Hepatitis B flare is a common complication of Chronic Hepatitis B (CHB) and is defined as an increase in HBV viral load associated with abnormal alanine aminotransferases (ALT), the consensus being an ALT≥5xupper limit of normal. The immunopathogenesis is related to induction of inflammatory cells and cytokines by the rise in HBV DNA. There are multiple causes of flares, and they carry the risk of progression to hepatic decompensation and acute-on-chronic liver failure (ACLF) with its associated mortality, potentially requiring liver transplantation. Initial assessment should be exclusion of other causes of liver dysfunction, determine severity, and prognosis. General prognostic models of ACLF are useful but the COSSH-ACLF II score is specific for HBV. Initiation of nucleos(t)ide analogues early is crucial and even in severe HBV flares reduces mortality by 73.6%. Once jaundice and coagulopathy occur, salvage by antivirals is challenging, and such patients should be considered for liver transplantation. However, many patients may not be suitable for transplant or may not have available donor livers as is common in Asia. Recently, there has been increasing evidence of benefit with adjunctive therapies such as corticosteroids and plasma exchange, but this needs to be balanced with the risks and should be considered as rescue therapies in severe HBV flares or ACLF. Liver transplant is the ultimate intervention when these other strategies fail to rescue patients. In summary, HBV flares are clinically serious events that can lead to hepatic decompensation and ACLF but strategies for rescue should be considered before liver transplantation.
Severe alcohol-associated hepatitis (SAH) is the most aggressive form of alcohol-associated liver disease and is associated with very high short-term mortality. It is characterized by the acute onset of jaundice in the context of ongoing alcohol use, most commonly defined by a Maddrey’s discriminant function ≥32 or a model for end-stage liver disease score ≥20. Despite its increasing global burden and substantial healthcare costs, therapeutic options remain limited, and outcomes are poor. The severity of liver failure, systemic inflammation, infectious complications, and extrahepatic organ dysfunction determines the prognosis in SAH. The pathophysiology of SAH is multifactorial, involving direct hepatotoxicity from alcohol metabolites, oxidative stress, dysregulated immune activation, gut dysbiosis with increased intestinal permeability, impaired hepatic regeneration, and genetic susceptibility. These interrelated mechanisms culminate in an exaggerated inflammatory response driven by macrophage activation and cytokine release, resulting in hepatocellular injury and multi-organ failure. Glucocorticoids remain the guideline-recommended standard of care for selected patients; however, their benefit is limited to modest short-term survival gains, with high rates of non-response and infection. Numerous investigational therapies targeting inflammation, oxidative stress, liver regeneration, bile acid signalling, epigenetic regulation, and the gut-liver axis have been evaluated, with largely disappointing results. Emerging approaches, including interleukin-22 agonists and epigenetic modulators such as larsucosterol, show promise but require validation in well-designed trials. This review synthesizes current evidence on the definition, prognostic assessment, and pathophysiology of SAH, critically appraises existing and emerging therapies, and highlights the need for combination strategies, improved patient stratification, and personalized treatment approaches.
Hepatitis B virus (HBV) remains a major cause of chronic liver diseases, especially in the Asia-Pacific region. In recent decades, coinfection with hepatitis C virus (HCV) and coexistence with metabolic dysfunction-associated steatotic liver disease (MASLD) have emerged as significant clinical concerns among HBV-infected patients. Although global HBV vaccination programs and curative therapies for HCV have led to a marked decline in HBV/HCV coinfection, MASLD is rapidly becoming the predominant comorbidity due to the global surge in metabolic risk factors. HBV/HCV coinfection typically results in more severe liver damage, with unique challenges in antiviral treatment and risk of HBV reactivation post-HCV clearance. In contrast, HBV/MASLD overlap demonstrates complex metabolic-viral interactions that may influence viral replication, hepatitis B surface antigen seroclearance, fibrosis progression, and risk of hepatocellular carcinoma. This review critically compares the epidemiology, clinical outcomes, and management strategies of HBV patients with concurrent HCV or MASLD, while addressing current research gaps and proposing directions for future investigations.
