Shira Zelber-Sagi, Sven Francque, and Sarwa Darwish Murad discuss public health, steatotic liver disease, and the future of hepatology
Towards a Functional Cure for Chronic HBV Infection: Progress, Setbacks, and New Hope Article:
Pulmonary Manifestations among Patients with Liver-Affected Alpha-1
Antitrypsin Deficiency in the USA
Keaveny A et al.
Donor Relation and Timing in Paediatric
Alqahtani
Advancing Primary Biliary Cholangitis Management Through Continuing
Rohani-Montez
Concomitant Medications
Optimising Hepatitis B Prophylaxis After Liver Transplantation: Combination Therapy and the HBV/ HCC Connection
Improving Disease Management in Primary Biliary Cholangitis
Lasington
Leith
Editor's Pick: Towards a Functional Cure for Chronic HBV Infection: Progress, Setbacks, and New Hope Antonio Bertoletti
Metabolic DysfunctionAssociated Steatotic Liver Disease in Challenging Care Settings: Clinical Implications from the MENA Region Desoky and El-Kassas
Clinical Outcomes of CrossSectional Imaging to Investigate Hepatic Focal Fatty Sparing in Patients with Advanced Chronic Liver Disease
Prada
Editorial Board
Editor-in-Chief
Markus Peck-Radosavljevic
Klinikum Klagenfurt am Wörthersee, Austria
Markus Peck-Radosavljevic is a renowned expert in gastroenterology and hepatology, currently serving as Professor of Medicine and Chairman of the Department of Internal Medicine & Gastroenterology at Klinikum Klagenfurt, Austria. With a distinguished career spanning clinical practice, research, and academia, he has contributed extensively to the study of liver diseases, including end-stage cirrhosis, liver transplantation, viral hepatitis, and liver cancer.
Kieron B.L. Lim
Mount Elizabeth Hospital Liver Transplant Program, Singapore
Dhiraj Tripathi
Fabio Marra
University of Florence, Italy
Frank Tacke
Charité – Universitätsmedizin Berlin, Germany
Ashwani Singal
University of South Dakota Sanford School of Medicine, USA
Queen Elizabeth Hospital Birmingham,UK
Amr Amin
United Arab Emirates University, UAE
Mark McPhail
King’s College Hospital, UK
Aims and Scope
EMJ Hepatology is an open access, peer-reviewed ejournal committed to helping elevate the quality of practices in interventional cardiology globally by informing healthcare professionals on the latest research in the field.
The journal is published annually, six weeks after the European Association for the Study of the Liver (EASL) Event, and features highlights from this event, alongside interviews with experts in the field, reviews of abstracts presented at EASL, as well as in-depth features on sessions from this event. The journal also covers advances within the clinical and pharmaceutical arenas by publishing sponsored content from congress symposia, which is of high educational value for healthcare professionals. This undergoes rigorous quality control checks by independent experts and the in-house editorial team.
EMJ Hepatology also publishes peer-reviewed research papers, review articles, and case reports in the field. In addition, the journal welcomes the submission of features and opinion pieces intended to create a discussion around key topics in the field and broaden readers’ professional interests. The journal is managed by a dedicated editorial team that adheres to a rigorous double-blind peer-review process, maintains high standards of copy editing, and ensures timely publication.
EMJ Hepatology endeavours to increase knowledge, stimulate discussion, and contribute to a better understanding of practices in the field. Our focus is on research that is relevant to all healthcare professionals in this area. We do not publish veterinary science papers or laboratory studies not linked to patient outcomes. We have a particular interest in topical studies that advance knowledge and inform of coming trends affecting clinical practice in interventional cardiology.
Further details on coverage can be found here: www.emjreviews.com
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• Guidance from an Editorial Board consisting of leading authorities from a wide variety of disciplines.
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Staff members attend medical congresses as reporters when required.
All information obtained by EMJ and each of the contributions from various sources is as current and accurate as possible. However, due to human or mechanical errors, EMJ and the contributors cannot guarantee the accuracy, adequacy, or completeness of any information, and cannot be held responsible for any errors or omissions. EMJ is completely independent of the review event (EASL 2026) and the use of the organisations does not constitute endorsement or media partnership in any form whatsoever. The cover photo is of Barcelona, Spain, the location of EASL 2026.
Helena Bradbury, Katrina Thornber, Aleksandra Zurowska
Senior Editorial Co-ordinator
Bertie Pearcey
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Welcome
Dear Readers,
Welcome to the 2026 issue of EMJ Hepatology. This edition brings together congress coverage, expert interviews, peer-reviewed research, and feature articles exploring key developments in liver disease. From advances in MASLD screening and predictive analytics powered by AI, to progress towards a functional cure for chronic hepatitis B infection, this issue showcases the innovations shaping the future of hepatology.
This issue features coverage of the European Association for the Study of the Liver (EASL) Congress 2026, held in Barcelona, Spain, during EASL's landmark 60th anniversary year. Reflecting the meeting's focus on scientific excellence, collaboration, and global liver health, our review highlights advances across hepatology. Key developments include integrated approaches to MASLD screening and risk stratification, machine learning models for mortality prediction in cirrhotic sepsis, and novel insights into paediatric transplantation, cholestatic liver diseases, and drug-induced liver injury. Together, these studies demonstrate how precision medicine, digital innovation, and multidisciplinary collaboration are helping to shape the next generation of liver care.
We are also delighted to present exclusive interviews with EASL’s Governing Board, alongside internationally recognised leaders from across the hepatology community.
Our peer-reviewed content examines the role of cross-sectional imaging in investigating hepatic focal fatty sparing in advanced chronic liver disease, offering important insights into diagnostic decisionmaking in complex clinical settings. Additionally, a feature from Antonio Bertoletti discusses progress towards achieving a functional cure for chronic hepatitis B virus infection, highlighting both recent advances and ongoing challenges.
As liver disease remains a global health challenge, the need for innovation, collaboration, and evidence-based practice has never been greater. I would like to thank our Editorial Board, peer reviewers, authors, interviewees, and readers, for your continued support. I hope you find this issue insightful, informative, and relevant to your clinical practice and research interests.
Roli Omamuli, Editorial Assistant
EMJ would like to thank these contributors:
Saeed Akhtar
Moktadirul Hoque Shuvo
Tiffany Smith
Salvatore Scibetta
Mahmoud Al-Desoky
Christopher Emmer
Tarini Prasad Dandasena
Stay at the Forefront of Modern Medicine
High-level perspectives. Global experts. Essential updates.
Join us for conversations with the minds shaping healthcare's future. Gain the distilled insights you need to lead in your field and make maximum impact.
Jonathan Sackier: Non Executive Director & CMO, AiM Medical Robotics, Florida, USA
Saranya Ravindran: Paediatric Emergency Medicine Registrar, Imperial College Healthcare NHS Trust
Catherine Glass: Associate NHS GP and Senior Appraiser, NHS England
Foreword
Welcome to EMJ Hepatology 14.1. This edition brings together congress coverage, expert interviews, peer-reviewed research, and feature articles highlighting advances across hepatology. From predictive analytics and precision medicine to progress towards a functional cure for chronic hepatitis B virus infection, this issue reflects the innovation driving the field forwards.
This issue features extensive coverage of the European Association for the Study of the Liver (EASL) Congress 2026, held in Barcelona, Spain, during EASL's 60th anniversary year. Reflecting the meeting's focus on scientific excellence, collaboration, and global liver health, our congress review examines advances across the full spectrum of hepatology. Highlights include novel insights into paediatric liver transplantation, emerging research into genetic and cholestatic liver diseases, and new data on drug-induced liver injury and liver cancer outcomes. Together, these studies highlight how advances in genetics, transplantation, and therapeutic development are reshaping hepatology practice.
We are also delighted to present exclusive interviews with leading experts in the field. In conversations with Sven Francque, Shira Zelber-Sagi, and Sarwa Darwish Murad, we explore key developments in MASLD, lifestyle medicine, public health policy, and liver transplantation. From disease prevention and risk stratification to emerging therapies
and the future of transplant care, these discussions offer valuable insights into the evolving challenges and opportunities in modern hepatology.
These studies highlight how advances in genetics, transplantation, and therapeutic development are reshaping hepatology practice
Our peer-reviewed content examines the role of cross-sectional imaging in investigating hepatic focal fatty sparing among patients with advanced chronic liver disease, providing important insights for diagnostic decision-making in complex clinical settings. In addition, I am pleased to highlight this issue's Editor's Pick, in which Antonio Bertoletti explores progress towards achieving a functional cure for chronic hepatitis B infection, one of the most rapidly evolving areas in hepatology research.
I would like to thank our Editorial Board, peer reviewers, authors, interviewees, and most importantly, you, our readers, for your continued support. I hope you find this issue insightful, informative, and relevant to your clinical practice and research interests.
Markus Peck-Radosavljevic Professor of Medicine and Chairman, Department of Gastroenterology and Hepatology, Endocrinology and Nephrology, Klinikum Klagenfurt am Wörthersee, Austria
EASL 2026
Scientific progress never happens in isolation. Every discovery opens the door to the next question
Congress Review
Review of the European Association for the Study of the Liver (EASL) Congress 2026
THE EUROPEAN Association for the Study of the Liver (EASL) Congress 2026 brought together the global hepatology community in Barcelona, Spain, from 27th–30th May, 2026, marking a significant milestone in the organisation’s history: 60 years since the first EASL meeting was held in Marburg, Germany, in 1966 under the leadership of the late Gustav-Adolf Martini.
CELEBRATING 60 YEARS OF PROGRESS IN HEPATOLOGY THROUGH SCIENCE, COLLABORATION, AND EDUCATION
Hosting more than 8,300 participants from over 120 countries across six continents, EASL Congress 2026 reflected both the remarkable growth of the organisation and the increasingly global nature of liver disease. The meeting showcased advances spanning basic, translational, and clinical hepatology through a diverse scientific programme featuring plenary lectures, symposia, workshops, wet-lab training sessions, interprofessional forums, educational masterclasses, and poster presentations.
Barcelona provided a fitting backdrop for the 60th anniversary celebration. Renowned for its architectural landmarks, Mediterranean coastline, and rich scientific heritage, the city was once home to the pioneering neuroscientist Santiago Ramón y Cajal. While serving as a Professor of Histology at the University of Barcelona between 1887 and 1892, Ramón y Cajal
developed his groundbreaking neurone theory, a discovery that transformed modern biomedical science.
HONOURING THE PAST WHILE SHAPING THE FUTURE
A central theme of the opening ceremony was the importance of collective effort in driving scientific progress. Reflecting on EASL’s evolution from a group of 70 pioneers, consisting of an overwhelmingly Caucasian group of 68 men and two women, to today’s diverse international community, EASL Secretary General Debbie Shawcross emphasised the cumulative nature of scientific advancement: “Scientific progress never happens in isolation. Every discovery opens the door to the next question, every breakthrough creates new possibilities, every generation stands on the shoulders of those that came before.”
She went on to highlight how curiosity, resilience, and collaboration have shaped hepatology over the past six decades and reiterated EASL’s mission “to advance liver health and improve the lives of patients.”
Shawcross also stressed that innovation depends upon inclusivity, noting that progress has been driven not only by clinicians and scientists, but also by educators, nurses, allied health professionals, public health experts, pharmacists, patients, trainees, and young investigators. As she remarked, “Innovation flourishes when every voice has the opportunity to contribute and lead.”
EXPANDING OPPORTUNITIES THROUGH EDUCATION AND COLLABORATION
EASL leadership highlighted ongoing efforts to strengthen representation to foster multidisciplinary collaboration across the hepatology community. Vice-Secretary Ana Lleo also underscored the importance of ensuring that scientific excellence is supported by diverse perspectives. She highlighted EASL’s collaboration with sister societies such as the American Association for the Study of Liver Diseases (AASLD),
The best science comes from the best and the broadest range of perspectives
and the Asian Pacific Association for the Study of the Liver (APASL), saying: “The best science comes from the best and the broadest range of perspectives. From different experiences, from different questions, from different ways of looking at the same problem.”
Education remained a cornerstone of the organisation’s activities. Speaking during the ceremony, Educational Councillor Professor Sven Francque stated that “Science does not go without education, and education does not go without science,” before highlighting initiatives such as the EASL online campus learning platform, mentorship programmes, and international masterclasses delivered in partnership with AASLD.
The multidisciplinary nature of liver care was also recognised through dedicated programmes for nurses and allied health professionals. Interprofessional forums held during the congress promoted collaboration across healthcare disciplines, reflecting the growing recognition that optimal patient outcomes depend on coordinated teambased care.
ADVANCING GLOBAL LIVER HEALTH
Several speakers emphasised the need to translate scientific discoveries into meaningful public health action. Shawcross noted that liver disease remains one of the few non-communicable diseases continuing to rise globally and highlighted that “viral hepatitis remains one of the greatest global health challenges of our time.”
Despite major scientific advances, many people remain undiagnosed or unable to access appropriate care, while health systems continue to struggle with implementing effective solutions at scale. With WHO’s viral hepatitis elimination targets rapidly approaching, speakers stressed that scientific innovation alone will not be enough. Achieving elimination will require political commitment, healthcare system integration, and stronger partnerships to translate evidence into real-world impact. To help address remaining gaps in care, EASL announced its new Hepatitis Outcomes and Pathways to Elimination (HOPE) initiative, which will focus on areas of unmet need such as hepatitis D.
The importance of policy and public health action was further highlighted by Shira Zelber-Sagi, Chair of the EASL Policy and Public Health Committee. Addressing the growing health, social, and economic burden of liver disease, she emphasised that meaningful progress will require systemic change that extends beyond national borders and the scientific community. One notable development was the adoption of the first-ever World Health Assembly resolution on steatotic liver disease at the 79th World Health
Assembly, marking a significant milestone in global recognition of the condition. Zelber-Sagi also outlined EASL's broader public health efforts, including free liver testing initiatives launched during World Liver Day and continued collaboration with the European Health Alliance on Alcohol (EHAA), a coalition of 28 European medical organisations representing more than two million health professionals working to reduce alcohol-related harm across Europe.
Together, these initiatives reflected a common message throughout the congress: scientific advances must be accompanied by effective public health strategies, policy development, and equitable access to care, if meaningful improvements in liver health are to be achieved worldwide.
SCIENTIFIC EXCELLENCE AND EMERGING LEADERS
The scientific programme reached a record level of engagement, with 2,278 abstracts accepted and presented, the highest number reported by EASL in the past decade. Organisers also highlighted progress in gender representation among presenters and contributors, with participation approaching parity at 48% female and 52% male.
Several awards were presented during the opening ceremony. Marie Skaarup Christiansen, Senior liver nurse specialist at Odense University Hospital, Denmark, received the Excellence in Liver Care Award 2026 in recognition of her outstanding
contribution to nursing and allied health professional-led liver care. The Daniel Alagille Award 2026 was presented to Juan Bañares, Liver Unit, Vall d’Hebron University Hospital; Vall d’Hebron Research Institute; Universitat Autònoma de Barcelona, Spain; CIBERehd, for his work in the exploration of paediatric and adult genetic cholestatic diseases. Meanwhile, the Emerging Leader Awards recognised Panu Luukkonen, University of Helsinki; Helsinki University Hospital; Minerva Foundation Institute for Medical Research, Helsinki, Finland; Laura J. Pallett, Associate Professor, University College London Institute of Infection, Immunity and Transplantation, UK; and Elisa Pose, Liver Unit, Hospital Clínic de Barcelona, Spain; IDIBAPS; and CIBERehd, as rising stars whose work is helping to shape the future of hepatology research and clinical practice.
As delegates gathered to celebrate six decades of progress, EASL Congress 2026 reinforced a clear message for the future. In the words of Shawcross, “Knowledge must travel across borders and disciplines. Knowledge has no impact if it stays confined to one laboratory, one hospital, or one country.” Through collaboration, education, and innovation, the global hepatology community continues its pursuit of better liver health for all.
Scientific advances must be accompanied by effective public health strategies, policy development, and equitable access to care
Direct-Acting Antivirals for Hepatitis C Linked to Longer Liver Cancer Survival
MORE patients with hepatitis C-related hepatocellular carcinoma (HCC) lived substantially longer when treated with direct-acting antiviral therapies, according to new data presented at EASL 2026.1
HCC, the most common form of primary liver cancer, was assessed in patients with hepatitis C virus (HCV)-related disease. Patients with HCV-related HCC have often been excluded from national treatment registries, leaving uncertainty about the impact of treatment on long-term outcomes.
Researchers analysed data from 343 patients with HCV-related HCC recorded in the National Hepatitis C Registry in Greater London between 2015–2025. Outcomes were compared between those who initiated direct-acting antiviral (DAA) therapy and those who did not.
DAA therapy was started in 78.7% (270) of patients, with 88.7% achieving of this group achieving sustained virological response (SVR), indicating successful clearance of the virus. Patients receiving DAA treatment were more likely to have earlier-stage cancer, with 64.4% classified as Barcelona Clinic Liver Cancer (BCLC) Stage 0/A, 16.7% Stage B, 10% Stage C, and 4.4% Stage D, compared with 45.7%, 5.7%, 18.6% and 30%, respectively, among patients who did not receive DAA therapy (p<0.005).
Median overall survival was 68 months (95% CI: 48–87) in patients who initiated DAA therapy, compared with 15 months (95% CI: 7–23) in those who did not (log-rank p<0.001). The association was particularly notable in patients with early-stage disease,
Median overall survival was 68 months (95% CI: 48–87) in patients who initiated DAA therapy, compared with 15 months (95% CI: 7–23) in those who did not (log-rank p<0.001)
%
where those achieving SVR had a median overall survival of 128 months versus 25 months in untreated patients. These findings suggest successful viral clearance was associated with longer survival across cancer stages.
A survival advantage was also observed in patients with BCLC Stage B/C disease. Those achieving SVR had a median overall survival of 35 months, compared with 9 months among patients who did not receive DAA therapy.
Multivariable analysis showed that noninitiation of DAA therapy was associated with a seven-fold increase in mortality risk (hazard ratio [HR]: 7.0; 95% CI: 3.8–13.0; p<0.001). Failure to achieve SVR (HR: 2.3;
p<0.001), BCLC Stage C/D disease (HR: 1.43; p<0.001), and non-curative cancer treatment (HR: 1.95) were also associated with increased mortality risk. Notably, antiviral treatment remained associated with improved survival after adjustment for sex, age, liver function, and cancer stage.
Almost 80% of patients had untreated HCC when DAA therapy was initiated. As an observational study, the findings demonstrate an association rather than a causal effect. However, the results suggest that eligible patients with HCV-related HCC may benefit from antiviral treatment irrespective of BCLC stage. Further prospective studies could help define the optimal timing of antiviral therapy within liver cancer treatment pathways.
Eligible patients with HCV-related HCC may benefit from antiviral treatment irrespective of BCLC stage
A PHASE 2b study, presented at EASL 2026, showed that pemvidutide has demonstrated clinically meaningful improvements in metabolic dysfunction-associated steatohepatitis at Week 48, with significant reductions in liver fat, fibrosis markers, and body weight.2
At Week 48, patients with metabolic dysfunction-associated steatohepatitis receiving pemvidutide achieved substantial improvements across multiple non-invasive assessments of liver health. Liver fat content was reduced by 45.2% and 54.7% in the 1.2 mg and 1.8 mg groups, respectively, compared with 8.2% in the placebo group, with both active doses reaching statistical significance at p<0.0001. Hepatic inflammation, assessed using corrected T1 relaxation time, improved by 124 ms and 140 ms versus 21 ms with placebo, also demonstrating strong statistical significance (p<0.0001).
Markers of fibrosis showed consistent dose-dependent improvements in metabolic dysfunction-associated steatohepatitis. A reduction in Enhanced Liver Fibrosis score of 0.49 and 0.58 was observed with pemvidutide compared with an increase of 0.16 with placebo. A greater proportion of treated patients achieved a 30% or more reduction in liver stiffness measurement compared with placebo, reaching 61.1% in the 1.2 mg group and 63.9% in the 1.8 mg group, versus 21.2% for placebo. Concurrent improvements in fibrosis and enhanced liver fibrosis response were also higher in the active treatment arms, with up to 32.4% of patients achieving combined responses in the 1.8mg group compared with 3.2% on placebo.
Patients with metabolic dysfunctionassociated steatohepatitis treated with pemvidutide also experienced clinically meaningful reductions in alanine aminotransferase of 37.8 IU/L in the 1.2 mg group and 37.4 IU/L in the 1.8 mg group, compared with 10.3 IU/L in the placebo group. Mean weight loss in the 1.2 mg, 1.8 mg, and placebo groups was 4.5%, 7.5% and 0.2%, respectively, highlighting additional metabolic benefits. The treatment was generally well tolerated, with low discontinuation rates due to adverse events reported as 0% and 1.2% in the active arms compared with 3.5% in the placebo group.
Markers of fibrosis showed consistent dose-dependent improvements in metabolic dysfunction-associated steatohepatitis
These findings support pemvidutide as a potential therapeutic option for metabolic dysfunction-associated steatohepatitis, demonstrating consistent improvements in liver health biomarkers and metabolic parameters over 48 weeks in a randomised controlled setting.
GLP-1 RAs Show Promise for Patients with Alcohol-Related Liver Disease
A STUDY presented at EASL 2026 investigated whether Glucagonlike peptide-1 (GLP-1) receptor agonist use was associated with reduced alcohol-related events and liver complications in a large real-world population.3
Alcohol use disorder is a major driver of poor outcomes in people with alcohol-related liver disease (ALD), contributing to ongoing liver injury, hepatic decompensation, hospitalisation, and removal from transplant waiting lists. Achieving and maintaining abstinence remains the cornerstone of treatment, with currently available medications to prevent relapse showing only modest effectiveness.
GLP-1 receptor agonists have attracted growing interest because they may reduce alcohol cravings through effects on brain reward pathways while also improving metabolic dysfunction, which commonly coexists with ALD.
The analysis included 9,293 patients in each study group after matching. Researchers conducted a retrospective cohort study
using data from the TriNetX™ (TriNetX, LLC, Cambridge, Massachusetts, USA) United States Collaborative Network. Adults with alcohol-related liver disease who received a GLP-1 receptor agonist were compared with patients who had not received these medicines. The index date was defined as the first GLP-1 prescription for exposed patients and the corresponding diagnosis date for controls. Outcomes were assessed between 30–365 days after the index date. Propensity score matching was
GLP-1 receptor agonist exposure was associated with significantly lower risks of several alcohol-related outcomes
used to balance clinical characteristics and laboratory measures between groups. Primary outcomes included alcoholrelated events, liver disease progression, hospitalisation, transplant listing and phosphatidylethanol positivity. Time-toevent analyses were performed using Kaplan–Meier methods and hazard ratios.
GLP-1 receptor agonist exposure was associated with significantly lower risks of several alcohol-related outcomes. Compared with controls, treated patients had lower rates of alcohol remission events (hazard ratio [HR]: 0.76; 95% CI: 0.69–0.84), alcohol withdrawal (HR: 0.43; 95% CI: 0.37–0.51), and alcohol intoxication (HR: 0.37; 95% CI: 0.31–0.45). Treatment was also associated with reduced risks of alcoholassociated hepatitis (HR: 0.49; 95% CI: 0.43–0.57), cirrhosis progression (HR: 0.58; 95% CI: 0.46–0.72), all-cause hospitalisation (HR: 0.46; 95% CI: 0.39–0.55), and hepatic decompensation (HR: 0.58; 95% CI: 0.51–0.66). No significant differences
were observed for liver transplant listing or phosphatidylethanol positivity.
The findings suggest that GLP-1 receptor agonists may have a useful adjunctive role in the management of alcoholrelated liver disease, potentially helping to reduce relapse-related events while slowing disease progression and lowering hospitalisation rates. For clinical practice, these results support further investigation of GLP-1 therapies as part of a broader multidisciplinary approach to patients with ALD, particularly where metabolic comorbidities are present. However, the study was observational and retrospective, meaning causality cannot be established. Residual confounding, reliance on routinely collected healthcare data, and the absence of randomisation are important limitations. Prospective clinical trials are needed to confirm whether GLP-1 receptor agonists directly improve alcohol-related and liverrelated outcomes in this patient population.
Treatment was also associated with reduced risks of alcohol-associated hepatitis, (HR:
progression,
hospitalisation, and hepatic decompensation
Prolonged Fasting Emerges as a Risk Factor in Cirrhosis
HOSPITALISED patients with cirrhosis who experience prolonged fasting may face increased risks of sarcopenia and mortality, according to new data presented at EASL 2026.4
Fasting is a frequent occurrence during hospitalisation for patients with cirrhosis, often driven by procedures, clinical instability, and disease-related complications. However, new findings from Margáin et al.4 highlight that extended periods without nutritional intake may represent an important and potentially modifiable contributor to poorer short-term outcomes.
The retrospective cohort study evaluated hospitalised patients with cirrhosis between 2023– 2025 to investigate the frequency, duration, and clinical impact of fasting episodes. The primary outcome was threemonth mortality, with total fasting days defined as the cumulative number of full fasting days, whether continuous or intermittent.
Among 228 patients included, 81.6% experienced at least one fasting period during hospitalisation, with recurrent episodes observed in some patients. The most common indications were preprocedural fasting (63.6%), followed by high-dose vasopressor use (14.1%), postprocedural fasting (8.1%), and delayed initiation of nutritional support (5.1%).
While many fasting periods were clinically justified, duration frequently extended beyond the immediate indication. Patients fasting for ≥6 days experienced a greater decline in phase angle, a validated marker associated with muscle quality and sarcopenia, compared with those fasting for shorter periods.
Three-month survival was lower among patients fasting ≥6 days compared with <6 days (45% versus 70%; p=0.002). After adjustment for liver disease severity and length of hospital stay, prolonged fasting remained independently associated with
This work highlights the importance of integrating nutritional strategies into inpatient cirrhosis management. Future research may help define optimal approaches to minimise avoidable fasting exposure while maintaining safe procedural and clinical care pathways.
Further prospective studies could help clarify whether structured minimisation of avoidable fasting periods, alongside earlier and more consistent nutritional support strategies, translates into improved preservation of muscle mass and reduced short-term mortality in hospitalised patients with cirrhosis. This may also support the development of more standardised inpatient nutrition protocols tailored to disease severity and clinical stability.
Primary Biliary Cholangitis
Associated with Increased Cardiovascular Risk
PATIENTS with primary biliary cholangitis (PBC) may face a significantly increased risk of major adverse cardiovascular events (MACE), according to a nationwide Swedish study, presented at EASL 2026, that also identified substantially higher rates among those with cirrhosis.5
PBC is a chronic autoimmune liver disease in which the body’s immune system attacks the bile ducts within the liver, potentially leading to progressive liver damage and cirrhosis. Previous research has produced conflicting findings on whether the condition increases cardiovascular morbidity and mortality.
In this nationwide register-based study, researchers assessed the risk of MACE in people diagnosed with PBC between 2002–2022. A total of 3,332 patients with PBC were matched with 28,076 controls from the general population based on age, sex, year of diagnosis, and municipality. The primary outcome was incident MACE, with analyses adjusted for cardiovascular risk factors using a Cox regression model.
A total of 743 (22%) of patients with PBC experienced MACE. The incidence rate for the PBC group was calculated at 30.5 per 1,000 person-years, compared with 18.9 per 1,00 person-years among matched controls. This equated to approximately 12 additional MACE events per 100 people with PBC over 10 years.
The strongest associations were observed for cardiovascular death and congestive heart failure. After adjustment
for cardiovascular risk factors, patients with PBC had more than twice the risk of cardiovascular death compared with controls (adjusted hazard ratio: 2.19; 95% CI: 1.95–2.46). Risk of congestive heart failure was also substantially elevated (adjusted hazard ratio: 1.73; 95% CI: 1.50–2.00).
Disease severity appeared to have an important influence on outcomes. Among patients with both PBC and cirrhosis, the incidence rate of total MACE reached 87 per 1,000 person-years, compared with 27 per 1,000 person-years in those without cirrhosis.
As an observational study, the findings cannot establish causality. However, the findings indicate a clear association between PBC and an increased risk of MACE, particularly among patients with advanced liver disease.
The results suggest that cardiovascular risk assessment and management could play an important role in the care of patients with PBC. Further research might help clarify the mechanisms underlying this association and determine whether targeted interventions could reduce cardiovascular risk in this population.
Procalcitonin Shows Promise as Biomarker for Fibrolamellar Carcinoma
RESEARCHERS have identified serum procalcitonin (PCT) as a potentially sensitive and specific biomarker for fibrolamellar carcinoma (FLC), a rare primary liver cancer that predominantly affects young adults without underlying cirrhosis.6
The findings, presented at EASL 2026, suggest that PCT could address a major unmet need in the diagnosis and monitoring of this uncommon malignancy, for which established serum tumour markers are often normal.
The study was prompted by the observation of markedly elevated PCT levels in a patient with FLC. Investigators subsequently assessed serum PCT concentrations in 18 patients with metastatic FLC and compared results with cohorts of patients with hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and cirrhosis without cancer. Molecular analyses included RNA sequencing, spatial transcriptomics, and immunohistochemistry across a broad range of liver tumour samples.
In the European cohort, the median serum PCT level among eight patients with FLC was 55.2 µg/L, significantly higher than levels observed in patients with HCC (0.14 µg/L), CCA (0.16 µg/L), or cirrhosis (0.11 µg/L; p=0.0005). These findings were independently validated in the USA cohort. Overall, elevated PCT levels were detected in 83% of patients with FLC compared with only 3% of patients with HCC or CCA (p<0.0001), highlighting the marker’s strong discriminatory potential.
Importantly, longitudinal monitoring in four patients demonstrated that serum PCT levels tracked with disease status according to RECIST 1.1 criteria. In one case, PCT rose dramatically from 51 µg/L to 581 µg/L during tumour progression under immunotherapy, suggesting a potential role in treatment monitoring and early detection of disease progression.
At the molecular level, RNA sequencing revealed marked overexpression of the
CALCA gene, which encodes procalcitonin, in FLC compared with other primary liver tumours. Diagnostic performance was excellent, with area under the curve values of 0.975 versus CCA and 0.994 versus HCC. Spatial transcriptomic analyses localised CALCA expression to tumour cells carrying the characteristic DNAJB1-PRKACA fusion, while immunohistochemistry confirmed PCT overexpression in 77% of FLC samples but not in other primary or secondary liver cancers.
The investigators concluded that procalcitonin represents a highly promising biomarker for both the diagnosis and monitoring of fibrolamellar carcinoma, with potential clinical applications in routine patient management.
The investigators concluded that procalcitonin represents a highly promising biomarker for both the diagnosis and monitoring of fibrolamellar carcinoma
International Survey Exposes Nutritional Support Gap in PSC
RESEARCH presented at EASL 2026 has highlighted a substantial unmet need for dietary support among individuals with primary sclerosing cholangitis (PSC), with many patients reporting foodrelated symptoms and dietary changes while receiving little professional guidance.7
PSC is a progressive cholestatic liver disease that is frequently associated with inflammatory bowel disease (IBD) and currently has no cure. Many individuals with PSC seek information about how diet may affect their symptoms and disease progression, yet evidence-based nutritional recommendations remain limited. To better understand patients’ experiences, researchers conducted a large international survey examining dietary beliefs, practices, symptoms, and sources of nutritional advice among people living with PSC.
The anonymous online survey was developed by the PSC working group within the European Reference Network on Hepatological Diseases (ERN RARELIVER) and was available in 11 languages between January–June 2025. A total of 839 individuals with PSC from 33 countries completed the survey. Participants had a mean age of 48 years, 55% were female, 57% reported IBD, 28% had liver cirrhosis, and 16% had previously undergone liver transplantation.
Results revealed a strong demand for nutritional support, with 88% of respondents reporting that they wanted dietary advice. However, only 38% had received guidance specifically related to PSC. More than half of the participants indicated that they would prefer to receive advice from a healthcare professional. Use of vitamins or supplements was also common, with 32% reporting prescribed supplementation, 24% self-initiating supplements, and 16% using both prescribed and self-directed approaches.
Two-thirds of respondents reported changing their dietary habits following their PSC diagnosis. Additionally, 42%
stated that specific foods worsened their symptoms, with fatty foods most frequently identified, followed by red meat and dairy products. Eating-related symptoms were common, with only 26% reporting no symptoms. Nearly half experienced two or more symptoms, and abdominal pain was the most frequently reported issue affecting eating, followed by diarrhoea and digestive difficulties.
The impact extended beyond physical symptoms. Almost one-third of respondents reported that PSC reduced their enjoyment of eating, largely because certain foods triggered unpleasant symptoms. Among those with both PSC and IBD, many found it difficult to determine which condition had the greatest influence on their dietary choices.
