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Background: The Fibrosis-4 (FIB-4) index is widely recommended as a first-tier method for screening advanced hepatic fibrosis; however, its diagnostic performance is known to be suboptimal in patients with Type 2 diabetes mellitus (T2DM). We aim to propose a modified FIB-4, using the parameters of the existing FIB-4, tailored specifically for diabetic patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: A total of 1503 patients who underwent liver biopsy were divided into T2DM ( n = 517) and non-T2DM ( n = 986) groups. The model was developed using multiple regression analysis in the derivation cohort and validated in the validation cohort. Diagnostic accuracy was evaluated using the area under the receiver operating characteristic (AUC) curves. Results: Among the 1503 individuals, those with T2DM were older, more likely to be male, and had a higher prevalence of advanced hepatic fibrosis (≥F3) compared to non-T2DM individuals. Independent risk factors for advanced fibrosis in T2DM included age, AST, AST/ALT ratio, albumin, triglycerides, and platelet count. The optimized FIB-4 model for T2DM with MASLD (Diabetes Fibrosis Index) demonstrated superior diagnostic accuracy (AUC 0.771) compared to the FIB-4 (AUC 0.735, p = 0.012). The model showed a higher negative predictive value than the original FIB-4 across all age groups in the diabetic group. Conclusions: The newly optimized FIB-4 model for T2DM with MASLD (Diabetes Fibrosis Index), incorporating a non-linear predictive model, improves diagnostic performance (AUC) and the negative predictive value in MASLD with T2DM.

Aim: The term MetALD has been introduced to describe individuals who have metabolic dysfunction-associated steatotic liver disease (MASLD) with greater alcohol consumption, according to the new nomenclature for steatotic liver disease (SLD). This study aims to evaluate the prevalence and clinical characteristics of MetALD in the general population., Methods: This study is a retrospective, cross-sectional analysis that utilizes the population-based data from the Korea National Health and Nutrition Examination Survey (KNHANES) undertaken between 2019 and 2021. A total of 16 521 participants aged over 18 years were included in the analysis. The presence of hepatic steatosis was determined based on a hepatic steatosis index of 36 or higher., Results: The prevalence of MetALD was 2.8% (95% confidence interval, 2.5-3.2). Individuals with MetALD were predominantly men (85.4%) and tended to be younger compared to those with MASLD. They showed a higher prevalence of hypertension and had significantly higher levels of fasting glucose, triglycerides, high-density lipoprotein cholesterol, and creatinine compared to individuals with MASLD. The average daily total energy intake was higher in the MetALD group. In addition, the MetALD group had a lower proportion of unemployment with higher income compared to the MASLD group., Conclusion: Patients with MetALD showed distinct clinical characteristics from those with MASLD. The characteristics of MetALD were similar to those with alcohol-related liver disease. Further analysis of MetALD across various regions and ethnic groups would be needed., (© 2024 The Author(s). Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Aims: We aimed to explore the extent to which individuals previously diagnosed with nonalcoholic fatty liver disease (NAFLD) meet the criteria fulfilled with the new nomenclature, metabolic dysfunction-associated steatotic liver disease (MASLD), within an Asian primary clinic cohort. Additionally, we assessed the reliability of the diagnostic performance of FIB-4 and NAFLD fibrosis score (NFS) for MASLD within the primary clinic cohort., Methods: This retrospective cross-sectional study included participants who underwent magnetic resonance elastography and abdominal ultrasonography during their health checkups at nationwide health promotion centers (n = 6740)., Results: The prevalence rates of NAFLD and MASLD diagnosed based on ultrasonography results were 36.7% and 38.0%, respectively. Notably, 96.8% of patients in the NAFLD cohort fulfilled the new criteria for MASLD. A small proportion of patients with NAFLD (n = 80, 3.2%) did not meet the MASLD criteria. Additionally, 168 patients (6.6%) were newly added to the MASLD group. The areas under the receiver operating characteristic curves for diagnosing advanced hepatic fibrosis for FIB-4 (0.824 in NAFLD vs. 0.818 in MASLD, p = 0.891) and NFS (0.803 in NAFLD vs. 0.781 in MASLD, p = 0.618) were comparable between the MASLD and NAFLD groups. Furthermore, the sensitivity, specificity, positive predictive value, and negative predictive value of FIB-4 and NFS for advanced fibrosis in MASLD were also comparable to those in NAFLD., Conclusions: Most patients (96.8%) previously diagnosed with NAFLD fulfilled the new criteria for MASLD in an Asian primary clinic cohort. Diagnostic performance of FIB-4 in the MASLD cohort demonstrated satisfactory results., (© 2024 Japan Society of Hepatology.)

Background & Aims: Non-invasive tests (NITs) for liver fibrosis have been recognized for their clinical utility in metabolic dysfunction-associated steatotic liver disease (MASLD). However, their diagnostic efficacy in detecting liver fibrosis is notably reduced in patients with alcohol-related liver disease. Therefore, ascertaining the reliability of NITs in patients with MASLD with moderate alcohol intake (MetALD) is essential., Methods: In this cross-sectional study, we reviewed data from 7,918 health check-up participants who underwent both magnetic resonance elastography (MRE) and ultrasound for the diagnosis of hepatic steatosis. The participants were categorized into MASLD and MetALD groups, and the performance of fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS) were assessed. Advanced hepatic fibrosis (F3) was defined as MRE ≥3.6 kPa., Results: The prevalence of MetALD was 5.8% in this health check-up cohort, and 1.5% of these patients exhibited advanced hepatic fibrosis. Both MetALD and MASLD displayed similar metabolic profiles and hepatic fibrosis burdens. The diagnostic performance of FIB-4 and NFS for MRE ≥3.6 kPa showed no noticeable differences in the area under the receiver-operating characteristic values between the two groups (0.85 vs. 0.80 in FIB-4). Moreover, the sensitivity (71.4%), specificity (77.3%), and both positive (4.6%) and negative (99.4%) predictive values of NITs for MetALD closely mirrored those observed for MASLD., Conclusion: FIB-4 performed well for the initial screening of advanced hepatic fibrosis in MetALD, demonstrating reasonable sensitivity and negative predictive values., Impact and Implications: In this cross-sectional study, data from 7,918 participants who underwent MRE were analyzed to assess the performance of fibrosis-4 (FIB-4) and non-alcoholic fatty liver disease fibrosis scores in metabolic dysfunction-associated steatotic liver disease (MASLD) and MASLD with moderate alcohol intake (MetALD). We found that FIB-4 had high diagnostic accuracy in the newly identified MetALD group, similar to that in the MASLD population. These results highlight the potential of FIB-4 as a reliable screening tool for MetALD, even when specific subgroups are considered. Therefore, FIB-4 is a valuable screening tool for identifying advanced fibrosis in the MetALD population., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Previous studies have investigated the influence of diabetes on alcoholic liver cirrhosis patients, leaving its impact unclear. Thus, we conducted a study to reveal the association of diabetes and clinical outcomes of such patients., Materials and Methods: We prospectively collected data from multicenter pertaining to 965 patients diagnosed with alcoholic liver cirrhosis, all of whom were admitted due to acute decompensation between 2015 and 2019. Risk of major precipitating factors and incidences of death or liver transplantation in patients with and without diabetes was comparatively assessed. Propensity score (PS) matching was performed at a 1:2 ratio for accurate comparisons., Results: The mean age was 53.4 years, and 81.0% of the patients were male. Diabetes was prevalent in 23.6% of the cohort and was positively correlated with hepatic encephalopathy and upper gastrointestinal bleeding, although not statistically significant. During a median follow-up of 903.5 person-years (PYs), 64 patients with and 171 without diabetes died or underwent liver transplantation, with annual incidence of 33.6/100 PYs and 24.0/100 PYs, respectively. In the PS-matched cohort, the incidence of death or liver transplantation was 36.8/100 PYs and 18.6/100 PYs in the diabetes and matched control group, respectively. After adjusting for various factors, coexisting diabetes significantly heightened the risk of death or liver transplantation in the short and long term, in addition to prolonged prothrombin time, low serum albumin, elevated total bilirubin and creatinine, and decreased serum sodium levels., Conclusions: Diabetes increases the risk of death or liver transplantation in patients with alcoholic liver cirrhosis., (© 2024. Asian Pacific Association for the Study of the Liver.)

