Trending Topics in Gastroenterology | GastroAGI

MELD Exceptions in PSC Under Scrutiny : Liver Transpl | June 2026

Introduction: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that frequently progresses to liver failure, recurrent bacterial cholangitis, and the need for liver transplantation. Because the Model for End-Stage Liver Disease (MELD) score may not fully capture the disease burden experienced by some patients with PSC, exception policies have been developed to provide additional transplant priority in selected circumstances. However, the appropriateness and effectiveness of these exceptions remain an area of ongoing debate. Problem Statement: MELD exception policies are intended to address clinical situations in which standard MELD scores underestimate transplant urgency. In PSC, exceptions have often been granted for recurrent cholangitis and other disease-related complications, yet the supporting evidence has been limited and inconsistent. Determining whether these policies accurately identify patients with increased mortality risk or improved transplant benefit is essential to maintaining fairness in organ allocation. Summary: This editorial examines the current practice of granting MELD exception points for patients with PSC and questions whether existing policies are sufficiently supported by robust clinical evidence. The authors highlight a central challenge in transplant allocation: balancing the need to recognize PSC-specific complications while ensuring equitable organ distribution across all liver disease populations. Although recurrent bacterial cholangitis and related complications can significantly impair quality of life and contribute to morbidity, evidence linking these events to a clearly increased waitlist mortality risk remains limited. The editorial argues that exception policies should be driven by objective data demonstrating measurable transplant benefit rather than historical practice patterns or expert consensus alone. The authors emphasize the need for contemporary outcome-based studies that evaluate waitlist mortality, post-transplant outcomes, and the true impact of PSC-related complications on patient prognosis. As transplant medicine increasingly moves toward evidence-based allocation systems, reassessment of PSC exception policies may be necessary to ensure fairness, transparency, and optimal use of scarce donor organs. The article ultimately calls for stronger data to guide future policy decisions and to determine whether current MELD exception practices for PSC remain justified in modern liver transplantation.

Precision HBV Care Moves Toward Functional Cure : Frontline Gastroenterology | May 2026

Introduction Chronic Hepatitis B remains a leading global cause of cirrhosis and Hepatocellular Carcinoma despite the availability of potent antiviral therapy. However, management strategies are rapidly evolving from simple viral suppression toward precision, biomarker-driven care focused on long-term disease modification and functional cure. Problem Statement Traditional hepatitis B management has relied heavily on alanine aminotransferase levels and HBV DNA thresholds, which may fail to identify patients at ongoing risk of fibrosis progression and hepatocellular carcinoma, particularly those with concurrent metabolic dysfunction. Summary This contemporary review highlights the major clinical and conceptual advances incorporated into the 2025 European Association for the Study of the Liver hepatitis B guidance, outlining a shift toward earlier treatment, integrated metabolic assessment and personalized biomarker-led management. A central theme is the movement toward achieving “functional cure,” defined by sustained loss of hepatitis B surface antigen with durable viral suppression. This represents a major evolution from the previous strategy of indefinite viral suppression alone. The review emphasizes that patients with concurrent Metabolic Dysfunction-Associated Steatotic Liver Disease may experience fibrosis progression even in the setting of low viral replication or normal liver enzymes. This recognition substantially broadens the clinical framework for treatment decision-making. Novel viral biomarkers are increasingly reshaping hepatitis B management. Quantitative HBsAg, hepatitis B core-related antigen and HBV RNA are emerging as clinically important tools for refining disease phase classification, predicting treatment response and identifying patients suitable for safe therapy discontinuation. These biomarkers may also help identify patients with lower intrahepatic viral transcriptional activity who are closer to achieving immune control. Importantly, the review highlights that hepatitis B is no longer viewed solely as a virological disease but increasingly as a complex interaction between viral activity, host immunity, fibrosis biology and metabolic dysfunction. The updated paradigm supports earlier antiviral initiation in selected patients before advanced fibrosis develops, reflecting growing evidence that cumulative inflammatory injury drives long-term hepatocarcinogenesis. Special populations receive significant attention, including pregnant individuals, patients receiving immunosuppressive therapy and those with Hepatitis D co-infection, where tailored management strategies are essential. The review also highlights emerging minimally invasive liver fine needle aspiration approaches that allow intrahepatic immune and virological profiling. These technologies may accelerate development of individualized immunotherapeutic and antiviral strategies. Clinically, this transition mirrors broader trends in hepatology toward precision medicine, where treatment decisions increasingly integrate virological, metabolic, immunologic and fibrosis-related data rather than relying on isolated laboratory thresholds. The article is particularly relevant because current nucleos(t)ide analogues rarely achieve HBsAg loss, creating strong interest in finite-treatment and immune-restorative strategies. Several investigational therapeutic approaches are discussed indirectly within this evolving framework, including siRNA therapies, capsid assembly modulators, therapeutic vaccines and immune checkpoint-targeting approaches designed to restore antiviral immunity. The review additionally underscores the importance of improving screening and linkage-to-care pathways, especially in migrant and underserved populations where hepatitis B burden remains concentrated. Limitations remain substantial. Many emerging biomarkers are not yet globally standardized, treatment cessation strategies remain incompletely validated and access to advanced testing varies considerably across healthcare systems. Future hepatitis B care will likely involve integrated risk prediction models combining viral biomarkers, metabolic phenotyping, fibrosis assessment and immune profiling to individualize treatment intensity and duration. Overall, this review captures a major transition in chronic hepatitis B management—from static viral suppression algorithms toward biomarker-guided precision hepatology focused on earlier intervention, individualized monitoring and ultimately functional cure.