Researchers concluded that structured nutritional support should become a more prominent component of PSC care
The findings suggest that dietary concerns are a significant aspect of life for many individuals with PSC. Researchers concluded that structured nutritional support should become a more prominent component of PSC care, helping patients manage symptoms while reducing reliance on self-directed dietary changes and supplementation.
Multi-Biomarker Model Improves Risk Prediction in Primary Sclerosing Cholangitis
A NOVEL multi-biomarker model may improve the prediction of liver transplantation-free survival in patients with primary sclerosing cholangitis (PSC), according to data presented at EASL 2026.8
PSC is a chronic cholestatic liver disease characterised by highly variable disease progression, making it difficult for clinicians to accurately predict outcomes and tailor follow-up strategies. Current risk prediction tools provide useful prognostic information but often fail to fully capture the complex biological processes driving disease progression.
To address this challenge, researchers developed and evaluated a multi-biomarker approach incorporating markers of fibrosis, extracellular matrix turnover, inflammation, and microbial metabolism. The international study included 906 patients with PSC from Norway, Sweden, and the USA. Participants had a median age of 47 years,
64% were male, and 79% had concomitant inflammatory bowel disease. Approximately half of the cohort was followed for at least 7 years.
The investigators assessed eight serum biomarkers, including the enhanced liver fibrosis (ELF) test, collagen formation and degradation markers, the kynureninetryptophan ratio, neopterin, and pyridoxal 5′-phosphate. Using multivariable Cox regression analysis, they developed models predicting liver transplantation-free survival at both 2 and 5 years.
During follow-up, 12% of patients reached the composite endpoint of liver transplantation or death within 2 years,
Researchers developed and evaluated a multi-biomarker approach incorporating markers of fibrosis, extracellular matrix turnover, inflammation, and microbial metabolism
increasing to 23% by 5 years. The full eight-biomarker model demonstrated strong predictive performance, achieving optimism-corrected C-indices of 0.834 and 0.822 at 2 and 5 years, respectively.
Notably, a simplified model incorporating only three biomarkers, ELF, kynureninetryptophan ratio, and pyridoxal 5′-phosphate, performed almost as well as the full model. At 5 years, this pragmatic model achieved a C-index of 0.817 and demonstrated improved calibration compared with the full model. Both biomarker-based approaches outperformed an ELF-only model and provided additional prognostic value beyond established clinical tools, including the Amsterdam-Oxford PSC model and the PSC Risk Estimate Tool.
The findings suggest that combining biomarkers reflecting multiple disease pathways may offer a more comprehensive assessment of PSC progression than existing approaches. Importantly, the strong performance of the simplified three-marker model could enhance clinical feasibility while maintaining robust predictive accuracy.
The authors concluded that integrating markers of fibrosis, inflammation, and gut microbial metabolism provides proof-ofprinciple that multi-pathway biomarker strategies can improve risk prediction in PSC, potentially supporting more personalised patient management and future clinical trial design.
During follow-up, 12% of patients reached the composite endpoint of liver transplantation or death within 2 years,
12 %
increasing to 23% by 5 years
23 %
Most Recent Liver Stiffness Measurements Best Predict Autoimmune Hepatitis Outcomes
LATEST liver stiffness measurements may offer the clearest indication of future liver-related complications in patients receiving treatment for autoimmune hepatitis (AIH), according to new research presented at EASL 2026.9
AIH is a chronic inflammatory liver disease in which the body’s immune system mistakenly attacks the liver, with the potential to cause fibrosis, cirrhosis, and liver failure if not adequately controlled. While liver stiffness measurements (LSM) are widely used to assess liver scarring in chronic liver disease, their value in monitoring risk over time in treated AIH has remained uncertain.
Researchers analysed data from the Canadian Network for Autoimmune Liver Disease (CaNAL) registry, including 523 patients diagnosed with AIH between 2010 and 2025 across 13 Canadian centres. All participants underwent serial LSM assessments following diagnosis and treatment.
Over a median follow-up of 150 months, outcomes were generally favourable, reflecting the effectiveness of
contemporary management. During followup, 4.2% of patients developed hepatic decompensation, while 1% underwent liver transplantation, and 3% died. Median liver stiffness decreased from 11.0 kPa at the first assessment to 7.9 kPa at the most recent measurement.
While liver stiffness measurements (LSM) are widely used to assess liver scarring in chronic liver disease, their value in monitoring risk over time in treated AIH has remained uncertain
Researchers reported that both baseline and the most recent liver stiffness independently predicted hepatic decompensation. However, the most recent
During follow-up, 4.2% of patients developed hepatic decompensation,
while 1% underwent liver transplantation, and 3% died 4.2 1 3 % % %
measurement emerged as the strongest predictor of liver-related outcomes overall. Patients with a most recent liver stiffness value of at least 15 kPa faced a significantly higher risk of adverse liverrelated events.
The study also found that patients who later developed hepatic decompensation had higher liver stiffness values at both points, alongside lower platelet counts and IgG levels (p<0.05). In contrast, biochemical response at 6 months was not associated with subsequent hepatic decompensation or liver-related events.
Most recent liver stiffness was found to outperform biochemical response measures, and neither changes in liver stiffness over time nor complete biochemical response added meaningful prognostic information beyond the latest LSM result. Similar patterns were observed even among patients without evidence of advanced liver disease.
Serial monitoring identified patients at ongoing risk despite achieving biochemical remission, suggesting that routine post-treatment liver stiffness assessment could help clinicians identify patients who may benefit from closer surveillance.
The researchers noted that event rates were low in the cohort, which is likely to reflect effective modern treatment options. Nevertheless, the findings support the use of serial liver stiffness measurements as a practical tool for dynamic risk stratification in treated AIH.
The findings suggest that incorporating serial liver stiffness measurements into post-treatment monitoring could help refine risk assessment in AIH, although further research may clarify how best to integrate these measurements into routine clinical practice.
Intrahepatic Cholestasis of Pregnancy Linked to Increased Long-Term Liver Disease Risk, Large UK Study Finds
WOMEN diagnosed with intrahepatic cholestasis of pregnancy (ICP) face a significantly increased risk of developing hepatobiliary disease later in life, according to findings presented at EASL 2026.10
The large population-based study, which analysed more than 3.7 million women in England, also identified important ethnic disparities in both ICP incidence and subsequent liver-related outcomes.
ICP is a pregnancy-specific liver disorder characterised by impaired bile flow and is associated with adverse maternal and fetal outcomes. While previous studies have suggested a potential link between ICP and future liver disease, evidence has largely been limited to smaller cohorts from predominantly European populations.
To investigate this association in a diverse population, researchers linked Hospital Episode Statistics birth records from 2000–2021 with primary and secondary care data. Women diagnosed with ICP during their first recorded pregnancy were compared with those without the condition. The incidence of a range of hepatobiliary outcomes was assessed over time, including gallstone disease, pancreatitis, liver fibrosis and cirrhosis, hepatobiliary malignancy, infectious liver disease, and end-stage liver disease.
Among 3,701,995 women included in the analysis, 31,082 (0.8%) had a diagnosis of ICP during their first recorded pregnancy. The median follow-up period was 10.4 years.
Women with ICP were significantly more likely to develop subsequent hepatobiliary disease than those without the condition. The risk of composite hepatobiliary disease was more than doubled (adjusted hazard ratio [aHR]: 2.38; 95% CI: 2.29–2.48).
The researchers also reported increased risks of pancreatitis (aHR: 2.43), gallstone disease (aHR: 2.24), other liver disease
(aHR: 2.52), fibrosis and cirrhosis (aHR: 2.92), infectious liver disease (aHR: 2.10), and end-stage liver disease (aHR: 2.05). Notably, women with ICP were more than four times as likely to develop hepatobiliary malignancy compared with women without ICP (aHR: 4.05).
The incidence of ICP varied between ethnic groups, affecting 1.3% of South Asian women compared with 0.8% of White women, 0.5% of Black women, 0.7% of women of Mixed ethnicity, and 0.9% of women in other ethnic groups.
Women with ICP were significantly more likely to develop subsequent hepatobiliary disease than those without the condition
The study also found that Black and South Asian women experienced a higher risk of severe subsequent hepatobiliary morbidity compared with White women, highlighting important ethnic inequalities in long-term liver health outcomes.
The authors describe these findings as the strongest evidence to date linking ICP with long-term hepatobiliary morbidity. They suggest that postpartum follow-up may play an important role in identifying women at elevated risk of future liver disease and that a history of ICP should be considered in hepatobiliary risk stratification strategies.
The researchers also emphasised the need for targeted interventions to address ethnic disparities in hepatobiliary outcomes following ICP.
References
1. Guerra Veloz M et al. Long term survival benefits of DAA in HCV related HCC patients: results from England National HCV registry. Abstract OS-102. EASL Congress, 27-30 May, 2026.
2. Noureddin M et al. Week 48 top-line results from the phase 2b, multicenter, randomized, placebo-controlled IMPACT trial of pemvidutide in metabolic dysfunction-associated steatohepatitis. Abstract OS-016. EASL Congress, 27-30 May, 2026.
3. Mohamed I et al. Impact of glucagonlike peptide-1 therapy on alcoholrelated outcomes in cirrhosis: real-world evidence from a multi-center United States cohort. Abstract OS-035. EASL Congress, 27-30 May, 2026.
4. Ruiz Margáin A et al. Prolonged fasting during hospitalization is associated
with poor prognosis in patients with cirrhosis. Oral Presentation OS-022-YI. EASL Congress, 27-30 May, 2026.
5. Henriksson I et al. Increased risk of major adverse cardiovascular events in patients with primary biliary cholangitis, a population-based national cohort study in Sweden. Abstract OS-090. EASL Congress, 27-30 May 2026.
6. Nault JC et al. Serum procalcitonin: a new tumor biomarker for the diagnosis and monitoring of fibrolamellar hepatocellular carcinoma. Oral Presentation OS-055. EASL Congress, 27-30 May, 2026.
7. Lindqvist C et al. Dietary practices and beliefs in individuals with primary sclerosing cholangitis – associations with symptoms and pleasure in eating. Oral Presentation OS-O25. EASL Congress, 27-30 May, 2026.
8. Helgadottir H et al. Development of a multi-biomarker model to predict transplantfree survival in primary sclerosing cholangitis: a multicenter retrospective study. Abstract OS 006 Y1. EASL Congress, 27-30 May, 2026.
9. Wong YU et al. Latest liver stiffness best predicts long-term outcomes in autoimmune hepatitis undergoing serial assessment: a large multicentre cohort study from canal. Abstract OS-008. EASL Congress, 27-30 May, 2026.
10. Lissmann R et al. Understanding long-term hepatobiliary morbidity after intrahepatic cholestasis of pregnancy in the UK, and how this varies by ethnicity. Abstract OS-026-YI. EASL Congress, 27-30 May, 2026.
Immune and Cholestatic Liver Disease at the EASL Congress 2026
Author: *Joost P.H. Drenth1
1. Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, the Netherlands
*Correspondence to joostphdrenth@cs.com
Disclosure: The author reports no conflicts of interest. This work received no financial support.
THIS YEAR, at the European Association for the Study of the Liver (EASL) Congress, there were exciting new developments in immune and cholestatic liver disease, with two packed abstract sessions fully devoted to primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH).
PRIMARY BILIARY CHOLANGITIS
PBC, and specifically the role of bile acids, was on full display during the Karl Wilhelm von Kupffer Basic Science lecture. This state-of-the-art lecture series showcases key opinion leaders, and this year, Ulrich Beuers, Amsterdam UMC, the Netherlands, was the laureate. His lecture focused on the biology of bile acids, which is of relevance for PBC. Beuers highlighted how the therapeutic strategy for PBC will eventually move beyond the current treatment sequence of ursodeoxycholic acid (UDCA), followed by a farnesoid X receptor agonist (e.g., obeticholic acid) and a peroxisome proliferator-activated receptor (PPAR) agonist (e.g., elafibranor). Future therapies are expected to directly target bile acid signalling networks, cholangiocyte function, and immune responses. He highlighted that bile acids serve as hormone-like signalling molecules with pleiotropic mechanism of action, and that they have the potential to become future therapies for PBC.
Future therapies are expected to directly target bile acid signalling networks, cholangiocyte function, and immune responses
There were also novel developments in the therapeutic arena. During the latebreaker session, the results of the doubleblind RCT evaluating saroglitazar, a dual PPARα/γ agonist, were presented.1 The target population was patients with PBC who had an inadequate response to or intolerance to UDCA. Patients were treated with saroglitazar 1 mg daily (n=97) or placebo (n=51) for 52 weeks. Saroglitazar managed to lower alkaline phosphatase (ALP) in 56.7% below the pre-set barrier for biochemical response (<1.67x ULN), compared with 9.8% in the placebo group.
PRIMARY SCLEROSING CHOLANGITIS
Next on the list is PSC, a disease for which there is currently no approved drug available, representing a clear unmet need. Antonio Molinaro, University of Gothenburg, Sweden, set out to identify targets that are potentially druggable in PSC. Extensive metabolic profiling across a wide set of human and experimental models allowed identification of the gut microbial metabolite imidazole propionate (ImP) as a key factor associated with PSC.2 ImP was consistently elevated in PSC, remained high after transplantation, and predicted poorer transplant-free survival. They provided evidence that ImP originates from the gut and mediates proinflammatory and pro-fibrotic responses. These sets of experiments suggest that targeting ImP production or its downstream pathway may represent a novel therapeutic strategy for PSC. Then, Michael Trauner, University of Vienna, Austria, presented the NUC-5 trial that examined norucholic acid (NCA), a bile acid derivative, in PSC.3 NCA demonstrated superiority over placebo. Trauner dug deeper and examined the
effect of the use of UDCA as a covariate. He used a combined endpoint (no worsening in histological disease stage and reduction of ALP to <1.5x ULN). At the primary analysis, assessed at 96 weeks, 12.7% of NCA patients and 5.1% of placebo patients taking UDCA met the primary endpoint (p=0.08), compared to 23.4% and 0% in the population without UDCA (p<0.001). Histologic disease stage improvement was observed for 23.4% of NCA+UDCA versus 11.9% of placebo+UDCA patients (p=0.18), compared with 30.3% of patients with NCA alone versus 6.7% with placebo alone (p=0.13) among patients with paired biopsies. These findings reinforce the efficacy signal observed in the overall NUC-5 trial and suggest that the therapeutic effects of NCA may be most pronounced when used without concomitant UDCA. A large Norwegian study addresses the major challenge of predicting liver transplantation or death in PSC.4 The investigators developed a multi-biomarker model integrating markers of fibrosis, extracellular matrix turnover, inflammation, and gut microbial metabolism, and demonstrated that it outperformed individual biomarkers and conventional
clinical risk scores. They also tested a simplified pragmatic model incorporating these key biological pathways and found similar predictive performance comparable to the full model.
The findings suggest that combining disease mechanism biomarkers may improve risk stratification in PSC.
Combining disease mechanism biomarkers may improve risk stratification in PSC
AUTOIMMUNE HEPATITIS
Lastly, for AIH, Lotte Slooter, Amsterdam UMC, presented the 3-year follow-up of the CAMARO-trial.5 This trial established mycophenolate mofetil (MMF) plus prednisolone as an effective first-line treatment for treatment-naïve AIH, demonstrating superior tolerability and better biochemical response rates at 24 weeks compared with azathioprine (AZA) plus prednisolone. To assess whether these early advantages were sustained over time, Slooter spearheaded a 3-year follow-up study and evaluated outcomes in patients from the original CAMARO trial. This, in essence, confirmed the durability of MMF therapy, with a numerically higher proportion of patients maintaining on trial-assigned treatment and achieving normal transaminase levels at 3 years compared with AZA (78% versus 57%; p=0.067). Importantly, MMF led to a substantially faster biochemical remission, with a median time to normalisation of liver
enzymes of 16 weeks versus 64 weeks for AZA (p<0.05). While rates of treatment discontinuation after the initial 24-week study period, loss of response, steroid-free remission, and prednisolone withdrawal were comparable between groups, the faster achievement of remission and higher long-term normalisation rates on trialassigned treatment support MMF as the clinically superior strategy. These data were confirmed in a retrospective study from Spain that found that with MMF, complete biochemical remission was seen in 90% (6 months) and 97% (12 months).6 MMF came with rapid disease control and allowed for a corticosteroid sparing strategy. Relapses were rare and treatment discontinuation due to adverse events was uncommon. All in all, MMF has been included as a valid first-line alternative to AZA in the updated 2025 EASL Clinical Practice Guidelines on AIH, given its efficacy and lower rate of adverse events.7
The central concept in AIH is to reach complete biochemical remission with immunosuppression to protect patients from a poor prognosis. The question is whether we are successful there. A singlecentre study from the UK (496 patients) suggests that the mortality in AIH exceeds that of the general population, and that extrahepatic cancer, infection, and vascular disease are the main drivers.8 Indeed, there are worries that the immunosuppressive regimens used may be associated with an increased incidence of cancer. A number of studies presented at the EASL Congress tried to quantify this risk. In a Swedish registry study (SweHep), data were collected for 1,086 patients with AIH (follow-up time of 18,091 patient-years).9
The standardised incidence ratio (SIR) for any cancer was 2.60 and was significantly higher in men. Specifically, the risk for hepatobiliary cancer among patients with cirrhosis was high (SIR: 24.39). Moreover, 12% of those who progressed to cirrhosis on follow-up developed hepatocellular carcinoma, compared to 5% with cirrhosis at diagnosis. The increased risk appears not to be confined to the hepatobiliary tract. An Israeli cohort study amongst 685 patients with AIH (83.5% female; mean age: 53.1 years; mean follow-up: 7.5 years), found that nine patients developed non-Hodgkin lymphoma, corresponding to a SIR of 36.5.10 However, it remains difficult to disentangle the effect of the disease itself from those of long-term immunosuppressive treatment. Some of the cancers are clearly related to thiopurines, such as non-melanoma skin
References
1. Vuppalanchi R et al. LBO-001 a phase 2b/3 trial of saroglitazar in primary biliary cholangitis (EPICS III). J Hepatol. 2026;84(Suppl 1):S7-8.
2. Molinaro A et al. GS-002 The microbe-derived metabolite imidazole propionate promotes the pathogenesis of primary sclerosing cholangitis via p38–mTORC1 signaling. J Hepatol. 2026;84(Suppl 1):S2.
3. Trauner M et al. OS-007 Norucholic acid leads to biochemical and histologic improvement in primary sclerosing cholangitis: impact of concomitant ursodeoxycholic acid therapy. J Hepatol. 2026;84(Suppl 1):S14.
4. Helgadottir H et al. OS-006-YI Development of a multi-biomarker model to predict transplant-free survival in primary sclerosing cholangitis: a multicenter retrospective study. J Hepatol. 2026;84(Suppl 1):S13.
cancers and non-Hodgkin lymphoma, whereas others such as hepatocellular carcinoma are more likely to be related to (development of) cirrhosis.
CONCLUSION
Across the PBC, PSC, and AIH sessions, EASL 2026 highlighted a clear shift towards mechanism-based therapies. We witnessed promising advances in bile acid signalling, microbial-metabolic targets, and immunosuppression strategies. While important efficacy signals emerged for several novel treatments, improving longterm outcomes remains a key priority across these rare immune and cholestatic liver diseases.
5. Slooter C et al. OS-009-YI Mycophenolate mofetil in combination with prednisolone as potential first-line maintenance therapy in treatmentnaïve autoimmune hepatitis: 3-year follow-up of the CAMARO-trial. J Hepatol. 2026;84(Suppl 1):S15.
6. Fernández R et al. SAT-273 Clinical outcomes of mycophenolate mofetil as first-line therapy in autoimmune hepatitis: a real-world cohort study. J Hepatol. 2026;84(Suppl 1):S12.
7. European Association for the Study of the Liver (EASL). EASL Clinical Practice Guidelines on the management of autoimmune hepatitis. J Hepatol. 2025;83(2):453-501.
8. Flatley S et al. SAT-275 Long-term extrahepatic mortality in autoimmune hepatitis: a cohort study. J Hepatol. 2026;84(Suppl 1):S313.
9. Thörn R et al. SAT-411-YI Long-term outcome of autoimmune hepatitis: complications, cancer risk and survival in a large nationwide swedish cohort. J Hepatol. 2026;84(Suppl 1):S346.
10. Tatour M et al. SAT-288 Increased risk of non-Hodgkin lymphoma in autoimmune hepatitis: a large retrospective cohort study. J Hepatol. 2026;84(Suppl 1):316-7.
Beyond Diagnosis, Towards Treatment Effect: The Biomarker Stories at EASL 2026
Author: *Maja Thiele1,2
1. Department of Clinical Research, University of Southern Denmark, Odense, Denmark
2. Evido Health, Copenhagen, Denmark
*Correspondence to maja.thiele@evido.health
Disclosure:
Keywords:
Thiele has received speaker's fees from Echosens, Madrigal, and Novo Nordisk; advisory fees from AstraZeneca and GSK; and is Co-founder and full-time employee of Evido Health.
NON-INVASIVE tests (NIT) were one of the strongest organising themes at the European Association for the Study of the Liver (EASL) Congress 2026, spanning the liver disease aetiology and severity spectrum: from steatotic liver diseases to hepatocellular carcinoma, and from early case findings to cirrhosis and portal hypertension.
The postgraduate course kicked off the theme with its devotion to diagnostics in liver diseases and sessions covering broad topics such as histology, imaging, bloodbased testing, and future technologies. The dedicated MASLD session made especially clear that the approval of semaglutide and resmetirom as pharmaceutical interventions for pre-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) has created a need for highly accurate biomarkers that support clinical care beyond cross-sectional diagnosis, extending into prediction, monitoring, and stopping rules.
However, many hepatologists remain anchored to past practices. This became clear in Isabel Graupera’s, Hospital Clinic de Barcelona, Spain, talk on moving beyond Fibrosis-4 (FIB-4), where audience voting captured a discordance: one-third of attendees still viewed FIB-4 as an ideal rule-out test because of its high negative predictive value (NPV), whereas a 58%
majority supported the more cautious, correct position that FIB-4 may be useful as a first-line tool but needs second-line confirmation.
Graupera highlighted that FIB-4’s suboptimal sensitivity means the test will miss many cases, despite its high NPV.1 In low-prevalence settings, a high NPV is almost inevitable: if disease prevalence is 5%, even a coin toss would have an NPV of 95%. She then discussed newer multivariable tools developed for screening in general populations (CIRRhosis Using Standard tests [CIRRUS], LiverRisk score, CORE, Chronic Liver Disease [CLivD]), at-risk MASLD populations (Metabolic Dysfunction-Associated Fibrosis 5 [MAF-5] and Steatosis-Associated Fibrosis Estimator [SAFE]), and across the steatotic liver disease spectrum (LiverPRO, Evido Health, Copenhagen, Denmark).
Laurent Castera’s, Université Paris-Cité, France, subsequent presentation on
patient selection for MASH pharmaceutical therapy placed NITs at the centre.2 He highlighted data from the LiverScreen study suggesting that approximately 2.0% of the screened population would be eligible for treatment using a vibration-controlled transient elastography (VCTE; Echosens, Paris, France) range of 10–20 kPa. These data underscore both the opportunity for treatment, but also the future workload for hepatologists, if population-level case finding is broadly implemented.
The last day of the Congress included the multisociety initiatives session that elegantly looped back to the postgraduate course theme. Frank Tacke, Charité –Universitätsmedizin Berlin, Germany, presented the updated EASL–European
Association for the Study of Diabetes (EASD)–European Association for the Study of Obesity (EASO) guidance on MASHtargeted pharmacotherapy, where NITs are now recommended to support treatment initiation, monitor response, and help decide whether therapy should be continued or considered futile.3 Figure 1 sums up main points on how patients with MASH may be detected in primary care, referred for subsequent confirmative testing in specialist care, started on pharmaceutical treatment, and monitored for treatment effect or futility.
Following the postgraduate course, the scientific programme included several newsworthy sessions revealing three overall themes of biomarker use: longitudinal NITs
Figure 1: Biomarker strategies to select patients for MASLD therapies, based on presentations at the EASL Congress 2026.
Adapted from presentations at the EASL Congress 2026.1,3
The treatment algorithm is adapted from the presentation of the updated EASL–EASD–EASO guidance. This guidance had not been published in full at the time of writing and may therefore change after review. pSWE was not included in the figure presented during the multisociety initiatives session, but was added by the author, interpreted according to the WFUMB-endorsed ‘rule of four’. The original figure also presented a lower ELF threshold of 9.2; the author has assumed that this was a typographical error.
CIRRUS: Cirrhosis Risk Score; CLivD: Cross-Liver Disease score; CORE: Composite Risk Evaluation score; CVD: cardiovascular disease; EASD: European Association for the Study of Diabetes; EASL: European Association for the Study of the Liver; EASO: European Association for the Study of Obesity; ELF: Enhanced Liver Fibrosis (test/score); FIB-4: Fibrosis-4 Index; LiverPRO: Liver Prognostic Risk Outcome score (Evido Health, Copenhagen, Denmark); LiverRisk: Liver Risk score; MAF-5: Metabolic Dysfunction-Associated Fibrosis-5 score; MRE: magnetic resonance elastography; NFS: non-alcoholic fatty liver disease Fibrosis Score; NIT: non-invasive tests; pSWE: point shear wave elastography; SAFE: Steatosis-Associated Fibrosis Estimator; VCTE: vibration-controlled transient elastography.
for monitoring, added accuracy by combining tests, and revealing a divide between what is recommended by guidelines, and what is implemented in clinical care.
REDEFINING BIOMARKER USAGE FROM SINGLE SNAPSHOTS TO LONGITUDINAL TRENDS
Many of the biomarker-centred studies presented a shift from one-off diagnostic evaluation towards longitudinal NITs for monitoring and early prediction of pharmacodynamic effect. Data from the MAESTRO-NASH Phase III resmetirom trial showed that reductions in alanine aminotransferase (ALT) at Week 12, MRIproton density fat fraction and magnetic resonance elastography at Week 16, and PRO-C3 at Week 24 correlated with histological MASH resolution and fibrosis improvement at end-of-study after 52 weeks.4 This indicates that early changes in NITs can be used as indicators for long-term treatment response. In the 2-year open-label extension of the MAESTRO-NAFLD-1 trial of 180 patients with compensated cirrhosis, nearly half (49.3%) exhibited a significant response according to the ANTICIPATENASH model (VCTE, platelet count, and BMI), indicating improvement in clinically significant portal hypertension, albeit without liver vein catheterisation to confirm actual portal pressure improvement.5
NITs for monitoring in low prevalence
settings perform very differently from monitoring in MASH trial patients with high prevalence of advanced fibrosis. On Saturday, Jesse Pustjens, Erasmus MC, Rotterdam, the Netherlands, and colleagues from the European LiverScreen consortium, presented data from community-based liver stiffness screening programmes in 4,538 participants.6 Here, only 38% of the 251 participants with elevated VCTE ≥8 kPa at baseline had persistently elevated VCTE elevation at the repeat visit after a median follow-up of 4.3 years. However, combination with other NITs improved the ability to detect persistent elevation in VCTE: among individuals with elevated baseline VCTE but low FIB-4, LiverPRO, LiverRisk, or MAF-5, transient VCTE elevation rates were high, ranging from 81% (LiverPRO) to 74% (FIB-4). Conversely, when baseline NIT-scores were high, persistent VCTE elevation rates ranged from 43% (LiverPRO) to 47% (MAF-5). These findings underscore the importance of combining different NITs to improve fibrosis case finding in low prevalence settings.
FROM CONCOMITANT TESTING TO FAILED REAL-WORLD IMPLEMENTATION
The advantage of moving from singletest interpretation towards combined NIT strategies extends beyond screening populations. In endocrinology patients with a BMI exceeding 35 kg/m² and a 30%
prevalence of significant fibrosis based on magnetic resonance elastography ≥3.3 kPa, Ajmera et al.7 showed that combining VCTE ≥8 kPa with Enhanced Liver Fibrosis (ELF; Siemens Healthineers, Erlangen, Germany) score ≥9.2 lowered the false-positive rate to 9%. Discordant results also hold valuable information: in a prospective MASLD cohort, approximately half of patients with VCTE ≥8 kPa had discordant
Many of the biomarker-centred studies presented a shift from one-off diagnostic evaluation towards longitudinal NITs for monitoring and early prediction of pharmacodynamic effect
ELF <9.8.8 Such discordance was commonly associated with abdominal obesity and low FIB-4, suggestive of false positive VCTE.
The Cirrhosis-7 score took the logic of NITs combination further, deriving a multivariable model containing VCTE, controlled attenuation parameter (CAP; Echosens), ELF, platelet count, ALT, international normalised ratio, and BMI to detect MASH cirrhosis with a significant discriminative accuracy, and with sensitivity and specificity both above 80%.9
Finally, several studies cast a shadow over the biomarker optimism, revealing an enormous gap between evidencebased recommendations versus real-word implementation. German laboratory data showed that more than one in five out of 1.4
million patients had metabolic dysfunction rendering them eligible for fibrosis risk stratification.10 Yet, FIB-4 was measured in only 0.11–0.75% of at-risk cohorts, despite its input variables being available for most of the patients. For example, 0.15% of patients with Type 2 diabetes had FIB-4 measured, while ALT, aspartate aminotransferase, and platelet count was available in 61%.
Another study highlighted an even more concerning lack of action following elevated FIB-4: in a 1-year Duke Health pilot study of ELF implementation, endocrinologists saw 1,113 patients with Type 2 diabetes and a FIB-4 ≥2.67.11 Such results should trigger quick referral to hepatology care, but only 25% of those with highly elevated FIB-4 had a subsequent visit at the liver clinic, and a meagre 64 patients received an ELF test to supplement the FIB-4.
CONCLUSION
NITs have moved from diagnostic tests to multi-purpose tools supporting decisions from case finding, risk stratification, treatment selection, and efficacy of intervention, to longitudinal monitoring. The challenge now is implementation, where integration in laboratory information systems, automated reporting in electronic health records, reflex ELF/ADAPT or elastography pathways, and education for non-hepatology physicians and patients on what NIT results mean will be essential to translate the scientific biomarker progress into better access to treatment in real-world clinical care.
References
1. Graupera I. Case finding- FIB4 and beyond. Postgraduate Course. EASL Congress, 27-30 May, 2026.
2. Castera L. Patient selection for treatment. Postgraduate Course. EASL Congress, 27-30 May, 2026.
3. Tacke F. Updates on EASL–EASD–EASO guidance for MASH-targeted pharmacotherapy. Symposium. EASL Congress, 27-30 May, 2026.
4. Loomba R et al. Early and week 52 biomarker (MRI-PDFF, ALT, MRE and PRO-C3) responses to resmetirom predict improvements in MASH and liver fibrosis. Abstract FRI-179. EASL Congress, 27-30 May, 2026.
5. Alkhoury N et al. Baseline ANTICIPATE score and response predicts liver outcome events in an 180 patient MASH cirrhosis cohort treated with resmetirom. Abstract TOP-177. EASL Congress, 27-30 May, 2026.
6. Pustjens J et al. Distinguishing persistent from transient liver stiffness elevation using blood-based noninvasive tests: longitudinal results from the European LiverScreen consortium. Abstract OS-098-YI. EASL Congress, 27-30 May, 2026.
7. Ajmera V et al. Combining vibration controlled transient elastography and enhanced liver fibrosis score lowers the false positive rate for identifying MASLD with significant fibrosis in patients with class 2 or higher obesity. Abstract WED-043. EASL Congress, 27-30 May, 2026.
8. Pagés L et al. Evaluating discordant enhanced liver fibrosis® test and transient elastography results in patients with metabolic dysfunctionassociated steatotic liver disease: insights for risk stratification and management. Abstract WED-168-YI. EASL Congress, 27–30 May, 2026.
9. Noureddin M et al. Development and validation of a highly accurate noninvasive-based model to predict cirrhosis due to MASH (cirrhosis-7 score). Abstract TOP-064. EASL Congress, 27-30 May, 2026.
10. Jensen T et al. FIB-4 in clinical laboratory data: reporting and feasibility evaluation in Germany. Abstract WED-095. EASL Congress, 27–30 May, 2026.
11. Furley M et al. Implementation of enhanced liver fibrosis testing in type 2 diabetes to improve detection of at-risk metabolic dysfunctionassociated steatohepatitis to optimize hepatology referrals: a duke health analysis. Abstract WED-092-YI. EASL Congress, 27-30 May, 2026.
Precision Oncology Across the Spectrum of Liver Tumours: Highlights from the Liver Tumours–Clinical Session at EASL Congress 2026
Authors: Sagnik Biswas,1 *Shalimar1
1. Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India *Correspondence to drshalimar@gmail.com
Disclosure: The authors have declared no conflicts of interest.