Background/Aims Natural killer (NK) cell function is generally considered dampened in chronic hepatitis B virus (HBV) infection; however, the NK cell pool exhibits phenotypic and functional heterogeneity, and the antibody--mediated effect of NK cells remains less characterized. This study evaluated the dynamic changes in antibody-mediated NK cell responses and the involvement of distinct NK subsets across disease stages and during antiviral treatment.
Methods A T-cell receptor-like antibody specific for the HBV core 18–27 peptide (cTCRL-Ab) was used to determine the antibody-mediated effect of NK cells, and an array of NK cell surface markers were analyzed in cross-sectional and longitudinal cohorts of patients with chronic HBV infection. Single-cell RNA sequencing (scRNA-seq) was performed to identify the heterogeneity of NK subsets.
Results The cTCRL-Ab enabled the detection of NK cell cytolytic activity and IFNγ production. Notably, cTCRL-Ab-mediated NK cell responses were compromised in chronically HBV-infected patients, particularly in those receiving pegylated interferon-α (Peg-IFNα), which was associated with the downregulation of CD16 expression. Correspondingly, Peg-IFNα inhibited cTCRL-Ab-mediated NK cell function by reducing CD16 expression in vitro. scRNA-seq revealed that CD16 downregulation occurred mainly within a dysfunctional CD16hi NK subset exhibiting exhaustion properties. In contrast, an activated CD16hiNK subpopulation (CX3CR1⁺KLRC2–CD16hi) with high cytotoxicity was enriched in patients who experienced favorable treatment responses. Furthermore, the intrahepatic CX3CR1+KLRC2–CD16hi subset tended to exhibit functional restoration in HBsAg-loss individuals.
Conclusions Our data contribute to the understanding of antibody-mediated responses of NK cells in chronic HBV infection, and highlight a previously unappreciated functional CX3CR1+KLRC2–CD16hiNK subset as a potential therapeutic target.
Background/Aims Acetyl coenzyme A (acetyl-CoA) is one of the most essential metabolites in cell metabolism but its function and concentration in hepatocellular carcinoma (HCC) remain elusive and controversial.
Methods A comprehensive analysis of acetyl-CoA levels and acetyl-CoA synthetase 2 (ACSS2) expression across a range of samples, including patient specimens from both hepatitis B virus (HBV) positive and HBV negative HCC individuals, HBV-transgenic mouse HCC models, and multiple cell lines. Furthermore, to evaluate the functional significance of ACSS2 in HBV-related HCC, we implemented both genetic and pharmacological inhibition strategies targeting ACSS2. Molecular mechanism and mitophagy assessment were revealed by cleavage under target and tagmentation sequencing, RNA sequencing, bioinformatic analyses, transmission electron microscopy and JC-1 staining.
Results Our study revealed a distinct metabolic signature of HBV-related HCC, marked by elevated acetyl-CoA, which was driven by ACSS2. ACSS2 was upregulated by the carbohydrate response element-binding protein in HBV-related HCC. Furthermore, ACSS2 improved tumor cell proliferation, an effect that was dependent on its enzymatic activity. Mechanistically, ACSS2-induced acetyl-CoA accumulation activated voltage-dependent anion channels 1 transcription through increased H3K27ac occupancy, which subsequently promoted mitophagy and HBV-related HCC tumorigenesis. Notably, targeting ACSS2 by depletion or inhibition with a catalytic inhibitor significantly suppressed tumor growth.
Conclusions These findings not only illustrate the interplay between metabolic reprogramming, epigenetic modification, and tumorigenesis in the context of HBV infection, but also highlight ACSS2 as a novel metabolic vulnerability in HBV-related HCC. Therefore, targeting ACSS2 could be a novel strategy against HBV-related HCC.