PLEX Shows Limited Overall Benefit in HAV-ALF : Indian J Gastroenterol | May 2026

Introduction Acute Liver Failure caused by Hepatitis A remains an important cause of mortality in young adults in developing countries. Although Therapeutic Plasma Exchange has shown benefit in acute liver failure overall, disease-specific evidence in hepatitis A virus-related ALF has been lacking. Problem Statement The role of plasma exchange in HAV-related acute liver failure remains uncertain, particularly regarding patient selection and hemodynamic status. Existing data are limited, and it is unclear whether all patients benefit equally from extracorporeal support strategies. Summary This large Indian multicenter cohort study evaluated the real-world effectiveness of plasma exchange compared with standard medical treatment in patients with hepatitis A-related acute liver failure across 13 tertiary centers. The study included more than 230 patients, making it one of the largest HAV-ALF cohorts evaluating plasma exchange to date. Overall in-hospital native liver survival did not significantly differ between patients treated with plasma exchange and those receiving standard medical therapy alone. This finding suggests that routine universal application of plasma exchange in all HAV-ALF patients may not improve outcomes. However, an important signal emerged in a clinically relevant subgroup. Among hemodynamically stable patients not requiring inotropes, survival appeared substantially better in the plasma exchange cohort on univariate analysis. This observation is biologically plausible because patients without advanced circulatory collapse may better tolerate extracorporeal therapy and may still possess reversible hepatic injury amenable to supportive immune and toxin-modulating interventions. Nevertheless, the survival advantage was not maintained after propensity score matching and regression adjustment, indicating potential selection bias and residual confounding within this retrospective dataset. The findings therefore suggest that hemodynamic stability may be an important determinant of response to plasma exchange rather than plasma exchange being universally beneficial across all HAV-ALF phenotypes. Clinically, the study highlights the heterogeneity of acute liver failure and reinforces the need for individualized extracorporeal support strategies rather than protocolized blanket therapy. The work is particularly relevant in the Indian setting, where hepatitis A continues to contribute significantly to acute liver failure burden and transplant access remains limited. Importantly, the cohort also included patients fulfilling King's College Criteria, reflecting inclusion of severe disease presentations encountered in real-world hepatology practice. The study further raises important questions regarding optimal timing, patient selection and intensity of plasma exchange in viral acute liver failure. Potential mechanisms of benefit may include reduction of inflammatory mediators, removal of circulating toxins, correction of coagulopathy and temporary support of systemic homeostasis during hepatic recovery. However, advanced multiorgan dysfunction and vasoplegia may limit the efficacy of extracorporeal support once systemic decompensation becomes established. The retrospective design, inter-center variability and non-randomized treatment allocation remain important limitations. Additionally, differences in disease severity and referral patterns may have influenced treatment selection. Future prospective randomized studies focused specifically on hemodynamically stable HAV-ALF populations are needed to clarify whether an early “window of opportunity” exists where plasma exchange can alter native liver survival. The findings also support development of more refined prognostic models integrating hemodynamic status, inflammatory biomarkers and dynamic organ failure assessment to guide extracorporeal therapy decisions. Overall, this multicenter Indian study suggests that plasma exchange does not improve survival across all patients with hepatitis A-related acute liver failure, but it may offer benefit in carefully selected hemodynamically stable patients who are not yet requiring inotropic support.