PRIMARY LIVER cancers pose substantial clinical challenges despite significant advances in surveillance, diagnosis, and systemic therapy. Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, while rarer malignancies such as intrahepatic cholangiocarcinoma (ICC) and fibrolamellar carcinoma (FLC) continue to be diagnosed at advanced stages with limited curative options.1 The Liver Tumours–Clinical session at European Association for the Study of the Liver (EASL) Congress 2026 highlighted how innovations in supportive care, biomarker development, AI, microbiome science, and immunotherapy can be used to reshape the management of liver malignancies. Although the studies varied in scope and methodology, a common theme of all the presentations was the transition from a conventional one-size-fits-all approach to a more pragmatic, precision-based approach guided by tumour biology, host factors, and technological advances.
IMPROVING OUTCOMES BEYOND TUMOUR CONTROL
Cancer cachexia remains a major yet often under-recognised contributor to morbidity and mortality in patients with advanced HCC.2 In a multicentre RCT, Biswas et al.3 evaluated the use of oral olanzapine as an adjunct to nutritional counselling in patients with intermediate or advanced HCC and cachexia. The study demonstrated significant improvements in appetite, weight gain, and quality of life among patients receiving olanzapine, without major safety concerns.
Importantly, the benefits extended beyond just weight gain. Improvements in anorexia scores, caloric intake, and patient-reported quality of life suggest that supportive care interventions can meaningfully influence daily functioning and symptom burden. While no significant changes were observed in muscle mass or functional performance, these findings reinforce that
A common theme of all the presentations was the transition from a conventional one-size-fitsall approach to a more pragmatic, precision-based approach
clinically relevant outcomes in advanced cancer extend beyond radiological response and survival. As systemic therapies continue to prolong survival in HCC, interventions addressing cachexia and quality of life will become increasingly important components of comprehensive cancer care.
ADVANCING EARLY DETECTION THROUGH LIQUID BIOPSY
Early diagnosis remains the cornerstone of improving HCC outcomes, yet current surveillance strategies based on ultrasound with/without α-fetoprotein (AFP) remain suboptimal. Oussalah and colleagues presented results from a prospective Phase III validation study evaluating circulating methylated SEPT9 (mSEPT9), a cell-free DNA-based epigenetic biomarker, in patients with cirrhosis undergoing HCC surveillance.4
The study demonstrated superior diagnostic performance of mSEPT9 compared with AFP alone and showed that combining both biomarkers substantially enhanced sensitivity for early-stage disease. Particularly noteworthy was the marked improvement in detecting
Barcelona Clinic Liver Cancer (BCLC) Stage 0–A tumours, a stage at which curative interventions remain feasible.
These findings reflect the growing influence of liquid biopsy technologies in hepatology. Rather than replacing existing surveillance approaches, mSEPT9 may complement current algorithms by improving risk stratification and reducing missed opportunities for early intervention. However, implementation will require assessment of costeffectiveness, integration with imaging pathways, and validation across diverse patient populations. Nevertheless, this study represents a major prospective evaluation of an epigenetic biomarker for HCC surveillance presented in recent years.
OVERCOMING IMMUNOTHERAPY RESISTANCE THROUGH GUT MICROBIOME MODULATION
Resistance to immune checkpoint inhibition is a major obstacle in the management of advanced HCC. One of the most innovative studies in the session explored whether modulation of the gut
microbiome could restore treatment sensitivity to immune checkpoint inhibition.
The FAB-HCC pilot study evaluated faecal microbiota transplantation via the colonic route combined with continued atezolizumab and bevacizumab therapy in patients whose disease had progressed on the same regimen. Although limited by its single-arm design and small sample size, the study reported encouraging response rates and demonstrated successful microbiome engraftment following faecal microbiota transplantation.5
Beyond clinical activity, the investigators documented alterations in microbial composition, bile acid profiles, and systemic immune responses, providing mechanistic evidence that microbiome modulation may influence antitumour immunity. These findings align with a growing body of evidence linking gut microbial diversity to immunotherapy responsiveness across multiple tumour types.6
While larger randomised studies are needed before clinical adoption, the work highlights an emerging paradigm in oncology: therapeutic manipulation of the
host ecosystem rather than the tumour alone. If confirmed, microbiome-based interventions could become an important strategy for overcoming resistance to immunotherapy in HCC.
AI MOVES CLOSER TO CLINICAL PRACTICE
Diagnostic uncertainty remains a significant challenge in liver pathology, particularly when distinguishing ICC from metastatic adenocarcinoma on limited biopsy specimens. Cheng et al.7 addressed this problem through development of a confidence-aware AI pathology model capable of differentiating ICC from metastatic tumours using routine digital histopathology slides.
A notable feature of the model was its incorporation of confidence estimation. Rather than generating a binary prediction for every case, the algorithm identified situations in which it was most likely to be correct, thereby improving reliability and reducing false-positive classifications. Prospective validation across European and Asian
The concept of confidence-aware AI may ultimately prove as important as diagnostic accuracy itself. One of the major barriers to clinical implementation of AI tools has been the ‘black box’ nature of predictions. By explicitly quantifying uncertainty, this approach offers a more realistic framework for integrating AI into pathology workflows, where human expertise and machine learning can operate synergistically rather than competitively.
Although widespread deployment will require regulatory approval and real-world validation, the study provides a glimpse into how digital pathology may streamline diagnostic pathways, reduce unnecessary investigations, and accelerate treatment decisions.
NOVEL BIOMARKERS FOR RARE LIVER TUMOURS
The session concluded with an important contribution addressing FLC, a rare liver cancer that predominantly affects young individuals and lacks reliable biomarkers. Nault et al.8 identified serum procalcitonin (PCT) as a highly sensitive and specific biomarker for FLC.
Across independent European and North American cohorts, serum PCT levels were markedly elevated in most patients with FLC, but rarely in conventional HCC or cholangiocarcinoma. Furthermore, longitudinal analyses suggested that PCT levels could be used to assess disease response and progression, supporting a potential role in treatment monitoring.
Mechanistic investigations strengthened the biological plausibility of the findings. Tumour-specific expression of the CALCA gene and localisation of procalcitonin production to tumour cells harbouring the characteristic DNAJB1PRKACA fusion provide evidence that elevated PCT is directly linked to tumour biology rather than a nonspecific inflammatory phenomenon.
For a disease that often lacks effective biomarkers, these findings could have substantial clinical implications. Future studies will determine whether PCT can facilitate earlier diagnosis, improve surveillance following treatment, or serve as a surrogate marker in therapeutic trials.
While many findings remain investigational, they provide a compelling roadmap for future research
FUTURE PERSPECTIVES
Collectively, the studies presented in this session highlight the multidimensional nature of innovation in liver tumour research. Developments in anticancer therapy are being paralleled by advances in supportive care, molecular diagnostics, microbiome science, computational pathology, and biomarker discovery.
Several themes warrant particular attention. First, precision medicine is expanding beyond tumour genomics to include epigenetic biomarkers, host immune responses, and microbiome composition. Second, AI is moving from proof-of-concept studies toward clinically deployable tools capable of supporting diagnostic decisionmaking. Third, patient-centred outcomes such as quality of life and symptom burden are receiving greater recognition as meaningful therapeutic targets.
Despite these advances, important challenges remain. Most promising biomarkers require broader validation before incorporation into routine practice. Microbiome-based therapies demand randomised evaluation and mechanistic clarification. AI applications must demonstrate robustness across diverse healthcare settings. Nevertheless, the studies presented at EASL 2026 illustrate a field rapidly embracing interdisciplinary approaches to improve outcomes for patients with liver tumours.
CONCLUSION
The Liver Tumours–Clinical session showcased how liver cancer management is increasingly becoming personalised, biologically informed, and technologically enabled. From improving quality of life in advanced HCC to enhancing early detection, overcoming immunotherapy
References
1. Chan SL et al. The Lancet Commission on addressing the global hepatocellular carcinoma burden: comprehensive strategies from prevention to treatment. The Lancet 2025;406(10504):731-78.
2. Rich NE et al. Cachexia is prevalent in patients with hepatocellular carcinoma and associated with worse prognosis. Clin Gastroenterol Hepatol. 2022;20(5):e1157-e1169.
3. Biswas S et al. OS-051-YI olanzapine improves appetite, weight and quality of life in patients with hepatocellular carcinoma: a multicenter, randomized controlled trial. J
resistance, refining pathological diagnosis, and identifying novel tumour biomarkers, the presented studies collectively underscore the evolution of liver oncology research. While many findings remain investigational, they provide a compelling roadmap for future research and offer optimism that more precise and effective care for patients with liver tumours is within reach.
Hepatol. 2026;DOI:10.1016/S01688278(26)00361-2.
4. Oussalah A et al. Circulating methylated SEPT9 for detection of hepatocellular carcinoma in patients with cirrhosis: a prospective multicenter phase 3 diagnostic validation study. Presentation OS-052. EASL Congress, 27-30 May, 2026.
5. Pomej K et al. Fecal microbiota transplantation combined with atezolizumab plus bevacizumab in hepatocellular carcinoma refractory to atezolizumab plus bevacizumab: final results of the open label, single-arm, FAB-HCC pilot study. Presentation OS053. EASL Congress, 27-30 May, 2026.
6. Thu MS et al. Impact of microbiomemodulating strategies in cancer patients receiving immunotherapy (MSIT): a systematic review and metaanalysis. Sci Rep. 2026;16(1):13859.
7. Cheng Y et al. A confidence-aware artificial intelligence pathology model for cholangiocarcinoma diagnosis. Presentation OS-054. EASL Congress, 27-30 May, 2026.
8. Nault J-C et al. Serum procalcitonin: a novel tumor biomarker for diagnosis and disease monitoring in fibrolamellar hepatocellular carcinoma. J Hepatol. 2026;84(6):1121-30.
Practical Tips for the Interprofessional Management of MASLD
Author: *Anastasia Ntikoudi1,2
1. WHO Athens Office Quality of Care and Patient Safety, Greece
2. University of West Attica, Aigaleo, Greece
*Correspondence to antikoudi@uniwa.gr
Disclosure: The author has declared no conflicts of interest.
MASLD IS now recognised as the most common chronic liver disease worldwide and a major contributor to liver-related morbidity and mortality. Importantly, MASLD should not be viewed solely as a liver disease; it is a multisystem metabolic disorder associated with increased risks of cardiovascular disease, Type 2 diabetes, chronic kidney disease, hepatocellular carcinoma, and premature death.1 Consequently, effective management requires collaboration between hepatologists, primary care physicians, endocrinologists, obesity specialists, dietitians, exercise physiologists, psychologists, and specialist nurses.2,3
A key challenge for clinicians is communicating risk effectively to patients. Many individuals perceive MASLD as a relatively benign condition because they are often asymptomatic.1 However, helping patients understand the broader cardiometabolic implications of MASLD may improve engagement with treatment and support long-term behavioural change.1,2 Explaining that liver disease progression is only one component of the overall risk profile can help patients appreciate the importance of sustained lifestyle modification.2,3
Lifestyle intervention remains the cornerstone of MASLD management, despite the emergence of new pharmacological therapies.3-5 Weight loss remains the most effective treatment strategy, with evidence showing that reductions in body weight can improve
hepatic steatosis, resolve steatohepatitis in some patients, and reduce fibrosis progression.1,3,6 Rather than focusing on individual nutrients, clinicians should encourage sustainable dietary patterns that create a long-term energy deficit and improve overall diet quality.6,7 Practical approaches include reducing consumption of ultra-processed foods and sugarsweetened beverages, increasing intake of minimally processed foods, and tailoring recommendations to individual cultural preferences and socioeconomic circumstances.6,7
Explaining that liver disease progression is only one component of the overall risk profile can help patients appreciate the importance of sustained lifestyle modification
Long-term success depends on maintaining behavioural changes that support weight management and overall metabolic health
Physical activity should be promoted as a therapeutic intervention in its own right. Exercise improves insulin sensitivity, reduces liver fat, and enhances cardiometabolic health, even in the absence of substantial weight loss.6,7 Helping patients identify enjoyable and achievable forms of activity may be more effective than prescribing rigid exercise programmes. Current recommendations continue to support regular moderate-intensity aerobic activity combined with resistance training where feasible.1,3,6
The growing role of weight-lowering medications, particularly glucagon-like peptide-1 receptor agonists and related incretin-based therapies, represents one of the most significant developments in MASLD management.5-9 These agents can produce clinically meaningful weight loss and may improve liver-related outcomes in selected patients.8-10 Nevertheless, experts increasingly emphasise that pharmacological treatment should complement rather than replace lifestyle intervention.10 Long-term success depends on maintaining behavioural changes that support weight management and overall metabolic health.3,8
An often underappreciated aspect of MASLD management is the impact of mental health. Anxiety, depression, stress, and other psychological conditions are common among individuals living with obesity and metabolic disease, and may significantly influence adherence to dietary
and physical activity recommendations.6,7 Identifying and addressing psychological barriers is therefore critical. Behavioural support, motivational interviewing, and integration of mental health professionals into multidisciplinary care pathways may improve patient engagement and long-term outcomes.8
The European Association for the Study of the Liver (EASL) 2026 forum reinforces the ongoing shift from a liver-centric model of care towards a comprehensive cardiometabolic approach. As new therapies become available, successful management of MASLD will increasingly depend on interprofessional collaboration that combines evidence-based lifestyle intervention, appropriate use of pharmacotherapy, and attention to the psychological and social factors that
References
1. Tilg H et al. Metabolic dysfunctionassociated steatotic liver disease in adults: a review. JAMA. 2026;335(2):163-174.
2. Sheikh MY et al. Diet and lifestyle interventions in metabolic dysfunction-associated fatty liver disease: a comprehensive review. Int J Mol Sci. 2025;26(19):9625.
3. Chew NWS et al. Cardiovascular-livermetabolic health: recommendations in screening, diagnosis, and management of metabolic dysfunction-associated steatotic liver disease in cardiovascular disease via modified Delphi approach. Circulation. 2025;151(1):98-119.
4. Ali SMJ, Lai M. Metabolic dysfunctionassociated steatotic liver disease. Ann Intern Med. 2025;178(1):ITC1-ITC16.
5. Vettor R et al. Obesity management in individuals with MASLD. Available at: https://iris.unito.it/ bitstream/2318/2123650/1/Vettor_ JHEPAT-D-25-02766_R1.pdf. Last accessed: 22 June 2026.
6. Schattenberg JM, George J. The weight of choices: prioritizing lifestyle over GLP-1 receptor agonist therapy in managing MASLD. JHEP Rep. 2025;7(7):101401.
7. Rajewski P et al. Dietary interventions and physical activity as crucial factors in the prevention and treatment of metabolic dysfunction-associated steatotic liver disease. Biomedicines. 2025;13(1):217.
8. Bril F. Metabolic liver disease: a summary of major guidelines and identifying opportunities to improve future guidelines. Diabetes Obes Metab. 2026;28(Suppl 2):63-80.
9. Rinella ME, Sookoian S. Therapeutic targets for metabolic dysfunctionassociated steatohepatitis: a personalized approach to disease management. Nat Rev Gastroenterol Hepatol. 2026;23(6):460-74.
10. Knorr JP et al. Metabolic dysfunctionassociated steatotic liver disease (MASLD): integrating metabolic and hepatic management into pharmacy practice. Am J Health Syst Pharm. 2026:zxag095. [Online ahead of print].
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Looking Beyond the Numbers: Addressing the Full Burden of PBC
This symposium took place at the European Association for the Study of the Liver (EASL) Congress, held between 27th–30th May, 2026, in Barcelona, Spain
For UK readers: According to UK ABPI regulations, this article is promotional and is intended for healthcare professionals only.
Click here for elafibranor▼UK prescribing and adverse event reporting information.
The symposium and publication of this article were funded by Ipsen.
Chairperson: David Jones1
Speakers:
Disclaimer:
Marco Carbone,2,3 Puneeta Tandon4
1. Faculty of Medical Science, Newcastle University, UK
2. Division of Hepatology and Gastroenterology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
3. University of Milano-Bicocca, Italy
4. Department of Medicine, University of Alberta, Canada
The information contained in this article reflects the latest available scientific evidence, personal experiences and opinions of the speakers and not necessarily those of IPSEN.
Disclosure: Carbone has received consultancy or speaker fees from Advanz, Alentis, Albireo, Alfasigma, Amgen, Calliditas, Echosens, Genetic, GSK, Ipsen, Intercept, Kowa, Malesci, Mayoly, Mirum, Perspectum, Umecrine, and Zydus; has been a scientific board advisor for Advanz/Intercept, CymaBay, Falk, Gilead, GSK, Ipsen, Kowa, Mirum, and Moderna; and an investigator for Advanz, Albireo, Amgen, AstraZeneca, Calliditas, Falk, Genkyotex, Gilead, GSK, Mirum, and Roche. Jones has received honoraria, consultation fees, and speaker fees from Advanz, CymaBay, Falk, GSK, Intercept, Ipsen, and Umecrine; and grant support from Intercept. Tandon has received consulting fees from Ipsen, Gilead, and Lupin Pharma.
Acknowledgements: Medical writing assistance was provided by Caroline E. Cross, Reading, UK.
Primary biliary cholangitis (PBC) is a chronic, inflammatory, autoimmune cholestatic liver disease, affecting mainly women over 40 years old, that, if left untreated, can progress to intrahepatic ductopenia and end-stage biliary cirrhosis. Recommended first-line pharmacotherapy for all patients with PBC is ursodeoxycholic acid (UDCA). However, treatment failure is common, with at least 40% of patients having an inadequate response. Increasingly, second-line treatments, including
peroxisome proliferator-activated receptor (PPAR) agonists, are used to reduce biochemical serum markers and manage symptoms. This symposium focused on the unmet needs in management of PBC, with experts David Jones, Newcastle University, UK; Marco Carbone, University of Milano-Bicocca, Italy; and Puneeta Tandon, University of Alberta, Canada, discussing the need for regular monitoring of treatment responses with earlier intervention when biochemical markers remain raised or symptoms persist. They also discussed the need for comprehensive risk stratification and ensuring optimisation of symptom management to improve quality of life (QoL) for patients.
The expert panel highlighted recent clinical trials that demonstrate the efficacy of PPAR agonists in normalising alkaline phosphatase (ALP) and total bilirubin (TB) levels. Additional data were presented that suggest PPAR agonists can reduce the debilitating PBC symptoms fatigue and pruritus. Overall, the discussions highlighted the importance of considering ALP normalisation (ALP ≤1.0x ULN; TB <0.6x ULN) as a treatment goal.
To help improve patient outcomes, the panel recommends a holistic approach to PBC management to avoid disease progression and improve survival, highlighting that, alongside disease control, symptom management is a priority for patient wellbeing.
Looking Beneath the Surface: Unmet Needs in PBC
David Jones
Jones opened the symposium by explaining that PBC is much like other chronic liver diseases, but with an important twist. “In PBC, injury to the bile ducts is associated with inflammation that becomes chronic, and the traditional view is that this drives fibrosis and can progress to cirrhosis,” Jones explained. “However, in PBC there is a second pathway of injury where chronic inflammation is accompanied by the loss of bile ducts” (Figure 1).1-5
There are clear unmet needs in PBC management, and “if left untreated, this disease causes real harm,” Jones emphasised. Although the rate of disease progression is variable, approximately 40% of patients with PBC develop cirrhosis within 10 years of diagnosis.5,6
“The questions we need to ask are ‘How do we prevent cirrhosis? How do we prevent ductopenia and how do we make sure people survive?’” Jones emphasised. Firstly, early detection of treatment response is important, and identifying patients who are eligible for second-line therapy earlier, rather than waiting for UDCA first-line treatment to fail, could reduce the risk of disease progression.7 Secondly, comprehensive risk stratification
is important, Jones went on. “We need to think about not only what treatment [is most suitable], but who needs what treatment and when.” The likelihood of disease progression and poor clinical outcomes is influenced by certain risk factors, including older age, male gender, higher biochemical marker levels, and poor response to firstline therapy.6-10 Thirdly, proactive symptom assessment is important. “We need to be asking our patients about symptoms at every clinic visit,” Jones emphasised. “We need to do something with that information to work out how to escalate treatment and determine the best treatment approach.”
Looking beneath the surface of these unmet needs, Jones said, will help us to address them. For example, some patients (up to 40%) do not respond effectively to first-line treatments,11 increasing their risk of cirrhosis, liver transplantation, or death.6 In risk stratification, Jones added, biochemical marker levels are used to measure treatment responses and risk of disease progression, but thresholds above the upper limit of normal (ULN) are considered acceptable. “Anything other than normal biochemistry is associated to some degree with residual risk,”7,12 Jones emphasised, and continued that normalising surrogate markers, such as TB and ALP (ALP ≤1.0x ULN; TB ≤0.6x ULN), should be a key therapeutic goal.13 In addition, according to Jones, inadequate evaluation of firstline treatment response and assessment
primary biliary cholangitis.
of symptoms, and lack of timely escalation to second-line therapies, represent key treatment gaps in PBC.7,12
“When we talk about symptoms, we are really talking about itch (pruritus) and fatigue,” Jones said. “We’ve had rapid development in PBC management options, and this is beneficial for patients, but it adds complexity.” Jones continued by explaining that the model for first-line therapy followed by second-line therapy is well established.1,14
“We have multiple second-line options, including obeticholic acid (OCA), elafibranor (a dual PPAR-α and PPAR-δ agonist), and seladelpar (a PPAR-δ agonist).”15-17
“It’s important that we understand who requires treatment and how we should change treatment if we don’t see improvements in biochemistry, symptoms, or both,” Jones said, and introduced a hypothetical case study to illustrate the point: a female patient diagnosed with PBC, aged 52 years, who is given first-line treatment of UDCA (15 mg/kg/day) with a
12-month follow-up assessment1 and then proactively managed after that. The patient presented with elevated ALP (325 U/L), which decreased to 247 U/L at 12 months. Tests showed a Liver Stiffness Measure (LSM) of 9.1 kPa that had increased 12 months post-treatment.
Jones explained that ALP and TB are key measures to consider when managing the risk of disease progression.13 In this case, Jones elaborated, the patient showed improvements in biochemistry, but key measures remained outside first-line response criteria, LSM had worsened, and TB was rising. “This is typical of patients who respond to first-line therapy but have ongoing issues that require further treatment,” Jones explained, and continued, the question is, “what do we do about them?” This highlights the need to monitor and assess disease progression to inform treatment option decision-making.
Figure 1: Pathways of inflammation in PBC.
PBC:
Optimising Second-Line Treatment Pathways
Marco Carbone
Carbone presented a deep dive into how PBC biochemistry results can be used to inform treatment options. “We know that ALP and TB are important markers in PBC, and they each give us different information,” Carbone explained. “ALP is a marker of cholestatic bile duct injury and gives an indication of the speed of disease progression, whereas TB is a marker of duct loss and liver failure, and can inform us more about the disease stage.”
The higher the ALP, the higher the risk of liver transplantation and risk of death, Carbone explained. Normalising blood biochemistry in PBC can reduce the risk of liver-related events, including risk of hospitalisation for hepatic decompensation, liver transplantation, or death.13,18 The primary endpoint in recent trials for secondline PBC treatments was achievement of an ALP <1.67x ULN and TB <1.0x ULN, with a secondary endpoint assessing patients that achieve <1.0x ULN ALP.13 In PBC, the risk of complications increases with the time patients spend above the ULN for these biochemical markers of ongoing liver damage, both before and after first-line therapy.13,18 “It’s also important to remember that patients can lose their response to therapies during treatment, so we need to keep monitoring,”2 Carbone added.
Carbone then highlighted data showing a nearly sixfold increase in the risk of adverse long-term outcomes in patients with elevations of TB ≥0.6× ULN and ALP ≥1.0x ULN relative to those who never exceeded the normal thresholds.11 Clinical risk is influenced by both the magnitude and duration of biochemical abnormalities, reinforcing the need for early and systematic risk assessment. Any deviation out of normal ranges for ALP and TB levels is an indicator of ongoing cholestatic bile duct injury and impaired hepatic function.11 In addition, disease activity is higher in patients with PBC who only achieve biochemical response (ALP <1.67× ULN) but not ALP normalisation (<1.0× ULN), as
suggested by the increase in mechanistic and inflammatory markers.7
Carbone reiterated that it is important to individualise treatment goals, recognising that patients may have different disease severity and require varying intensity of follow-up. He continued by drawing on the hypothetical case study of the 52-year-old female with PBC to illustrate how a patient can experience improved ALP measures on first-line therapy, but still not achieve normal levels. “This represents increased risk of disease progression and makes the patient a good candidate for second-line therapy,” Carbone confirmed.
There are several second-line treatment options for PBC, and Carbone went on to outline trials that demonstrate the efficacy of PPAR agonists. “PPAR agonists are used in PBC for their anti-cholestatic, inflammatory-regulating, and anti-fibrotic effects, and are approved for use in patients who do not respond to or are intolerant to UDCA,”19 Carbone outlined.
The ELATIVE trial demonstrated that elafibranor has a significant effect on cholestasis across patients with varying disease severity.20 The primary endpoint was met by Week 52 in 51% of patients treated with elafibranor, compared to 4% receiving placebo (p<0.001).20 The proportion of patients who reached ALP normalisation was over 15% (p<0.002) at Week 52, and when stratified by baseline ALP levels, this increased to 52% of cases.21 ALP reductions were measurable as early as Week 4 and were sustained to Week 156 in an open-label extension study.22
Elafibranor has been shown to reduce markers of fibrogenesis and stabilise fibrosis (LSM).22 It is generally well tolerated, with no difference in the proportion of patients experiencing adverse events leading to treatment discontinuation.20 Carbone also said that, importantly, there were no clinically meaningful changes in the glomerular filtration rate over the trial, and bone density remained stable.23
Data from the RESPONSE trial showed that seladelpar treatment led to sustained
reductions in ALP levels and normalisation of ALP was reached in 25% of the treatment group, compared to 0% of the placebo group by Week 52.24 LSM was also stabilised with seladelpar treatment.25 There were no adverse events, such as changes in renal function, that were any more common than with placebo.26
Carbone went on to describe preliminary data from investigator-led real-world practice cohorts. A global Phase 4 study (ELFINITY, funded by Ipsen, Paris, France) supports the safety and efficacy of elafibranor. An interim analysis of 51 patients with baseline data showed that 27/51 (53%) had ALP ≥1.67× ULN, and of these, 55% achieved a biochemical response and ALP improvement by Month 3.23 In the ELEVATEPBC study from Italian registry data, an analysis of 281 patients with baseline data who started elafibranor, 78 patients achieved ALP normalisation (80%) 3 months after initiation.27 “These are very preliminary data, and we need to wait until we have the 6-month follow-up data for 300 patients before reporting fully, but these are very promising results,” Carbone clarified.
Further preliminary data from a Spanish cohort from the CoIHAI registry,28 where 20% of patients had liver cirrhosis and the median ALP was 1.5x ULN, showed a 36% reduction in median ALP for those treated with elafibranor and a 33% reduction for those treated with seladelpar.28 Further real-world evidence comes from the IDEAL study, using the USA HealthVerity Network (HealthVerity, Philadelphia, Pennsylvania, USA) claims database, in which more than 45% of patients treated with elafibranor achieved ALP normalisation within 6 months, with and without prior secondline treatment.29 Overall, elafibranor and seladelpar are shown to be effective and well-tolerated second-line treatment options for patients with PBC who have an inadequate response or intolerance to UDCA in clinical trials and real-world settings.
“Normalisation of ALP should be the treatment goal,” Carbone reiterated, adding that we should be more ambitious for young patients to avoid fibrosis, and also for
patients with cirrhosis. “We have strong trial data, and we look forward to seeing more real-world evidence,”20,22,26 Carbone added. The loss of biochemical response to UDCA can occur at any time, so early and routine monitoring of response to UDCA treatment is crucial for timely intervention.11,30
Looking Beyond the Biochemistry: A Full-Spectrum View of the Symptomatic Burden for Patients with PBC
David Jones and Puneeta Tandon
“We have effective therapies, and we are on the cusp of normalisation as a target for therapy,” Jones reiterated. However, he added, “We do need to understand better the mechanisms of action around fibrosis, cirrhosis, and ductopenia. And importantly, we need to look more closely at what these treatments do for symptoms in patients.”
Tandon highlighted that PBC has a significant symptom burden, with up to 80% of patients reporting fatigue, and pruritus affecting up to 75% of patients (Figure 2).31-33 Other symptoms include brain fog, abdominal pain, and bone and joint aches.1,31,32,34
Importantly, Tandon emphasised, “the impact of the disease on patients with regards to symptoms does not correlate with disease progression, or the biochemical response. A patient with many symptoms can have normal liver enzymes. It’s important to continue to screen for symptoms as up to 60% of patients can be asymptomatic at diagnosis, but half of these are likely to go on to develop symptoms.”1,33
Tandon referred to the hypothetical case study of a 52-year-old female who has been fully compliant with UDCA. At the 12-month review, when asked about symptoms, the patient reported mild pruritus with a Numeric Rating Scale (NRS) of 2, and described significant fatigue, reduced productivity, withdrawal from social situations, and lack of motivation.
“When we ask patients which symptoms most affect their QoL, we see a range, including fatigue, anxiety, depression, and cognitive effects,” Tandon explained. “When we look at fatigue, it is affecting patients across all domains of wellness, including physical, cognitive, and psychosocial aspects. Almost 60% of patients with PBC say fatigue negatively affects their social and family life.35-37 “We need to understand that fatigue is different from tiredness. Fatigue is a distinct experience which does not improve with rest,” Tandon emphasised, and “if we don't understand it, we undermine it during clinic visits.”
Tandon went on to highlight studies that demonstrate functional MRI changes in the brains of people with PBC and fatigue.38
“In the thalamus of people reporting fatigue, the neural networks are different,” Tandon explained. This is objective and validates the symptoms that patients
are experiencing. It can be central (poor concentration and memory) and peripheral (reduced muscle power and increased pain), and it is not uncommon for patients to experience both types.38,39 It is also important to remember that fatigue and pruritus are independent.35 Individual patient PBC-40 fatigue scores show no correlation with pruritus scores.40 This is a reminder that, Tandon added, “we need to ask patients about both fatigue and pruritus and assess and manage them separately.”
Despite its prevalence, fatigue is often overlooked in clinical care and underreported by patients during consultations. Tandon presented Canadian data showing that of 167 patients who did not verbally report fatigue during consultation, 88% reported fatigue when using the PBC-40 questionnaire.35 In the UK, insights from PBC patient surveys12 reported that 43% of patients had not been assessed for fatigue
Figure 2: PBC symptom burden.
PBC: primary biliary cholangitis.
in the past 2 years (N=8,968), and the most common clinical responses to fatigue queries were (N=227): 45% no advice offered, and 35% were told there were no treatments available.12
Tandon was keen to stress that both pharmacological and non-pharmacological approaches are available to manage fatigue. In a trial of 31 patients involving a 12week individualised home-based exercise programme (EXCITED),41 the primary outcome of a reduction in fatigue score by >5 at 12 weeks was met in 26/31 patients (p<0.001). Additional improvements were also observed in daytime somnolence, cognitive function, and overall QoL.41 Tandon went on to explain that there is also evidence that cognitive behavioural therapy, in combination with mindful moving, breathing and meditation, and other mind-
body combinations, can help patients with PBC experiencing fatigue and psychosocial symptoms.42
Jones recapped, emphasising that conversations with patients about symptoms are always positive for patient wellbeing, and data on brain connectivity also help because this evidence helps to validate the patients’ experience of symptoms like fatigue. “Exercise and wellness apps are also helpful because they allow people to ‘own’ the problem and ‘own’ solutions,” Jones added, “but we want to do more than that.” Jones went on to outline the European Reference Network (ERN) rare liver disease algorithm tool (ASK-MEASURETREAT),36 which helps physicians to start conversations with patients to identify symptoms and develop an effective plan to treat them (Figure 3).
Jones then focused on how elafibranor and seladelpar can be used in symptom control.16,17 Interim results from the ELFINITY Phase IV global study in patients with PBC showed rapid reductions in symptom burden in real-world practice.23 But, Jones said, more work is needed. Seladelpar did not show clinically significant improvement in patients with moderate-to-severe fatigue, but provided improvements in PBC40 fatigue scores in patients with severe pruritus (PBC-40 itch domain >7 score).20,25 In summary, Jones said, “fatigue is the most debilitating symptom of PBC, and although complicated, it can be managed.31,35,36 Routinely asking patients about symptoms ensures early intervention as symptoms arise.”
References
1. European Association for the Study of the Liver. EASL clinical practice guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017;67(1):145-72.