Background and Aim: The Model for End-Stage Liver Disease (MELD) is a reliable prognostic tool for short-term outcome prediction in patients with end-stage liver disease. MELD 3.0 was introduced to enhance the predictive accuracy. This study assessed the performance of MELD 3.0, in comparison to MELD and MELD-Na, in patients with alcoholic liver cirrhosis., Methods: This multicenter prospective cohort study comprised patients with alcoholic cirrhosis admitted for acute deterioration of liver function in the Republic of Korea between 2015 and 2019. This study compared the predictive abilities of MELD, MELD-Na, and MELD 3.0, for 30-day and 90-day outcomes, specifically death or liver transplantation, and explored the factors influencing these outcomes., Results: A total of 1096 patients were included in the study, with a mean age of 53.3 ± 10.4 years, and 82.0% were male. The mean scores for MELD, MELD-Na, and MELD 3.0 at the time of admission were 18.7 ± 7.2, 20.6 ± 7.7, and 21.0 ± 7.8, respectively. At 30 and 90 days, 7.2% and 14.1% of patients experienced mortality or liver transplantation. The areas under the receiver operating characteristic curves for MELD, MELD-Na, and MELD 3.0 at 30 days were 0.823, 0.820, and 0.828; and at 90 days were 0.765, 0.772, and 0.776, respectively. Factors associated with the 90-day outcome included concomitant chronic viral hepatitis, prolonged prothrombin time, elevated levels of aspartate transaminase, bilirubin, and creatinine, and low albumin levels., Conclusion: MELD 3.0 demonstrated improved performance compared to previous models, although the differences were not statistically significant., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aims: As practice patterns and hepatitis C virus (HCV) genotypes (GT) vary geographically, a global real-world study from both East and West covering all GTs can help inform practice policy toward the 2030 HCV elimination goal. This study aimed to assess the effectiveness and tolerability of DAA treatment in routine clinical practice in a multinational cohort for patients infected with all HCV GTs, focusing on GT3 and GT6., Methods: We analyzed the sustained virological response (SVR12) of 15,849 chronic hepatitis C patients from 39 Real-World Evidence from the Asia Liver Consortium for HCV clinical sites in Asia Pacific, North America, and Europe between 07/01/2014-07/01/2021., Results: The mean age was 62±13 years, with 49.6% male. The demographic breakdown was 91.1% Asian (52.9% Japanese, 25.7% Chinese/Taiwanese, 5.4% Korean, 3.3% Malaysian, and 2.9% Vietnamese), 6.4% White, 1.3% Hispanic/Latino, and 1% Black/African-American. Additionally, 34.8% had cirrhosis, 8.6% had hepatocellular carcinoma (HCC), and 24.9% were treatment-experienced (20.7% with interferon, 4.3% with direct-acting antivirals). The largest group was GT1 (10,246 [64.6%]), followed by GT2 (3,686 [23.2%]), GT3 (1,151 [7.2%]), GT6 (457 [2.8%]), GT4 (47 [0.3%]), GT5 (1 [0.006%]), and untyped GTs (261 [1.6%]). The overall SVR12 was 96.9%, with rates over 95% for GT1/2/3/6 but 91.5% for GT4. SVR12 for GT3 was 95.1% overall, 98.2% for GT3a, and 94.0% for GT3b. SVR12 was 98.3% overall for GT6, lower for patients with cirrhosis and treatment-experienced (TE) (93.8%) but ≥97.5% for treatment-naive patients regardless of cirrhosis status. On multivariable analysis, advanced age, prior treatment failure, cirrhosis, active HCC, and GT3/4 were independent predictors of lower SVR12, while being Asian was a significant predictor of achieving SVR12., Conclusions: In this diverse multinational real-world cohort of patients with various GTs, the overall cure rate was 96.9%, despite large numbers of patients with cirrhosis, HCC, TE, and GT3/6. SVR12 for GT3/6 with cirrhosis and TE was lower but still excellent (>91%)., Competing Interests: FJ: Speaker fees: Gilead Sciences, MSD, and Ascletis. Consultancy: Gilead Sciences, MSD. FJ has been an Editorial Board Member of Journal of Clinical and Translational Hepatology since 2023. YJW: Speaker fees: Gilead Science, AbbVie. Research Grant: Medicine Academic Clinical Program, SingHealth, Singapore. YJW has been an Editorial Board Member of Journal of Clinical and Translational Hepatology since 2020. HT: Speaker fees: Gilead Science, AbbVie, Eisai, Fujifilm WAKO, Takeda, Kowa, Terumo, Astra Zeneca. VWSW: Consultancy: AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet Biosciences, TARGET PharmaSolutions, Visirna. Speaker fees: Abbott, AbbVie, Gilead Sciences, Novo Nordisk, Unilab. Research grants: Gilead Sciences. Stock: Co-founder of Illuminatio Medical Technology Limited. MA: Speakers’ fees: AbbVie, Gilead Sciences. SD: Speakers fees: Gilead Sciences. MFY: Speakers’ fees: Fujirebio Incorporation, Gilead Sciences, Roche, Sysmex Corporation. Consulting or advisory board: AbbVie, Abbott Diagnostics, Aligos Therapeutics, AiCuris, Antios Therapeutics, Arbutus Biopharma, Arrowhead Pharmaceuticals, Assembly Biosciences, Clear B Therapeutics, Dicerna Pharmaceuticals, Finch Therapeutics, Fujirebio Incorporation, GlaxoSmithKline, Gilead Sciences, Immunocore, Janssen, Precision BioSciences, Roche, Sysmex Corporation, Tune Therapeutics, Vir Biotechnology and Visirna Therapeutics. Research grant: AbbVie, Assembly Biosciences, Arrowhead Pharmaceuticals, Fujirebio Incorporation, Gilead Sciences, Immunocore, Sysmex Corporation and Roche. MFY has been an Associate Editor of Journal of Clinical and Translational Hepatology since 2021. CW: Research grant: Gilead Sciences. MLYu: Research support (grant) from Abbvie, BMS, Gilead, Merck, and Roche diagnostics. Consultant of Abbvie, BMS, Gilead, Roche, and Roche diagnostics. Speaker of Abbvie, BMS, Eisai, Gilead, Roche, and Roche diagnostics. MLYu has been an Associate Editor of Journal of Clinical and Translational Hepatology since 2023. MHN: Research grants via institution: Pfizer, Enanta, Astra Zeneca, GSK, Delfi, Innogen, Exact Science, CurveBio, Gilead, Vir Biotech, Helio Health, National Cancer Institute, Glycotest. Consulting/Advisory board: Intercept, Exact Science, Gilead, GSK. JL, MLYe, WLC and JFH have been Editorial Board Members of Journal of Clinical and Translational Hepatology since 2022. HR has been an Editor-in-Chief of Journal of Clinical and Translational Hepatology since 2013. The other authors have no conflict of interests related to this publication., (© 2024 Authors.)

Background: The importance of primary care physicians (PCPs) in managing metabolic dysfunction-associated steatotic liver disease (MASLD) has increased. This study aimed to assess the effectiveness of an online educational program on MASLD among physicians., Methods: In total, 869 physicians (72 physicians at referral centers and 797 PCPs) participated in this study. They completed an initial survey regarding their clinical practices for patients with MASLD, followed by a second online survey 8 weeks after receiving a series of seven weekly sets of educational materials on MASLD., Results: In the baseline survey, most PCPs did not routinely evaluate the stage of hepatic fibrosis in MASLD; they typically initiated assessments based on elevated liver enzyme levels. Only a limited number of PCPs used vibration-controlled transient elastography. The main hurdles in managing MASLD were "the absence of a fee for patient education" for PCPs and "short consultation time" for referral-center physicians. In the follow-up survey, the percentage of liver fibrosis assessments using noninvasive tests increased from 7.0 to 11.2%. Additionally, evaluations for cardiovascular disease increased from 3.9 to 8.2%, and the risk of ischemic stroke increased from 13.7 to 16.9%. The percentage of immediate referrals of patients to specialists after an MASLD diagnosis decreased from 15.4 to 12.3%., Conclusion: The discrepancies in management strategies and viewpoints regarding MASLD between PCPs and referral-center physicians can hinder efforts to mitigate the disease burden. Increasing awareness among PCPs regarding MASLD through a 7-week education program led to a reduction in unnecessary referral rates and an increase in cardiovascular evaluations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lee, Yoon, Oh, Kim, Ahn and Jun.)

Background/aims: Quick sequential organ failure assessment (qSOFA) is believed to identify patients at risk of poor outcomes in those with suspected infection. We aimed to evaluate the ability of modified qSOFA (m-qSOFA) to identify high-risk patients among those with acutely deteriorated chronic liver disease (CLD), especially those with acute-onchronic liver failure (ACLF)., Methods: We used data from both the Korean Acute-on-Chronic Liver Failure (KACLiF) and the Asian Pacific Association for the Study of the Liver ACLF Research Consortium (AARC) cohorts. qSOFA was modified by replacing the Glasgow Coma Scale with hepatic encephalopathy, and an m-qSOFA ≥2 was considered high., Results: Patients with high m-qSOFA had a significantly lower 1-month transplant-free survival (TFS) in both cohorts and higher organ failure development in KACLiF than those with low m-qSOFA (Ps<0.05). Subgroup analysis by ACLF showed that patients with high m-qSOFA had lower TFS than those with low m-qSOFA. m-qSOFA was an independent prognostic factor (hazard ratios, HR=2.604, 95% confidence interval, CI 1.353-5.013, P=0.004 in KACLiF and HR=1.904, 95% CI 1.484- 2.442, P<0.001 in AARC). The patients with low m-qSOFA at baseline but high m-qSOFA on day 7 had a significantly lower 1-month TFS than those with high m-qSOFA at baseline but low m-qSOFA on day 7 (52.6% vs. 89.4%, P<0.001 in KACLiF and 26.9% vs. 61.5%, P<0.001 in AARC)., Conclusion: Baseline and dynamic changes in m-qSOFA may identify patients with a high risk of developing organ failure and short-term mortality among CLD patients with acute deterioration.