Bepirovirsen Achieves Functional Cure in Chronic Hepatitis B: NEJM | May 2026

• Bepirovirsen is an antisense oligonucleotide that targets HBV transcripts, aiming to reduce viral proteins and achieve a functional cure rather than lifelong viral suppression. • In two large Phase 3 trials (B-Well 1 and B-Well 2), approximately 20% of treated patients achieved functional cure, compared with 0% in the placebo group. • Functional cure was defined as sustained HBV DNA suppression below the limit of quantification together with HBsAg loss, maintained for at least 24 weeks after treatment. • The results were highly consistent across both studies, with cure rates of 20% in B-Well 1 and 19% in B-Well 2, providing strong validation of the treatment effect. • All patients were receiving stable nucleos(t)ide analogue therapy at study entry, and antiviral therapy was subsequently discontinued, demonstrating the potential for finite-duration treatment. • The study provides some of the strongest evidence to date that chronic HBV infection can be functionally cured without indefinite antiviral therapy. • Adverse events were more common with bepirovirsen than placebo. The most frequent significant adverse event was ALT elevation, which may reflect immune-mediated clearance of infected hepatocytes. • Serious adverse events were relatively uncommon, occurring in 7% of bepirovirsen-treated patients compared with 4% of placebo-treated patients. • Although highly encouraging, approximately 80% of patients did not achieve functional cure, indicating that further improvements are still needed. • Bepirovirsen is likely to become an important component of future combination cure strategies, potentially alongside siRNA therapies, therapeutic vaccines, and immune modulators. • The trial represents a major milestone in HBV therapeutics and moves the field closer to the long-sought goal of a practical and scalable cure for chronic hepatitis B. Bottom Line: Bepirovirsen is the first antisense oligonucleotide to demonstrate Phase 3 functional cure rates of approximately 20% in chronic hepatitis B, marking one of the most important advances in HBV treatment in the past decade.

High Placebo Response Rates Continue to Challenge MASH Drug Trials : Clinical Gastroenterology and Hepatology | May 2026

Introduction Metabolic dysfunction–associated steatohepatitis (MASH) has become a major global liver disease burden and a central focus of therapeutic development. Despite intense pharmaceutical activity and numerous late-phase clinical trials, demonstrating meaningful histologic improvement remains challenging, partly because placebo groups frequently exhibit substantial spontaneous or treatment-associated improvement. Problem Statement Elevated placebo response rates complicate interpretation of MASH clinical trials by reducing apparent treatment effect size and increasing the risk of failed endpoints despite biologically active therapies. The extent and determinants of placebo responses across modern MASH trials remain poorly characterized, limiting optimal trial design and endpoint selection. Summary This large systematic review and meta-analysis demonstrates that placebo responses in MASH trials are both substantial and highly variable depending on the endpoint evaluated. Approximately one in ten placebo-treated noncirrhotic patients achieved histologic MASH resolution without fibrosis worsening, while meaningful reductions in hepatic fat content and alanine aminotransferase normalization were also frequently observed in placebo arms. Importantly, the analysis found no consistent patient or study-level factors that reliably predicted placebo response, emphasizing the inherent complexity and heterogeneity of MASH trial populations. These findings reinforce that lifestyle modification, behavioral changes triggered by trial participation and the fluctuating natural history of metabolic liver disease likely contribute significantly to placebo-associated improvement. The study also highlights that placebo effects differ across histologic, biochemical and imaging endpoints, suggesting that endpoint selection critically influences perceived therapeutic efficacy in MASH drug development. Overall, this analysis provides important context for interpreting contemporary MASH trials and underscores the need for improved trial design strategies, including more precise patient phenotyping, optimized endpoint selection and potentially longer study durations to better distinguish true drug efficacy from background placebo-associated improvement.