2. Galoosian A et al. Clinical updates in primary biliary cholangitis: trends, epidemiology, and management. J Clin Transl Hepatol. 2020;8(1):49-60.
3. Khot R et al. Acquired ductopenia: an insight into imaging findings. Abdom Radiol (NY). 2025;50(1):152-68.
4. Cleveland Clinic. Cholestasis. Available at: https://my.clevelandclinic.org/ health/diseases/24554-cholestasis. Last accessed: 24 June 2026.
5. Younossi ZM et al. Diagnosis and management of primary biliary cholangitis. Am J Gastroenterol. 2019;114(1):48-63.
6. Prince M et al. Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years. Gastroenterology. 2002;123(4):1044-51.
7. Jones DEJ et al. The relationship between disease activity and UDCA response criteria in primary biliary cholangitis: a cohort study. EBioMedicine. 2022;80:104068.
8. Peters MG et al.; PUMPS Group. Differences between Caucasian, African American, and Hispanic patients with primary biliary cirrhosis
Closing Remarks
Jones summarised the session, reiterating the importance of taking a holistic approach to PBC management to address both disease progression and symptom control. “We are always going to control the disease first, but we should aim to prevent advanced disease and achieve normalisation of biochemistry and symptom control. We must ensure that every patient gets the therapy they need,” Jones concluded.
ELA-ALL-002412 Date of preparation: July 2026
in the United States. Hepatology. 2007;46(3):769-75.
9. Cholankeril G et al. Increased waitlist mortality and lower rate for liver transplantation in Hispanic patients with primary biliary cholangitis. Clin Gastroenterol Hepatol. 2018;16(6):965-73.e2.
10. Gatselis NK et al. Factors associated with progression and outcomes of early stage primary biliary cholangitis. Clin Gastroenterol Hepatol. 2020:18(3);684-92.e6.
11. Kowdley KV et al. Longitudinal relationship between elevated liver biochemical tests and negative clinical outcomes in primary biliary cholangitis: a population-based study. Aliment Pharmacol Ther. 2025;61(11):1775-84.
12. Abbas N et al. Critical shortfalls in the management of PBC: results of a UK-wide, population-based evaluation of care delivery. JHEP Rep. 2023;6(1):100931.
13. Murillo Perez CF et al. GLOBAL PBC Study Group. Goals of treatment for improved survival in primary biliary cholangitis: treatment target should be bilirubin within the normal range and normalization of alkaline phosphatase. Am J Gastroenterol. 2020;115(7):1066-74.
14. Invernizzi P, Lleo A. EASL Clinical Practice Guidelines on management of primary biliary cholangitis and PBC. Presention. EASL Congress, 27-30 May, 2026.
15. Jamal F et al. Second-line therapies in primary biliary cholangitis: a comparative review of obeticholic acid, fibrates, seladelpar, and elafibranor. Biomedicines. 2025;13(10):2335.
16. European Medicines Agency (EMA). Iqirvo - Summary of Product Characteristics. Available at: https:// www.ema.europa.eu/en/documents/ product-information/iqirvo-eparproduct-information_en.pdf. Last accessed: 23 June 2026.
17. European Medicines Agency (EMA). Lyvdelzi- Summary of Product Characteristics. Available at: https:// www.ema.europa.eu/en/documents/ product-information/lyvdelzi-eparproduct-information_en.pdf. Last accessed: 23 June 2026.
18. Lammers WJ et al. Global PBC Study Group. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology. 2014;147(6):1338-49.e5.
19. IPSEN. Ipsen’s Iqirvo® receives U.S. FDA accelerated approval as a firstin-class PPAR treatment for primary biliary cholangitis. 2024. Available at: https://www.ipsen.com/press-release/ ipsens-iqirvo-receives-u-s-fdaaccelerated-approval-as-a-first-inclass-ppar-treatment-for-primarybiliary-cholangitis/. Last accessed: 3 June 2026.
20. Kowdley KV et al. ELATIVE Study Investigators’ Group. Efficacy and
safety of elafibranor in primary biliary cholangitis. N Engl J Med. 2024;390(9):795-805.
21. Levy C et al. Baseline alkaline phosphatase impacts response rates in primary biliary cholangitis: exploring response to elafibranor in ELATIVE. Liver Int. 2026;46(5):e70630.
22. Levy C et al. Long-term treatment with elafibranor leads to biochemical and symptomatic improvements for at least 3 years in patients with primary biliary cholangitis. Poster 5016. AASLD, 7-11 November, 2025.
23. Schattenberg JM et al. Elafibranor treatment results in rapid reductions in biochemical markers and symptom burden in real-world practice: interim results from the prospective, noninterventional ELFINITY phase IV global study in patients with primary biliary cholangitis. Poster SAT-033. EASL Congress, 27-30 May, 2026.
24. Gordon SC et al. Sustained efficacy and safety of seladelpar for up to 36 months in patients with primary biliary cholangitis from the placebocontrolled RESPONSE study to the open-label ASSURE study. Poster 4434. AASLD, 7-11 November, 2025.
25. Bowlus CL et al. 36 Months of treatment with seladelpar is associated with stable or improved liver stiffness in patients with primary biliary cholangitis. Poster 5031. AASLD, 7-11 November, 2025.
26. Hirschfield GM et al.; RESPONSE Study Group. A Phase 3 trial of seladelpar in primary biliary cholangitis. N Engl J Med. 2024;390(9):783-94.
27. Bonfichi A, et al. Real-world validation of elafibranor in UDCA non-responders previously treated with OCA or fibrates – results from the ELEVATE-PBC study. Poster LBP 004. EASL Congress, 27-30 May, 2026.
28. Diaz-Gonzalez A et al. Management of patients with primary biliary cholangitis in the post-obeticholic era: real-world effectiveness data on elafibranor and seladelpar from the ColHai registry. Abstract OS-010. EASL Congress, 27-30 May, 2026.
29. Levy C et al. Real world outcomes in patients with biliary cholangitis who initiated elafibranor treatment with baseline alkaline phosphatase levels between 1x to 1.67x the upper limit of normal. Poster LBP-023. EASL Congress, 27-30 May, 2026.
30. Roberts SB et al. Loss of biochemical response at any time worsens outcomes in UDCA-treated patients with primary biliary cholangitis. JHEP Rep. 2024;6(10):101168.
31. Faisal A. Understanding fatigue and pruritus in primary biliary cholangitis. Clin Liver Dis (Hoboken). 2024;23(1):e0216.
32. Gungabissoon U et al. Disease burden of primary biliary cholangitis and associated pruritus based on a cross-sectional US claims analysis. BMJ Open Gastroenterol. 2022;9(1):e000857.
33. Hirschfield GM et al. The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines. Gut. 2018;67(9):1568-94.
34. Newton JL et al. Cognitive impairment in primary biliary cirrhosis: symptom impact and potential etiology. Hepatology. 2008;48(2):541-9.
35. Koc OM et al. Fatigue in people with primary biliary cholangitis: a position paper from the European Reference Network for Rare Liver Diseases. Lancet Gastroenterol Hepatol 2026;11(1):71-86.
36. Mells GF et al. UK-PBC Consortium. Impact of primary biliary cirrhosis on perceived quality of life: the UK-PBC national study. Hepatology. 2013;58(1):273-83.
37. Witt-Sullivan H et al. The demography of primary biliary cirrhosis in Ontario, Canada. Hepatology. 1990;12(1):98-105.
38. Swain MG et al. Fatigue in chronic liver disease: new insights and therapeutic approaches. Liver Int. 2019;39(1):6-19.
39. Mosher VAL et al. Primary biliary cholangitis alters functional connections of the brain's deep gray matter. Clin Translat Gastroenterol. 2017;8(7):e107.
40. Newton JL et al. Fatigue in primary biliary cirrhosis is associated with excessive daytime somnolence. Hepatology. 2006;44(1):91-8.
41. Freer A et al. A home-based exercise programme attenuates fatigue in primary biliary cholangitis: results from the EXCITED clinical trial. JHEP Rep. 2024;6(12):101210.
42. Watt M et al. An online mindbody program improves mental health and quality of life in primary biliary cholangitis: a randomized controlled trial. Hepatol Commun. 2023;7(11):e0316.
Albumin Therapy for Advanced Liver Disease: New Data from the EASL Congress 2026
These poster/oral presentations took place between 27th–30th May 2026, as part of the European Association for the Study of the Liver (EASL) Congress held in Barcelona, Spain
Support: The publication of this article was supported by CSL Behring.
Speakers: Siddharth Sood,1 W. Ray Kim,2 Enrico Pompili,3 Javier Fernández,4,5 Sagnik Biswas6
1. Northern Health, Melbourne, Australia
2. Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine & Science-Arizona, Phoenix, USA
3. Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Italy
4. EF CLIF, EASL-CLIF Consortium and Grifols Chair, Barcelona, Spain
5. Hospital Clínic, IDIBAPS and CIBERehd, Barcelona, Spain
6. All India Institute of Medical Science, New Delhi, India
Disclosure: Sood has received support from CSL Ltd and Grifols Ltd. Kim serves as an advisor to Grifols SSNA; has contributed to research supported by Grifols SSNA; and has received no personal financial remuneration for this study. Fernández has received research support from Grifols (Albutein 5%). Pompili and Biswas have declared no conflicts of interest.
Acknowledgements: Medical writing assistance was provided by Juliet George, Chester, UK.
The role of human albumin therapy in the management of advanced liver disease is not yet fully established across all settings and remains a topic of debate. The significant and complicated burden of the disease, coupled with limited therapeutic options, presents ongoing challenges. At the European Association for the Study of the Liver (EASL) Congress 2026, studies in patient populations worldwide delivered new insights to add to the debate on the use of human albumin therapy at the most severe end of the liver disease spectrum. This article reviews a selection of the latest data, evaluating long-term albumin therapy for decompensated cirrhosis, as well as Phase III study evidence on the use of therapeutic plasma exchange (TPE) for acute-on-chronic liver failure (ACLF).
Long-Term Albumin Therapy for Decompensated Cirrhosis
Real-World Data From an Australian Cohort
In the largest real-world cohort study of albumin therapy outside Europe, Sood et al.1 (investigator-initiated study, sponsored by CSL Ltd, Melbourne, Australia) retrospectively examined the safety and efficacy data for long-term (6-month), outpatient use of human albumin in the routine clinical setting in Australia. Taken from a larger cost-comparison study (described in the following section), patient cohort data were derived from 11 centres in Australia,2 and included patients with decompensated cirrhosis who had received regular albumin treatment. Patients with a transjugular intrahepatic portosystemic shunt, transplant, or portal vein thrombosis were excluded. The cohort included 134 patients, the majority of whom had cirrhosis due to alcohol-related liver disease (64.2%) or steatotic liver disease (34.3%). Most patients had ascites (93.3%), and 17 patients (12.7%) had a recent history of hepatocellular carcinoma. Human albumin (20% concentrated; CSL Ltd, Melbourne, Australia) was given at a mean dose of 40 g, across a total of 2,298 infusions (median: 19 infusions/patient). Data were assessed across a 6-month assessment window from treatment initiation, with patients censored at 6 months, liver transplant, or death.
Clinical outcomes were available for 105/134 patients (29 excluded: death, n=21, or transplant, n=8, prior to 6 months). Longterm albumin therapy was associated with a 17.3% decrease in the use of diuretics (from 91.8% to 74.5% of patients), a statistically significant improvement in the severity of ascites (p<0.0001),1 and an accompanying decrease in the proportion of patients requiring outpatient paracentesis (from 67.9% to 44.8% of patients). There was also a significant increase in median serum albumin from 30 g/L to 35 g/L (p<0.0001), and a numerical improvement in disease severity (Model for End-Stage Liver Disease [MELD-Na] score: 19 to 17; p=0.08). Recompensation was reported as ‘rare’,
and seven patients (5%) were referred for transjugular intrahepatic portosystemic shunt. Notably, 94 patients (70%) remained on therapy at 6 months, and the plan was for most patients (78/105; 74%) to continue albumin therapy beyond 6 months. In terms of safety, deaths that occurred prior to 6 months occurred at a median of 118 days after starting therapy, with most (17/21) being liver-related. Across the long-term treatment period, there were only two minor complications associated with infusion (nausea and painful cannulation).
While a real-world study lacks the controlled environment of a randomised trial, it provides valuable insight into the use of albumin therapy across the wide and complex range of patients with decompensated cirrhosis who are treated in routine clinical practice. Expanding the existing evidence base beyond Europe, these data represent a relatively large sample of approximately 2,300 infusions of human albumin in a severely affected, predominantly palliative, baseline population. Long-term outpatient albumin therapy was associated with clinically meaningful improvements in ascites alongside a reduced requirement for paracentesis, and no safety concerns were identified. The investigators conclude that long-term albumin therapy is a ‘pragmatic strategy’ to lower demand on healthcare resources and benefit patients with substantial disease burden in routine clinical practice.
Real-World Cost-Comparison Study
Looking to examine the wider healthcare impact of long-term albumin therapy, this retrospective Australian study by Sood et al.2 (investigator-initiated study, sponsored by CSL Ltd, Melbourne, Australia) investigated healthcare utilisation and costs across 6 months of treatment. The analysis was based on a cohort of 134 patients with decompensated cirrhosis from 11 treatment centres in Australia (as described in the study above),1 and compared with a historical cohort of 140 patients who did not receive albumin treatment, but who were matched for age, gender, and disease severity (median MELD-Na: 19.0 albumin versus 17.8 control; p=0.07). Cost estimates
for albumin, day unit infusion, outpatient paracentesis, and inpatient/emergency admissions were predetermined. Patients in the albumin group received 2,298 infusions in total (mean: 40 g/session) across the 6-month period.
After 6 months of albumin therapy, more patients experienced improvement in ascites severity (57.1%), as compared with controls (26.7%; risk ratio: 2.14; p<0.0001). This correlated with a significant reduction in paracentesis: 405 in the albumin group (median: 0 per 100 patient days [ptd]), compared with 763 in the control group (median: 2.7 per 100 ptd; p<0.0001). There was no difference between the groups in mortality rate (16.4% albumin versus 23.6% control; p=0.67), although investigators noted a divergence in the Kaplan–Meier curve appearing at 6 months. Liver transplants occurred in more albumin-treated patients (eight patients; 6.0%) than control patients (two patients; 1.4%; p=0.045). In terms of healthcare utilisation, the groups did not differ in the number of hospital admissions, nor in length of stay. Despite the additional drug and administration costs of albumin treatment itself, the total healthcare costs across 6 months were numerically lower in the albumin-treated group (4,643,788 AUD compared with 5,761,856 AUD in the control group), with the median cost per patient/100 ptd being similar: 12,627 AUD (interquartile range: 7,459–28,369 AUD) in the albumin group, and 12,966 AUD (interquartile range: 5,127–33,389 AUD) in the control group (p=0.72).
Thus, based on a retrospective analysis and compared with a historical control cohort, findings from this large, realworld study suggest that, at 6 months, long-term albumin therapy delivered improvements in the control of ascites, reducing the need for paracentesis, without increasing overall healthcare costs for patients with decompensated cirrhosis. The study authors conclude that albumin treatment may offer a cost-neutral approach (at least) to generating clinically meaningful outcomes for patients with decompensated cirrhosis.
Do Clinical Data Support a Change in Practice?
The use of long-term albumin as a diseasemodifying therapy to target mortality rates and prevent cirrhosis-related complications is an area of active debate, due to conflicting evidence from clinical trials. To re-evaluate this situation, Kim et al.3 performed a systematic literature review and meta-analysis (study funded by Grifols Worldwide Operations) of all published clinical trials from 1995 to the present, plus congress abstracts from 2022–2025, to capture the most recent published data. Studies were eligible for inclusion if they included adults with cirrhosis and ascites, compared long-term albumin therapy with placebo or standard medical treatment (SMT) for ≥4 weeks, and reported mortality rates over ≥12 months.
Seven of the 22 available studies met the eligibility criteria, including a total of 1,431 patients. Across the seven studies, patients treated with albumin showed a significant reduction in 12–36-month mortality (primary endpoint; random effects model) compared with the control (SMT/placebo) group (odds ratio [OR]: 0.66; 95% CI: 0.47–0.93; p=0.02).3
Patients receiving long-term albumin therapy also had significantly lower odds of developing ascites (OR: 0.30; 95% CI: 0.16–0.54; p<0.0001), refractory ascites (OR: 0.52; 95% CI: 0.33–0.81; p<0.01), hepatic encephalopathy (OR: 0.62; 95% CI: 0.41–0.95; p=0.03), renal dysfunction (OR: 0.45; 95% CI: 0.21–0.97; p=0.04), or spontaneous bacterial peritonitis (OR: 0.30; 95% CI: 0.16–0.54; p<0.0001) at ≥12 months’ follow-up, which were all examined as secondary endpoints.3 There were no significant differences between the albumin and control groups in the secondary endpoints of hyponatraemia (OR: 0.62; 95% CI: 0.36–1.06; p=0.08), or gastrointestinal bleeding (OR: 1.15; 95% CI: 0.60–2.23; p=0.67) at ≥12 months’ follow-up.
Meta-analyses have inherent limitations, and there was heterogeneity in outcome definitions across studies, with variable sample sizes across the different analyses due to all endpoints not being included in all the studies. In addition, any differences in patient inclusion criteria, albumin dosing/
regimen, and means of follow-up between the individual studies may add further variation. However, using this approach also facilitated the evaluation of albumin therapy in a large, pooled population of approximately 1,500 patients. The metaanalysis was supportive of a role for long-term albumin therapy as a diseasemodifying intervention for patients with decompensated cirrhosis, being associated with significant reductions in mortality and key cirrhosis-related complications. The study authors advise that further research is needed to define those patients who will respond best to this therapeutic strategy, and to optimise protocols and enable individualised treatment plans.
Predicting Clinical Response: Post-hoc Analysis of the ANSWER Study
As noted in the previous poster, identifying those patients who are likely to benefit most from long-term albumin therapy is currently a key topic of discussion. The ANSWER study was a Phase IV, open-label, randomised, multicentre, Italian trial (investigator-initiated study, funded by the Italian Medicines Agency, Rome, Italy), which demonstrated that long-term albumin administration prolongs overall survival and reduces cirrhosis-related complications in patients with decompensated cirrhosis.4,5 In a posthoc analysis of the ANSWER study, Pompili et al.6 examined the association between serum albumin levels at baseline and clinical response to albumin therapy (18-month mortality; Fine-Gray model adjusted for age, viral aetiology, Child-Pugh score, and MELD-Na), alongside an exploratory analysis to examine treatment effect by different baseline serum albumin thresholds (from 2.5 to 4.2 g/dL). The study included 431 patients with cirrhosis and uncomplicated Grade 2/3 ascites who were randomised to SMT or SMT+albumin therapy (40 g weekly, maintenance dose), for up to 18 months, with 18-month survival as the primary endpoint and cirrhosis-related complications as secondary endpoints. The two treatment groups were stratified by baseline serum albumin concentration, and similar numbers of patients discontinued the study early in the SMT+albumin and SMT treatment arms (42 versus 41 patients, respectively).
The model revealed that the SMT+albumin treatment effect (survival benefit) was linked to lower baseline serum albumin values. A baseline serum albumin cutoff of 3.2 g/dL was associated with the greatest survival benefit (confirmed by internal validation via bootstrap analysis). In patients with baseline serum albumin ≤3.2 g/dL (n=275; 64%), the 18-month survival rate was significantly higher in the SMT+albumin subgroup, compared with the subgroup receiving SMT alone (hazard ratio [HR]: 0.47; 95% CI: 0.29–0.77; p=0.002). In patients with serum albumin >3.2 g/dL, the mortality rate was low in both subgroups (HR: 1.04; 95% CI: 0.41–2.63; p=0.93). The incidence of paracentesis, cirrhosis-related complications, and hospital admissions was also significantly improved (lower) in the SMT+albumin subgroup compared with the SMT subgroup across all the baseline albumin strata.
Thus, findings from this post-hoc investigation indicate that addition of longterm albumin therapy to SMT provides advantages independent of baseline serum albumin levels, reducing cirrhosisrelated complications and paracentesis; but appears to provide additional benefit in terms of mortality only in patients with mild-to-moderate hypoalbuminaemia (i.e., ≤3.2 g/dL at baseline). While the posthoc, exploratory nature of the study is recognised, investigators note that costs and logistical issues currently restrict the widespread use of long-term albumin therapy and suggest that this evidence may help prioritise its use when resources are constrained. This could direct treatment towards patients who are most likely to gain a survival benefit, and so create more individualised treatment plans.
TPE in ACLF
The Phase III, Multicentre APACHE
Study
In an oral presentation at EASL 2026,7 Javier Fernández, EF CLIF, EASL-CLIF Consortium and Grifols Chair; Hospital Clínic, IDIBAPS and CIBERehd, Barcelona, Spain, outlined
the results of the landmark APACHE study (sponsored by Instituto Grifols, S.A., Barcelona, Spain), evaluating the efficacy and safety of high-volume plasma exchange with 5% albumin replacement (PE-A5%; Albutein 5%®, Grifols, Barcelona, Spain) in patients with ACLF. Following on from the promising findings of a pilot study,8 APACHE was a Phase III, multicentre, randomised, controlled, parallel-group, open-label trial performed at 29 sites in nine countries across Europe and North America. In total, 274 patients who had been hospitalised with ACLF (Grades 1b–3a; 55% Grade 2) were randomised to receive SMT+PE-A5% (n=135; 4–9 sessions; median: 4 sessions of PEA5%) or SMT (n=139). The primary endpoint was 90-day survival, censored at the point of liver transplant. Overall, the number of patients who terminated the study prior to 90 days was similar in the two treatment groups: 99 patients in the SMT+PE-A5% group (including 40 deaths, 30 transplants), and 110 patients from the SMT group (including 56 deaths, 18 transplants).
SMT+PE-A5% was associated with a significant increase in 90-day survival rate without prior liver transplant, compared with SMT alone (HR: 0.65; 95% CI: 0.45–0.94; p=0.021; primary endpoint).7 The 90-day survival benefit was most prominent in patients with ACLF Grade 2 (HR: 0.55 [95% CI: 0.34–0.90]) (Grade 1b HR: 0.73 [95% CI: 0.27–2.02]; Grade 3a (HR: 0.83 [95% CI: 0.43–1.59]) (exploratory subgroup analysis). The 28-day survival rate also approached significance, with an HR of 0.67 (95% CI: 0.44–1.01; p=0.06). While the 90-day transplant-free survival rate was similar between groups (HR: 0.83; 95% CI: 0.62–1.12; p=0.22), this was based upon 51 deaths and 36 transplants (total n=87) in the SMT+PE-A5% group, compared with 69 deaths and 20 transplants in the SMT group (total n=89). The study authors suggest that these findings point towards PE-A5% acting mainly as a bridge to liver transplant.
Total treatment-emergent adverse events (TEAE) were more frequent in the SMT+PE-A5% group (85.2% patients) than in the SMT group (71.9% patients), which the authors note is consistent with the known side effects of plasma exchange.
However, despite differences in the overall rate of TEAEs, the number of deaths due to TEAEs was similar between groups (SMT+PE-A5%: 7.0% of patients; SMT: 7.2% of patients), as was the rate of study withdrawal due to TEAEs (7.0% versus 5.0%, respectively). In addition, adverse reactions or suspected adverse reactions due to PEA5% were reported in only <5% of patients, with no new safety concerns raised.
The study authors suggest that SMT+PE-A5% demonstrates a favourable benefit–risk profile in the treatment of patients with ACLF, significantly increasing 90-day survival compared with SMT alone, mainly in patients with less severe forms of ACLF (Grade 2), and with TEAEs reflecting known risks. It is noted that for non-clinical reasons, study enrolment was terminated early, when only 274 (72%) of the 370-participant target had been enrolled, which may have affected the power of the planned statistical tests. However, the study remains a pivotal controlled Phase III study, gaining evidence from a large patient population across multiple centres worldwide.
Single-Centre Study in India
Data were presented from another largescale study examining the use of TPE for ACLF in a single centre in India. In this open-label, parallel group, randomised controlled study (investigator-initiated study at the All India Institute of Medical Sciences, New Delhi, India), Biswas et al.9 examined the impact of TPE on the survival of patients with ACLF (Grades 1–3b), in comparison with SMT.9,10 The study enrolled 194 patients who were randomised 1:1 to receive SMT+TPE (5 sessions) or SMT alone. At baseline, most patients had Grade 2 ACLF (64.5%), there was a median of two organ failures per patient, and alcohol use was the most common aetiology of liver disease (67.5%). Just over half of patients completed all five sessions of TPE (56/97 patients; 57.7%), with haemodynamic instability being the leading cause of discontinuation of TPE (18/41 patients; 43.9%). The formulation of TPE/albumin dose is not reported.
The all-cause 28-day mortality rate (primary endpoint) was significantly lower in the SMT+TPE group than in the SMT group (44.3% versus 63.9%; p=0.006). However, the 90-day mortality rate (secondary endpoint) was similar in both groups (SMTTPE 66% versus SMT 69.1%; p=0.64). These findings were independent of the severity of disease (ACLF Grades 1–3) or alcohol/ non-alcohol aetiology (subgroup analyses). At Day 7, organ failure (hepatic and coagulopathy) was resolved in more patients treated with SMT+TPE than with SMT alone (hepatic: 35.5% versus 25.7%, p=0.013; coagulation: 48% versus 22%, p=0.001). There were also greater reductions in serum bilirubin, international normalised ratio, and plasma ammonia in the SMT+TPE group, and lower prognostic scores (MELD and Chronic Liver Failure-Consortium [CLIF-C] ACLF) for mortality risk at Day 7, compared with SMT alone. In addition, more patients receiving TPE had resolution of systemic inflammatory response syndrome (20.8% versus 8%; p=0.039), with a greater decline in serum levels of 25 cytokines from baseline to Day 5 versus the SMT group (proof-of-principle study). Regarding safety, dyselectrolytaemia and shivering were the most common complications after TPE, and, at Day 7, there was a higher incidence of new-onset infections in the TPE group than in patients receiving SMT alone (21.7% versus 11.8%; p=0.062).
While highlighting the benefit of TPE on 28day mortality rates and resolution of organ failure in patients with ACLF, the authors noted that this did not extend to a benefit in 90-day mortality. They also cited concerns over safety outcomes (infections and fluid and electrolyte imbalances) and expressed concern over tolerability in this critically ill patient group.
Clinical Implications
The decompensated phase of cirrhosis is characterised by the emergence of serious clinical signs such as ascites and bleeding, heralding accelerated disease progression towards liver transplant or death.11 Strategies to prevent disease progression
involve suppression of causative factors (e.g., alcohol, hepatitis infection), and targeting key pathogenic events.11 However, evidence for the effectiveness of these two approaches across the patient spectrum is limited. Long-term albumin therapy has been proposed as a strategy to improve pathogenic abnormalities in systemic circulatory function, but existing clinical data on its use are conflicting.11 As a result, the current EASL treatment guidelines do not recommend albumin therapy for decompensated cirrhosis, stating that further clinical evidence is required.11
Thus, the latest study findings presented at EASL 2026 contribute valuable evidence to the ongoing discussion on the role of albumin therapy for decompensated cirrhosis. The abstracts reviewed in this article demonstrate the survival benefits of long-term albumin therapy in real-world and post-hoc clinical analyses, strengthened by a meta-analysis of seven individual clinical studies that support a role for long-term albumin therapy as a diseasemodifying intervention.1-3,6 Alongside the improved mortality rate (versus SMT), the studies indicate that albumin therapy may produce improvements in disease severity and cirrhosis-related complications, including a lower incidence of ascites (often associated with reduced survival) and the accompanying need for paracentesis. There is also preliminary evidence that patients with less severe disease may benefit most in terms of survival outcome, presenting the opportunity for a more individualised treatment approach.6 The abstracts present safety findings in less detail, though they clearly state that no new safety concerns were identified.
Two of the abstracts considered the impact of costs on the use of long-term albumin therapy.2,6 Pompili et al.6 suggested that the direct drug and administration costs present a barrier to wider uptake, while Sood et al.2 showed that albumin is a cost-neutral (and potentially cost-saving) therapy, linked to its efficacy in reducing the need for paracentesis and hospital admission. Therefore, further research into the health economics of albumin therapy across different settings may serve to
educate healthcare authorities around the cost-benefit balance of treatment. In addition, identifying the specific subgroups of patients who benefit most from albumin therapy may not only improve patient outcomes, but also favour the efficient and cost-effective use of healthcare resources.
ACLF is a severe form of decompensated cirrhosis associated with organ failure and a high risk of mortality in the short-term.12 Liver transplant is the only life-saving treatment for ACLF, and there is a need for therapies that can quickly stabilise patients prior to transplantation.12 At EASL 2026, data presented from two prospective studies augmented the evidence base for using TPE in ACLF.7,9 Both studies indicated that TPE can improve short-term survival in patients with ACLF, and data from the pivotal, multicentre APACHE trial supported the use of TPE as a ‘bridge to liver transplant’ with higher 90-day survival rates and more liver transplants than in patients receiving SMT alone. However, there were conflicting opinions on the safety of TPE. The APACHE investigators presented a favourable benefit-risk profile for TPE, while in the single-centre study, Biswas et al.9 conclude that tolerability (related to infections, electrolyte disturbance, and catheter-related complications) is a limiting factor in this critically ill patient population.
The role of albumin in these settings remains under discussion and is not fully established across all treatment scenarios.
References
1. Sood S et al. Regular human albumin therapy in decompensated cirrhosis: six-month clinical outcomes from a multicentre Australian cohort. Abstract THU-496. EASL Congress, 27-30 May, 2026.
2. Sood S et al. Outpatient albumin infusions reduce paracentesis without increasing costs in cirrhosis: a national real-world cost-comparison study. Abstract WED-513. EASL Congress, 27-30 May, 2026.
3. Kim WR et al. Impact of long-term albumin administration on mortality and cirrhosis-related complications: are these data sufficient to change practice? Abstract WED-467. EASL Congress, 27-30 May, 2026.
However, there is an urgent need to address the high disease burden and meet the clinical challenges of acute treatment or prevention of complications in chronic liver disease. Taking account of the latest data in decision-making processes and guidelines, with contributions from clinical and routine practice settings worldwide, is key to keeping the debate moving forward and optimising patient outcomes.
Conclusion
The combined data from prospective, retrospective, and meta-analysis studies presented at EASL 2026 contribute to the evolving evidence base for the use of human albumin therapy in severe liver disease. The studies are supportive of potential benefits in survival, ascites control, liver-related complications, healthcare utilisation, and costs, while remaining mindful of safety concerns for this critically ill population. As the studies display different advantages and limitations in the information they deliver, with heterogeneity in designs and settings, their collective findings cannot be considered definitive. However, new and emerging evidence is necessary to inform the future management of advanced liver disease, shaping treatment strategies, and identifying those patients most likely to benefit from therapy.
4. Caraceni P et al.; ANSWER Study Investigators. Long-term albumin administration in decompensated cirrhosis (ANSWER): an openlabel randomised trial. Lancet. 2018;391(10138):2417-29.
5. University of Bologna. Human albumin for the treatment of ascites in patients with hepatic cirrhosis (ANSWER). NCT01288794. https://clinicaltrials. gov/study/NCT01288794.
6. Pompili E et al. Pre-treatment serum albumin concentration predicts clinical outcomes in patients with cirrhosis receiving long-term albumin. Abstract TOP-455-YI. EASL Congress, 27-30 May, 2026.
7. Fernández J et al. Plasma exchange with albumin 5% significantly increases 90-day overall survival in acute-onchronic liver failure: topline results of the APACHE trial. Abstract LBO-002. EASL Congress, 27-30 May, 2026.
8. Fernández J et al. Effect of plasma exchange with albumin replacement on albumin functionality and organ dysfunction in acute-on-chronic liver failure. JHEP Rep. 2024;6(4):101017.
9. Biswas S et al. Therapeutic plasma exchange improves short-term survival in patients with acute-on-chronic liver failure: a randomised controlled trial. Abstract TOP-423. EASL Congress, 27-30 May, 2026.
10. Swaroop S et al. Therapeutic plasma exchange improves short-term survival in patients with acute-on-chronic liver failure: a randomized controlled trial. Hepatology. 2026;DOI:10.1097/ HEP.0000000000001755.
11. European Association for the Study of the Liver (EASL). EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018;69(2):406-60.
12. European Association for the Study of the Liver (EASL). EASL Clinical Practice Guidelines on acute-on-chronic liver failure. J Hepatol. 2023;79(2):461-91.
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EASL 2026
Abstract Reviews
Drawing on the breadth of cutting-edge research presented at the European Association for the Study of the Liver (EASL) 2026, these abstract reviews spotlight key topics in hepatology, including rare genetic diseases, machine learning models for cirrhotic sepsis, biliary disease, and liver transplantation.
