for standardized protocols for early diagnosis and appropriate management for patients with ESLD complicated by infections. Asia Pacific region has the largest number of ESLD patients, due to hepatitis B and the growing population of alcohol and NAFLD. Concomitant infections not only add to organ failure and high mortality but also to financial and healthcare burdens. This consensus document assembled up-to-date knowledge and experience from colleagues across the Asia-Pacific region, providing data on the principles as well as evidence-based current working protocols and practices for the diagnosis and treatment of patients with ESLD complicated by infections., (© 2024. Asian Pacific Association for the Study of the Liver.)