Hepatitis B Vaccination: A Success Story - Gastroenterology | March 26

Introduction Hepatitis B virus (HBV) infection remains a major global health threat, with an estimated 254 million people living with chronic infection and more than 1.1 million deaths annually from cirrhosis and hepatocellular carcinoma (HCC). Because HBV infection acquired in infancy carries up to a 90% risk of chronic infection, prevention through vaccination—particularly the birth dose—has become the cornerstone of global elimination strategies. Summary This commentary highlights the profound public health impact of hepatitis B vaccination and underscores the need to sustain universal infant immunization. Since the introduction of HBV vaccines in the 1980s, global vaccination programs have prevented millions of infections and deaths. Universal infant vaccination, including a birth dose within 24 hours, has been especially transformative. Taiwan’s national program reduced chronic HBV prevalence from 10% in 1984 to 0.5% by 2019 and significantly lowered childhood hepatocellular carcinoma incidence. Globally, vaccination has reduced HBsAg prevalence among children under five years from approximately 5% to below 1%, preventing an estimated 22 million deaths. Hepatitis B vaccines are among the safest and most effective vaccines ever developed, with over one billion doses administered worldwide and protective immunity lasting more than three decades. The combination of maternal screening, birth dose vaccination, hepatitis B immunoglobulin for exposed infants, and antiviral therapy during pregnancy can prevent up to 99% of mother-to-child transmission. Despite these successes, challenges remain. Global birth-dose coverage is only about 46%, with particularly low uptake in Africa. In addition, policy debates in some countries about delaying infant vaccination risk reversing decades of progress. The authors emphasise that universal birth-dose vaccination is the most effective and cost-efficient strategy to eliminate HBV transmission and prevent future liver disease and cancer. Sustaining and expanding vaccination coverage is essential to achieving global hepatitis B elimination goals.

Prognostic value of LSM in PBC- AJG Feb.26

Risk stratification in primary biliary cholangitis (PBC) traditionally relies on biochemical response to ursodeoxycholic acid, but liver stiffness measurement (LSM) is increasingly used to assess fibrosis and portal hypertension. In everyday practice, clinicians often encounter a dilemma: biochemistry and LSM do not always move in the same direction, and it has been unclear how to interpret these discordant results. This large international multicenter study clarifies that uncertainty. The investigators evaluated patients with PBC who had serial LSM assessments and no prior hepatic decompensation, transplant, or liver cancer. They examined how biochemical response and changes in LSM relate to future liver-related outcomes, with a particular focus on discordant patterns. The key finding is that discordance between biochemical response and LSM is common, occurring in more than half of patients. Importantly, when discordance exists, the most recent LSM value is the strongest predictor of future liver-related events, including first hepatic decompensation. Once the current LSM is known, earlier LSM trends and biochemical response add little additional prognostic information. Patients who achieved biochemical response but had a persistently elevated current LSM remained at high risk of adverse liver outcomes. Conversely, patients with biochemical nonresponse but a low current LSM had a comparatively lower risk. This indicates that fibrosis burden and portal pressure—reflected by LSM—ultimately outweigh biochemical normalisation in determining prognosis. From a practical standpoint, this study simplifies clinical decision-making. Rather than integrating complex trajectories of past LSM values and biochemical fluctuations, clinicians can focus on the latest reliable LSM to guide surveillance intensity, timing of second-line therapy, and transplant referral discussions. In summary, while both biochemistry and LSM are important in PBC, the current LSM is the dominant prognostic marker. This finding supports routine, longitudinal elastography and emphasises that biochemical response alone does not guarantee low long-term risk in PBC.