Genome-Wide Association Study to Identify Novel Genetic Variants Associated with Primary Budd-Chiari Syndrome
1. AII India Institute of Medical Sciences, New Delhi, India
2. G.B. Pant Hospital, New Delhi, India
3. Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
4. Sir H. N. Reliance Foundation Hospital and Research Centre, Mumbai, India
*Correspondence to drshalimar@aiims.edu
Disclosure: Shalimar has received support for this work through grant funding (grant File No./5/4/3-2/2019-NCD-II) from the Indian Council of Medical Research (ICMR), with payment made to the individual. The other authors have declared no conflicts of interest.
Acknowledgements: The authors are highly thankful to Indian Council of Medical Research (ICMR) for providing funding support through grant File No./5/4/3-2/2019-NCD-II to conduct this study. The authors are very thankful to all the subjects who participated in this study.
Keywords: Budd-Chiari syndrome (BCS), coagulation, genome-wide association study, liver, single nucleotide polymorphism (SNP), thrombosis vessel.
Primary Budd-Chiari syndrome (BCS) is a rare hepatic vascular disorder characterised by hepatic venous outflow obstruction involving the hepatic veins and/or inferior vena cava secondary to thrombosis or intrinsic vascular abnormalities.1-5 Predisposing factors include inherited procoagulant states (factor V Leiden gene [G1691A] mutation, prothrombin gene [G20210A] mutation, protein C/S deficiency, antithrombin-III deficiency, and hyperhomocysteinaemia), or acquired procoagulant states including myeloproliferative disorders (polycythemia
vera with JAK2 [V617F] mutation).6 Marked geographic variation in vascular anatomy and prothrombotic profile suggests an underlying genetic predisposition.7 This study aimed to identify genetic variants associated with primary BCS using genome-wide association study and to characterise implicated biological pathways.
MATERIALS AND METHODS
This case-control study was conducted at the All-India Institute of Medical Sciences, New Delhi, a tertiary care centre in India between June 2020–May 2022. Consecutive adults (≥18 years) with primary BCS attending the outpatient department were prospectively enrolled after informed consent. A total of 310 adults with primary BCS and 312 age- and sexmatched healthy controls were recruited. Genotyping was performed using the Illumina Inc. (San Diego, California, USA) bead array-based high-density wholegenome single nucleotide polymorphism (SNP) genotyping kit (catalogue number: 20030773). Genotype calling, normalisation, and clustering were carried out using GenomeStudio (Illumina Inc., San Diego, California, USA) 2.0 software. After quality control, 262 cases and 265 controls were included. SNPs were mapped to genes and assessed using gene ontology (GO), pathway, and tissue-expression analyses. Quantile-quantile plots and Manhattan plots were produced by using the PLINK software (version 1.09).8 GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway plots were produced using the SRplot tool.9
RESULTS
Genome-wide SNP data quality was assessed by a quantile-quantile plot demonstrating minimal inflation (λ=1.048) and high-quality data. Overall, 778,783 high-quality SNPs were analysed; 1,549
were associated with BCS at p<0.05 and 340 lead SNPs at p<0.001. Fifteen top SNPs (p<5×10⁻⁵) were predominantly intronic, intergenic, or regulatory and mapped to loci including rs13164180, rs6883351, rs1558294, rs2656107, rs1413229, rs2903138, rs4919217, rs11948339, rs6936121, rs62218439, rs12966305, rs1609245, rs965428, rs697957, and rs34176204. GO enrichment analyses showed significant associations for biological processes including cell junction assembly, regulation of small guanosine triphosphatase (GTPase)-mediated signal transduction, and calcium ion sequestration and release. Molecular function enrichments included calcium/sodium/cation channel activity, extracellular matrix constituent, and GTPase regulator/activator activities. The adult Genotype-Tissue Expression (GTEx) analysis using GTEx version 8 in FUMA (Functional Mapping and Annotation) GENE2FUNC platform indicated significant expression of 340 lead SNP-associated genes in blood vessels and liver with no overlap between lead SNPs and canonical hypercoagulable genes (protein C/S, antithrombin III, factor V, JAK2, calreticulin).
Survival and restenosis were evaluated as per the genotypes of the top 15 SNPs using Kaplan–Meier analysis in BCS cases. For rs1558294, the heterozygous genotype was associated with significantly lower survival than the other genotypes (p=0.001), whereas for rs11948339, the wild-type homozygous genotypes were associated with lower survival (p=0.019). rs11948339 was also significantly associated with case status on Fisher’s exact test (p=0.015). The homozygous wild type of rs2903118 was associated with a significantly higher restenosis (p=0.038). Our findings suggest distinct genetic underpinnings beyond known thrombophilic states and support a shift in focus from purely somatic coagulation defects to vascular structural remodelling in the pathogenesis of BCS.10,11
CONCLUSION
This genome-wide association study in primary BCS identifies novel germline loci predominantly in non-coding and regulatory regions, implicating extracellular matrix remodelling, vascular tone, and cell-adhesion pathways rather than classical thrombophilia genes, and supports further functional studies to refine genetic risk stratification.
References
1. Kumar S et al. Genome-wide association study to identify novel genetic variants associated with primary Budd-Chiari syndrome. Abstract THU-299. EASL Congress, 26-30 May, 2026.
2. Aydinli M, Bayraktar Y. Budd-Chiari syndrome: etiology, pathogenesis and diagnosis. World J Gastroenterol. 2007;13(19):2693-6.
3. Li Y et al. Epidemiology of Budd-Chiari syndrome: a systematic review and meta-analysis. Clin Res Hepatol Gastroenterol. 2019;43(4):468-74.
4. Xu PQ et al. Surgical treatment of 1360 cases of Budd-Chiari syndrome: 20-year experience. Hepatobiliary Pancreat Dis Int. 2004;3(3):391-4.
5. Garcia-Pagán JC, Valla DC. Primary Budd-Chiari syndrome. N Engl J Med. 2023;388(14):1307-16.
6. Hernández-Gea V et al. Current knowledge in pathophysiology and management of Budd-Chiari syndrome and non-cirrhotic non-tumoral splanchnic vein thrombosis. J Hepatol. 2019;71(1):175-99.
7. Gavriilidis P et al. State of the art, current perspectives, and controversies of Budd-Chiari syndrome: a review. J Clin Med Res. 2022;14(4):147-57.
8. Purcell S et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559-75.
9. Tang D et al. SRplot: a free online platform for data visualization and graphing. PLoS One. 2023;18(11):e0294236.
10. Adam F et al. Apelin: an antithrombotic factor that inhibits platelet function. Blood. 2016;127(7):908-20.
11. Stark K, Massberg S. Interplay between inflammation and thrombosis in cardiovascular pathology. Nat Rev Cardiol. 2021;18(9):666-82.
Alpha-1 Foundation Research Registry: Highlighting Pulmonary Manifestations Among Patients with Liver-Affected Alpha-1 Antitrypsin Deficiency in the USA
Authors: Alison Keaveny,1 *Nadine Nuchovich,1
Jennifer Illarramendi,1 Randel Plant,1 Jeanine M. D’armiento,2 Monica P. Goldklang2
1. Alpha-1 Foundation, Coral Gables, Florida, USA
2. Columbia University Irving Medical Center, New York City, New York, USA
*Correspondence to nnuchovich@alpha1.org
Disclosure: The authors have declared no conflicts of interest.
Alpha-1 antitrypsin deficiency-associated liver disease (AATD-LD) is characterised by the accumulation of misfolded alpha-1 antitrypsin (AAT) protein in hepatocytes, causing cellular stress and inflammation.1,2 This intracellular buildup damages hepatocytes, causing liver fibrosis and leading to severe hepatic disease, including cirrhosis and cancer.3 Meanwhile, this backlog of mutated AAT protein results in reduced AAT protection in the lungs.2 Consequently, individuals with dysfunctional alleles may be at risk for both AATD-LD and pulmonary disease due to subsequent low circulating AAT protein. Therefore, the authors aim to analyse patients with AATD with AATD-LD and describe concomitant pulmonary disease burden.4
MATERIALS AND METHODS
The Alpha-1 Research Registry is an online database, supported by the Alpha-1 Foundation, of patients with AATD in the USA who answered a patient-reported questionnaire on health factors and comorbidities surrounding AATD. Among
3,569 patients who answered a liver disease burden questionnaire, the authors reviewed 1,776 liver-affected patients between June 2019–June 2026, who reported a positive history of abnormal liver function tests, liver symptoms, cirrhosis, metabolic dysfunction-associated steatohepatitis/metabolic dysfunctionassociated steatotic liver disease, ascites, cholestasis, hepatopulmonary syndrome, portopulmonary hypertension, or bacterial peritonitis, and assessed for co-occurring pulmonary conditions.
RESULTS
Liver-affected AATD participants identify largely as female (68.8%), white (97.3%), and have a mean age of 50.54 (±16.5 years). PiZZ genotype was most frequently reported (38.7%), followed by PiMZ (29.4%) and PiSZ (11.6%). Patients largely reported fatty liver (51.7%), cirrhosis (16.1%), and a history of childhood jaundice (30.5%). Even among those who were liver-affected, lung symptoms were the most reported reason for AATD testing (32.9%), followed by liver symptoms (21.4%).
Overall, 63.1% of patients who were liveraffected had obstructive pulmonary disease, including COPD (34.2%), adult asthma (36.8%), emphysema (25.4%), and bronchiectasis (17.8%). Patients also reported pulmonary symptoms occurring at least several days per week, including cough (48.5%), shortness of breath (44.8%), sputum production (33.0%), and wheezing (16.7%). More than two exacerbations in the previous year (defined as episodes requiring antibiotics or corticosteroids) were reported by 27.2% of patients.
Treatment for AATD lung disease (augmentation infusion therapy), either currently or in the past, was reported by 31.4%, with patients currently also on
A significant number of patients with liveraffected AATD also reported co-occurring lung involvement, symptoms, and impacted quality of life. Given the considerable multisystem overlap in patients with AATD, it is imperative patients with AATD be screened for both hepatic and pulmonary disease, and for hepatologist and pulmonologist to work collaboratively on patient care for those with AATD. Patient-led databases surveying the current scope of care for patients with AATD can also be utilised to analyse discrepancies in care and
highlight avenues for strengthening interdepartmental collaboration.
References
1. Loomba R et al. Multi-society expert panel consensus guidance regarding clinical assessment and clinical trial endpoints in adults with alpha-1 antitrypsin deficiency-associated liver disease. Gastroenterology. 2026;170(4):829-42.
2. Tejwani V, Stoller JK. The spectrum of clinical sequelae associated with alpha-1 antitrypsin deficiency. Ther Adv Chronic Dis. 2021;DOI: 10.1177/2040622321995691.
3. Patel D et al. Alpha-1 antitrypsin deficiency liver disease. Transl Gastroenterol Hepatol. 2021;DOI:10.21037/tgh.2020.02.23.
4. Keaveny A et al. Alpha-1 foundation research registry: highlighting pulmonary manifestations among liver-affected alpha-1 antitrypsin deficiency patients in the United States. Abstract THU-285. EASL Congress, 27-30 May, 2026.
Donor Relation and Timing of Paediatric Liver Transplantation in Genetically Inherited Liver Diseases: A Sibling Cohort Study
Authors: Mohammed Alqahtani,1 Ibrahim Hassan,1 Razan Bader,1 Ahmed Zidan,1 *Eyad Gadour1
1. Multiorgan Transplant Centre of Excellence, Liver Transplantation Unit, King Fahad Specialist Hospital, Dammam, Saudi Arabia *Correspondence to eyadgadour@doctors.org.uk
Disclosure: The authors have declared no conflicts of interest.
Paediatric liver transplantation (LT) is an established treatment for genetically inherited liver diseases (GILD),1-4 but the influence of donor source, specific donor relationship, and age at transplantation remains incompletely defined.5-8 In familial cohorts, these factors may affect technical complications and survival differently.9,10
METHODS
The authors performed a single-centre retrospective sibling cohort study of 26 children from 13 sibling pairs who underwent first-time LT for GILDs between 2015–2024.11 Outcomes were analysed by donor type, donor relation, and age at transplantation (<1 year versus >1 year). Primary outcomes were biliary complications, vascular complications, and graft survival. Patient survival and school performance were assessed as secondary outcomes. Familial clustering was addressed using generalised estimating equations and mixed-effects models.
RESULTS
Living-related donation was the most common graft source (20/26; 76.9%), followed by deceased donation (5/26; 19.2%) and living-unrelated donation (1/26; 3.8%). Donor type was not significantly associated with biliary complications (p=0.876), vascular complications (p=0.768), or graft survival (p=0.532). However, donor relation showed a significant association with vascular complications (p=0.026), which occurred only in recipients of grafts from brothers, aunts, and deceased donors, and not from mothers, fathers, or uncles. Biliary complications did not differ significantly by donor relation (p=0.739). Infants transplanted at <1 year had no biliary or vascular complications and similar graft survival to older children, but all deaths in the cohort occurred in this group (25% versus 0%; p=0.027). Cold and warm ischaemia times were not correlated with graft survival. Long-term school performance was not significantly associated with age at transplantation or donor type.
CONCLUSION
In this sibling cohort, living donation provided outcomes comparable to deceased donor LT for paediatric GILDs. Nevertheless, donor relations may influence vascular risk, and transplantation during infancy was associated with higher mortality despite favourable technical outcomes. These findings support careful donor selection and individualised timing of LT in children with GILDs.
Copyright
References
1. Barbetta A et al. Living donor versus deceased donor pediatric liver transplantation: a systematic review and meta-analysis. Transplant Direct. 2021;7(10):e767.
2. Boillot O et al. Determinants of short-term outcomes after pediatric liver transplantation: a single centre experience over 20 years. Clin Res Hepatol Gastroenterol. 2021;45(6):101565.
3. Feier FH et al. Analysis of factors associated with biliary complications in children after liver transplantation. Transplantation. 2016;100(9):1944.
4. Kasahara M et al. Evaluation of living donors for hereditary liver disease (siblings, heterozygotes). J Hepatol. 2023;78(6):1147-56.
5. Kasahara M et al. Pediatric living-donor liver transplantation. Semin Pediatr Surg. 2017;26(4):224-32.
6. McKiernan PJ et al. Liver transplant for inherited metabolic disease among siblings. Clin Transplant. 2020;34(11):e14090.
7. Pearson GD et al., "Clinical trials in children," Piantadosi S, Meinert CL (eds.), Principles and Practice of Clinical Trials (2022), Cham: Springer, pp.2379-95.
8. Vimalesvaran S et al. Outcomes of adults who received liver transplant as young children. eClinicalMedicine. 2021;38:101030.
9. Yazigi NA. Long term outcomes after pediatric liver transplantation. Pediatr Gastroenterol Hepatol Nutr. 2013;16(4):207-18.
10. Zhang R et al. Outcomes of pediatric liver transplantation: deceased donor liver transplantation vs living donor liver transplantation. Transplant Proc. 2018;50(10):3601-5.
11. Hassan I et al. Donor selection and timing in pediatric liver transplantation for genetic liver disorders: a retrospective sibling cohort analysis. Abstract FRI494. EASL Congress, 27-30 May, 2026.
Advancing Primary Biliary Cholangitis Management Through Continuing Medical Education
Authors: *S. Christy Rohani-Montez,1 Marinella Calle,1 Margaux Le Berre,1 Adriaan J. van der Meer,2 Emma Culver,3 David E. Jones4
1. Medscape Education Global, London, UK
2. Erasmus MC, Rotterdam, the Netherlands
3. John Radcliffe Hospital, Oxford, UK
4. University of Newcastle, Newcastle upon Tyne, UK
*Correspondence to srohani@medscape.net
Disclosure: van der Meer has received grants or contracts from Gilead, Ipsen, Mirum, and Intercept, with payments to the institution; consulting fees from Gilead, Ipsen, and Mirum; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Gilead, Ipsen, Norgine, Mirum, and AbbVie. Culver has received grants or contracts from NIHR BRC Oxford; consulting fees from Gilead, Mirum, GSK, Amgen, Ipsen, Zenus, Acepodia, Sanofi, Advance, and Intercept; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Gilead, Mirum, GSK, Amgen, Ipsen, Zenus, Acepodia, Sanofi, Advance, and Intercept; has participated on the Data Safety Monitoring Board or Advisory Board of Amgen, Zenus, Sanofi, Ipsen, Gilead, Mirum, and Advance; has been the Chair of BASL IMLD, Scientific Committee EASL, and Research Council UEG. Jones has received support for the present manuscript from Medscape as remuneration for unrelated educational activity delivery; grants from Intercept; consulting fees from Advanz, Ipsen, and Umecrine; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Ipsen and Gilead; has participated on the Data Safety Monitoring Board or Advisory Board of Mirum; and has been an unpaid Chair of the clinical advisory board for PBC Foundation. The other authors have declared no conflicts of interest.
Primary biliary cholangitis (PBC) management in Europe has undergone a significant transition following the European
Medicines Agency’s (EMA) withdrawal of obeticholic acid1 and the subsequent approval of peroxisome proliferatoractivated receptor (PPAR) agonists.2,3
AIMS
To address this overhaul in secondline therapies, the authors launched an educational initiative to increase gastroenterologists’ and hepatologists’ competence and confidence in using second-line therapy and assess their subsequent actions in clinical practice.4
METHODS
Physicians participated in a 38-minute, debate-style online continuing medical education (CME) activity on (re-) evaluation for second-line PBC therapy. The educational effects were measured in two phases: part A involved activity pre- and post-assessments, while part B was a Moore’s Level 5 performance survey completed 30 to 60 days after participation.
RESULTS
Of 1,413 gastroenterologists/hepatologists who had engaged with the programme, 58 completed all questions in part A and 33 in part B. Of which, 52% were community practitioners, 39% in academic settings, and 8% other.
Part A revealed significant improvements in physicians correctly identifying patient age and liver stiffness as critical indicators for second-line treatment, factors that were previously underestimated (preassessment: 16% correct versus postassessment 45% correct; p<0.001). Furthermore, physicians demonstrated an increased understanding that PPAR agonists improve patient itch and biochemical responses, normalising
alkaline phosphatase (pre-assessment: 62% correct versus post-assessment 76% correct; p<0.05).
This knowledge translated directly to increased confidence. While 84% of participants recognised they had patients requiring reassessment, 36% demonstrated measurably improved confidence in determining exactly which patients should be evaluated following the activity.
The programme subsequently successfully drove meaningful changes in clinical practice. The follow-up survey in part B revealed that 94% of respondents modified, implemented, or reinforced a clinical practice as a direct result of the education. Figure 1 outlines the specific practice changes implemented by specialists 30 to 60 days after the educational intervention.
Despite the high rate of overall reassessment (91% actively reassessing patients), physicians reported practical barriers that limit broader implementation. The primary barriers cited were capacity challenges related to scheduling patient clinics and difficulties in securing access to PPAR agonists.
CONCLUSION
Ultimately, the CME activity successfully boosted practitioner confidence and catalysed active reassessments of patients with PBC. Moving forward, continued education must focus on closing the gap between simply monitoring patients with PBC and actively prescribing these new second-line treatments by reinforcing clinical indicators and the expected benefits of PPAR agonists.
References
1. European Medicines Agency. EMA recommends revoking conditional marketing authorisation for Ocaliva. Available at: https://www.ema.europa.eu/ en/news/ema-recommends-revoking-conditionalmarketing-authorisation-ocaliva. Last accessed: 8 June 2026.
2. European Medicines Agency. Iqirvo. Available at: https://www.ema.europa.eu/en/medicines/human/ EPAR/iqirvo. Last accessed: 8 June 2026.
3. European Medicines Agency. Lyvdelzi (previously Seladelpar Gilead). Available at: https://www.ema. europa.eu/en/medicines/human/EPAR/lyvdelzi. Last accessed: 8 June 2026.
4. Rohani-Montez SC et al. Changes in gastroenterology and hepatology practice through primary biliary cholangitis education. Poster THU290. EASL Congress, 27-30 May, 2026.
Figure 1: Physician practice changes post-education.
Concomitant Medications Associated with Acute Liver Injury Risk Following Amoxicillin/ Clavulanate Exposure Unexplained by Other Causes: Signal Detection Analyses Using Electronic Health Record Data
Authors: Richard Noriega,1,2 Jimmy T. Efird,3,4
Tim Arnold,5,6 Chad A. Dorn,1,2 Ruth Reeves,1,2
*Ayako Suzuki1,7
1. Health Services Research, Tennessee Valley Healthcare System VA, Nashville, USA
2. Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
3. VA Cooperative Studies Program Coordinating Center, Boston VA, Massachusetts, USA
4. School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
5. Human Systems Integration, Office of Clinical Informatics, Office of Health Informatics, Digital Health Office, Veterans Health Administration, Washington, D.C., USA
6. College of Pharmacy, University of Michigan, Ann Arbor, USA
7. Gastroenterology, Duke University, Durham, North Carolina, USA
*Correspondence to Ayako.suzuki@duke.edu
Disclosure: The authors have declared no conflicts of interest.
Acknowledgements: This study was funded by the Burroughs Wellcome Fund. The authors thank the Durham Veterans Affairs (VA) Cooperative Studies Program Epidemiology Centers for administrative support during the conduct of the study at the Durham VA Medical Center, and Dong Wang (Biostatistics and Bioinformatics, National Center for Toxicological Research, Jefferson, Arkansas, USA) for his analytical expertise. This study was deemed exempt by the Institutional Review Boards of the Durham VA Health Care System and the VA Tennessee Valley Healthcare System as human subjects research under Category 4.
Keywords: Acute liver injury (ALI), adverse drug reactions, co-medications, electronic health records (EHR).
Drug-induced liver injury (DILI) remains a major adverse drug reaction and a leading cause of drug development failure and post-marketing withdrawal. It significantly impacts patient outcomes and quality of life, and limits therapeutic options. Despite advances, particularly in genetic susceptibility, DILI remains largely unpredictable, with limited understanding of modifiable clinical risk factors. In the context of increasing multimorbidity, ageing populations, and widespread polypharmacy, the role of concomitant medications as potential modifiers of DILI risk has gained increasing attention.
MATERIALS AND METHODS
Leveraging one of the largest unified electronic health record (EHR) systems in the USA from the Department of Veterans Health Administration, the authors applied a previously established framework to identify amoxicillin/clavulanate (AMX/CLAV)associated acute liver injury (ALI) while excluding competing aetiologies.1 Using this cohort, the study examined the association between concomitant medication use during AMX/CLAV exposure and AMX/CLAV–ALI events, with ALI attributable to other causes (ALI–OTR) serving as a disease referent for hypothesis generation.
Concomitant medications were defined as those with exposure periods overlapping the AMX/CLAV treatment window, based on the Observational Medical Outcomes Partnership (OMOP) Common Data Model, with combination products disaggregated into individual active ingredients. Multinomial logistic regression models were fitted for each medication, adjusting for demographic
and clinical covariates. Odds ratios were log-transformed and used in clustering analyses to classify medications into three groups: those associated with increased risk of AMX/CLAV–ALI only, ALI–OTR only, or concordant effects on both outcomes.
RESULTS
Among approximately 1.4 million AMX/ CLAV-exposed individuals, 1,582 unique concomitant medications were identified. Clustering analysis revealed 32 medications associated with increased odds of AMX/ CLAV–ALI only, 79 with ALI–OTR only, and 341 and 45 with increased and decreased odds of both outcomes, respectively. Medications uniquely associated with increased AMX/CLAV–ALI risk only included agents with immunomodulatory or proinflammatory properties, such as antiandrogens and anticholinergics. Bacillus Calmette–Guérin vaccination was also identified, supporting a potential role of immune activation. Additionally, several antivirals, including HIV medications, were identified. In contrast, medications associated with reduced ALI risk, showing concordant effects across outcomes, were predominantly anti-inflammatory, including commonly used agents such as simvastatin, metformin, and lisinopril.
Medications associated with increased risk for both AMX/CLAV–ALI and ALI–OTR included pneumococcal vaccination,
anti-cancer therapies, immunosuppressants, and antimicrobials, suggesting shared or multifactorial mechanisms of liver injury. This group included components of total parenteral nutrition, raising the possibility that nutritional status or lack of enteral intake may contribute to susceptibility of ALI.
CONCLUSION
This large, EHR-based analysis highlights distinct concomitant medications associated with altered risk of AMX/CLAVrelated liver injury, many with biologically plausible immunologic mechanisms. These findings underscore the potential of EHRdriven signal detection to identify clinical modifiers of DILI risk and generate testable mechanistic hypotheses. Further work incorporating genomic data; comorbidity burden in joint exposure modelling; subanalysis by age, sex, and injury types; and targeted hypothesis testing analysis will be important to further refine and validate these associations and ultimately support the development of predictive frameworks for individualised DILI risk assessment.
Reference
1. Noriega R et al. Concomitant medications associated with acute liver injury risk following amoxicillin/clavulanate exposure unexplained by other causes: signal detection analysis using electronic health record data. Abstract SAT-083. EASL Congress, 27-30 May, 2026.
mRNA COVID-19 Vaccination Following PD-1/PD-L1 Inhibitor Therapy and Survival in Liver Cancer
Authors: Chenyu Sun,1,2 Li Liu,3 Yuntao Zou,4
Yichen Wang,5,6 Yan Yan,6 Liu Yang,7
*Yuting Huang6
1. Division of Public Health, Infectious Diseases, and Occupational Medicine, Mayo Clinic, Rochester, Minnesota, USA
2. Mayo Clinic School of Graduate Medical Education, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
3. The Second People’s Hospital of Hefei, China
4. Division of Hospital Medicine, Department of Medicine, University of California San Francisco, USA
5. Mayo Clinic School of Graduate Medical Education, Mayo Clinic College of Medicine and Science, Jacksonville, Florida, USA
6. Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
7. Department of Transplant, Mayo Clinic, Jacksonville, Florida, USA
*Correspondence to Huang.yuting@mayo.edu
Disclosure: Wang has received an award for the development of algorithm in endoscopic image interpretation from the Mayo Clinic, Florida (Department of Medicine Team of Science Award). The other authors have declared no conflicts of interest.
Immune checkpoint inhibitors (ICI) targeting programmed cell death-1 (PD-1) and programmed death ligand-1 (PD-L1) have transformed the management of advanced hepatocellular carcinoma (HCC), with combination regimens such as atezolizumab plus bevacizumab now established as preferred first-line options.1 Despite these advances, objective response rates remain variable. This is attributed in part to the uniquely immunosuppressive tumour microenvironment of HCC, characterised by regulatory T cell enrichment, T cell
exhaustion, and myeloid-derived suppressor cell infiltration.2 Identifying strategies to enhance ICI efficacy in this setting remains a clinical priority.
Emerging preclinical and clinical evidence suggests that mRNA COVID-19 vaccination may serve as a potent immune adjuvant when administered in proximity to ICI initiation. Grippin et al.3 demonstrated that SARSCoV2 mRNA vaccination triggers a strong Type I interferon (IFN) response that activates innate antigenpresenting cells and enables efficient cluster of differentiation (CD)8⁺ T cell priming against tumour antigens. This occurs through an IFN-dependent process in which dendritic cells acquire and present peptide–major histocompatibility complex Class I complexes, thereby enhancing anti-tumour immunity.3 Concomitant ICI treatment was required for maximal anti-tumour efficacy, particularly in immunologically cold tumours. In large retrospective clinical cohorts, mRNA vaccination near ICI initiation was associated with significantly improved overall survival (OS) in patients with nonsmall cell lung cancer and melanoma.3 A real-world study in advanced non-small cell lung cancer further confirmed that COVID-19 vaccination enhanced antiPD-(L)1 immunotherapy efficacy, with vaccinated patients demonstrating superior progression-free survival and OS.4 More broadly, RNA vaccine platforms activate innate and adaptive immune pathways, including pattern recognition receptor signalling and dendritic cell maturation, thereby supporting potent anti-tumour T cell responses.5 A meta-analysis of 10 observational studies encompassing 4,929 patients corroborated these findings, demonstrating improved progression-free survival (pooled hazard ratio [HR]: 0.66; 95% CI: 0.48–0.90) and OS (pooled HR: 0.51; 95% CI: 0.39–0.66) in ICI-treated patients with cancer who received COVID-19 vaccination.6 However, whether this survival benefit extends to HCC had not been specifically investigated.
METHODS
This study evaluated the association between mRNA COVID-19 vaccination and OS among patients with HCC receiving PD-1/PD-L1 inhibitors using the Mayo Clinic Platform (Mayo Clinic, Rochester, Minnesota, USA). A retrospective cohort analysis included patients who received at least one dose of PD-1/PD-L1 inhibitors without liver surgery, stratified by receipt of mRNA COVID-19 vaccine within 6 weeks of immunotherapy initiation. Adjustments were made to include only BMI <30 and exclude patients with diabetes, cardiovascular disease, or heart failure history.
RESULTS
The study results demonstrate that among 4,768 patients (584 vaccinated; 4,184 controls), baseline demographics were comparable. The vaccination group demonstrated significantly improved 5-year OS compared to controls (37.9% versus 23.4%; HR: 0.59; 95% CI: 0.52–0.66; p<0.001; Figure 1). This benefit remained
consistent after covariate adjustment and was observed across both female (35.2% versus 22.1%; HR: 0.63; 95% CI: 0.53–0.76; p<0.001) and male subgroups (38.6% versus 22.8%; HR: 0.55; 95% CI: 0.47–0.64; p<0.001), with sustained benefit through 60 months.7
CONCLUSION
These findings extend prior observations in other malignancies to HCC, supporting the hypothesis that vaccine-induced immune priming may synergise with PD-1/PD-L1 inhibition to overcome the immunosuppressive HCC microenvironment.3-5 Importantly, COVID-19 vaccination has been shown to be safe in patients who are ICI treated, with no significant increase in immune-related adverse events.8 Limitations of this study include the retrospective design, potential residual confounding including healthy vaccinee bias, and incomplete follow-up for patients initiating therapy more recently. In conclusion, mRNA COVID-19 vaccination shortly after PD-1/PD-L1 inhibitor initiation
A: mRNA COVID-19 vaccine
Cohort B: Control
Cumulative survival probability over a 60-month follow-up period for patients in the vaccinated group (blue) compared to the control group (red).
Figure 1: Kaplan–Meier analysis of survival outcomes stratified by vaccination status.
Cohort A Cohort B
Cohort
may be associated with improved OS in liver cancer, warranting prospective validation and mechanistic investigation.
References
1. Singal AG et al. AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. 2023;78(6):1922-65.
2. Chen C et al. Tumor microenvironment-mediated immune evasion in hepatocellular carcinoma. Front Immunol. 2023;14:1133308.
3. Grippin AJ et al. SARS-CoV-2 mRNA vaccines sensitize tumours to immune checkpoint blockade. Nature. 2025;647(8089):488-97.
4. Qian Y et al. COVID-19 vaccination is associated with enhanced efficacy of anti-PD-(L)1 immunotherapy in advanced NSCLC patients: a realworld study. Infect Agent Cancer. 2023;18(1):50.
5. Huang D et al. RNA vaccines for cancer: revolutionizing immunization strategies. Trends Cancer. 2026;12(1):48-67.
6. Xi H et al. COVID-19 vaccination and clinical outcomes of immune checkpoint inhibitors therapy in cancer patients: a meta-analysis of real-world studies. Front Immunol. 2026;17:1807267.
7. Sun Y et al. mRNA COVID-19 vaccination shortly after PD-1/PD-L1 inhibitor is associated with better survival in liver cancer: a Mayo Clinic platform study. Abstract THU-362. EASL Congress, 27-30 May, 2026.
8. Kamboj M et al. Vaccination of adults with cancer: ASCO guideline. J Clin Oncol. 2024;42(14):1699-721.
Paolo Vaia,1 Claudio Basile,1 Marco Niosi,1 Alessandro Federico1
1. Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy *Correspondence to marcello.dallio@unicampania.it
Disclosure: The authors have declared no conflicts of interest.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognised as a systemic disorder driven by cardiometabolic risk factors (CMRF), including obesity, Type 2 diabetes mellitus (T2DM), hypertension, and dyslipidaemia.1-3 While advanced fibrosis (AF) is a major determinant of hepatocellular carcinoma (HCC) risk, the impact of cumulative metabolic burden and specific CMRF combinations on HCC trajectories remains unclear.2,3 This study aimed to evaluate how distinct metabolic profiles influence HCC risk in patients with MASLD with AF.