Background and Aim: The benefits of entecavir (ETV) versus tenofovir disoproxil fumarate (TDF) in reducing the development of chronic hepatitis B (CHB)-related hepatocellular carcinoma remain controversial. Whether mortality rates differ between patients with CHB treated with ETV and those treated with TDF is unclear., Methods: A total of 2542 patients with CHB treated with either ETV or TDF were recruited from a multinational cohort. A 1:1 propensity score matching was performed to balance the differences in baseline characteristics between the two patient groups. We aimed to compare the all-cause, liver-related, and non-liver-related mortality between patients receiving ETV and those receiving TDF., Results: The annual incidence of all-cause mortality in the entire cohort was 1.0/100 person-years (follow-up, 15 757.5 person-years). Patients who received TDF were younger and had a higher body mass index, platelet count, hepatitis B virus deoxyribonucleic acid levels, and proportion of hepatitis B e-antigen seropositivity than those who received ETV. The factors associated with all-cause mortality were fibrosis-4 index > 6.5 (hazard ratio [HR]/confidence interval [CI]: 3.13/2.15-4.54, P < 0.001), age per year increase (HR/CI: 1.05/1.04-1.07, P < 0.001), alanine aminotransferase level per U/L increase (HR/CI: 0.997/0.996-0.999, P = 0.003), and γ-glutamyl transferase level per U/L increase (HR/CI: 1.002/1.001-1.003, P < 0.001). No significant difference in all-cause mortality was observed between the ETV and TDF groups (log-rank test, P = 0.69). After propensity score matching, no significant differences in all-cause, liver-related, or non-liver-related mortality were observed between the two groups., Conclusions: Long-term outcomes of all-cause mortality and liver-related and non-liver-related mortality did not differ between patients treated with ETV and those receiving TDF., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: In relation to the new umbrella terminology for steatotic liver disease (SLD), we aimed to elucidate the prevalence, distribution, and clinical characteristics of the SLD subgroups in the primary care setting., Approach and Results: We retrospectively collected data from 2535 individuals who underwent magnetic resonance elastography and MRI proton density fat fraction during health checkups in 5 primary care health promotion clinics. We evaluated the presence of cardiometabolic risk factors according to predefined criteria and divided all the participants according to the new SLD classification. The prevalence of SLD was 39.13% in the total cohort, and 95.77% of the SLD cases had metabolic dysfunction (one or more cardiometabolic risk factors). The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) was 29.51%, with those of metabolic dysfunction and alcohol associated steatotic liver disease (MetALD) and alcohol-associated liver disease (ALD) at 7.89% and 0.39%, respectively. According to the old criteria, the prevalence of NAFLD was 29.11%, and 95.80% of the NAFLD cases fulfilled the new criteria for MASLD. The distribution of SLD subtypes was highest for MASLD, at 75.40%, followed by MetALD at 20.06%, cryptogenic SLD at 3.33%, and ALD at 1.01%. The MetALD group had a significantly higher mean magnetic resonance elastography than the MASLD or ALD group., Conclusion: Almost all the patients with NAFLD met the new criteria for MASLD. The fibrosis burden of the MetALD group was higher than those of the MASLD and ALD groups., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background and Aim: he mixed lineage kinase domain like pseudokinase (MLKL) is known to play a protective role in non-alcoholic fatty liver disease (NAFLD) via inhibition of necroptosis pathway. However, the role of MLKL in alcoholic liver disease (ALD) is not yet clear., Method: C57BL/6N wild-type (WT) and MLKL-knockout (KO) mice (8-10 weeks old) were randomly divided into eight groups. To establish ALD model of different durations, ethanol (EtOH) was fed to WT and MLKL KO for 10 days, 4 weeks, and 8 weeks. The control group was fed with Lieber-DeCarli control diet for 8 weeks. Mortality, degree of hepatic inflammation, and steatosis were compared among the groups. Bulk mRNA transcriptome analysis was performed. Abundance of transcript and gene expressions were calculated based on read count or Transcript by Million (TPM) value., Results: Survival rate of MLKL KO mice compared to WT was similar until 4 weeks, but the survival of MLKL KO mice significantly decreased after 8 weeks in ALD model. There was no difference in degree of inflammation, steatosis, and NAS scores between EtOH-fed MLKL KO and EtOH-fed WT mice at 10 days. However, at 4 weeks and 8 weeks, the degree of hepatic steatosis, NAS, and inflammation were increased in MLKL KO mice. RNA transcriptome data showed that fatty acid synthesis, and lipogenesis, mitochondria, and apoptosis-related pathways were upregulated in EtOH-fed MLKL KO mice compared to EtOH-fed WT mice. Although hepatocyte apoptosis (BAX/BCL2 ratio, caspase-3, and TUNEL staining) increased after EtOH intake; however, apoptosis was more significantly increased in EtOH-fed MLKL KO mice compared to the WT group. At the same time, hepatic cFLIP was decreased in EtOH-fed MLKL KO mice compared to the WT group., Conclusion: MLKL deletion did not prevent chronic alcohol-induced liver damage independently of necroptosis and exacerbated hepatic steatosis by increasing hepatocyte apoptosis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background & Aims: The cost-effectiveness to screen hepatic fibrosis in at-risk population as recommended by several professional societies has been limited. This study aimed to investigate the cost-effectiveness of this screening strategy in the expanded at-risk population recently proposed by several societies., Methods: A combined model of the decision tree and Markov models was developed to compare expected costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) between screening and no screening groups. The model included liver disease-related health states and cardiovascular disease (CVD) states as a base-case analysis. Screening strategy consisted of fibrosis-4 index (FIB-4) followed by vibration-controlled transient elastography (VCTE) and intensive lifestyle intervention (ILI) as a treatment for diagnosed patients., Results: Cost-effectiveness analysis showed that screening the at-risk population entailed $298 incremental costs and an additional 0.0199 QALY per patient compared to no screening (ICER $14 949/QALY). Screening was cost-effective based on the implicit ICER threshold of $25 000/QALY in Korea. When the effects of ILI on CVD and extrahepatic malignancy were incorporated into the cost-effectiveness model, the ICER decreased by 0.85 times from the base-case analysis (ICER $12 749/QALY). In contrast, when only the effects of liver disease were considered in the model, excluding cardiovascular disease effects, ICER increased from the baseline case analysis to $16 305. Even when replacing with medical costs in Japan and U.S., it remained cost-effective with the estimate below the countries' ICER threshold., Conclusions: Our study provides compelling evidence supporting the cost-effectiveness of FIB-4-based screening the at-risk population for advanced hepatic fibrosis., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Few studies have investigated the prognosis of patients with non-severe alcoholic hepatitis (Non-SAH). The study aimed to develop a new prognostic model for patients with especially Non-SAH., Methods: We extracted 316 hospitalized patients with alcoholic cirrhosis without severe alcoholic hepatitis, defined as Maddrey's discriminant function score lower than 32, from the retrospective Korean Acute-on-Chronic Liver Failure (KACLiF) cohort to develop a new prognostic model (training set), and validated it in 419 patients from the prospective KACLiF cohort (validation set). Prognostic factors for death and liver transplantation were analyzed to construct a prognostic model., Results: Twenty-one and 24 patients died within 6 months in both sets, respectively. In the training set, the highest area under the curve (AUC) of conventional prognostic models was 0.765, 0.732, and 0.684 for 1-, 3-, and 6-month mortality, respectively. Refractory ascites, vasopressor use, and hyponatremia were independently associated with mortality of cirrhotic patients with Non-SAH. The new model consisted of four variables: past deterioration, neutrophil proportion > 70%, Na < 128 mmol/L, and vasopressor use. It showed the highest accuracy for short-term mortality in the training and validation sets (0.803 and 0.786; 0.797 and 0.776; and 0.789 and 0.721 for 1-, 3-, and 6-month mortality, respectively)., Conclusion: There is a group of patients with high risk among those classified as Non-SAH. The new model will help stratifying cirrhotic patients with Non-SAH more accurately in terms of prognosis. The patients with high Non-SAH score need to monitor closely and might be considered for preemptive liver transplantation., Trial Regestration: ClinicalTrials.gov identifier: NCT02650011., (© 2023. Asian Pacific Association for the Study of the Liver.)