Chronic hepatitis B (CHB) infection remains a significant global public health concern. Functional cure, defined as hepatitis B surface antigen seroclearance with unquantifiable HBV DNA at 24 weeks off treatment, is a desirable endpoint in the treatment of CHB, yet challenging to achieve. Given the limitations of current therapies including nucleos(t)ide analogues and pegylated interferon alpha, novel agents targeting functional cure are emerging. As hepatitis B virus (HBV) is a non-cytolytic virus, liver damage stems from the host immune response towards HBV-infected cells. The innate immune response during the initial phase of HBV infection is crucial in establishing an adequate level of immunity against the virus. However, HBV adopts various mechanisms to evade the host’s innate immunity, partly contributing to the chronicity of infection. This article provides a comprehensive review on how the HBV life cycle interacts with the host’s innate immune system. The latest evidence of novel agents targeting the innate immunity will also be covered. Retinoic acid inducible gene I agonists, toll-like receptor agonists, and interferons are therapies that target the HBV evasion strategies against host’s innate immunity. While small interfering RNAs and antisense oligonucleotides are originally designed for antigen knockdown and reinvigoration of the adaptive immune response, they have also shown additional impacts on the innate immunity. With ongoing research and innovation in combination strategies, advancement in the management of CHB is anticipated in the future.
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Current Status and Prospects of Clinical Research on Low-Level Viremia in Chronic Hepatitis B after Treatment 颜 刘 Advances in Clinical Medicine.2026; 16(03): 1942. CrossRef
Eun Sun Jang, Nae Yun Heo, Jae Yoon Jeong, Jung Gil Park, Do Seon Song, Eun Ju Cho, Chang Hun Lee, Jae Seung Lee, Jae Hyun Yoon, Seul Ki Han, Young Kul Jung, on behalf of the Korean Association for the Study of the Liver (KASL)
Clin Mol Hepatol 2026;32(1):1-52. Published online October 23, 2025
Impact of Documented Social Vulnerability on Clinical Outcomes in Metabolic Dysfunction‐Associated Steatotic Liver Disease Pojsakorn Danpanichkul, Yanfang Pang, Maria Inggriani, Supapitch Sirimangklanurak, Matheus Souza, Ahmad Anouti, Andrew F. Ibrahim, Nikki Duong, Thomas G. Cotter, Thomas A. Kerr, Donghee Kim, Mazen Noureddin, Karn Wijarnpreecha Liver International.2026;[Epub] CrossRef
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Through the implementation of hepatitis B vaccination and effective antiviral treatment over the past four decades, the hepatitis B surface antigen (HBsAg) seroprevalence of the vaccinated generation dramatically decline. The incidence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) also decreases. However, the elimination of HBV is still a challenge to achieve. Novel HBV biomarkers, including quantitative HBsAg, hepatitis B virus core-related antigen and HBV RNA are promising in predicting clinical phases, risks of disease progression and HBV functional cure. Current antiviral therapies, nucleoside/nucleotide and pegylated alpha-interferon, effectively decrease HCC incidence in chronic hepatitis B (CHB) patients and minimize the recurrence of HCC in patients receiving curative therapy. Novel agents under development to achieve HBV cure include direct-acting antivirals that target various stages of the HBV lifecycle and host targeting agents that enhance HBV-specific immunity. The action plans for eliminating hepatitis B in the future are universal HBV screening, early and simplified treatment as well as precision lifelong management for CHB patients. This narrative review will summarize and discuss global strategies and initiatives aimed at eliminating HBV infection.
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Background/Aims Hepatitis B virus (HBV) mother-to-child transmission (MTCT) remains a global health concern, with over 90% of perinatal infections leading to chronic HBV. To evaluate long-term trends in MTCT rates and associated factors within Korea’s national program.
Methods Population-based cohort study using linked data from the Perinatal Hepatitis B Prevention Program (PHBPP) and National Health Insurance Service in Korea. The study included HBsAg-positive mother-infant pairs with post-vaccination serologic results from 2002 to 2021.