MATERIALS AND METHODS
In this Italian cohort study, patients with MASLD-AF were stratified into clusters based on the number and combination of CMRFs (from one to four). Individual metabolic dysfunction profiles were defined through non-redundant permutations of CMRFs.4 The primary endpoint was 5-year HCC incidence, while secondary endpoints included HCC staging at diagnosis (Milanout criteria)5 and identification of high-risk metabolic profiles. Multivariable competing
risk models adjusted for demographic and clinical variables were applied.
RESULTS
A total of 1,921 patients were retrospectively analysed after exclusions. Increasing metabolic burden was associated with worsening inflammatory and metabolic parameters. Patients with ≥3 CMRFs (Cluster III and IV) exhibited a significantly higher risk of HCC compared with lowerburden clusters (odds ratio: 2.81; 95% CI: 1.345–3.211). Moreover, cumulative metabolic burden correlated with more advanced tumour stage at diagnosis (odds ratio: 2.46; 95% CI: 1.226–3.035; p=0.0162; Figure 1).
Among specific profiles, the combination of T2DM, obesity, and hypertension conferred the highest HCC risk (odds ratio: 2.24; 95% CI: 1.562–2.985; p<0.001), including increased likelihood of Milanout criteria tumours (odds ratio: 1.541; 95% CI: 1.259–2.237; p=0.035; Figure 1).
Importantly, dynamic changes in metabolic status influenced disease trajectories: incident T2DM during follow-up acted as a disease-modifying event. Mediation analysis demonstrated that up to 82% of the association between metabolic burden and HCC risk was driven by diabetes onset, suggesting a central mechanistic role.
CONCLUSION
Distinct cardiometabolic profiles define heterogeneous HCC risk in patients with MASLD-AF. Risk is not solely determined by the number of CMRFs but by their specific combinations and dynamic interactions.2 In particular, T2DM emerges as a key mediator linking metabolic burden to carcinogenesis.2 These findings support a precision medicine approach, where individual metabolic signatures enable tailored HCC risk stratification and surveillance strategies.5
Figure 1: Hepatocellular carcinoma risk according to metabolic clusters and individual metabolic dysfunction profiles.
HCC Milan-out criteria at diagnosis (according to clusters)
n=97 1 CMRFs 2 CMRFs
HCC Milan-out criteria at diagnosis (according to MD profiles) (Cluster III)
Obe + Gly + Lip
Obe + Lip + Press
Obe + Gly + Press
Gly + Lip + Press
Obe + Gly + Lip Obe + Lip + Press Obe + Gly + Press
p: 0.0355 OR: 1.54; 95% CI: 1.259–2.237
Obe + Gly + Press
Gly + Lip + Press
Risk of HCC stratified by cumulative metabolic burden and specific MD profiles in patients with MASLD and AF.
Panel A shows the risk of advanced HCC at diagnosis according to metabolic clusters defined by the number of CMRFs. A progressive increase in HCC risk is observed with increasing metabolic burden.
Panel B illustrates the risk of advanced HCC at diagnosis according to individual MD profiles, highlighting heterogeneity within clusters based on specific combinations of CMRFs. Selected profiles, particularly those including T2DM, obesity, and hypertension, are associated with higher HCC risk.
1. Romeo M et al. Distinct cardiometabolic profiles drive divergent HCC risk trajectories in advanced fibrosis-affected MASLD patients. Abstract REG26128. EASL Congress, 27-30 May, 2026.
2. Napolitano C et al. Distinct cardiometabolic profiles drive divergent HCC risk trajectories in advanced fibrosis-affected MASLD patients. Poster THU-186YI, EASL Congress, 27-30 May 2026.
3. Elsabaawy M et al. Stratified cardiovascular risk in patients with metabolic dysfunction-associated steatotic liver disease (MASLD): impact of varying metabolic risk factor burden. Eur J Med Res. 2025;30(1):847.
4. European Association for the Study of the Liver; European Association for the Study of Diabetes; European Association for the Study of Obesity. EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunctionassociated steatotic liver disease (MASLD). J Hepatol. 2024;81(3):492-542.
5. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma. J Hepatol. 2025;82(2):315-74.
Machine Learning for Mortality Prediction in Cirrhotic Sepsis: Moving Beyond MELD, SOFA, and CLIF-SOFA
Authors: *Jeril Lasington,¹ Lawin Steve Mathew Lasington,² Arshiya Shabnam,¹ Harika Dadigiri,¹ Edward Barbarito¹
1. New York Medical College, New York, USA
2. Rutgers University, Newark, New Jersey, USA *Correspondence to jeril.lasington@gmail.com
Disclosure: The authors have declared no conflicts of interest.
Acknowledgements: The authors thank the MIT Laboratory for Computational Physiology for curating and openly distributing the MIMIC-IV database, which made this analysis possible. No medical writing assistance was used.
Keywords: Acute-on-chronic liver failure, cirrhosis, critical care, ICU, machine learning (ML), Model for End-Stage Liver Disease (MELD), MIMIC-IV, mortality prediction, risk stratification, sepsis.
Sepsis in patients with cirrhosis carries an in-hospital mortality exceeding 40%, reflecting a pathophysiology distinct from sepsis in non-cirrhotic hosts. Cirrhosisassociated immune dysfunction, gut bacterial translocation, splanchnic vasodilatation, and impaired hepatic clearance together amplify septic organ failure.1,2 Despite this, prognostication continues to rely on scores developed for unrelated purposes: Model for End-Stage Liver Disease (MELD) and MELD-Na for transplant allocation,3,4 Sequential Organ Failure Assessment (SOFA) for general critical illness,5 and Chronic Liver Failure-SOFA (CLIF-SOFA) for acute-onchronic liver failure.6 Each captures only part of the relevant biology. The authors therefore developed machine learning (ML) models that simultaneously integrate hepatic, renal, haemodynamic, and inflammatory variables, and benchmarked them against established scores.7
MATERIALS AND METHODS
Using the MIMIC-IV v3.1 database,8 the authors identified 1,612 adults (≥18 years) with cirrhosis and concurrent sepsis admitted to the ICU between 2008–2022, defined by validated International Classification of Diseases (ICD)-9/10 codes. Variables collected within the first 24 hours encompassed demographics, liver function tests, renal indices, sepsis markers (lactate, pH, white cell count, anion gap), haemodynamics, Glasgow Coma Scale (GCS), cirrhosis complications, and use of vasopressors or mechanical ventilation. Four algorithms such as logistic regression, random forest, XGBoost, and gradient boosting were trained on an 80/20 stratified split with five-fold cross-validation. Performance was assessed by area under the receiver operating characteristic curve (AUC), area under the precision-recall curve, and Brier score, with 1,000-iteration bootstrap 95% CIs.
RESULTS
In-hospital mortality was 45.7% (737/1,612), vasopressors were used in 48.4%, and mechanical ventilation in 46.1%. Random forest and logistic regression achieved the highest discrimination (AUC: 0.787; 95% CI: 0.740–0.834 and 0.737–0.832, respectively), outperforming CLIF-SOFA (0.710), SOFA (0.710), MELD (0.708), and MELD-Na (0.708) by an approximately 11% relative AUC gain. The random forest model yielded a sensitivity of 65.3%, a specificity of 77.8%, a positive predictive value of 71.1%, and a negative predictive value of 72.9%. The most influential predictors were maximum lactate, bilirubin, international normalised ratio, creatinine, and minimum pH, integrating sepsis-driven tissue hypoperfusion with hepatic synthetic and excretory failure.
DISCUSSION
The ceiling on prognostic performance in cirrhotic sepsis appears to be set not by the available data, but by the rigidity of legacy scoring systems. ML models capture non-linear interactions, for example, the disproportionate risk conferred by elevated lactate in patients already exhibiting coagulopathy that linear, equally-weighted scores cannot. The dominance of variables straddling both pathologies supports the concept that ICU mortality in this population is governed by the intersection, rather than the sum, of sepsis and hepatic failure.9 Translation to bedside use will require external validation in geographically and ethnically diverse cohorts, prospective recalibration, and integration into electronic health record workflows that preserve clinician interpretability.
CONCLUSION
Machine learning offers clinically meaningful gains over MELD-, SOFA- and CLIF-SOFAbased prognostication in patients with cirrhosis with sepsis. A cirrhosis-specific, sepsis-aware ML risk tool, once externally validated, could refine triage, resource allocation and goals-of-care discussions in this high-mortality population.
References
1. Arroyo V et al. The systemic inflammation hypothesis: towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis. J Hepatol. 2021;74(3):670-85.
2. Bajaj JS et al. Survival in infection-related acuteon-chronic liver failure is defined by extrahepatic organ failures. Hepatology. 2014;60(1):250-6.
3. Kamath PS et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33(2):464-70.
4. Kim WR et al. Hyponatremia and mortality among patients on the liver-transplant waiting list. N Engl J Med. 2008;359(10):1018-26.
5. Vincent JL et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Med. 1996;22(7):707-10.
6. Moreau R et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology. 2013;144(7):1426-37.
7. Lasington J et al. Beyond MELD: machine learning redefines mortality prediction in cirrhotic patients with sepsis. Abstract 1614. EASL Congress, 27-30 May, 2026.
8. Johnson AEW et al. MIMIC-IV, a freely accessible electronic health record dataset. Sci Data. 2023;10(1):1.
9. Singer M et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-10.
Integrated MASLD Screening Within the Precision iDiabetes Platform Achieves Universal FIB-4
Screening, Automated Secondary Care Referral, and New cACLD and HCC Diagnoses
Authors: *Damien Leith,1 Rachael Barrett,1 Yeun
Yi Lin,2 Mya Win,1 Evelyn Anyebe,2 Paul N Brennan,1 Ruairi Lynch,1 John F Dillon1
1. Ninewells Hospital and Medical School, Dundee, Scotland
2. University of Dundee School of Medicine, Scotland
*Correspondence to dleith001@dundee.ac.uk
Disclosure: Brennan has received consulting fees from Madrigal Pharmaceuticals and Novo Nordisk; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Madrigal Pharmaceuticals, Boehringer Ingelheim, Resolution Therapeutics, Novo Nordisk, and Takeda; has participated on Sonic Incytes Data Safety Monitoring Board or Advisory Board; and has an unpaid leadership or fiduciary role in Global NASH Council. Lynch has received the NHS Research Scotland Fellowship and is the Co-lead on the NIHR grant for the Scottish Hepatology Access Research Partnership. Dillon has received a CSO grant with payments to the institution. The other authors have declared no conflicts of interest.
Acknowledgements: The authors would like to thank the entire iDiabetes study team for their contribution to making this work possible.
Fibrosis-4 (FIB-4) screening for people with Type 2 diabetes (T2D) is recommended;1,2 however, screening and hepatology linkage for high-risk individuals remain a challenge. The authors integrated a reflexive MASLD fibrosis screening algorithm and referral pathway into iDiabetesPlus, a precision diabetes care platform being trialled in primary care in Scotland.3
Here, the authors present the key MASLD screening results from the first year of the iDiabetes study.
METHOD
iDiabetesPlus was implemented from 28 October 2024 in 16 primary care practices in Tayside, Scotland. All people with diabetes are automatically enrolled on iDiabetesPlus at their annual diabetes review. Automated FIB-4 screening is performed for all patients. FIB-4 is stratified as: low risk: <1.30 (aged <65 years)/ <2.0 (aged ≥65 years); intermediate risk: 1.30–2.67 (aged <65 years)/2.0–2.67 (aged ≥65 years); and high risk: >2.67. If alanine aminotransferase (ALT) >30, additional liver aetiological screening is performed, with reflexive enhanced liver fibrosis (ELF) testing in indeterminate or high-risk FIB-4. Automated referral to secondary care is generated for those with ALT ≤30 and FIB-4 >2.67; or ALT >30 and ELF ≥9.8, or FIB4 >3.25, or positive aetiology results. For all enrolled patients, iDiabetesPlus generates comprehensive diabetes and MASLD management recommendations for primary care practitioners and patients, and guidance on the timing of interval FIB-4 testing.
RESULTS
From 28th October 2024–31st December 2025, 4,695 people with T2D enrolled in iDiabetesPlus. Of these 1,954 (41.6%) were female, median age of 68.0 years (range: 18–98), BMI of 31.0 kg/m2, and HbA1c of 58.0 mmol/mol. ALT was ≤30 in 67.5% (n=3,170) and >30 in 32.5% (n=1,524).
99.3% (n=4,662) received successful FIB-4 screening. Most patients (n=3,913; 83.9%) had low-risk FIB-4, with advice to repeat FIB-4 in 2 years (Figure 1). Five hundred and
Figure 1: Schematic of FIB-4 results and categorisation.
4,663 FIB-4
569 (12.2%)
Intermediate FIB-4
181 (3.9%)
ªMissing ELF n=4.
FIB-4 and ELF distribution of screened patients (NAFLD Fibrosis Score not shown here for clarity).
FIB-4 is stratified as: low risk: <1.30 (aged <65 years)/<2.0 (aged ≥65 years); intermediate risk: 1.30-2.67 (aged <65 years)/2.0-2.67 (aged ≥65 years); and high risk: >2.67.
Advice to GP and patient for repeat FIB-4 in 2-3 years (green box). Advice to GP and patient on how to optimise metabolic health and repeat FIB-4 in 1 year (yellow box). Automated referral to secondary care hepatology for further assessment (red box).
ELF: enhanced liver fibrosis; FIB-4: fibrosis-4; GP: general practitioner.
sixty-nine (8.8%) had intermediate risk, with advice on optimising metabolic health and repeating FIB-4 in 12 months.
Of the 250 (5.3%) patients with T2D who received ELF testing, 83 (33.2% of ELF) were <9.8, and 167 (66.8%) had an ELF score ≥9.8. Three hundred and forty-eight (7.4%) patients with T2D were eligible for Fibroscan, with 258 (5.5%) receiving a scan.
One hundred and three patients had a liver stiffness measurement (LSM) ≥10 kPa (2.2% of enrolled patients), and 57 patients had LSM >15 kPa (1.2% of all enrolled patients).
A diagnosis of MASLD was made in 190 (69.6%) patients seen in clinic, metabolic and alcohol related liver disease in 31
(11.4%) and alcohol related liver disease in 1 (0.4%). No liver disease was identified in 42 (15.4%) patients, and other/mixed aetiology liver disease in 9 (3.3%) patients. One new chronic HBV and eight new haemochromatosis diagnoses were identified. Three patients were found to have hepatocellular carcinoma at the time of initial liver assessment. Just over half (n=146; 53.5%) of patients were discharged back to primary care following their index clinic assessment.
CONCLUSION
Automated MASLD screening within the precision iDiabetesPlus platform results in near universal FIB-4 screening in a real-
world primary care T2D population. Over 80% of FIB-4 screening is low-risk, meaning patients can safely be managed in primary care, with automated advice on MASLD management and interval FIB-4 testing generated for clinicians and patients. Targeted ELF testing reduced the need for Fibroscan and secondary care review by almost a third in those tested. The authors identified possible new compensated advanced chronic liver disease (LSM >10 kPa) in 2.2% of all patients screened for T2D. >50% of patients assessed in the clinic were discharged after their initial review.
References
1. Leith D et al. Incorporating an automated MASLD screening algorithm into a primary care precision diabetes care platform (iDiabetes) facilitates universal FIB4 screening, automated linkage to secondary care and identifies new cases of advanced fibrosis & cirrhosis. Abstract TOP-065YI. EASL Congress 2026, 27-30 May 2026.
2. EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunctionassociated steatotic liver disease (MASLD). J Hepatol. 2024;81(3):492-542.
3. Lin Y et al. iDiabetes platform—enhanced phenotyping of patients with diabetes for precision diagnosis, prognosis and treatment: study protocol for a cluster-randomised controlled study in Tayside, Scotland. BMJ Open. 2024;14(11):e086594.
Congress Interviews
In these exclusive interviews from the European Association for the Study of the Live (EASL) Congress 2026, leading hepatology experts reflect on a meeting defined by scientific progress, multidisciplinary collaboration, and a growing focus on translating research into meaningful patient outcomes. They discuss advances across liver disease prevention, diagnosis, and treatment, including developments in precision medicine, MASLD, autoimmune and cholestatic liver diseases, and the role of lifestyle interventions in long-term care. Key themes include earlier disease detection, personalised treatment strategies, patient-centred care, and the importance of collaboration across specialties to address the evolving global burden of liver disease.
Featuring: Sven Francque, Shira Zelber-Sagi, and Sarwa Darwish Murad
Sven Francque
Full Professor of Medicine, Faculty of Medicine and Health Sciences, University of Antwerp; Chairman and Head, Department of Gastroenterology and Hepatology, Antwerp University Hospital (UZA); Head of the Laboratory of Hepatology and Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, Belgium
There has been increasing discussion about whether steatotic liver diseases should be viewed as a spectrum rather than a single disease entity, particularly given metabolic, genetic, and alcoholrelated overlap. Do you think this ‘spectrum’ model better reflects what we see in clinical practice?
Yes, absolutely. I think we should go back a little bit to the pathophysiology of the disease, because this is largely driven by extrahepatic factors. The dysfunctional adipose tissue, mainly, with the release of free fatty acids and a lot of inflammatory mediators, has a huge impact on the liver. The second level or layer of complexities is how well the liver is equipped with machinery to cope with that metabolic and inflammatory stress. So, at both levels, there is a huge heterogeneity among patients. We know that with the same caloric
overload, some people will still be metabolically healthy despite living with obesity. Then there are others with minor degrees of obesity who will be very metabolically unhealthy. So, based on genetic, epigenetic, and environmental factors, you have a huge heterogeneity in the vulnerability of people to the deleterious consequences of caloric overload. But then, on top of that, you have that spectrum of liver vulnerability, and it's that complex constellation that makes the total population of patients with steatotic liver disease notoriously heterogeneous.
You have a huge heterogeneity in the vulnerability of people to the deleterious consequences of caloric overload
Q2
Metabolic dysfunctionassociated steatotic liver disease (MASLD) is increasingly recognised as a multisystem disease with significant metabolic and cardiovascular implications. How has this changed the way hepatologists approach patient care?
Traditionally, hepatologists were focused on the organ and very specific causes of liver damage, these being direct liver toxins like alcohol, viral hepatitis, and autoimmune hepatitis. We also are taking into account that some diseases have extrahepatic manifestations. But MASLD is something that is intrinsically correlated or related to dysfunctional adipose tissue. With the liver being such an important central organ to whole body metabolism, a chronically diseased liver also has an extrahepatic impact, most notably on the cardiovascular system. In MASLD, it's all so closely interconnected that we cannot just see it as a liver problem in isolation, because it’s mainly driven by factors that are coming from outside the liver, and it has important consequences, not just on the liver, but also on the extrahepatic tissue.
To complete our increasing understanding of how this is really happening, we are forced to think outside the liver and take into account both managing the causes of MASLD and the consequences of MASLD. We have to step out of our silo of a purely liver-centric approach. It's also what we have seen with some of the pharmacological approaches: some of them lean heavily towards improving the metabolic milieu that drives the disease, and some of them have very little direct intrahepatic targets, and still, they hugely benefit the liver.
Q3Despite advances in non-invasive testing, identifying patients at the highest risk of progression remains challenging. Where do you believe the biggest diagnostic gaps still exist?
The difficulty is that we need to gain insight into an organ that, beyond biopsy, is not easily accessible for direct assessment. And, as we discussed earlier, the patient population is highly heterogeneous. It is a challenge to get the precise idea about the severity of the disease, because what we can measure in the blood, or what we can measure in terms of imaging characteristics of the liver, is influenced by many factors, and we have been shaped by the liver biopsy to understand this disease and its severity, but of course, we cannot apply the liver biopsy to every potential patient at risk, and we can also not use it for the follow-up of the patient. So, we definitely need tools that help us better characterise the severity across the disease spectrum. We do have some tools that help us in a very rough classification of fibrosis, but fibrosis doesn't tell it all. When people get to more advanced stages of the disease, fibrosis is obviously still an important feature. But processes like the alterations of the vascular structure and function become increasingly important once the disease advances. Also, parenchymal extinction and bad regeneration become more and more important, and those aspects are still very difficult to capture with the tools that we currently have, or it's by very specialised tools that are available in the research context, but not for routine clinical practice. So, thinking in terms of disease, spectrum, and that tipping point where the risk of evolving towards
We're very framed by thinking in terms of cirrhotic versus noncirrhotic, but that's an oversimplification
the compensation and the point where regression of disease becomes less likely, even if you improve on the metabolic causes of the disease, identifying that tipping point in patients is still a big challenge. Because first of all, we don't know exactly where it is. As I said, we're very framed by thinking in terms of cirrhotic versus non-cirrhotic, but that's an oversimplification. So, there's a lack of knowledge and a lack of tools to identify disease.
Another challenge is that many patients initially present in primary care, where clinicians may not specialise in hepatology. How do you determine when these patients should be referred to a hepatologist?
That flow of patients and creating a system that really selects the ones that need to go to a more advanced step in the diagnostic and management framework is a huge challenge. Because the population is so heterogeneous, not every patient with liver steatosis needs to be seen by a highly specialised hepatologist. There needs to be a funnel. I think awareness and knowledge are, of course, one thing, but we still also need to improve the algorithms and the tools that we have to help primary care, but also secondary non-hepatology care to make an adequate diagnosis and have an adequate referral pattern.
We are not yet at the stage of truly personalised medicine in this disease, but a degree of treatment individualisation is certainly necessary
Q4
Given your involvement in clinical trials and consortia in NAFLD/MASLD, how do you see emerging pharmacological therapies being integrated into real-world practice over the next few years?
Well, there are a few challenges. First, there is the science and the results of the clinical trials, but then there's the implementation and how it is picked up in the community. That's a matter of awareness and education, but it's also something that has to do with policy change and reimbursement. So, at the level of regulators and payers, there's still a huge amount of work to be done in terms of education. Sometimes, even the scientific evidence that is generated is questioned. Because this is a very slowly evolving disease, its impact on patient outcomes often only becomes apparent over the long term. And even before they get to compensated liver disease, there's a huge impact on quality of life, although that's more difficult to quantify. But because it's so slowly evolving, and it's so closely interconnected with other conditions like obesity, it's very difficult to make people accept that this is something that needs a particular treatment, because the hard clinical evidence is very difficult to generate. If you really want to demonstrate that a drug has an impact on the long run in terms of mortality or clinical events, you need very long trials, in which you have many intercurrent events. So that's the kind of evidence that is very difficult to generate. As long as
we adhere to the view that the added value of a drug must be demonstrated solely through clinical event outcomes, without accepting surrogate endpoints or real-world evidence, progress will remain challenging.
I can't even imagine what it must have been like for researchers conducting long-term research and then having COVID happen and completely changing the mortality rates in studies. How did they account for that when analysing the data?
Yes, that's extremely challenging. The problem is that we still do not have well-validated surrogate markers. We do not have the equivalent of HbA1c for MASLD, for example. There is a huge unmet need for a marker that can serve, in the short term, as a validated surrogate for long-term clinical benefit.
Q5
There is growing interest in combination therapies for steatotic liver disease. Do you believe combination treatment approaches will become the future standard of care?
Standard of care is probably a little bit too strong a term, although combination therapies certainly make sense. One of the reasons is that, based on the results we have seen so far, we have drugs that are efficacious, but the effect size does not appear to be close to 50%, let alone 100%. That is partly due to the way the endpoints have been defined, because there are benefits beyond those
specific endpoints. However, it also reflects the complex pathophysiology of the disease. Targeting one particular aspect of the pathophysiology may provide meaningful benefit for some patients, but for others, it will not be sufficient. Therefore, the complexity of the disease, together with the fact that treatment outcomes are partly influenced by how success is defined, makes combination therapy a very plausible and attractive concept.
By taking that approach, especially in patients without advanced disease, a large proportion will probably improve, or at least disease progression will be halted. As such, they do not necessarily require combination therapy from the outset. In these patients, the first step should be to optimise all the cardiometabolic drivers and consequences of the disease and then assess the response. If, upon re-evaluation, the liver condition has not improved sufficiently, a second, more liver-targeted therapy could then be added. On the other hand, patients who already have advanced liver disease at presentation, or those whose cardiometabolic comorbidities are relatively well controlled, may be candidates for combination therapy from the start.
So, I think a more granular approach is needed than simply stating that combination therapies are the standard of care. At the very least, treatment needs to be individualised. We are not yet at the stage of truly personalised medicine in this disease, but a degree of treatment individualisation is certainly necessary.
Q6In your experience, what is the most common misconception clinicians still have about disease progression or risk stratification in MASLD?
It is my impression that, for many non-hepatologists and even some people in the hepatology space, there's still that conception that a little bit of liver steatosis or slightly elevated liver enzymes is not that dangerous. There is also that confusion with alcohol consumption. Alcohol and metabolic risk factors are frequently present together; it is easy to say drink a little less alcohol, lose a little weight, and that will solve the problem. The consequence of that attitude is that, even if most patients do not have advanced liver disease or have little risk of progressing to liver disease, it neglects the fraction of patients that do have advanced liver disease. At the very least, clinicians should
keep in mind the possibility that this may be more than just a little liver fat. The basic attitude should be, I should investigate this with a multi-tier approach. I should not minimise it; I should investigate. Moreover, even if there is just liver fat, it means that the patient is metabolically unhealthy. While this may not necessarily represent severe liver disease, it is nonetheless a condition of metabolic ill health that requires further investigation and appropriate management.
Do you think some of these misconceptions stem from the common belief that the liver can regenerate? Could that create a false sense of reassurance, leading clinicians or patients to delay action and simply reassess the situation a few months later?
It's an interesting point; it's true that compared to others, the liver is quite a robust organ with a
huge regenerative capacity. That's probably one of the reasons why the consequences of the disease, in most of the patients, tend to appear rather late in life, even though the disease itself often develops much earlier. It's important to emphasise that this is not the case for everybody. Although the liver is probably better equipped than many other organs and has more defence and regeneration capacity than many other organs, there’s still a huge difference in heterogeneity between people.
The capacity of the liver to cope with metabolic inflammatory stress might be, on average, better than the kidney or the heart, but it's still not perfect. So, neglecting that and ignoring that is one of the main reasons why people, in the end, still develop these deleterious consequences that could be prevented if tackled earlier.
What we also tend to forget is that the risk of Type 2 diabetes substantially increases if you have liver steatosis and steatohepatitis. So, it's not just about the liver; it's also, again, the liver being so central to metabolism. We still tend to think a little too much of the liver being the victim of metabolic syndrome, but it's more than that. It's really a motor of vicious circles, and it's very central to the pathophysiology of the consequences of metabolic syndrome, not just the victim.
Q7
As EASL 2026 comes to a close, which developments in advanced liver disease management have stood out to you most this year, and how might they shape clinical practice over the next decade?
Well, one of the added values of this Congress is that you get the newest scientific progress presented, and there were some interesting things about, for example, the refinement of the use of tips or data on treatments based on the use of albumin, so
We still tend to think a little too much of the liver being the victim of metabolic syndrome, but it's more than that
that's the cutting edge in terms of scientific novelties. But, of course, many of them will not immediately transform clinical practice because we need to generate more evidence, and it needs to be reviewed. So, one of the added values of a Congress like this is that it's also the place where we discuss the newest consensuses and guidelines. We also had the results of the Baveno VIII update on the treatment of portal hypertension presented. This is really transformative because it is shaping clinical practice throughout the globe. Another thing was the preconference session on the definition of acute-on-chronic liver failure.
These kinds of processes about guidelines, as well as consensus on definitions and nomenclature
from a worldwide perspective rather than just an isolated European one, are very important because they have a direct impact on daily clinical practice and on research. They help to harmonise research efforts. In that regard, I think those were two important highlights of the Congress. Another highlight was also the consensus on porto-sinusoidal vascular disorder, an important cause of portal hypertension. Again, this was a worldwide effort, not just an EASL effort, for which the conclusions were presented at Baveno VIII a few weeks ago, and also during this Congress, and were also published to coincide with the Congress.
Shira Zelber-Sagi
Professor of Nutrition and Epidemiology, School of Public Health, University of Haifa, Israel; Public Health Councillor, European Association for the Study of the Liver (EASL)
Lifestyle modification remains the cornerstone of metabolic dysfunctionassociated steatotic liver disease (MASLD) management, yet long-term patient adherence remains notoriously difficult. Why do conventional lifestyle interventions often fail in realworld practice?
Changing habits is difficult because these behaviours are established over decades, often from childhood. Weight loss is particularly challenging because the body actively resists it. When calorie intake falls, energy expenditure decreases as well, making sustained weight reduction difficult to achieve and even harder to maintain.
Many patients become discouraged when they encounter setbacks. It is therefore important to set realistic expectations from the outset and explain that periods of slower progress or temporary weight gain are a normal part of the process.
Q2
Given the limited time available during a standard consultation, what dietary advice should clinicians prioritise for patients newly diagnosed with MASLD?
Even brief consultations can be impactful. Many patients are unaware that liver disease is reversible in its earlier stages up to the stage of advanced liver scarring. Clinicians should use every encounter to emphasise that improving diet, increasing physical activity, reducing alcohol intake, and achieving modest weight loss can halt or even reverse disease progression.
I often recommend using the 5A model: ask permission to discuss lifestyle, assess current habits with open questions and without judgment, advise on changes, agree on realistic goals, and assist with follow-up and overcoming barriers.
We need to move away from putting all the responsibility on the individuals and recognise that behaviour is heavily shaped by factors beyond personal choice
Another challenge is the environment people live in. Obesity and liver disease are often described as self-inflicted conditions, but that overlooks the influence of food environments, marketing, and commercial determinants of health. We need to move away from putting all the responsibility on the individuals and recognise that behaviour is heavily shaped by factors beyond personal choice.
Lifestyle treatment is a lifelong process rather than a shortterm intervention. Patients need ongoing support, realistic goals, and regular follow-up if long-term success is to be achieved.
Importantly, I do not focus solely on weight loss. Small, achievable dietary changes can have a meaningful impact. Replacing sugar-sweetened beverages with water, for example, can significantly benefit liver health.
Positive reinforcement is equally important. Patients should be recognised for progress, however small, because building confidence and self-efficacy is essential for long-term behaviour change.
Q3 Intermittent fasting has become increasingly popular among patients. What does the evidence currently show?
Intermittent fasting has attracted considerable interest because of
its potential metabolic benefits. Randomised clinical trials suggest that when calorie reduction and weight loss are comparable, intermittent fasting performs similarly to conventional healthy dietary approaches in reducing liver fat and markers of liver scarring (fibrosis).
In other words, intermittent fasting is not necessarily superior, but it is an effective option for many patients. One of its advantages may be behavioural rather than physiological. Restricting eating windows can help reduce evening snacking and emotional eating, which are major contributors to excess calorie intake, especially coming from unhealthy foods we tend to eat at night in front of screens.
For patients who find it convenient and sustainable, intermittent fasting can be a useful tool. However, it is not suitable for everyone. Patients with cirrhosis or advanced liver disease should avoid prolonged fasting because it can accelerate muscle loss and worsen nutritional status.
Q4
You have long advocated for structural public health approaches alongside individual lifestyle interventions. Which policy measures could have the greatest impact on reducing liver disease burden?
Although direct evidence linking individual policies to reductions in MASLD prevalence remains limited, modelling studies suggest that population-level interventions could substantially reduce liver disease burden, liver cancer, and liver-related mortality.
Among the most promising measures are taxation of sugar-sweetened beverages and alcohol, warning labels on
harmful products, and restrictions on unhealthy food marketing. However, a combination of several approaches would have a greater impact. Healthy foods must also become more affordable and accessible. Taxation should be accompanied by subsidies for healthier options, alongside public education and awareness campaigns.
Education is particularly important because prevention starts early. Children who learn about nutrition and liver health often bring those messages home, influencing entire families. Integrating liver health into school curricula could therefore become an important preventive strategy.
Q5 With the rapid emergence of glucagon-like peptide-1 (GLP1) receptor agonists and other pharmacological therapies for metabolic dysfunction-associated steatohepatitis, what role will lifestyle medicine continue to play?
Lifestyle medicine will remain fundamental. These medications are highly effective, but they do not replace healthy eating and physical activity.
The benefits of lifestyle interventions extend far beyond weight reduction. They improve cardiovascular health, reduce cancer risk, enhance mental wellbeing, and improve quality of life. Those benefits cannot be replicated by medication alone.
In fact, nutritional support becomes even more important when patients receive weight-loss medications. Rapid weight loss can increase the risk of muscle loss, nutritional deficiencies, and gastrointestinal side effects. Dietitians therefore have a
crucial role in supporting patients receiving pharmacological treatment.
The future is not lifestyle medicine versus medication. It is the combination of both.
Q6
Looking ahead 5–10 years, how do you expect MASLD management to evolve?
I hope we will see much greater recognition of prevention and nutrition within healthcare systems. Access to dietitians should become routine, particularly for patients with obesity, Type 2 diabetes, and liver disease.