Our study aimed to conduct a comparative evaluation of various noninvasive tests (NITs) for risk stratification in at-risk population for non-alcoholic fatty liver disease (NAFLD), focusing on cardiovascular and liver-related mortality. A total of 21,715 adults aged 40 years and older were enrolled at baseline. The mean follow-up period was 12.39 years. Three types of NITs (fibrosis-4 index [FIB-4], NAFLD fibrosis score [NFS], and steatosis-associated fibrosis estimator [SAFE] score) were used. When using the low cut-off as a 'rule-out' strategy, there were no significant differences in cardiovascular mortality between the 'rule-out' (low-risk) group and the 'rule-in' (intermediate- or high-risk) group based on FIB-4 (aHR = 1.029, P = 0.845) or NFS (aHR = 0.839, P = 0.271) classification. However, the SAFE score exhibited higher sensitivity in predicting cardiovascular mortality compared to FIB-4 or NFS (73.3% in SAFE score vs. 29.6% in FIB-4 or 21.3% in NFS). Only the SAFE score could effectively differentiate the risk between low- and intermediate- or high-risk groups for all types of mortality (all P values for aHR < 0.001). The low cutoff value of the SAFE score discriminated not only liver-related mortality but also identified the cardiovascular high-risk group in the community cohort., (© 2024. The Author(s).)

Background/aims: The pathophysiology of lean nonalcoholic fatty liver disease (NAFLD) is unclear but has been shown to be associated with more diverse pathogenic mechanisms than that of obese NAFLD. We investigated the characteristics of genetic or metabolic lean NAFLD in a health checkup cohort., Methods: This retrospective cross-sectional study analyzed single nucleotide polymorphism data for 6,939 health examinees. Lean individuals were categorized according to a body mass index cutoff of 23 kg/m 2 . Single nucleotide polymorphisms were analyzed using genotyping arrays., Results: The prevalence of lean NAFLD was 21.6% among all participants with NAFLD, and the proportion of lean NAFLD was 18.5% among lean participants. The prevalence of metabolic syndrome and diabetes among lean patients with NAFLD was 12.4% and 10.4%, respectively. Lean NAFLD appeared to be metabolic-associated in approximately 20.1% of patients. The homozygous minor allele (GG) of PNPLA3 (rs738409) and heterozygous minor alleles (CT, TT) of TM6SF2 (rs58542926) were associated with lean NAFLD. However, the prevalence of fatty liver was not associated with the genetic variants MBOAT7 (rs641738), HSD17B13 (rs72613567), MARC1 (rs2642438), or AGXT2 (rs2291702) in lean individuals. Lean NAFLD appeared to be associated with PNPLA3 or TM6SF2 genetic variation in approximately 32.1% of cases. Multivariate risk factor analysis showed that metabolic risk factors, genetic risk variants, and waist circumference were independent risk factors for lean NAFLD., Conclusions: In a considerable number of patients, lean NAFLD did not appear to be associated with known genetic or metabolic risk factors. Further studies are required to investigate additional risk factors and gain a more comprehensive understanding of lean NAFLD.

Background & Aims: It is unclear if there may be sex differences in response to nucleos(t)ide analogs including virologic response (VR), biochemical response (BR), complete response (CR), and hepatocellular carcinoma (HCC) incidence among hepatitis B patients. We compared nucleos(t)ide analog treatment outcomes by sex., Methods: We performed a retrospective cohort study of 3388 treatment-naïve adult hepatitis B patients (1250 female, 2138 male) from the Real-World Evidence from the Global Alliance for the Study of Hepatitis B Virus consortium who initiated therapy with either entecavir or tenofovir from 22 sites (Argentina, Korea, Japan, Taiwan, and the United States). We used propensity-score matching to balance background characteristics of the male and female groups and competing-risks analysis to estimate the incidence and subdistribution hazard ratios (SHRs) of VR, BR, CR, and HCC., Results: Females (vs males) were older (52.0 vs 48.6 y); less likely to be overweight/obese (49.3% vs 65.7%), diabetic (9.9% vs 13.1%), or cirrhotic (27.9% vs 33.0%); and had a lower HBV DNA level (5.9 vs 6.0 log10 IU/mL) and alanine aminotransferase level (91 vs 102 IU/L) (all P < .01). However, after propensity-score matching, relevant background characteristics were balanced between the 2 groups. Females (vs males) had similar 5-year cumulative VR (91.3% vs 90.3%; P = .40) and HCC incidence rates (5.1% vs 4.4%; P = .64), but lower BR (84.0% vs 90.9%; P < .001) and CR (78.8% vs 83.4%; P = .016). Males were more likely to achieve BR (SHR, 1.31; 95% CI, 1.17-1.46; P < .001) and CR (SHR, 1.16; 95% CI, 1.03-1.31; P = .016), but VR and HCC risks were similar., Conclusions: Sex differences exist for treatment outcomes among hepatitis B patients. Male sex was associated with a 16% higher likelihood of clinical remission and a 31% higher likelihood of biochemical response than females, while virologic response and HCC incidence were similar between the 2 groups., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

(1) Background: Accurate statistics on the causes of death in patients with chronic hepatitis B (CHB) are lacking. We investigated mortality rates and causes of death over time. (2) Methods: Data on patients newly diagnosed with CHB from 2007 to 2010 (cohort 1, n = 223,424) and 2012 to 2015 (cohort 2, n = 177,966) were retrieved from the Korean National Health Insurance Service. Mortality data were obtained from Statistics Korea. The causes of death were classified as liver-related (hepatic decompensation or hepatocellular carcinoma [HCC]) or extrahepatic (cardiovascular-related, cerebrovascular-related, or extrahepatic malignancy-related). (3) Results: Over a 10-year follow-up period of 223,424 patients (cohort 1) with CHB, the overall mortality was 1.54 per 100 person-years. The mortality associated with HCC was the highest (0.65 per 100 person-years), followed by mortality related to extrahepatic malignancies (0.26 per 100 person-years), and cardio/cerebrovascular diseases (0.18 per 100 person-years). In the non-cirrhotic CHB (87.4%), 70% (11,198/15,996) of patients died due to non-liver-related causes over ten years. The 10-year overall mortality was 0.86 per 100 person-years. Among these, mortality due to extrahepatic malignancies had the highest rate (0.23 per 100 person-years), followed by mortality related to HCC (0.20 per 100 person-years), and cardio/cerebrovascular diseases (0.16 per 100 person-years). The 5-year mortality associated with extrahepatic malignancies increased from 0.36 per 100 person-years (cohort 1) to 0.40 per 100 person-years (cohort 2). (4) Conclusions: Mortality related to HCC decreased, whereas mortality related to extrahepatic malignancies increased in the antiviral era. Extrahepatic malignancies were the leading cause of death among patients with CHB without cirrhosis.