Results Among the 154,478 mother-infant pairs, the overall MTCT rate after prophylaxis was 2.3%. Antiviral use lowered MTCT rates (0.9% vs. 2.4%) particularly in HBeAg-positivity (1.0% vs. 5.9%; adjusted odds ratio [aOR] 0.21; 95% confidence interval [CI] 0.14–0.32). Lower MTCT rates were observed for cesarean section vs. vaginal delivery (1.9% vs. 2.6%; aOR 0.78; 95% CI 0.73–0.84) and breastfeeding vs. formula feeding (1.8% vs. 2.8%; aOR 0.65; 95% CI 0.56–0.76). Annual MTCT rates decreased from 3.6% (2002–2005) to 1.3% (2018–2021). Antivirals reduced MTCT rates; initiation at 14–27 weeks (0.39%), or 28–32 weeks (0.44%) vs. ≥33 weeks (1.47%); postpartum continuation (0.55%) vs. antepartum discontinuation (1.44%); use ≥61 days (0.51%) vs. 1–60 days (1.67%). Lower MTCT risk was associated with maternal (old age, high income) and infant (female sex, preterm birth) factors.
Conclusions This comprehensive analysis of the PHBPP in Korea demonstrates that the use of antivirals, breastfeeding, and cesarean section, combined with conventional immunoprophylaxis, has significantly reduced MTCT rates. These results are crucial for global HBV elimination and can help to guide HBV MTCT prevention strategies.
Moana Witte, Carlos Oltmanns, Jan Tauwaldt, Hagen Schmaus, Jasmin Mischke, Gordon Grabert, Mara Bretthauer, Lennart M. Roesner, Thomas Werfel, Katja Deterding, Benjamin Maasoumy, Heiner Wedemeyer, Tim Kacprowski, Anke R.M. Kraft, Markus Cornberg
Clin Mol Hepatol 2025;31(4):1269-1284. Published online June 4, 2025
Background/Aims Hepatitis C virus (HCV) infection remains a global health challenge, leading to chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Despite the high efficacy of direct-acting antiviral therapy in achieving sustained virologic response (SVR), concerns persist regarding long-term immune alterations and residual risks, particularly in cirrhotic patients.
Methods This study investigates 75 soluble immune mediator (SIM) profiles in 102 chronic HCV patients, stratified by cirrhosis status, at therapy initiation, end of treatment, and long-term follow-up (median 96 weeks). Findings were compared with 51 matched healthy controls and validated in an independent cohort of 47 cirrhotic patients, 17 of whom developed HCC.
Results We observed significant SIM alterations at baseline, with cirrhotic patients displaying a more profoundly dysregulated inflammatory milieu. Despite an overall decline in inflammatory markers following SVR, persistent alterations were evident, particularly in cirrhotic patients. Notably, those with liver stiffness exceeding 14 kPa exhibited sustained inflammatory dysregulation, correlating with liver elastography values. Key SIM such as interleukin (IL)-6, IL-8, urokinase plasminogen activator, and hepatocellular growth factor remained elevated and were associated with HCC development. Network analysis highlighted their roles in liver fibrosis, regeneration, and carcinogenesis.
Conclusions These findings underscore the importance of early antiviral intervention to prevent cirrhosis-related sequelae. Future studies should explore the mechanistic pathways linking chronic inflammation, fibrosis, and oncogenesis to identify predictive biomarkers and novel therapeutic targets. Addressing persistent immune alterations post-HCV clearance may improve long-term outcomes, particularly in patients with advanced liver disease.
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Effect of varenicline on major adverse liver outcomes in alcohol‐associated liver disease: An exploratory analysis Pojsakorn Danpanichkul, Yanfang Pang, Donghee Kim, Thanathip Suenghataiphorn, Donghyun Ko, Andrew F. Ibrahim, Vitchapong Prasitsumrit, Kwanjit Duangsonk, Mazen Noureddin, Karn Wijarnpreecha, Suthat Liangpunsakul Alcohol, Clinical and Experimental Research.2025; 49(11): 2451. CrossRef
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Contemporary trends in extrahepatic mortality of chronic liver disease in the United States from 2014 to 2023 Donghee Kim, Pojsakorn Danpanichkul, Karn Wijarnpreecha, Aijaz Ahmed Clinical and Molecular Hepatology.2026; 32(1): e24. CrossRef
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Background/Aims Berberine ursodeoxycholate (HTD1801) has been shown to significantly reduce liver fat content (LFC) in an 18-week, placebo-controlled Phase 2 study in patients with metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes mellitus. The purpose of this assessment was to establish proof of concept in liver histologic improvement with HTD1801 treatment based on preclinical and clinical evidence.