I also expect digital tools, mobile applications, and AI to play a larger role in supporting behavioural change and providing ongoing patient support between in-person professional consultations.
Pharmacological therapies will undoubtedly become more common, but long-term success will still depend on helping patients adopt sustainable lifestyle changes. The greatest opportunity remains prevention: improving nutrition, increasing physical activity, reducing alcohol consumption, and creating environments that make healthy choices easier.
Many patients are unaware that liver disease is reversible in its earlier stages up to the stage of advanced liver scarring
Sarwa Darwish Murad
Gastroenterologist and Hepatologist; Medical Director of the Liver Transplantation Program, Erasmus MC University Medical Center, Rotterdam, the Netherlands
In the Western world, around one in three people in the general population has some degree of steatosis
Q1MASLD is rapidly becoming one of the leading causes of chronic liver disease worldwide. Which trends in patient presentation or disease progression are you currently seeing most often in clinical practice?
The main trend is exactly what we have all been discussing over recent years: MASLD is becoming increasingly prevalent. We already know that, in the Western world, around one in three people in the general population has some degree of steatosis, largely driven by the obesity epidemic.
What we are seeing clinically is growing awareness of MASLD as a disease entity, alongside increasing prevalence. We also increasingly recognise it as a cofactor in many other liver diseases. Patients may present with a classical liver condition, but concurrent metabolic dysfunction and steatosis significantly affect outcomes as well.
One of the major challenges remains identifying which patients actually require referral from primary care. If one-third of the population has steatosis, we clearly cannot refer everybody. The difficulty lies in identifying those patients at highest risk of progressing to fibrosis, cirrhosis, and liver-related complications.
There is still considerable uncertainty within primary care regarding whom to refer, when referral is appropriate, and how to stratify high-risk candidates. We now have several non-invasive tools that can help, which is extremely valuable, but there is still a very large pool of patients
who require assessment before determining whether specialist hepatology input is needed.
From a transplant hepatology perspective, we are also seeing a much more complex patient population. Patients increasingly present with multiple comorbidities that we did not routinely encounter previously, which means hepatologists also need broader expertise in managing metabolic and cardiovascular complications, both before and after transplant.
Another important point is that, as with many chronic liver diseases, MASLD often presents late. Patients frequently only seek medical attention once they develop complications of cirrhosis, such as jaundice, ascites or other advanced manifestations.
Do you think there are still major barriers to early detection and referral?
We actually have very strong guidelines now. A major multidisciplinary guideline was recently developed involving not only hepatology societies, but also endocrinology and obesity societies, reflecting the fact that MASLD is truly a multisystem disease.
The issue is less about a lack of guidance and more about identifying the right patients. Again, if one in three people in the community has steatosis, the key challenge is finding those individuals at genuine risk of progression to advanced liver disease. That is where the real struggle lies.
There are also important differences between healthcare systems. In some parts of the world, primary care infrastructure is less well established, meaning patients may not even know they have diabetes, hypertension, or other metabolic risk factors.
Screening is another major topic of discussion. We recently saw important data from the large international Liverscreen consortium, which evaluated risk factors, prevalence, and disease progression across multiple countries and healthcare systems. These types of studies are helping us move towards more formalised screening strategies.
However, before implementing a true screening programme, several things need to be in place. First, you need to identify not simply the disease itself, but the patients at highest risk of clinically significant disease. Second, you must have something meaningful to offer once the disease is detected.
To use an analogy, there is little value in screening for lung cancer if no treatment options exist. Until recently, we did not have approved therapies specifically targeting MASLD and metabolic dysfunction-associated steatohepatitis. Only within the past few years have treatment options started to emerge.
What we have largely been doing so far is case finding: identifying higher-risk patients within the community who may benefit from referral to hepatology clinics. I think formal screening pathways will continue to evolve as therapeutic options expand.
One of the greatest long-term challenges is balancing immunosuppression
Q2Liver transplantation remains one of the most complex areas of medicine. What are the greatest challenges in long-term transplant management?
Liver transplantation is uniquely complex, both anatomically and physiologically. Unlike kidney disease, for example, we do not have an equivalent of dialysis for liver failure. We cannot simply place patients on a machine indefinitely while awaiting transplantation.
One of the greatest longterm challenges is balancing immunosuppression. On one hand, immunosuppression is essential to prevent graft rejection and preserve the transplanted liver. On the other hand, these therapies come with substantial risks, including infection, diabetes, obesity, kidney disease, metabolic syndrome, and malignancy.
The risk of malignancy in transplant recipients is several times higher than in the general population. Interestingly, when we examine causes of death following transplantation, many are no longer liver related. Cardiovascular disease, stroke, and cancer are major contributors. In part, these complications are consequences of the treatments we use.
Another major challenge is organ shortage, which has existed for as long as transplantation itself. Despite substantial efforts to increase organ donation rates and expand living donation programmes, globally we still only
provide transplantation to a small proportion of potentially eligible patients.
At the same time, the donor pool itself is changing. The general population is ageing and becoming increasingly affected by obesity and metabolic disease. As a result, donor organs are also increasingly affected by steatosis and other comorbidities.
We therefore face a difficult balance: increasing the number of usable organs often means accepting higher-risk or poorerquality grafts while if we wait only for ideal organs, more patients would die waiting.
What are the recurrence rates of primary liver disease following transplantation?
It depends heavily on the underlying disease. Autoimmune liver diseases such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis generally recur in approximately 10–20% of cases, depending on the type and cohort studied.
Historically, hepatitis C recurrence after transplantation was almost universal, but thankfully that has changed dramatically with modern antiviral therapies. Hepatitis B recurrence risk is also now relatively low because of effective suppression strategies.
We are now increasingly seeing recurrence of MASLD and steatosis following transplantation, as well as de novo steatosis developing post-
transplant. Immunosuppressive therapies themselves often contribute to weight gain and worsening metabolic health.
Q3 There is increasing discussion around expanding donor criteria. What developments are currently shaping this area?
One major area is increasing use of donation after circulatory death (DCD). In many countries, such as the Netherlands and the UK, DCD transplantation now represents a substantial proportion of liver transplants.
These grafts do come with increased risks, particularly biliary complications related to ischaemia reperfusion injury, which can result in development of difficult-totreat strictures in the biliary tree. However, many healthcare systems simply could not meet transplant demand without DCD organs.
The good news is that this increasing gap between the need for high quality donor organs on the one hand and its availability on the other, has fuelled technological innovations to generate more donors or find ways to better utilise the current donor pool.
One of these innovations is machine perfusion, which has undergone a very rapid evolution from conception to implementation and is now common clinical practice in many countries. With machine perfusion, we are now able to mitigate some of the ischaemia reperfusion injury to the graft as well have created a tool to test the viability of the organ before implantation. This has revolutionised the field, and its potential use continues to be explored further as we move forward.
As a rule, as a transplant community, we are constantly exploring whether organs previously considered unsuitable might still safely benefit selected patients.
Q4 In your experience, what misconceptions do clinicians still have about advanced liver disease or transplant candidacy?
Outside hepatology, one persistent misconception remains: many people still assume all liver disease is alcohol-related, which is clearly inaccurate and often harmful for patients.
Within transplantation specifically, the field has evolved enormously over the past 10–15 years, with major expansion of indications and reconsideration of previous contraindications.
For example, non-liver malignancy was historically viewed as a major contraindication, often requiring a 5-year cancer-free interval before transplantation could even be considered. We now have far more nuanced guidance depending on tumour type and prognosis.
Similarly, older age, obesity, sarcopenia, and frailty were once considered near-absolute contraindications. Today, many centres transplant selected patients well into their 70s, provided they remain biologically fit. High BMI alone is no longer an
Many people still assume all liver disease is alcoholrelated, which is clearly inaccurate and often harmful for patients
automatic exclusion either, and some centres have adopted to offer such patients a combined simultaneous bariatric gastric sleeve during the liver transplantation.
The problem is that clinicians outside transplant centres may still apply outdated assumptions and therefore be reluctant to refer patients for assessment. In reality, every patient presenting with decompensated cirrhosis should prompt the responsible physician to at least once consider a liver transplantation, even if only through discussion with a transplant centre.
Unfortunately, we still see many patients referred either too late or not at all. Ideally, referral should occur while patients remain relatively fit and before severe sarcopenia or advanced frailty develops, because outcomes are significantly better at that stage.
Q5Looking ahead, which advances in transplantology are most likely to move into routine clinical practice over the next 5–10 years?
Machine perfusion is one of the most exciting developments and is rapidly becoming standard of care, particularly for higher-risk donor organs such as DCD grafts.
Different perfusion strategies, including normothermic and hypothermic perfusion, are being refined, and over the coming years we will better understand which approaches are optimal for specific donor and recipient scenarios.
An especially important aspect is viability testing. Rather than relying purely on visual assessment of a donor liver, machine perfusion allows us to objectively evaluate organ function prior to transplantation.
Longer-duration perfusion also creates opportunities for therapeutic intervention. Studies are already exploring ‘defattening’ therapies delivered directly to steatotic donor livers while on the pump, with the aim of improving graft quality before transplantation. These developments could substantially expand treatment options in the future.
Beyond this, bioengineering and xenotransplantation are developing rapidly. While we are unlikely to see scalable bioartificial organs within the next 5 years, these technologies are advancing our understanding and may eventually transform the field.
We are also beginning to explore the concept of using xenografts, such as pig livers, extracorporeally as biological support devices,
Machine perfusion is one of the most exciting developments and is rapidly becoming standard of care, particularly for higher-risk donor organs such as DCD grafts
somewhat analogous to dialysis systems.
Ultimately, these innovations are urgently needed. As MASLD continues to rise globally, transplant waiting lists will continue to grow. We must both expand organ utilisation by innovation and at the same time to our best to improve donation systems.
Spain provides an excellent example of this. Their success has not simply been legislative; it reflects optimisation of the entire donation system and a societal and medical mindset in which organ donation is viewed as the norm rather than the exception. There is a great deal that other countries can learn from that approach.
Optimising Hepatitis B Prophylaxis After Liver Transplantation: Combination Therapy and the HBV/HCC Connection
Interviewee:
Patrizia Burra1
1. Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Italy
Support: The publication of this article was funded by Biotest.
Disclosure: Burra has acted as a consultant for Biotest, Kedrion, Sandoz, Chiesi Farmaceutici, GSK, Novo Nordisk, and Ipsen.
Acknowledgements: Medical writing assistance was provided by Amanda Barrell, freelance medical writer, Brighton, UK.
Disclaimer: The opinion expressed in this article belongs solely to the named interviewee. The content of the article was authored independently and does not necessarily reflect the opinions of Biotest.
Keywords: Combination prophylaxis, hepatitis B Ig (HBIG), hepatitis B surface antigen (HBsAg), hepatitis B virus (HBV), hepatitis B virus recurrence, hepatitis D virus (HDV), hepatocellular carcinoma (HCC), liver transplantation, nucleos(t)ide analogues (NUC), risk stratification.
Chronic hepatitis B virus (HBV) affects nearly 300 million people worldwide and is a major cause of cirrhosis and hepatocellular carcinoma (HCC). Although nucleos(t)ide analogues (NUC) effectively suppress viral replication, they rarely achieve cure, leaving liver transplantation as the only definitive option for patients with end-stage disease. Historically, HBV was considered an indication of high risk for liver transplant because of high recurrence rates and poor survival. The introduction of combination prophylaxis with hepatitis B Ig (HBIG) and third-generation NUCs has transformed this outlook, reducing recurrence to below 10% and achieving survival rates comparable to those of non-HBV transplant recipients.
Recent studies have proposed to withdraw HBIG and maintain NUC monotherapy as a potential alternative to ongoing combination prophylaxis. However, uncertainty remains regarding risk stratification, particularly in the growing population transplanted with HCC. Evidence increasingly suggests a close relationship between HBV recurrence and HCC recurrence. Though the causal direction remains to be seen, Patrizia Burra, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Italy, argues that the association alone is strong enough to justify a precautionary approach, and advocates for lifelong combination prophylaxis in patients transplanted for HCC.
PHARMA
PARTNERSHIP
INTRODUCTION
Chronic HBV, which affects almost 300 million people globally, can lead to severe complications, including liver cirrhosis and HCC.1 As such, it is a major cause of morbidity and mortality. While current NUC-based treatments can decrease viral load, they are curative in fewer than 5% of cases. Liver transplant is the only curative treatment for decompensated chronic HBV cirrhosis, with or without HCC.1
Historically, however, chronic HBV was a contraindication to liver transplant.1 This was due to the high risk of infection recurrence, leading to recurrent cirrhosis, graft losses, and a 5-year survival rate of just 40%.1,2 The introduction of prophylaxis regimens has transformed this picture. First, HBIG reduced the reinfection rate from around 80%3 to between 19–35%.4,5 Next, the introduction of NUCs and combination therapy further reduced the rate to approximately 10%.2 As such, graft and patient survival rates are now comparable to those of patients who undergo liver transplant for aetiologies other than HBV.5 HBV recurrence, defined by hepatitis B surface antigen (HBsAg) positivity in the serum, is less than 10%, and HBIG+NUC prophylaxis is recommended by most international liver societies.1 As such, the 10-year survival rate for patients undergoing liver transplantation for chronic HBV infection in Europe is now up to 80%.6
Some studies have suggested that NUC monotherapy might be a safe and effective option for low-risk patients transplanted for HBV, with and without HCC.1,7,8 However, these studies included mostly patients from Asia, with HBV and host-related factors for recurrence that may be different to those in Europe.5 In addition, there has been a significant shift in indications for liver transplant: HCC cases have been increasing, while those of decompensated cirrhosis have been decreasing.5
Understanding the optimal prophylaxis regimen for this group of patients is of paramount importance, according to Burra. “If you offer a treatment to a patient, it should be effective and safe in order to reduce the risk related to the reinfection of
the graft. It should give them the possibility to survive with a good quality of life and avoid medical complications, such as recurrence of the original disease,” she said.
HIGH VERSUS LOW RISK AND THE ROLE OF HCC
The question of optimal prophylaxis regimes is particularly pertinent in high-risk patients. Yet, the distinction between high and low risk is “not exactly black and white,” explained Burra. "We are pretty sure about the low-risk patients, but the contrary is not always so clear," she said. She noted that low-risk patients are generally those with undetectable HBV DNA at the time of transplant and a good response to antiviral therapy. Whereas patients with ongoing viral activity at the time of transplant, as well as those with poor medication compliance, are considered at higher risk.1,6 In addition, she went on, hepatitis D virus (HDV) coinfection increases the risk of advanced liver disease, HCC, and liver decompensation by two to three times, compared with HBV infection alone.5,6
What is still under discussion is the presence of HCC as an additional risk factor. Some centres, Burra explained, may withdraw combination prophylaxis in patients deemed to be at low risk.6 In her opinion, this may not be the best course of action in those transplanted for HCC because, while the research is still unsure on whether the HBV recurrence triggers the HCC recurrence (or vice versa), the association is clear.
A 2008 retrospective study stratified 99 patients who were HBsAg positive according to transplantation for cirrhosis, either with or without HCC. It found that patients with HCC at the time of transplant were more likely to experience HCC recurrence than those who did not, and that HBV recurrence was more common in patients who experienced HCC recurrence.9 There are two schools of thought on “which comes first,” explained Burra. One is, she went on, that residual HCC tumour cells contain HBV DNA, which can expand and replicate independently,
leading to both HBV and HCC recurrence, while the other is that residual HBV DNA or HBsAg cells produced by other non-tumour cells drive the reactivation of HBV, leading to HCC recurrence.9,10
“The best evidence we have so far demonstrates that, despite everything we do (combination prophylaxis), the presence of covalently closed circular DNA (cccDNA) in the liver means we still have the risk of recurrence,” Burra went on.1 “If we can avoid the recurrence of hepatitis, and possibly avoid the recurrence of HCC… why would we take the risk of lowering the power of the prophylaxis? My personal opinion is that it is safer to maintain the combination of immunoglobulins plus the NUCs, to avoid the recurrence of both HBV and HCC.”
HBV AND HCC: FURTHERING THE EVIDENCE BASE
Burra’s belief has been strengthened by the results of her latest study, which was published in March 2025.5 The first nationwide retrospective study assessing results of liver transplant for patients with HBV in Italy, it assessed current practices for infection recurrence prophylaxis in the country, evaluating rates, risk factors, and the clinical impact of HBV and HCC recurrence. A total of 20 transplant centres took part, and 1,205 patients who underwent liver transplant following decompensation of cirrhosis (472 without HCC and 733 with HCC) between 2010–2021 were included. All were over the age of 18 years, and the median follow-up time post-transplant was 55 (27–93) months.5
In total, 99.8% of those without HCC and 99.7% of those with HCC received HBIG+NUC prophylaxis.5 Of these, 83% of those without HCC and 84% of those with HCC were on long-life prophylaxis. Recurrence, which the study defined as HBsAg positivity and/or detectable HBV DNA in patients who previously achieved HBsAg negative status, was seen in 2.1% of those without HCC, and 3.1% of those with HCC. There was a “significantly lower rate of recurrence” in those receiving life-long HBIG+NUCs than those in which HBIGs
were withdrawn, in those who received HBIGs only at transplantation, and in those who received NUCs alone (1.3% versus 8.6% versus 4.5% versus 5.9%, respectively; p=0.047), though Burra acknowledged that “few cases experienced withdrawal of immunoglobulins.” Importantly, in those patients transplanted for decompensated cirrhosis without HCC, HBV recurrence was not associated with worse survival. In those transplanted with HCC, HBV recurrence was independently associated with HCC recurrence. “Therefore, 5-year survival was lower in this group than in those who did not experience HCC recurrence (32.5% versus 92.4%; p=<0.001),”5 said Burra. “This is why I am still convinced that we have to avoid the recurrence of HBV: it is associated with the recurrence of HCC, which is associated with worse outcomes.”
THE CHALLENGE OF IDENTIFYING LOW-RISK PATIENTS
Burra described the process of identifying which patients are truly at low risk of HBV recurrence after liver transplantation. “You need to identify the patient at low risk and then perform the follow-up in order to make sure all the estimations you made at the beginning are still the same,” she said. Considerations include viral load and antiviral therapy before liver transplantation, as well as compliance with both HBV prophylaxis and immunosuppressive therapy post-surgery.1,6 Another key concern is HDV, a documented risk factor that not all centres routinely screen for, said Burra.5,6 While it may be less common in some regions, failure to test means clinicians lack an understanding of the risk profile. “If you don’t think of it, you don’t look for it,” she said. Comorbidities can further complicate patient selection.6 “It is very rare that you have the perfect patient. They may be overweight, obese, or have experience of metabolic syndrome, with diabetes or arterial hypertension.” All these factors, she added, must be incorporated into the overall risk assessment.
While it is possible to personalise prophylactic regimens, Burra cautioned this was rarely feasible at the level of the
individual patient. As a result, she said she would “always stay in the safe part of management,” meaning combination prophylaxis with HBIG+NUC, even in the face of perceived cost pressures. The introduction of alternatives to intravenous administration of HBIG, such as subcutaneous and intramuscular, have contributed to a reduction in costs, in part due to lower use of resources, including infusion clinics and dose reductions, she explained.11,12 Burra went on to talk about how the data suggest that the cost impact of Igs is relatively modest. A 2024 Italian study, for example, reported that lifelong HBIG prophylaxis was associated with a 6.6% increase in overall transplant costs,13 which Burra described as “not too impressive.” That said, the choice of administration route should be based on patient preference rather than price, Burra pointed out.
THE IMPORTANCE OF SPECIALIST FOLLOW-UP
Despite advances in prophylaxis, Burra emphasised that long-term outcomes depend on structured, expert follow-up.
“The important thing is having a dedicated outpatient team to follow up these patients,” she said, particularly highlighting those
References
1. Villeret F et al. Early intrahepatic recurrence of HBV infection in liver transplant recipients despite antiviral prophylaxis. JHEP Rep. 2023;5(6):100728.
2. Muhammad H et al. HBV/ HDV management after liver transplantation: review. J Liver Transpl. 2021;4:100046.
3. Terrault NA et al. Prophylaxis in liver transplant recipients using a fixed dosing schedule of hepatitis B immunoglobulin. Hepatol. 1996;24(6):1327-33.
4. Samuel D et al. Liver transplantation in European patients with the hepatitis B surface antigen. N Engl J Med. 1993;329(25):1842-7.
5. Burra P et al. Liver transplantation for HBV-related liver disease: impact of prophylaxis for HBV
with HBV, HDV, and HCC. Burra noted that monitoring treatment and prophylaxis response, using anti-HBsAg levels, was essential to understanding disease activity and therapeutic efficacy. “You can have the best prophylaxis in the world but, if you release the patient who has that extra indication of HCC, they will experience recurrence and they will die, regardless of the recurrence of HBV.”
CONCLUSION
HBIG+NUC combination prophylaxis has changed the landscape of HBV-related endstage liver disease treatment.1,2 However, debate continues over whether some patients could be safely managed with NUC monotherapy, either from the point of transplant or following post-transplant HBIG withdrawal. According to Burra, the close relationship between HBV recurrence and HCC recurrence adds complexity to this argument. While studies demonstrate a clear association exists, it remains uncertain which condition drives the other.7 As such, she advocates for a precautionary approach, in which patients transplanted for HCC receive lifelong combination prophylaxis, rather than stepping down to monotherapy.
on HCC recurrence. JHEP Rep. 2025;7(3):101278.
6. Cornberg M et al. EASL clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2025;8(2):502-83.
7. Cholongitas E, Papatheodoridis GV. High genetic barrier nucleos(t)ide analogue (s) for prophylaxis from hepatitis B virus recurrence after liver transplantation: a systematic review. A Transplant. 2013;13(2):353-62.
8. Fung J et al. Oral nucleoside/ nucleotide analogs without hepatitis B immune globulin after liver transplantation for hepatitis B. Am J Gastroenterol. 2013;108(6):942-8.
9. Faria LC et al. Hepatocellular carcinoma is associated with an increased risk of hepatitis B virus recurrence after liver transplantation. Gastroenterology. 2008;134(7):1890-9.
10. Schemmer P et al. State of the art treatment of hepatitis B virus hepatocellular carcinoma and the role of hepatitis B surface antigen post‐liver transplantation and resection. Liver Int. 2022;42(2):288-98.
11. Lebray P et al. Subcutaneous immunoprophylaxis as a cost-effective treatment alternative for hepatitis B virus-related transplant patients in France. Value Health. 2017;20(9):A783.
12. Hulstaert E et al. Intramuscular hepatitis B immunoglobulins for reinfection control after liver transplantation: a cost-saving alternative. J Comp Eff Res. 2015;4(3):259-65.
13. Marzano A et al. Estimation of lifetime costs for patients receiving a transplant: the case of liver transplantation related to hepatitis B in Italy. Front Public Health. 2024;12:1328782.
Improving Disease Management in Primary Biliary Cholangitis
Interviewees: Emma Culver,1 David Jones2,3
1. Department of Hepatology, John Radcliffe Hospital, Oxford, UK
2. Department of Hepatology, Freeman Hospital, Newcastle, UK
3. Newcastle University, UK
Support: The publication of this article was funded by Ipsen who were involved in its creation and development.
Disclosure: Culver has participated in advisory boards for Amgen, Zenus, Sanofi, GSK, Mirum, and Dr Falk; has received research support from NIHR BRC Oxford; consulting fees from Ipsen, Mirum, Intercept, GSK, Amgen, Zenus, Sanofi, Acepodia, Sail Biopharma, and Dr Falk; and payments or honoraria for lectures from Gilead, Ipsen, Mirum, GSK, Amgen, Zenus, and Dr Falk.
Jones has received honoraria, consultation fees, and speaker fees from Advanz, CymaBay, Falk, GSK, Intercept, IPSEN, and Umecrine; and grant support from Intercept.
Disclaimer: The opinions expressed in this article belong solely to the named interviewees.
Acknowledgements: Medical writing assistance was provided by Caroline E. Cross, Reading, UK.
Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease that can progress from persistent inflammation to intrahepatic ductopenia, fibrosis, and ultimately end-stage biliary cirrhosis if inadequately treated. Although many patients are asymptomatic at diagnosis, fatigue and pruritus frequently develop and can severely impact quality of life, irrespective of disease stage. Diagnosis relies on cholestatic liver enzyme patterns, particularly raised alkaline phosphatase (ALP), alongside antimitochondrial antibodies (AMA). Failure to normalise ALP and bilirubin correlates with ongoing inflammation and future liver-related complications. While ursodeoxycholic acid (UDCA) remains the established first-line therapy, around 40% of patients show an inadequate biochemical response, leaving patients at continued risk of progression. EMJ spoke to PBC experts Emma Culver, Department of Hepatology, John Radcliffe Hospital, Oxford, UK; and David Jones, Department of Hepatology, Freeman Hospital, Newcastle, UK, who emphasise that optimal outcomes depend on timely access to second-line therapies, targeted symptom management, and a broader clinical appreciation of the disease’s full impact. They highlight that normalising biochemical markers, addressing symptoms proactively, and intervening early are key to preventing disease progression and improving patients' quality of life.
PARTNERSHIP
INTRODUCTION
PBC is a chronic inflammatory autoimmune cholestatic liver disease, affecting approximately 0.33–5.80 in 100,000 people, predominantly females over 40 years old.1 If left untreated, the disease can progress to intrahepatic ductopenia and end-stage biliary cirrhosis.2 PBC is diagnosed through a combination of cholestatic liver enzyme patterns and the presence of AMAs, with either non-invasive fibroscan or a liver biopsy used to confirm diagnosis and stage the disease.2 Raised serum ALP (>1.67×ULN) indicates the current activity of the disease, whilst raised TB (>1.0×ULN) and an elevated liver stiffness measurement (LSM) are markers of disease progression towards liver cirrhosis and end-stage liver disease.2 Patients may be asymptomatic at diagnosis, but debilitating symptoms, including fatigue and pruritus, are common and can develop over time, independently of the extent of disease.3 While first-line therapy with UDCA (13–15 mg/kg) is well established,2 in approximately 40% of patients it is not sufficiently effective, and further intervention through second-line treatments and symptom management is needed to normalise biochemical markers, prevent disease progression, and improve patient quality of life.4-6 Recent studies to explore the pathogenesis of PBC disease demonstrate that chronic inflammation and subsequent destruction of intrahepatic bile ducts can accompany liver cirrhosis in PBC.7 In addition, inflammation can persist even when a biochemical response to first-line treatment is evident, indicating an ongoing risk of disease progression.4 EMJ spoke to two PBC experts, Culver and Jones, who shared their expertise on how best to manage PBC. They highlighted the need for a wider understanding of the full impact of disease on individuals and how physicians might improve patient care with timely access to second-line treatments, with the aim of normalising biochemical markers and managing symptoms to help prevent disease progression and improve quality of life.
UNDERSTANDING THE FULL SPECTRUM OF PBC
According to Jones, there is no such thing as a ‘typical’ patient with PBC. In rare cases, patients present with advanced PBC-related cirrhosis, jaundice, and complications such as variceal bleeds. However, both Culver and Jones said that in their clinical experience, most PBC cases are identified at an earlier disease stage, when blood tests show abnormal liver function, such as raised ALP and TB, and/or autoantibodies that may indicate autoimmune liver disease.2
Another group of patients present with symptoms of severe fatigue or pruritus (itch). Culver elaborated that the impact of the disease on patients can be significant: “It can affect people physically, emotionally, and socially.” In Culver’s clinical experience, around 80% of patients with PBC seen in clinic describe fatigue, and this can be independent of disease severity. “Fatigue can manifest centrally as brain fog, difficulty concentrating, memory impairment, or more peripherally, with muscle weakness,” Culver added. "Fatigue often occurs independently of pruritus." Clinically significant pruritus affects at least a third of patients with PBC, and the itch can be severe, negatively impacting sleep and mood, leading to anxiety and depression, Jones explained. Culver added that dry eyes and mouth (sicca complex) are also common, and in women, who may also be experiencing menopause, symptoms can include vaginal dryness and issues with sexual health.8
Although PBC is typically diagnosed in individuals between 40–60 years old, Jones said that as awareness grows, age at diagnosis is decreasing. “It is critical to look carefully at younger patients, because if they have PBC, they tend to have worse symptoms than older patients, and they may have more aggressive disease.”
Furthermore, Jones outlined, “the burden of disease and its impacts are greater in younger people because symptoms such as fatigue can have a greater impact on lifestyle than for older people who may not have the same caring responsibilities or work ambitions.” Culver concurred and added that all patients with PBC are “living
with a rare, chronic autoimmune condition for which there is no cure, and although there are treatments to slow disease progression and help with symptoms, we often underestimate the concern and anxiety that a chronic condition can cause.”
Jones went on to explain that “it’s now clear there is a divergence between people who are at high risk of progression to more severe liver disease, and those where the disease processes are causing symptoms such as fatigue,"9 adding that "if we can treat earlier with better treatment, we can stop that divergence and prevent people developing profound symptoms that impact quality of life.”
TREATING PBC: BEYOND FIRST-LINE TREATMENT
Current treatment guidelines for PBC2 take a step-up approach, with first-line therapy for all patients with PBC being UDCA at a weight-optimised dose of 13–15 mg/kg. “We explain to patients that this could be a lifelong medication and is effective in slowing disease progression and increasing transplant-free survival,”2 Culver explained.
However, at least 40% of people prescribed UDCA do not respond adequately.4 “When there is an inadequate response to UDCA,” explained Jones, “we add in an additional second-line therapy, and we now have three or four therapies that we know are effective in the majority of people.”10 However, Jones continued, there are two problems with this treatment model. “Firstly, the model accepts that a degree of abnormality is okay, because to be a UDCA responder your blood tests can still be abnormal, and those individuals still have some risk of disease progression,”4 Jones emphasised. “The guidelines say that an ALP of 1.67×ULN is okay, but it is not okay.” Jones went on to explain that the second problem with the current model is that it builds in delay. “Currently, we have to wait a year to find out whether the patient responds to the first-line treatment, giving 12 months for the disease to get worse.” The step-up model works best for people with the mildest disease, Jones continued. “I agree, we don’t want to over treat, but I also don’t
want to under treat. If we could intervene early in disease, for those at high risk of progressing, we could change the whole natural history of the disease,” Jones said.
Culver agreed, saying: “We know now that early prediction [of treatment response] is really important. We need to consider risk stratification at an early stage, at diagnosis, to identify patients who will have a higher risk of disease progression. We have evidence that decisions can be made much earlier, at 6 months, or even sooner, rather than waiting for the 12-month time point to assess biochemical response.”4,6
SETTING APPROPRIATE TREATMENT GOALS WITH REGULAR MONITORING
“The conversation about treatment goals starts at diagnosis,” Culver explained. “In my risk stratification process I am thinking about age, biochemistry, liver stiffness measurements, and symptoms. With those in mind, and in discussion with the patient, we agree on the treatment goals.” Jones concurred and said “the combination of fibroscan to assess what injury has happened in the past, and biochemical markers that tell us what injury is happening now that will cause damage in the future, is effective for deciding whether second-line treatment should be introduced.”
Personalising treatment goals is paramount for both Culver and Jones, and as part of this, both experts aim to normalise ALP and TB levels and halt progression of LSM in as many cases as possible. The evidence from the Global PBC study data are clear, said Jones. “The risk of disease increases as ALP increases.”5 In addition, Jones said: “We looked at how much inflammation there was ongoing in people in different groups; UDCA non-responders, UDCA responders with abnormal liver blood tests, and also responders with normal liver test results.4 It’s clear that disease is active and ongoing in people with any degree of abnormality in liver blood tests, even if they are UDCA responders.4 If inflammation drives the disease and inflammation is still present, we need to control it.”
In clinic, Jones uses a traffic light system to assess risk of PBC disease progression. “If you’ve got normal bloods and normal LSM you are on green, whereas if either of these is abnormal you are red or amber, depending on other factors such as age.” Jones illustrated the point by saying that for a 30-year-old patient, the liver needs to function for another 50 years or so. “If there is existing liver scarring, we need to normalise blood markers,” Jones continued. “People are reassured when we say we are going to set a target of normal blood tests.”
To manage symptoms, both experts stressed the importance of setting targets that are patient centric. Jones used specific examples to illustrate this for fatigue, saying, “it could be something very specific like having the energy to go ballroom dancing, or improving memory sufficiently to remember the names of stations on a particular train line.” Culver concurred and added that "there are additional targets we need to consider, such as bone mineral density and lipid levels.” During early consultations, Culver discusses available second-line treatment options, the risks and benefits of these, and explains to patients that ongoing monitoring of biochemistry, liver stiffness, and symptoms is essential. Culver highlights the importance of monitoring for trajectory over time: “Even if ALP improves or normalises, it can rise again, and if the fibroscan is elevated, or on an increasing trajectory, I want to be able to take pre-emptive action as soon as possible.” Culver emphasised: “It’s also important to escalate treatment if symptoms are problematic, and I don’t wait for the 6-month or 12-month time point to start therapy in those cases.”