Elevated serum gamma-glutamyl transferase (GGT) levels are associated with chronic hepatitis B (CHB)-related hepatocellular carcinoma. However, their role in predicting mortality in patients with CHB treated with nucleotide/nucleoside analogs (NAs) remains elusive. Altogether, 2843 patients with CHB treated with NAs were recruited from a multinational cohort. Serum GGT levels before and 6 months (Month-6) after initiating NAs were measured to explore their association with all-cause, liver-related, and non-liver-related mortality. The annual incidence of all-cause mortality was 0.9/100 person-years over a follow-up period of 17,436.3 person-years. Compared with patients who survived, those who died had a significantly higher pretreatment (89.3 vs. 67.4 U/L, p = 0.002) and Month-6-GGT levels (62.1 vs. 38.4 U/L, p < 0.001). The factors associated with all-cause mortality included cirrhosis (hazard ratio [HR]/95% confidence interval [CI]: 2.66/1.92-3.70, p < 0.001), pretreatment GGT levels (HR/CI: 1.004/1.003-1.006, p < 0.001), alanine aminotransferase level (HR/CI: 0.996/0.994-0.998, p = 0.001), and age (HR/CI: 1.06/1.04-1.07, p < 0.001). Regarding liver-related mortality, the independent factors included cirrhosis (HR/CI: 4.36/2.79-6.89, p < 0.001), pretreatment GGT levels (HR/CI: 1.006/1.004-1.008, p < 0.001), alanine aminotransferase level (HR/CI: 0.993/0.990-0.997, p = 0.001), age (HR/CI: 1.03/1.01-1.05, p < 0.001), and fatty liver disease (HR/CI: 0.30/0.15-0.59, p = 0.001). Pretreatment GGT levels were also independently predictive of non-liver-related mortality (HR/CI: 1.003/1.000-1.005, p = 0.03). The results remained consistent after excluding the patients with a history of alcohol use. A dose-dependent manner of <25, 25-75, and >75 percentile of pretreatment GGT levels was observed with respect to the all-cause mortality (trend p < 0.001). Pretreatment serum GGT levels predicted all-cause, liver-related, and non-liver-related mortality in patients with CHB treated with NAs., (© 2023 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Background & Aims: Recent studies reported that moderate HBV DNA levels are significantly associated with hepatocellular carcinoma (HCC) risk in hepatitis B e antigen (HBeAg)-positive, non-cirrhotic patients with chronic hepatitis B (CHB). We aimed to develop and validate a new risk score to predict HCC development using baseline moderate HBV DNA levels in patients entering into HBeAg-positive CHB from chronic infection., Methods: This multicenter cohort study recruited 3,585 HBeAg-positive, non-cirrhotic patients who started antiviral treatment with entecavir or tenofovir disoproxil fumarate at phase change into CHB from chronic infection in 23 tertiary university-affiliated hospitals of South Korea (2012-2020). A new HCC risk score (PAGED-B) was developed (training cohort, n = 2,367) based on multivariable Cox models. Internal validation using bootstrap sampling and external validation (validation cohort, n = 1,218) were performed., Results: Sixty (1.7%) patients developed HCC (median follow-up, 5.4 years). In the training cohort, age, gender, platelets, diabetes and moderate HBV DNA levels (5.00-7.99 log 10 IU/ml) were independently associated with HCC development; the PAGED-B score (based on these five predictors) showed a time-dependent AUROC of 0.81 for the prediction of HCC development at 5 years. In the validation cohort, the AUROC of PAGED-B was 0.85, significantly higher than for other risk scores (PAGE-B, mPAGE-B, CAMD, and REAL-B). When stratified by the PAGED-B score, the HCC risk was significantly higher in high-risk patients than in low-risk patients (sub-distribution hazard ratio = 8.43 in the training and 11.59 in the validation cohorts, all p <0.001)., Conclusions: The newly established PAGED-B score may enable risk stratification for HCC at the time of transition into HBeAg-positive CHB., Impact and Implications: In this study, we developed and validated a new risk score to predict hepatocellular carcinoma (HCC) development in patients entering into hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) from chronic infection. The newly established PAGED-B score, which included baseline moderate HBV DNA levels (5-8 log 10 IU/ml), improved on the predictive performance of prior risk scores. Based on a patient's age, gender, diabetic status, platelet count, and moderate DNA levels (5-8 log 10 IU/ml) at the phase change into CHB from chronic infection, the PAGED-B score represents a reliable and easily available risk score to predict HCC development during the first 5 years of antiviral treatment in HBeAg-positive patients entering into CHB. With a scoring range from 0 to 12 points, the PAGED-B score significantly differentiated the 5-year HCC risk: low <7 points and high ≥7 points., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Data on patients switched to tenofovir alafenamide (TAF) from nucleos(t)ide analogues (NUCs) other than tenofovir disoproxil fumarate are limited., Aims: To assess the treatment and renal/bone safety outcomes following the switch to TAF., Methods: We prospectively enrolled adult patients with chronic hepatitis B (CHB) who switched from any NUC to TAF at 14 centres in Japan, Korea, Taiwan and the U.S. Study outcomes were viral suppression (VR; HBV DNA < 20 IU/mL), biochemical response (BR; alanine aminotransferase normalisation), and changes in estimated glomerular filtration rate (eGFR) and T-scores (L-spine) by bone absorptiometry by 24 months after switch to TAF., Results: We enrolled 270 eligible patients. Mean age was 58.1; 58.2% were male; 12.2% had cirrhosis and 73.3% previously received entecavir monotherapy. VR rate increased significantly from 95.2% to 98.8% by 24 months after the switch to TAF (p = 0.014). Between the switch and 24 months later, the mean spine T-score improved significantly from -1.43 ± 1.36 to -1.17 ± 1.38 (p < 0.0001), while there was no significant change in mean eGFR (88.4 ± 16.9-89.5 ± 16.3 mL/min/1.73 m 2 , p = 0.13). On multivariable analysis adjusted for age, sex, baseline spine T-score and prior TDF or adefovir dipivoxil use, male sex was significantly associated with lower risk of worsening spine T-score (odds ratio: 0.29, p = 0.020), while age was significantly associated with a higher risk of worsening chronic kidney disease stage (OR: 1.07, p = 0.019)., Conclusions: At 24 months after the switch to TAF, VR rates and spine bone density improved significantly while renal function remained stable., (© 2023 John Wiley & Sons Ltd.)

Guidelines vary on alpha-fetoprotein (AFP) testing for hepatocellular carcinoma (HCC) screening. This study aims to reassess AFP's role in HCC surveillance, utilizing a comprehensive, recent, nationwide cohort. Utilizing the National Health Claims Database from the Korean National Health Insurance Service, this research included data from 185,316 HCC patients registered between 2008 and 2018. Specifically, 81,520 patients diagnosed with HCC from 2008 to 2014 were analyzed. The study focused primarily on mortality and, secondarily, on the status of curative treatments. Multivariate analysis revealed that frequent AFP testing significantly impacts overall survival in HCC patients. Specifically, each additional AFP test correlated with a 6% relative improvement in survival (hazard ratio = 0.94, 95% CI: 0.940-0.947, p < 0.001). Patients who underwent AFP testing three or more times within two years prior to HCC diagnosis showed improved survival rates, with 55.6% receiving liver transplantation or hepatectomy. This trend was particularly pronounced in hepatitis B patients undergoing antiviral treatment. The findings highlight the potential of regular AFP testing to enhance survival in HCC patients, especially those with hepatitis B. Integrating frequent AFP testing with ultrasonography could increase the likelihood of early detection and access to curative treatments.

Background: The European Foundation for the Study of Chronic Liver Failure (EF-CLIF) consortium suggested that the clinical courses after acute decompensation (AD) stratify the long-term prognosis: stable decompensated cirrhosis (SDC), unstable decompensated cirrhosis (UDC), pre acute-on-chronic liver failure (pre ACLF), and ACLF. However, previous studies included patients with a history of previous AD and had limitations associated with identifying the clinical factors related to prognosis after the first AD., Method: The prospective Korean Acute-on-Chronic Liver Failure (KACLiF) cohort included cirrhotic patients who were hospitalised with first AD between July 2015 and August 2018. We analysed the factors associated with readmission after the first AD and compared the characteristics and prognosis among each subgroup to evaluate the risk factors for the occurrence of pre ACLF after AD., Result: A total of 746 cirrhotic patients who were hospitalised with first AD were enrolled. The subgroups consisted of SDC ( n = 565), UDC ( n = 29), pre ACLF ( n = 28), and ACLF ( n = 124). Of note, pre ACLF showed a poorer prognosis than ACLF. The risk factors associated with readmission within 3 months of first AD were non-variceal gastrointestinal (GI) bleeding, hepatic encephalopathy (HE), and high MELD score. Viral aetiology was associated with the occurrence of pre ACLF compared with alcohol aetiology regardless of baseline liver function status., Conclusion: Cirrhotic patients with first AD who present as non-variceal GI bleeding and HE can easily relapse. Interestingly, the occurrence of AD with organ failure within 3 months of first AD (pre ACLF) has worse prognosis compared with the occurrence of organ failure at first AD (ACLF). In particular, cirrhotic patients with viral hepatitis with/without alcohol consumption showed poor prognosis compared to other aetiologies. Therefore, patients with ACLF after AD within 3 months should be treated more carefully and definitive treatment through LT should be considered.

Background and Aim: Necroptosis is an emerging cell death pathway that allows cells to undergo "cellular suicide" in a caspase-independent manner. We investigated the fate of hepatic stellate cells (HSCs) under necroptotic stimuli., Methods and Results: The RNA level of mixed lineage kinase domain-like protein (MLKL) is higher in patients with non-alcoholic fatty liver disease than in healthy controls. Hepatic fibrosis was significantly lower in MLKL-KO bile duct ligation (KO-BDL) mice than in wild-type-BDL mice. Necroptotic stimuli caused the death of HT-29 and U937 cells. However, necroptotic stimuli activate HSCs instead of inducing cell death. MLKL inhibitors attenuated fibrogenic changes in HSCs during necroptosis. Unlike HT-29 and U937 cells, MLKL phosphorylation and oligomerization were not observed during necroptosis in HSCs. RNA sequencing showed that NF-κB signaling-related genes were upregulated in HSCs following necroptotic stimulation. Necroptotic stimuli in HSCs increased the nuclear expression of NF-κB, which decreased after MLKL inhibitor treatment. Induction of necroptosis in HSCs led to autophagosome activation and formation, which were attenuated by MLKL inhibitor treatment., Conclusion: HSCs avoid necroptosis due to the absence of MLKL phosphorylation and oligomerization and are activated through autophagosome and NF-κB pathways., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background/aims: The 2030 hepatitis C virus (HCV) elimination targets of the World Health Organization are an 80% reduction in incidence and 65% reduction in mortality compared to the 2015 rates. However, information on the nationwide incidence and treatment rates of HCV infection are limited. We aimed to investigate the nationwide incidence and status of the care cascade for HCV infection in Korea., Methods: This study used data from the Korea Disease Control and Prevention Agency linked with the data of the Korea National Health Insurance Service. Linkage to care was defined as visiting hospitals twice or more due to HCV infection within 1.5 years of the index date. The treatment rate was the number who had been prescribed antiviral medication within 1.5 years from the index date out of patients newly diagnosed with HCV., Results: The new HCV infection rate was 17.2 per 100,000 person-years (n=8,810) in 2019. The number of new HCV infections was the highest in patients aged 50 to 59 years (n=2,480), and the new HCV infection rate significantly increased with age (p<0.001). Among newly infected patients with HCV, the linkage to care rate was 78.2% (78.2% men, 78.2% women) and the treatment rate was 58.1% (56.8% men, 59.3% women) within 1.5 years., Conclusions: The new HCV infection rate was 17.2 per 100,000 person-years in Korea. It is necessary to continuously monitor the incidence and care cascade of HCV to establish proper strategies to reach the goal of HCV elimination by 2030.