Methods The efficacy of HTD1801 was evaluated in a preclinical MASH/dyslipidemia model (golden hamsters fed a high fat diet, eight/group) after six weeks of daily treatment. Additionally, in a secondary analysis of a Phase 2 clinical study, 100 patients with presumed MASH were evaluated by multiple noninvasive markers associated with MASH resolution and/or fibrosis improvement. These include magnetic resonance imaging proton density fat fraction (MRIPDFF; ≥30% LFC reduction), iron-corrected T1 (≥80 ms reduction), alanine aminotransferase (≥17 U/L reduction), weight loss (≥5% reduction), Fibrosis-4 index (shift to <1.3), and MASH resolution index (achieving ≥–0.67).
Results Preclinical findings in the MASH/dyslipidemia hamster model showed that HTD1801 significantly improved histologic fibrosis and the Nonalcoholic Fatty Liver Disease Activity Score to such a degree that improvements approximated the appearance of the normal controls. In the clinical study, 52% of HTD1801-treated patients achieved MRI response criteria compared to 24% of placebo (p<0.05). Dose-dependent improvements were observed across biomarkers, with more HTD1801-treated patients achieving response criteria associated with improvements in the histologic features of MASH.
Conclusions These findings suggest that HTD1801 has strong potential to produce histological improvements in patients with MASH.
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Metabolic dysfunction-associated steatotic liver disease, formerly referred to as non-alcoholic fatty liver disease, is the most common liver disease in Western countries and has emerged as the leading indication for liver transplantation. Metabolic dysfunction-associated steatohepatitis (MASH), a more advanced stage, carries a high risk of progression to liver fibrosis, cirrhosis, liver failure, and hepatocellular carcinoma. Until recently, lifestyle intervention remained the mainstay of MASH management, with no pharmacological treatments specifically approved. However, advances in understanding its pathophysiological mechanisms have fueled numerous clinical trials, culminating in the Food and Drug Administration’s (FDA) approval of resmetirom as the first treatment for MASH in 2024. Additionally, many investigational drugs are nearing FDA approval or progressing through late-stage clinical trials. This review examines the current therapeutic landscape, highlights strategies for identifying patients suitable for liver-directed therapies in real-world settings, and discusses the challenges that remain.
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Background/Aims Given the increase in prevalence of metabolic diseases, we investigated their long-term impacts on the outcomes of chronic hepatitis B (CHB) patients receiving nucleos(t)ide analogue (NA) treatment.
Methods We analyzed data from CHB patients for whom initiated NA treatment from 30 centers. We balanced patient characteristics with and without metabolic disease (diabetes, obesity, dyslipidemia, and hypertension) via propensity-score matching (PSM) to evaluate adverse outcomes.
Results The study included 4,500 patients. PSM yielded 909 pairs of patients with balanced characteristics. When stratified by the number of metabolic diseases, only patients with ≥2 metabolic diseases had an increased cumulative incidence of cirrhosis and overall death. However, when stratified by the presence of diabetes (regardless of the presence or number of other metabolic diseases), patients with diabetes (versus those without) had a significantly higher cumulative incidence of all outcomes: cirrhosis (P=0.009), hepatocellular carcinoma (HCC, P=0.023), and overall, liver-related, and non-liver-related death (P<0.001, P=0.026 and P<0.001, respectively). Having ≥2 metabolic diseases was associated with cirrhosis, overall death, and non-liver-related death but not HCC or liver-related death, while diabetes was significantly associated with a higher risk of all outcomes: cirrhosis (hazard ratio [HR]=3.75, P=0.004), HCC (HR=2.02, P=0.020), and overall, liver-related, and non-liver-related death (HR=2.53, P<0.001; HR=2.65, P=0.016; HR=2.38, P<0.001).
Conclusions Having two or more metabolic diseases was associated with a higher risk of cirrhosis, overall death, and non-liver-related death, but having diabetes as a single metabolic disease was significantly associated with all adverse outcomes including cirrhosis, HCC, and overall, liver-related, and non-liver-related death.
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