How Alcohol Acts as a ‘Second Hit’ in HBV-Driven Liver Cancer- AJG Feb.26

Introduction Hepatocellular carcinoma (HCC) commonly arises from chronic liver injury due to hepatitis B virus (HBV), alcohol use, metabolic dysfunction, or combinations of these factors. While each risk factor independently promotes carcinogenesis, how alcohol synergises with HBV to accelerate tumor development has remained incompletely understood. This study addresses that gap by identifying a novel metabolic and lysosomal pathway through which alcohol acts as a powerful “second hit” in HBV-driven HCC. What the study shows Using HBx-transgenic mouse models of spontaneous HBV-related hepatocarcinogenesis, the authors demonstrate that chronic alcohol exposure markedly accelerates HCC development. Mechanistically, alcohol induces endoplasmic reticulum (ER) stress, activating the transcription factor ATF4. ATF4 directly upregulates lysosomal phospholipase A2 (LPLA2), an enzyme that drives accumulation of bis(monoacylglycero)phosphate (BMP)—a lipid enriched in lysosomes. BMP accumulation stabilises lysosomal membranes, helping tumour cells survive under metabolic and oxidative stress. At the same time, increased BMP activates MAPK/ERK signalling, promoting hepatocyte proliferation and tumor growth. Silencing LPLA2 or enzymes involved in BMP synthesis blunted alcohol-driven tumor growth and restored apoptotic sensitivity. Why this matters clinically 1) Explains synergy between HBV and alcohol This work provides a biologically coherent explanation for why alcohol consumption dramatically worsens outcomes in HBV-infected patients, beyond additive toxicity. 2) Highlights lipid–lysosomal metabolism as a cancer driver Rather than focusing solely on DNA damage, this study emphasises metabolic reprogramming and lysosomal adaptation as key oncogenic processes in HCC. 3) Identifies actionable targets LPLA2 and BMP metabolism emerge as potential: therapeutic targets, and prognostic biomarkers, especially in patients with combined HBV and alcohol exposure. 4) Reinforces the clinical importance of alcohol abstinence in HBV The findings offer strong mechanistic support for strict alcohol avoidance in HBV-infected individuals—not just for fibrosis prevention, but for cancer risk reduction. Limitations and open questions Animal models cannot fully replicate human HBV–alcohol interactions. Whether this pathway also drives fibrosis or HCC in non-HBV liver diseases remains unclear. Long-term safety of targeting LPLA2/BMP pathways needs careful evaluation. Bottom-line takeaway from GastroAGI Alcohol potentiates HBV-related hepatocarcinogenesis through an ER stress–driven, lipid–lysosomal survival pathway involving LPLA2 and BMP. This work strengthens the biological rationale for alcohol abstinence in HBV and identifies new metabolic vulnerabilities in HCC. One-line GastroAGI takeaway In HBV infection, alcohol is not just an additive—it is a molecular accelerator of liver cancer.

EUS-guided liver biopsy – a novel technique (GIE, Jan-2026)

### Indications of EUS-Guided Liver Biopsy EUS-guided liver biopsy (EUS-LB) is increasingly utilized as a minimally invasive technique for obtaining liver tissue samples. Common indications for EUS-LB include: 1. Evaluation of unexplained liver abnormalities, such as elevated liver enzymes or abnormal imaging findings. 2. Diagnosis and staging of liver diseases, including nonalcoholic fatty liver disease (NAFLD), autoimmune hepatitis, and cirrhosis. 3. Assessment of focal liver lesions to distinguish benign from malignant pathology. 4. Sampling in patients with challenging anatomies or high risk for adverse events associated with percutaneous or transjugular liver biopsy. ### Difference Between 22-Gauge and 19-Gauge Needles The gauge of the needle used during EUS-LB significantly impacts specimen quality and procedural outcomes: 1. **19-Gauge Needle**: - Traditionally preferred for EUS-LB due to its ability to obtain larger tissue samples with higher adequacy rates. - Provides specimens with longer aggregate length and higher counts of complete portal tracts (CPTs), which are critical for accurate pathological evaluation. - Associated with higher rates of blood contamination and may pose a greater risk of adverse events, particularly in patients with challenging anatomies. 2. **22-Gauge Needle**: - Historically considered inferior due to smaller sample sizes and lower adequacy rates compared to 19-gauge needles. - Emerging evidence suggests that the use of novel techniques, such as hydrostatic sampling, can improve performance and tissue adequacy, making 22-gauge needles a viable option. - Offers advantages in patients with high-risk profiles or difficult anatomical considerations due to its smaller size and reduced invasiveness. ### Hydrostatic Sampling Technique (HST) The hydrostatic sampling technique (HST) is a novel method that enhances the quality of tissue samples obtained during EUS-LB. Key features include: 1. Improved tissue adequacy: In the study provided, the HST achieved high adequacy rates (≥93%) for both 22-gauge and 19-gauge needles, meeting clinical standards. 2. Reduced blood contamination: The 22-gauge HST demonstrated significantly less blood contamination compared to both 19-gauge HST and wet suction (WS). 3. Comparable performance to traditional techniques: The HST allows 22-gauge needles to achieve similar specimen adequacy as 19-gauge needles, making it a promising option for patients at high risk for procedural complications. ### Conclusion The findings in the study suggest that the hydrostatic sampling technique is a significant advancement in EUS-guided liver biopsy. Specifically: 1. The HST enables the use of 22-gauge needles with tissue adequacy rates comparable to 19-gauge needles, while reducing blood contamination. 2. This technique may be particularly beneficial for patients with challenging anatomies or high risk of adverse events, providing a safer and equally effective alternative to traditional biopsy approaches. 3. The adoption of HST could expand the indications and applicability of EUS-LB, making it a more versatile and patient-centered diagnostic tool.