Introduction: Tenofovir disoproxil fumarate (TDF) is reportedly superior or at least comparable to entecavir (ETV) for the prevention of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B; however, it has distinct long-term renal and bone toxicities. This study aimed to develop and validate a machine learning model (designated as Prediction of Liver cancer using Artificial intelligence-driven model for Network-antiviral Selection for hepatitis B [PLAN-S]) to predict an individualized risk of HCC during ETV or TDF therapy., Methods: This multinational study included 13,970 patients with chronic hepatitis B. The derivation (n = 6,790), Korean validation (n = 4,543), and Hong Kong-Taiwan validation cohorts (n = 2,637) were established. Patients were classified as the TDF-superior group when a PLAN-S-predicted HCC risk under ETV treatment is greater than under TDF treatment, and the others were defined as the TDF-nonsuperior group., Results: The PLAN-S model was derived using 8 variables and generated a c-index between 0.67 and 0.78 for each cohort. The TDF-superior group included a higher proportion of male patients and patients with cirrhosis than the TDF-nonsuperior group. In the derivation, Korean validation, and Hong Kong-Taiwan validation cohorts, 65.3%, 63.5%, and 76.4% of patients were classified as the TDF-superior group, respectively. In the TDF-superior group of each cohort, TDF was associated with a significantly lower risk of HCC than ETV (hazard ratio = 0.60-0.73, all P < 0.05). In the TDF-nonsuperior group, however, there was no significant difference between the 2 drugs (hazard ratio = 1.16-1.29, all P > 0.1)., Discussion: Considering the individual HCC risk predicted by PLAN-S and the potential TDF-related toxicities, TDF and ETV treatment may be recommended for the TDF-superior and TDF-nonsuperior groups, respectively., (Copyright © 2023 by The American College of Gastroenterology.)

Steatotic liver disease was suggested as an overarching term encompassing various etiologies of hepatic steatosis. Experts from multinational liver societies went through the Delphi process, including four rounds of surveys, and consented to adopt a new nomenclature and definition instead of the conventional nonalcoholic fatty liver disease (NAFLD). This was to improve the understanding of the patients and primary care physicians, with an explanation of the pathophysiology in the name of the disease. Also, it could minimize the stigmatization of patients by using the histological neutral term "steatosis" instead of "fatty". Herein, we will discuss the changes and continuity between the two nomenclatures, metabolic dysfunction-associated steatotic liver disease (MASLD) and NAFLD, as well as the challenges to MASLD which need to be addressed in future.

Background/aims: Chronic hepatitis C is a major risk factor for liver cirrhosis, hepatocellular carcinoma, and hepatic failure. Although traditional practices, including acupuncture, tend to increase the risk of HCV infection, the association remains controversial. Therefore, the current meta-analytical study was undertaken to evaluate the risks of acupuncture and hepatitis C transmission., Methods: Two researchers independently screened studies from the databases encompassing the period from inception to May 12, 2022. Baseline demographics, HCV transmission OR, and 95% CIs were extracted, pooled, and analyzed using random-effect models. Subgroup analyses utilizing study design and ethnicity were performed. Heterogeneity and publication bias were analyzed using the Higgins I 2 test and funnel plots, respectively., Results: In all, 28 studies with 194,826 participants (178,583 controls [91.7%] vs. 16,243 acupuncture users [8.3%]) were included in the final analysis. The pooled analysis showed that acupuncture users had a significantly higher HCV transmission rate than controls with heterogeneity (OR, 1.84 [1.46-2.32]; p<0.001; I 2 =80%). In the subgroup analysis, both cross-sectional case-control (n=14; OR, 1.96 [1.47-2.61]; p<0.001; I 2 =88%) and cross-sectional studies (n=12; OR, 1.85 [1.32-2.61]; p<0.001; I 2 =0%) showed significantly higher HCV infection rates in the acupuncture group than in the control group. Both Asian and non-Asian acupuncture users showed a higher HCV transmission risk than the controls (all P s <0.001). No significant publication bias was observed., Conclusions: Our findings indicate that acupuncture increases the risk of HCV transmission. Due to HCV's contagiousness, unsafe medical and social practices (including acupuncture) should be performed with caution.

Background: The fibrosis-4 index (FIB-4) and the NAFLD fibrosis score (NFS) have been used as noninvasive screening methods for advanced fibrosis in patients with NAFLD. However, their diagnostic performance has not been evaluated in at-risk individuals regardless of hepatic steatosis. This study evaluated the performance of the FIB-4 and NFS in at-risk groups of health check-up examinees at mass screening centers., Methods: This retrospective, cross-sectional study included 8545 participants who underwent voluntary magnetic resonance elastography at a discounted fee during their regular health check-ups at 13 mass screening centers nationwide. The at-risk group was defined as those with any of the following conditions: NAFLD, 2 or more metabolic abnormalities, diabetes mellitus, or abnormal aminotransferase levels. A magnetic resonance elastography cutoff of ≥3.6 kPa was used to define conventional advanced fibrosis., Results: According to the proposed criteria, the proportion of at-risk individuals was 67.4%-80.2% in the health check-up cohort without viral or alcohol-associated liver disease. The prevalence of individuals with advanced hepatic fibrosis in each at-risk group was ~2.3%-2.8% according to various criteria. It was higher in patients without NAFLD than in those with NAFLD. A total of 28.2%-39.6% of those in each at-risk group did not show hepatic steatosis on ultrasonography. The performance of FIB-4 for advanced fibrosis in the at-risk group was comparable with that in the NAFLD group. FIB-4 showed a better area under the receiver operating characteristic curve and sensitivity than NFS in the at-risk group., Conclusions: FIB-4 demonstrated superior performance compared with the NFS, and its performance in at-risk individuals was similar to that observed for patients with NAFLD., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

We aimed to evaluate the frequency and causes of discordant results in fatty liver (FL) diagnosis between B-mode ultrasonography (B-USG) and magnetic resonance imaging proton density fat fraction (MRI-PDFF). We analyzed patients who underwent both B-USG and MRI-PDFF within a 6-month interval. We made a confusion matrix for FL diagnosis between B-USG and MRI-PDFF and identified four discordant groups as follows: (1) the "UFL-MnFL-wo" group [B-USG FL-MRI-PDFF no FL without chronic liver disease (CLD) or liver cirrhosis (LC)]; (2) the "UFL-MnFL-w" group (B-USG FL-MRI-PDFF no FL with CLD or LC); (3) the "UnFL-MFL-wo" group (B-USG no FL-MRI-PDFF FL without CLD or LC); and (4) the "UnFL-MFL-w" group (B-USG no FL-MRI-PDFF FL with CLD or LC). We compared the "UFL-MnFL-wo" group with the control group in terms of various parameters. We found 201 patients (201/1514, 13.3%) with discordant results for FL diagnosis between B-USG and MRI-PDFF. The "UFL-MnFL-wo" group accounted for the largest portion at 6.8% (103/1514), followed by the "UFL-MnFL-w" group (79/1514, 5.2%) and the "UnFL-MFL-w" group (16/1514, 1.1%). The mean and right PDFF values, body mass index, and abdominal wall thickness were significantly higher in the "UFL-MnFL-wo" group than in the control group (p ≤ 0.001). The frequency of discordant results in the diagnosis of FL between B-USG and MRI-PDFF could be identified. The causes of discordant results were that B-USG was fairly accurate in diagnosing FL disease and that accompanying CLD or LC hindered the evaluation of FL., (© 2023. Springer Nature Limited.)

Non-alcoholic fatty liver disease (NAFLD) is often diagnosed incidentally during medical evaluation for diseases other than liver disease or during health checkups. This study aimed to investigate the awareness, current status, and barriers to the management of NAFLD in the general population. This cross-sectional study used an online survey, which consisted of 3-domain and 18-item questionnaires. The content validity index for each item of the questionnaire was rated above 0.80. Most respondents (72.8%) reported having heard of the term 'NAFLD', and a large proportion of the general population (85.7%) recognized the possibility of developing fatty liver without consuming alcohol. Awareness of the terminology of NAFLD and that NAFLD is a disease that needs to be managed is relatively high. However, the knowledge that NAFLD can progress to end-stage liver disease and new cardiovascular diseases is lacking. Only 25.7% of the general population is aware that NAFLD increases the incidence of heart and cerebrovascular diseases. Only 44.7% of those who were incidentally diagnosed during a health check-up were provided with any specific guidance on NAFLD, and more than half (55.3%) were not provided with education or guidance on NAFLD or did not remember it. Only 40.2% of people diagnosed with NAFLD incidentally visited a clinic. The reason for not visiting a clinic for the evaluation of NAFLD varied greatly depending on sex and age group. Only 40.2% of patients visited the clinic after being diagnosed with NAFLD. The reasons for not visiting the clinic after NAFLD diagnosis differed significantly according to sex and age., (© 2023. Springer Nature Limited.)

The response rate to obeticholic acid (OCA), a potential therapeutic agent for non-alcoholic fatty liver disease, is limited. This study demonstrated that upregulation of the alternative bile acid synthesis pathway increases the OCA treatment response rate. The hepatic transcriptome and bile acid metabolite profile analyses revealed that the alternative bile acid synthesis pathway (Cyp7b1 and muricholic acid) in the OCA-responder group were upregulated compared with those in the OCA-non-responder group. Intestinal microbiome analysis also revealed that the abundances of Bacteroidaceae, Parabacteroides, and Bacteroides, which were positively correlated with the alternative bile acid synthesis pathway, were higher in the OCA-responder group than in the non-responder group. Pre-study hepatic mRNA levels of Cyp8b1 (classic pathway) were downregulated in the OCA-responder group. The OCA response rate increased up to 80% in cases with a hepatic Cyp7b1/Cyp8b1 ratio ≥ 5.0. Therefore, the OCA therapeutic response can be evaluated based on the Cyp7b1/Cyp8b1 ratio or the alternative/classic bile acid synthesis pathway activity., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The socioeconomic burden of alcohol-related liver disease has been increasing worldwide. Its prevalence is underestimated, and patients with alcohol-related liver disease are rarely diagnosed in the earlier phase of the disease spectrum. Alcoholic hepatitis is a distinct syndrome with life-threatening signs of systemic inflammation. In severe alcoholic hepatitis, prednisolone is indicated as the first-line treatment even with the possibility of various complications. Early liver transplantation can be another option for highly selected patients with a null response to prednisolone. Most importantly, abstinence is the mainstay of long-term care, but relapse is frequent among patients. Recent findings on the pathogenesis of alcoholic hepatitis have enabled us to discover new therapeutic targets. Preventing hepatic inflammation, reducing oxidative stress, improving gut dysbiosis, and enhancing liver regeneration are the main targets of emerging therapies. Herein, we review the pathogenesis, current treatment, and barriers to successful clinical trials of alcoholic hepatitis. Additionally, clinical trials for alcoholic hepatitis, either ongoing or recently completed, will be briefly introduced., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Importance: The diagnostic performance of the fibrosis-4 index (FIB-4) and nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) for advanced fibrosis in lean patients with NAFLD is limited., Objective: To evaluate the diagnostic performance of the FIB-4 and NFS in lean individuals with NAFLD., Design, Setting, and Participants: This diagnostic study included adults with biopsy-proven NAFLD from 6 referral centers in Asia from 1995 to 2019. Cohorts were matched by age and sex between the lean and nonlean groups. All statistical analyses were executed from October 2022 to March 2023., Main Outcomes and Measures: The diagnostic performance of the FIB-4 and NFS at the current cutoff for advanced hepatic fibrosis in lean (body mass index [BMI] below 23 [calculated as weight in kilograms divided by height in meters squared]) and nonlean (BMI above 23) patients were evaluated., Results: A total of 1501 patients were included in analysis (mean [SD] age, 46.1 [16.4] years); 788 male (52.5%), 115 lean (7.7%), 472 (30.2%) Korean, 821 (48.7%) Japanese, and 341 (21.3%) Taiwanese. Among the age- and sex-matched cohort, the mean (SD) age was 52.3 (15.1) years and 41.2% (47 of 114) were male. The diagnostic performance and areas under the operating characteristic curve of the FIB-4 (lean, 0.807 vs nonlean, 0.743; P = .28) and NFS (lean, 0.790 vs nonlean, 0.755; P = .54) between the 2 groups were comparable in the age- and sex-matched cohort. The sensitivity and specificity of the NFS showed increasing and decreasing tendency according to the BMI quartiles (P for trend < .001), while those of the FIB-4 did not (P for trend = .05 and P = .20, respectively). Additionally, although the areas under the operating characteristic curve of the FIB-4 and NFS were not significantly different in the lean group (0.807 vs 0.790; P = .09), the sensitivity of the current NFS cutoff values was lower in the lean group than in that of FIB-4 (54.4% vs 81.8%; P = .03)., Conclusions and Relevance: In this cohort study, the performance of the FIB-4 and NFS in diagnosing advanced fibrosis did not differ significantly between the 2 groups overall. However, in lean NAFLD, while the sensitivity for diagnosing advanced hepatic fibrosis remained reasonable at the current cutoff level, the sensitivity of NFS at the current cutoff was too low to be an adequate screening tool.

Background & Aims: Most noninvasive tests (NITs) for hepatic fibrosis are designed for middle-aged patients with chronic liver disease. We compared the diagnostic performance of major NITs (aspartate aminotransferase-to-platelet ratio index [APRI], Fibrosis-4 index, and nonalcoholic fatty liver disease fibrosis score) for a community-based cohort., Methods: This cross-sectional study analyzed 8775 participants who underwent magnetic resonance elastography at community health check-up centers. Advanced hepatic fibrosis (≥F3) was defined by magnetic resonance elastography thresholds of 3.6 kPa. The diagnostic performance of 3 NITs was evaluated according to the etiology of liver disease, sex, metabolic syndrome, obesity, and increased aminotransferase levels in 4 age groups., Results: The APRI generally showed the best area under the receiver operating characteristic curve in patients aged 45 years or younger, and it was statistically significant in patients with chronic viral hepatitis and alcoholic fatty liver disease (P < .043). The best APRI cut-off value for detecting advanced hepatic fibrosis was 0.4, with a sensitivity and specificity of 75.8% and 73.5%, respectively, in the community-based cohort. The APRI showed balanced sensitivity and specificity across all age groups, whereas the other metrics showed low sensitivity in those aged <45 and low specificity in those >65 years., Conclusions: The APRI showed better sensitivity and negative predictive value than the Fibrosis-4 index and the nonalcoholic fatty liver disease fibrosis score in community-based populations with mixed etiology, and, thus, can be performed as the primary test in young adults (age, ≤45 y)., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: Previous studies have shown that ultrasonography has high specificity (80%-100%) but low sensitivity (50%-70%) in diagnosing fatty liver; sensitivity is especially low for mild steatosis. In this study, we aimed to reappraise the diagnostic performance of B-mode ultrasonography (B-USG) for fatty liver disease., Methods: We performed a retrospective, multinational, multicenter, cross-sectional, observational study (6 referral centers from 3 nations). We included 5,056 participants who underwent both B-USG and magnetic resonance proton density fat fraction (MRI-PDFF) within a 6-month period. The diagnostic performance of B-USG was compared with that of MRI-PDFF as a reference standard for fatty liver diagnosis, using sensitivity, specificity, positive and negative predictive values, diagnostic accuracy, and area under the receiver operating characteristic curve (AUC)., Results: B-USG showed a sensitivity of 83.4%, specificity of 81.0%, and AUC of 0.822 in diagnosing mild liver steatosis (6.5% ≤MRI-PDFF ≤14%). The sensitivity, specificity, and AUC in diagnosing the presence of fatty liver disease (MRI-PDFF ≥6.5%) were 83.4%, 81.0%, and 0.822, respectively. The mean PDFF of B-USG-diagnosed nonfatty liver differed significantly from that of diagnosed mild liver steatosis (3.5% ± 2.8% vs 8.5% ± 5.0%, P < 0.001). The interinstitutional variability of B-USG in diagnosing fatty liver was similar in diagnostic accuracy among the 6 centers (range, 82.8%-88.6%, P = 0.416)., Discussion: B-USG was an effective, objective method to detect mild liver steatosis using MRI-PDFF as comparison, regardless of the etiologies and comorbidities., (Copyright © 2022 by The American College of Gastroenterology.)