HBV Genotype and Biomarkers Predict Severe Flares After NA Cessation

The study highlights the significant role of HBV genotype and end-of-treatment (EOT) biomarkers in predicting severe virologic relapses (SVRel) and severe biochemical flares (SBF) after nucleos(t)ide analogue (NA) cessation in patients with chronic hepatitis B virus (HBV) infection. Here's a detailed breakdown of the findings: ### HBV Genotype and Treatment Response: 1. **Genotype Influence**: - Different HBV genotypes were associated with varying risks of SVRel and SBF. - Genotypes C, D, and E were linked to higher rates of relapse and flares. - Notably, none of the patients with genotype A developed severe biochemical flares (SBF), indicating a potentially protective role of genotype A against severe post-cessation events. 2. **Genotype as a Predictive Marker**: - Non-A genotypes were significantly associated with a higher risk of severe biochemical flares (SBF) after NA cessation. This was supported by a multivariate analysis, where non-A genotype had an adjusted odds ratio (aOR) of 19.03 (p=0.018) for predicting SBF. ### Biomarkers and Predictive Value: 1. **Key Biomarkers**: - HBcrAg (Hepatitis B core-related antigen): Detectable levels at the end of treatment were strongly associated with severe virologic relapses (SVRel). The adjusted odds ratio (aOR) for SVRel was 3.93 (p=0.01). - HBV RNA: Detectable HBV RNA was independently predictive of severe biochemical flares (SBF) with an aOR of 7.84 (p=0.005). - Anti-HBc IgG: Lower levels of anti-HBc IgG were associated with a higher risk of SBF (aOR 0.31, p=0.016). 2. **COBRA Score**: - A risk stratification tool, called the COBRA score, was developed using three biomarkers: HBcrAg, HBV RNA, and anti-HBc IgG. - A COBRA score ≥2 was effective in identifying patients at increased risk for severe biochemical flares (SBF), with a sensitivity of 80.0% and a negative predictive value (NPV) of 90.7%. ### Conclusion of the Study: - The study concludes that both HBV genotype and EOT biomarkers (HBcrAg, HBV RNA, and anti-HBc IgG) are valuable predictors of severe virologic relapses (SVRel) and severe biochemical flares (SBF) after NA cessation in patients with chronic HBV infections. - Among the genotypes, non-A genotypes (C, D, and E) were associated with higher risks of severe events, whereas genotype A appeared to confer a lower risk of SBF. - The COBRA score provides a practical tool for individualized risk stratification, enabling clinicians to identify patients at the highest risk and tailor post-cessation monitoring and management strategies accordingly. These findings underscore the importance of incorporating genotype and biomarker assessments into clinical decision-making to improve patient outcomes when discontinuing NA therapy in chronic HBV management.