Preclinical data have shown that the herbal extract, ALS-L1023, from Melissa officinalis reduces visceral fat and hepatic steatosis. We aimed to assess the safety and efficacy of ALS-L1023 as the treatment of non-alcoholic fatty liver disease (NAFLD). We conducted a 24-week randomized, double-blind, placebo-controlled 2a study in patients with NAFLD (MRI-proton density fat fraction [MRI-PDFF] ≥ 8% and liver fibrosis ≥ 2.5 kPa on MR elastography [MRE]) in Korea. Patients were randomly assigned to 1800 mg ALS-L1023 ( n = 19), 1200 mg ALS-L1023 ( n = 21), or placebo ( n = 17) groups. Efficacy endpoints included changes in liver fat on MRI-PDFF, liver stiffness on MRE, and liver enzymes. For the full analysis set, a relative hepatic fat reduction from baseline was significant in the 1800 mg ALS-L1023 group (-15.0%, p = 0.03). There was a significant reduction in liver stiffness from baseline in the 1200 mg ALS-L1023 group (-10.7%, p = 0.03). Serum alanine aminotransferase decreased by -12.4% in the 1800 mg ALS-L1023 group, -29.8% in the 1200 mg ALS-L1023 group, and -4.9% in the placebo group. ALS-L1023 was well tolerated and there were no differences in the incidence of adverse events among the study groups. ALS-L1023 could reduce hepatic fat content in patients with NAFLD.

Background & Aims: The purpose of this study was to investigate the proportion of subjects with metabolic dysfunction-associated fatty liver disease (MAFLD) and to assess the degree of hepatic fibrosis and cardiovascular risk in metabolically healthy MAFLD subjects., Methods: A total of 6740 subjects who underwent both magnetic resonance elastography and abdominal ultrasound were included in this study. Significant (≥3.0 kPa) and advanced (≥3.6 kPa) hepatic fibrosis were evaluated by magnetic resonance elastography. The metabolic unhealthy status among subjects with MAFLD was defined as the presence of diabetes or 2 or more metabolic risk abnormalities., Results: The prevalence of MAFLD among the health examination cohort was 44.5% (3002 of 6740). A total of 26.6% (800 of 3002) of MAFLD subjects were metabolically healthy (≤1 risk factors and no diabetes), and 56.3% of MAFLD subjects (1691 of 3002) did not have metabolic syndrome. Hepatic fibrosis burden and cardiovascular risk were significantly higher in the metabolic unhealthy MAFLD group than in the healthy control group. However, the prevalence of significant (5.8% vs 4.3%; P = .099) and advanced hepatic fibrosis (0.8% vs 0.7%; P = .934) did not differ between the metabolically healthy MAFLD and healthy control groups. The prevalence of carotid artery plaque in the metabolically healthy MAFLD (32.7% vs 30.7%; P = .453) group was not different from that in the healthy control group., Conclusions: Contrary to the definition of MAFLD, a non-negligible number of metabolically healthy individuals are included in the MAFLD group. The metabolic healthy MAFLD group showed a comparable fibrosis burden and prevalence of carotid artery plaque compared with the healthy control group., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Serum-based noninvasive tests (NITs) have been widely used to assess liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). However, the diagnostic efficacy of NITs across ranges of age, body mass index (BMI), and presence of type 2 diabetes (T2DM) may vary and have not been well-characterized., Methods: We analyzed 1489 patients with biopsy-proven NAFLD from 6 centers in Japan, Taiwan, and Korea. Using histology as the gold standard, we compared the areas under the receiver operating characteristic (AUROCs) of Fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), and the new Hepamet fibrosis score (HFS), with a focus on performance in subgroups as stratified by age, BMI, and the presence of T2DM., Results: By histology, 44.0% of the overall cohort (655/1489) had F2-4, and 20.6% (307/1489) had F3-4 fibrosis. FIB-4 had the highest AUROCs for both F2-4 (0.701 vs NFS 0.676 and HFS 0.682, P = .001) and F3-4 (0.767 vs NFS 0.736 and HFS 0.752, P = .002). However, for F3-4 fibrosis, the AUROCs of all 3 NITs were generally higher in older (>60 years), nonobese (BMI <25 kg/m 2 ), and non-diabetic patients, although overall the best performance was observed with FIB-4 among nonobese (BMI<25) diabetic patients (AUROC, 0.92). The worst performance was observed in younger patients with T2DM for all NITs including FIB-4 (AUROC, 0.63-0.66)., Conclusions: FIB-4 had higher diagnostic efficacy for F3-4 than NFS or HFS, but this varied greatly by age, BMI, and T2DM, with better performance in older, nonobese, and nondiabetic patients. However, all NITs including FIB-4 had unacceptably poor performance in young or obese diabetic patients., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease, with a global prevalence estimated at approximately 25%. NAFLD is also the leading cause of liver cirrhosis, hepatocellular carcinoma, and death. Additionally, the risk of cardiovascular disease increases with greater NAFLD severity. The liver- and cardiovascular disease-related mortality incident rate ratios among the NAFLD population were 0.77 and 4.79 per 1,000 person-years, respectively. We intend to discuss the risk factors associated with NAFLD in terms of development and progression. Obesity or higher body mass index is closely associated with NAFLD in a dose-dependent manner, but growing evidence suggests that central obesity plays a more important role in the development of NAFLD. Saturated fat and fructose have been reported to be closely related to NAFLD. Fructose intake promotes lipogenesis and impairs mitochondria fat oxidation. The presence of type 2 diabetes is the most powerful predictive risk factor for hepatic fibrosis in patients with NAFLD. Single nucleotide polymorphism is not only associated with the prevalence of NAFLD but also associated with increased liver disease mortality. Obstructive sleep apnea, intestinal dysbiosis, and sarcopenia are associated with the development of NAFLD.

ALS-L1023 is an ingredient extracted from Melissa officinalis L. (Labiatae; lemon balm), which is known as a natural medicine that suppresses angiogenesis. Herein, we aimed to determine whether ALS-L1023 could alleviate liver fibrosis in the non-alcoholic fatty liver disease (NAFLD) model. C57BL/6 wild-type male mice (age, 6 weeks old) were fed a choline-deficient high-fat diet (CDHFD) for 10 weeks to induce NAFLD. For the next 10 weeks, two groups of mice received the test drug along with CDHFD. Two doses (a low dose, 800 mg/kg/day; and a high dose, 1200 mg/kg/day) of ALS-L1023 were selected and mixed with feed for administration. Obeticholic acid (OCA; 10 mg/kg/day) was used as the positive control. Biochemical analysis revealed that the ALS-L1023 low-dose group had significantly decreased alanine transaminase and aspartate transaminase. The area of fibrosis significantly decreased due to the administration of ALS-L1023, and the anti-fibrotic effect of ALS-L1023 was greater than that of OCA. RNA sequencing revealed that the responder group had lower expression of genes related to the hedgehog-signaling pathway than the non-responder group. ALS-L1023 may exert anti-fibrotic effects in the NAFLD model, suggesting that it may provide potential benefits for the treatment of liver fibrosis.

Although universal vaccination has been administered to toddlers, South Korea has had periodic nationwide outbreaks of acute hepatitis A since the late 2000s. We examined the chronological changes in the seroprevalence of anti-hepatitis A virus (HAV) immunoglobulin G (IgG) over the past 15 years (2005-2019). We retrospectively collected data from 45,632 subjects who underwent anti-HAV IgG testing without evidence of acute HAV infection at four centers in the capital area of South Korea between January 2005 and December 2019. The seroprevalence of anti-HAV IgG was analyzed according to age and compared among seven age groups and five time periods. Additionally, age-period-cohort analyses were used to identify the age, period, and cohort effects of the seroprevalence of anti-HAV IgG. The mean age of the enrolled subjects was 39.2 ± 19.2 years, and the average anti-HAV IgG positivity rate was 66.4%. During the 15 years, the seroprevalence of anti-HAV IgG in people aged 0 to 19 years significantly increased over time (P < .001). In people aged 20 to 29 years, the seroprevalence slightly decreased to that of the early 2010s (31.3% in 2005-2007 to 19.7% in 2011-2013) but rebounded to 39.5% in 2017 to 2019. In contrast, the seroprevalence of anti-HAV IgG in those aged 30 to 49 years decreased over time (P < .001). The seroprevalence of anti-HAV IgG in those aged 20 to 39 years in 2017 to 2019 was still less than 40%. In addition, the seroprevalence of anti-HAV IgG in people aged 50 to 59 years has recently decreased. Since the introduction of the universal vaccination, the seroprevalence of anti-HAV IgG in children and young adults has gradually increased. However, the seroprevalence of anti-HAV IgG in people in their 20s remains low, and the seroprevalence of anti-HAV IgG in people in their 30s and 40s is gradually decreasing. Therefore, a new strategy for HAV vaccination is needed for those in their 20s to 40s., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)