In Jones’ clinic, patients are seen at least once a year, and more frequently depending on the patients’ needs and circumstances. “If we are starting UDCA, or second-line treatment, we have a phone review at 2 months to check everything is okay, and then we see the patient in clinic at 6 months to assess response. At that point, we offer a prediction of where we are likely to go next,” Jones explained. “Our service includes a specialist nurse-led clinic so patients can be seen every 3–6 months if treatment has
changed, or symptoms are developing. We also include a drop-in session for anyone who is struggling with symptoms such as itch, keeping things as flexible as possible to meet the changing needs of patients,” Jones added.
ASSESSING TREATMENT RESPONSES AND DELIVERING EFFECTIVE CARE
A combination of clinical and biochemical criteria is used to assess treatment responses, using the Global PBC scoring system, or similar.11 Historically, an ALP level 1.67×ULN has been considered adequate for patients with PBC receiving first-line UDCA.2 Age is also an important consideration as Culver and Jones explained, saying that younger patients are more likely to progress over time and experience the complications of their liver disease. Fibrosis is another important measure, explained Culver. “An LSM of >10 shows historic disease progression, and if the trajectory of fibrosis is upwards, even if the baseline LSM is <10, it can indicate disease progression is ongoing and thus a concern,” Culver said.
Regular monitoring for patients is crucial. Ideally, Culver stated, “after starting a therapy, we want to assess patients within 1–2 months to see whether there is any response to therapy, or an intolerance, and also to check for symptoms. Biochemical responses to therapy may not be evident until 6 months, and follow-up appointments should be scheduled according to individual patient risk and needs,” Culver added. “At each consultation, I consider the combination of biochemistry, fibrosis scoring, and symptoms collectively to decide whether escalation to second-line treatment is necessary.”
The PBC service is supported by a clinical nurse specialist and gastrointestinal pharmacist. “It is important that we identify where patients may struggle with adherence to medication, need additional psychosocial support, and discuss the role of scheduled exercise programmes,” Culver said. “Our pharmacist monitors medication
adherence and side effects and ensures we don’t have patients stopping medication abruptly,” Culver explained, adding that this multidisciplinary approach is vital to deliver effective patient care.
However, according to Jones, gaps in PBC care services are common, as highlighted in a recent audit of PBC care across the UK.12 “What we found is that in a populationbased evaluation of PBC care across the UK, overall, Centres of Excellence do well, but patients living more than 10 miles away from a specialist centre were more likely to receive poor quality care,” Jones outlined. “In the UK, 95% of patients receive firstline UDCA, which is good, but for those requiring second-line therapies, that figure drops to 60% and less than 60% of patients were asked about PBC symptoms.”12 Jones explained that, in response to the findings, “we have developed a PBC care bundle that aims to minimise variation in clinical practice and improve adherence to key guideline standards.”13,14 In the UK there is also now a campaign led by The PBC Foundation, called Project 90:90, which aims for at least 90% of patients to receive at least 90% of the care standards set out in the current PBC guidelines.2,15
EFFECTIVE MANAGEMENT OF PBC SYMPTOMS
The main symptoms of PBC, fatigue and pruritus, are independent of each other, but each can affect 40–80% of patients.7 Despite the high prevalence of symptoms, patients are reticent about discussing them at consultations. According to Culver and Jones, there are two reasons for this. “Firstly, patients often don’t realise their fatigue or itch could be linked to PBC,” explained Jones. “Secondly, doctors sometimes don’t recognise fatigue as a problem, which is very disappointing.”
Fatigue is very debilitating. “You have to take it seriously because it really has an impact on quality of life,” Culver emphasised, continuing: “For younger patients it can dramatically impact their ability to function both as parents and socially and also as part of the working
community.” While Jones assesses fatigue in terms of what patients feel they can no longer do, Culver also uses numerical rating scores. “I think it helps to give fatigue a numerical rating score that you can objectively monitor over time, as well as assessing its impact on the patient’s life. This allows you to document over time if things are changing. A similar approach to itch,” Culver added.
In addition to central fatigue, which includes brain fog and lack of concentration, fatigue can be peripheral, affecting muscle strength and physical power. Imaging studies confirm that fatigue is associated with measurable changes in brain function.16
To encourage open discussion about symptoms during consultations, Jones said: “In clinic, we never use the word fatigue, we often talk about brain fog and ‘batteries running down’, and if this doesn’t resonate with the individual, we move on. If it does resonate, then we drill down into it to find out what it is in their life that they cannot do anymore as a result.”
“We talk about drug therapies, exercise, and coping strategies. Sometimes we need to rehabilitate people because the symptoms have been going on for a long time and they have adapted their lifestyles already,” Jones continued. “However, in terms of drug therapies, we can struggle because UDCA does not treat fatigue. This means someone who responds to UDCA and has fatigue, under current guidelines and regulations in the UK, they are not eligible for a secondline treatment that could treat fatigue,” Jones said.
Culver added: “It’s important to engage people in the treatments that are available for associated conditions such as anaemia, low vitamin D, and thyroid disorders. In addition, we discuss non-pharmacological management strategies,17 and available opportunities to go on a clinical trial of potential new treatments for fatigue.”
“We should choose treatments according to their benefit,” said Jones. “We are currently doing mechanistic studies to explore which drugs might help symptoms, and
there are ongoing clinical trials that use fatigue as an endpoint irrespective of other disease measures.” Culver added: “For patients who experience persistent itch, we follow an escalation pathway from nonpharmacological measures, recommending they wear light clothing and take cool showers, to topical agents such as emollients."10
CONCLUSION
First- and second-line treatments for PBC are licensed and can be used effectively to slow disease progression and control symptoms. Experts recommend that
References
1. Galoosian A et al. Clinical updates in primary biliary cholangitis: trends, epidemiology, and management. J Clin Transl Hepatol. 2020;8:49-60.
2. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017;67(1):145-72.
3. Koc OM et al. Fatigue in people with primary biliary cholangitis: a position paper from the European Reference Network for Rare Liver Diseases. Lancet Gastroenterol Hepatol. 2026;11(1):71-86.
4. Jones D et al. The relationship between disease activity and UDCA response criteria in primary biliary cholangitis: a cohort study. EBioMedicine. 2022;80:104068.
5. Kowdley KV et al. Longitudinal relationship between elevated liver biochemical tests and negative clinical outcomes in primary biliary cholangitis: a population-based study. Aliment Pharmacol Ther. 2025;61(11):1775-84.
patients are monitored more closely to identify a lack of response to first-line therapy and ensure timely escalation to second-line treatment, with liver biomarker normalisation as a key target for treatment. They recommend better symptom recognition and management, and improvements in standards of patient care to ensure all patients with PBC maintain their quality of life without fear of significant disease progression.
6. Prince M et al. Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years. Gastroenterol. 2002;123:1044-51.
7. Louie JS et al. Primary biliary cholangitis: a brief overview. Clin Liver Dis (Hoboken). 2020;4;15(3):100-4.
8. Khanna A et al. Symptoms of PBC –pathophysiology and management. Best Pract Res Clin Gastroenterol. 2018;34:41-7.
9. Jones DEJ. Pathogenesis of primary biliary cirrhosis. Gut. 2007;56:1615-24.
10. Hirschfield GM et al. The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines. Gut. 2018;67(9):1568-94.
11. Lammers WJ et al. Development and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholic acid therapy. Gastroenterology. 2015;149(7):1804-12.e4.
12. Abbas N et al. Critical shortfalls in the management of PBC: results
of a UK-wide, population-based evaluation of care delivery. JHEP Rep. 2023;6(1):100931.
13. Smith R et al. Implementation of a care bundle improves PBC management. JHEP Rep. 2025;7(9):101422.
14. British Society of Gastroenterology (BSG). Primary biliary cholangitis (PBC) care bundle & guidelines. Available at: https://www.bsg.org.uk/clinicalresource/primary-biliary-cholangitis(pbc)-care-bundle. Last accessed: 16 June 2026.
15. PBC Foundation. Project 90:90. Available at: https://www. pbcfoundation.international/getinvolved/project-9090/. Last accessed: 16 June 2026.
16. Swain MG et al. Fatigue in chronic liver disease: new insights and therapeutic approaches. Liver Int. 2019;39(1):6-19.
17. Freer A et al. A home-based exercise programme attenuates fatigue in primary biliary cholangitis: results from the EXCITED clinical trial. JHEP Rep. 2024;6(12):101210.
Interviews
EMJ spoke with three leading voices in hepatology, exploring the evolution of liver disease research and care. Frank Tacke discusses advances in immune-mediated liver disease and personalised therapies, while Nancy Reau reflects on progress from antiviral treatments to expanding transplant frontiers. Massimo Pinzani highlights the impact of translational science, from liver fibrosis research to regenerative medicine. Together, the interviews showcase major advances in hepatology and the continuing importance of collaboration and patient-centred research in driving the field forward.
Featuring: Frank Tacke, Nancy Reau, and Massimo Pinzani
Frank Tacke Chairman and Director, Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Germany
CAR-T cells targeting activated hepatic stellate cells, the principal matrixproducing cells in liver fibrosis, have shown very promising results in preclinical models
Your research has consistently focused on immune-mediated mechanisms in liver disease. How has our understanding of hepatic inflammation evolved in recent years, and what implications does this have for clinical management?
The field of liver research has benefited enormously from technological breakthroughs. We now have access to singlecell sequencing technologies, spatial transcriptomics at singlecell resolution, and advanced proteomic analyses. These tools have allowed us to understand inflammatory processes in the liver in far greater detail.
We can now identify the different cell types involved, how they communicate with one another and with parenchymal liver cells, and how distinct ‘flavours’ of inflammation emerge. Importantly, we have come to appreciate that while inflammation drives fibrosis
and hepatocyte injury, it also plays a crucial role in orchestrating tissue repair. Once the injurious stimulus ceases, inflammatory cells such as macrophages can promote regeneration and coordinate repair mechanisms.
So, inflammation has become a much more complex concept. We now better understand the balance between pro- and antiinflammatory mechanisms in the injured liver, and how these pathways interact dynamically rather than acting in a purely detrimental way.
In terms of clinical management, the biggest therapeutic breakthroughs so far, particularly in steatotic liver disease, have focused more on modulating hepatic metabolism and metabolic injury rather than directly targeting inflammation. Many of the drugs currently entering clinical practice primarily influence metabolic pathways in hepatocytes and
their crosstalk with inflammatory cells, rather than suppressing inflammation per se.
However, with the growing body of knowledge around inflammatory pathways, I believe we are in a strong position to develop therapies that more directly modulate inflammation and fibrosis. We are not quite there yet, but the data and technologies are in place to help close this translational gap.
Q2
You work at the interface between basic science and clinical hepatology. Where do you see the biggest challenges in translating mechanistic discoveries into effective treatments for patients?
One of the major challenges is patient heterogeneity. In clinical practice, patients are affected by numerous factors: comorbidities, concomitant medications, genetic background, and environmental influences. These variables shape disease trajectory in complex ways.
In contrast, experimental models often rely on a limited number of animals or highly controlled cellular systems, where pathways are more clearly defined. In real life, however, we see overlapping conditions and far greater biological variability. The idea that a single treatment will
markedly reduce fibrosis or liver inflammation across a broad patient population is probably unrealistic.
We observe this in clinical trials, where efficacy often does not exceed placebo by large margins. Many confounding factors influence disease progression, and some clinical trial endpoints, such as histological improvement over a relatively short timeframe, are very demanding. It is possible that we have promising drug candidates, but they may not demonstrate sufficient efficacy across a heterogeneous patient population under current trial designs.
Q3
Liver fibrosis remains a key determinant of prognosis across chronic liver diseases. Which fibrotic or immunofibrotic pathways currently appear most promising as therapeutic targets?
From an experimental perspective, cell-based therapies are particularly exciting. For example, CAR-T cells targeting activated hepatic stellate cells, the principal matrix-producing cells in liver fibrosis, have shown very promising results in preclinical models. There have also been impressive data on genetically modified or autologous macrophages that are conditioned to maintain
a more anti-inflammatory, immunomodulatory phenotype.
However, given the global burden and scale of chronic liver disease, including fibrosis and cirrhosis, I do not expect these highly sophisticated approaches to enter routine clinical practice in the near future.
A more realistic strategy may be to modulate the inflammatory microenvironment. Macrophage activation, for instance, is strongly shaped by the surrounding signals. If we can shift this environment towards a reparative rather than injurious phenotype, we could harness the liver’s intrinsic capacity for repair, suppress fibrogenesis, and promote fibrosis resolution. Modulating the inflammatory milieu towards less injury and more repair may ultimately prove the most feasible and impactful approach.
Q4 Are there therapies in development that move in this direction of modulating the inflammatory environment?
Yes, some of the newer drugs may exert such effects, even if they were not originally designed as purely anti-inflammatory agents.
For example, peroxisome proliferator-activated receptor
agonists, transcription factor modulators with different isoforms expressed across tissues, appear to improve metabolism and also influence inflammatory cell polarisation towards a more reparative phenotype. Panperoxisome proliferator-activated receptor agonists are a good example of agents that may act through both metabolic and inflammatory pathways.
Fibroblast growth factor 21, a hormone produced in the liver and adipose tissue, also shows strong antifibrotic potential
Fibroblast growth factor 21, a hormone produced in the liver and adipose tissue, also shows strong antifibrotic potential. We do not yet fully understand whether its effects are entirely indirect or whether there are direct antifibrotic mechanisms involved.
Similarly, acetyl-CoA carboxylase inhibitors, targeting de novo lipogenesis and developed primarily as metabolic therapies for metabolic dysfunction-associated steatohepatitis (MASH), may also reduce hepatic stellate cell activation and fibrosis. So, while these drugs are not exclusively anti-inflammatory or antifibrotic, they may exert meaningful effects on these pathways.
Q5 In MASH, how do you view the role of immune dysregulation and inflammation in disease progression beyond metabolic risk factors alone?
If we consider disease progression, simple steatosis is not yet true liver disease. It represents a risk state associated with cardiometabolic burden and visible hepatic response to metabolic stress. The liver disease begins when inflammation develops, when steatosis transitions to steatohepatitis.
It is this inflammatory stage that confers risk for fibrosis, cirrhosis, and hepatocellular carcinoma. If we could decouple steatosis from steatohepatitis, preventing inflammation from being triggered, this would significantly reduce progression to clinically meaningful liver disease. The transition from steatosis to steatohepatitis is therefore critical.
Q6
Liver biopsy remains a key diagnostic tool. How close are we to replacing it with non-invasive biomarkers?
We have already made significant progress in reducing the need for liver biopsy in clinical practice. What we still cannot reliably diagnose without biopsy is steatohepatitis itself. Current routine biomarkers lack sufficient sensitivity and specificity for diagnosing MASH.
However, for staging liver disease, particularly identifying advanced fibrosis, non-invasive tools are extremely valuable. Serum-based tests and especially imaging biomarkers, such as elastography measuring liver stiffness, are widely used and very effective in identifying patients with advanced fibrosis.
Blood-based tests can also capture advanced fibrosis and cirrhosis reasonably well. In hepatocellular carcinoma detection, progress has also been substantial. α-fetoprotein (AFP) alone is insufficient, as many cancers are AFP-negative. When combined with additional markers into composite scores, such as the Gender, Age, AFP-L3, AFP, and Des-carboxy-prothrombin (GALAD) score, diagnostic performance improves significantly. While these tools cannot yet replace imaging modalities such as ultrasound or MRI, the advances are encouraging.
There are also promising approaches using cell-free DNA to detect tumour-specific signatures, a form of liquid biopsy. These strategies aim at early cancer detection rather than advanced disease. Although not yet definitive, progress in this area is rapid.
Q7Looking ahead, what developments in hepatology research are most likely to meaningfully change patient outcomes over the next decade?
One particularly exciting area is the concept of disease clusters and heterogeneity. For many patients, liver disease is only one component of a broader cardiometabolic risk profile. In MASH, for example, patients may face competing risks, progression to liver cancer, or death from myocardial infarction or stroke.
Understanding these risk clusters and tailoring management accordingly will be crucial. Hepatology should be integrated into a broader, multidisciplinary, multimodal risk management framework.
Personalised strategies for therapy, diagnostics, surveillance, and long-term monitoring will likely incorporate factors such as the microbiota, the gut–liver axis, and even the gut–brain axis. We already have therapeutic options from hepatology, diabetology, and cardiology. The challenge is to combine them appropriately for the individual patient.
Integrating hepatology more closely with other disciplines, and tailoring management according to individual risk, will likely represent one of the most meaningful advances for patient outcomes in the coming decade.
Nancy Reau Professor of Internal Medicine; Richard B. Capps Chair of Hepatology; Associate Director of Solid Organ Transplantation; and Section Chief of Hepatology, Rush
University Medical Center, Chicago, Illinois, USA
Motivating the next generation to love hepatology and to think critically is really what motivates me to come to work every day
You have built a career spanning hepatology, gastroenterology, and internal medicine. What originally drew you to liver disease as a specialty, and what continues to motivate your work today?
I studied neuroscience in college and initially planned to pursue neurology. However, once I started to work with patients, I really found my passion for hepatology. I still remember my time as a fellow, when pegylated interferon was emerging as a ‘miracle’ drug for hepatitis C. The fact that science was delivering curable options to patients with chronic illness, coupled with the lifesaving opportunities liver transplant offered to those with end-stage disease, cemented my career in hepatology. Yet, it was really my mentors who kept me engaged in academic medicine and focused on the future. When we hear ‘mentor’, we envision a student looking up to a teacher, yet the individuals who shaped my career path when I was a student continued to be my best resource to bounce off ideas and to help me work through difficult clinical and academic issues. Motivating the next generation to love hepatology and to think critically is really what motivates me to come to work every day. It is also important to define the next generation. This is not just our medical students, residents, and fellows, but also our clinical staff, advanced practice providers, and admins. Patient care requires a village. I love my hepatology family. Making the care pathway accessible, equitable, and enjoyable is what healthcare should also strive for.
Q2
Your work has focused extensively on viral hepatitis, drug development, and liver transplantation. How have your research interests evolved over the course of your career?
Viral hepatitis has always been my passion. The virus of the year has shifted. When I started my academic career, there was drug development in hepatitis B; however, hepatitis C really stole the limelight. It wasn’t just that oral curative options were being developed; diagnostics were also exploding. I witnessed a disease that drove liver transplantation become an infection that was easily diagnosed and cured. We have now pivoted back to hepatitis B, where the cure has been elusive, but the therapeutic pipeline is really exciting. Hepatitis D also has several options that can mitigate disease progression. Still, I am a clinician more than a scientist. I like to be involved when drug development can help change the prognosis of the patient in front of me.
Q3 Your work has also examined the impact of COVID-19 on liver function. What have you learned about how SARS-CoV-2 affects the liver, particularly in patients with pre-existing liver disease?
When the pandemic hit, we all examined the impact of COVID-19 on the patients we were caring for. As a hepatologist, this included patients with liver disease who were infected and patients without liver disease who developed hepatic complications from the infection. People with advanced liver disease
are immunocompromised. The liver is an integral part of the immune response, and thus, if liver function is poor, an infection (including COVID-19) is going to be harder to recover from. Liver complications from SARS-CoV-2 infection remain uncommon; however, patients with advanced liver disease were more likely to have a worse outcome.
Q4
Your recent work has explored topics such as sustained virologic response in hepatitis C treatment and the cost-effectiveness of universal childhood screening. How do these findings contribute to improving long-term management and prevention of hepatitis C?
Simple rules are always the easiest to follow. Risk-based screening (irrespective of what you’re looking for) falls short. When everyone needs to be screened at time
point x, screening occurs. Think of colorectal cancer screening. We all know we need a colonoscopy at the age of 45 (or 50) years. This isn’t because we do things that increase our risk of colorectal cancer, it’s because that is the time to identify high-risk polyps before they become cancer. Childhood screening removes the stigma of high-risk behaviours and captures an important group of chronically infected individuals who are at risk of transmission. We looked at the cost-effectiveness of universal childhood screening to help show that this was financially smart, moved screening to a time when it was not stigmatised by high-risk behaviours, and the infection could be cured before engaging in activities that would lead to transmission.
Q5 With increasing interest in optimising marginal organs and expanding donor pools, including hepatitis-positive organs and those donated after circulatory death, what innovations or research directions do you think will most improve access to liver transplantation?
Both innovations will improve access. Donors who died from circulatory death represent a large pool, with many donated organs still going unused. We are already starting to see increased organ utilisation with peri-transplant strategies. At the same time, organs from donors with hepatitis B and C can further expand options. I think it’s important to reassure people that these organs perform as well as traditional organs. Hepatitis C is curable, and hepatitis B is easily controlled and may be curable in the future. Although donation after
circulatory death organs have the ability to expand the donor pool more substantially, organs infected with viral hepatitis are a safe and predictable option.
Q6
You serve on the governing board of the American Association for the Study of Liver Diseases (AASLD) and previously chaired the Hepatology Committee of the World Gastroenterology Organisation (WGO). How important are professional organisations in shaping clinical practice, research priorities, and global policy around liver disease?
Our societies are the mouthpiece of the membership. Like elected officials, we represent those who supported us during the journey that led us to our position. As such, we have a significant impact on priorities related to outreach and clinical practice. We help dictate policy, often with a bigger megaphone, because of our position. That said, we reflect our membership, and we are real people. Do not hesitate to send your feedback to your governing board.
Q7 As Associate Director of Solid Organ Transplantation and Section Chief of Hepatology at Rush University Medical Centre, Chicago, Illinois, USA, how do you balance clinical work, research, and leadership responsibilities?
Work-life balance is always important and reflects your stage of life. Time management is imperative and delegating it to someone you trust allows you to concentrate your efforts elsewhere. I am always available if someone needs me; however, the individuals that support me are amazing, whether it is our research staff, my administrative assistant, or the amazing nurses
and advanced practice providers who help support our patients. Academic achievement takes a village, and when we succeed, the entire village should celebrate.
Q8
As you prepare to become President of the AASLD in 2029, what priorities do you hope to focus on for the field, and what advice would you give to earlycareer clinicians or researchers interested in hepatology?
Presidency is like a relay race; some of my priorities will be carried forward from the presidents who preceded me. I do hope to focus on mentoring and education. It is important to recruit the next generation of academic hepatologists who will love the field as much as I have. Part of this message is to recognise the incredible legacy that was laid as a foundation. It is important to never forget where we started and how we got here, but it is equally important to be flexible and adapt to new technology and priorities. My message to an early-career clinician is to embrace your passion and find a good mentor and sponsor. Don’t get discouraged by the pace as long as you’re working toward your goal. Also, it’s important to see the crossroads in your career. Sometimes what you thought you should do and what you want to do are different, and that’s ok. We are not on an express highway without exits; you can pause, reflect, and choose a new direction.
Academic achievement takes a village, and when we succeed, the entire village should celebrate
Massimo Pinzani
Emeritus Professor of Medicine, University College London (UCL), UK
This approach directly enabled the discovery of reliable non-invasive diagnostics and biomarkers for fibrosis
You began integrating laboratory research within a clinical liver unit in the late 1980s. What initially inspired you to pursue a physician–scientist career, and how did your early experiences shape your translational approach to hepatology?
I became a physician–scientist because I had difficulties accepting the gap between diagnosing chronic liver disease and the understanding of the relative mechanisms of disease. I was also fortunate to be offered the right opportunities at the right time and to meet inspiring mentors who showed me the way to satisfy my curiosity. My work has always been guided by patient centred questions and human relevant models to discover and validate biomarkers and suitable therapeutic targets. This bedside to bench loop focused me on hepatic stellate cell biology, extracellular matrix remodelling, non invasive diagnostics, and biotechnology partnerships to translate discoveries into therapies.
Q2
Liver fibrosis and chronic liver disease became central to your life’s work. What drew you specifically to this area, and what unanswered questions continue to motivate you today?
I found the area of tissue fibrosis very fascinating, because, while it is the ultimate remedy ensuring tissue continuity following chronic damage according to the concept of chronic wound healing, the progressive changes of tissue structure lead to disease complication and organ failure. I was and I am still attracted by the different features of fibrogenesis in different diseases within the
same organ and in different organs and systems. I became especially passionate about cell–cell and cell–extracellular matrix interactions, soluble inflammatory mediators, and intracellular signalling in hepatic stellate cells. After more than a decade of deep dive in the cell and molecular biology of liver fibrogenesis, my research returned to address clinical needs, and particularly the non-invasive assessment of fibrotic stage by serum markers and elastography, and the correlation with key clinical complications, such as portal hypertension. Among many unanswered questions that still motivate me, I am very puzzled by the individual genetic variability in handling fibrogenesis both in progression and in regression.
Q3
You are considered one of the pioneers in cellular and molecular mechanisms of liver fibrosis, regenerative medicine, and extracellular matrix scaffold bioengineering. What do you see as your most transformative scientific contribution to the field?
My most transformative contribution has been establishing a bedside to bench translational model focused on human liver biology. By embedding laboratory research within a clinical liver unit and prioritising human tissue and cells, I helped shift the field from reliance on animal models to human relevant studies centred on hepatic non-parenchymal cells, immune–stromal interactions, and extracellular matrix dynamics. This approach directly enabled the discovery of reliable non-invasive diagnostics and biomarkers for fibrosis and portal hypertension,
and the translation of extracellular matrix biology into regenerative platforms and scaffold technologies now fully pursued in industry. In short, integrating human mechanistic science with practical diagnostics and biotech translation changed how we diagnose, monitor, and target liver fibrosis.
Q4 Across more than four decades and 400 publications, your work has continuously evolved. How have you sustained scientific originality, and what does your 2026 ‘Cell Death and Disease’ paper signal about where your research is heading?
I sustain scientific originality by letting clinical problems shape basic questions, using
human relevant systems (patient tissue, primary cells, organoids, extracellular matrix scaffolds) and adopting new tools (single cell omics, advanced imaging, and matrix engineering), while building tight industry partnerships to accelerate translation. A recent paper, produced by the research team lead by Giovanni Zito at Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (ISMETT) in Palermo, Italy, reports on the mechanisms regulating inflammation and hepatocyte senescence in an in vitro model of ischaemia-reperfusion injury and represents a further expansion of my interest in regenerative and transplant medicine.
Q5
As an Emeritus Professor of Medicine at University College London (UCL), UK, Founder of the UCL Institute for Liver and Digestive Health, and now Scientific Director of University of Pittsburgh Medical (UPMC) ISMETT, how has your leadership philosophy evolved, and how do you build environments where translational science can truly thrive?
My leadership evolved from managing research projects as a ‘one-man band’ to enabling large and articulated groups of researchers as an orchestra conductor. I prioritise a shared patient centred purpose, removing barriers to collaboration, and protecting time and resources for high-risk, high-reward
work. Concretely, by building a community of physicians and scientists within the same academic unit and ensuring easy access to samples and data, I established multidisciplinary cores (omics, imaging, biostatistics, bioengineering) with strong translational potential. I keep communication flat, track clear translation metrics, and sustain industry partnerships while safeguarding academic independence.
Q6
You co-founded Engitix Therapeutics, London, UK to translate extracellular matrix research into therapeutic development. What have been the key lessons in bridging academia and biotech, and how can physician–scientists engage more effectively with industry?
Co-founding Engitix Therapeutics in 2016 with PhD student Giuseppe Mazza at the UCL Institute for Liver and Digestive Health, London, UK, has been one of the highlights of my academic career. Several former PhD students and postdoctoral researchers now work at Engitix under Mazza’s leadership. He is among the youngest and most successful CEOs in the biotech sector. I’m extremely proud to learn from my former trainees and this generational continuity in science brings me great satisfaction. Working in biotech has also reshaped my approach to science and research. Compared with the traditional academic path, industry demands clearer alignment of science with patient impact, pragmatic timelines and milestones, and fluency in industry concepts (investigational new drug enabling work, regulatory milestones). It requires designing studies with translational readouts, starting with focused sponsored projects,
and building multidisciplinary networks that include regulatory and translational experts. Dayto-day efforts at the company reinforce my sense that we are on the right track to develop effective treatments for patients.
Q7
As Treasurer of the European Association for the Study of the Liver (EASL) and a long-standing contributor to international scientific bodies, how do you see the role of professional societies in shaping research priorities, public health policy, and global liver disease awareness?
Professional societies, such EASL, play a fundamental role: they set research agendas by convening experts to identify unmet needs and fund priority initiatives; they translate evidence into clinical guidelines and policy recommendations that influence public-health decisions; and they amplify awareness through education, advocacy, and capacity-building worldwide. The position of EASL Treasurer is tightly linked to the responsibility of the association leadership to make the right investments at the right time and ensure longterm growth and continuity. Investments include support to large research endeavours and consortia, professional task forces, training fellowships, and education and public health advocacy to reduce the global burden of liver disease.
Q8
Over four decades, hepatology has shifted from limited therapeutic options to targeted molecular and regenerative strategies. What major breakthroughs have most changed patient outcomes, and what developments (AIdriven diagnostics, organ bioengineering, antifibrotic therapies) do you believe will define the next 10–20 years?
Over the past 40 years hepatology has progressed from mainly supportive care to precision and regenerative approaches. Major advances that improved outcomes include curative direct-acting antivirals for hepatitis C, effective long-term control of hepatitis B, development of non-invasive diagnostics (biomarkers and elastography), improved management of portal hypertension, and refinements in transplantation. Over the next 10–20 years, I anticipate AI-driven diagnostics that fuse imaging with multi-omics for individualised risk stratification, truly anti-fibrotic therapies that halt or reverse extracellular matrix deposition, and regenerative or bioengineered organ platforms (extracellular matrix scaffolds, organoids, and cell therapies) to restore function or bridge patients to transplant. Combined, these developments should move care earlier in the disease course and toward disease-modifying interventions.
They amplify awareness through education, advocacy, and capacity-building worldwide
Towards a Functional Cure for Chronic HBV Infection: Progress, Setbacks, and New Hope
Editor's Pick
The pursuit of a functional cure for chronic hepatitis B (HBV) has been marked by periods of optimism, disappointment, and, more recently, renewed hope. In this compelling feature, Bertoletti examines the progress and setbacks that have shaped HBV cure research, from the early promise of RNA-targeting therapies to the recognition that hepatitis B surface antigen (HBsAg) reduction alone is insufficient to achieve sustained immune control. The article highlights emerging evidence that combination strategies involving small interfering RNA, peginterferon alfa, and therapeutic vaccination may substantially improve rates of HBsAg seroconversion and functional cure. Importantly, it underscores the growing appreciation of immune recovery, particularly HBV-specific B and T cell responses, as a critical determinant of treatment success. By exploring both the scientific rationale underpinning these advances and the challenges that remain, this timely review offers valuable insight into the next chapter of HBV therapy and the prospects for achieving a durable functional cure.
Markus Peck-Radosavljevic
Klinikum Klagenfurt am Wörthersee, Austria
Author: *Antonio Bertoletti1
1. Duke-NUS Medical School, Singapore *Correspondence to antonio@duke-Nus.edu.sg
Disclosure: Bertoletti is the founder and holds stock of T Cell Diagnostics (TCD), a biotech company developing immune assays for measuring antiviral immunity (NK, virus-specific T and B cells). He also acts as a consultant for BRII Biotech and AstraZeneca.
The quest for new therapies able to achieve a functional cure for chronic hepatitis B virus (HBV) infection has been characterised over the last 5 years by phases of hope followed by severe disillusionment.1
It is well established that excellent drugs for the treatment of chronic HBV infection exist and have been in use for decades. Potent nucleoside and nucleotide analogues with a high barrier to resistance can be taken lifelong without severe side effects and achieve excellent control of HBV replication (undetectable serum HBV-DNA),
thereby reducing liver inflammation and the development of clinical complications of chronic hepatitis B (CHB), including liver cirrhosis and hepatocellular carcinoma.2
However, long-term treatment with nucleoside or nucleotide analogues rarely achieves a functional cure, defined as the sustained undetectable level of hepatitis B surface antigen (HBsAg) and HBV-DNA in serum in the absence of any treatment. This virological profile represents the ultimate goal of HBV therapy: it removes the social stigma of HBsAg positivity and carries clear clinical relevance, further lowering the risks of cirrhosis and hepatocellular carcinoma and allowing the safe discontinuation of nucleotide analogue therapy.
It is important to note, however, that functional cure does not reflect HBV elimination, which cannot be achieved in any HBV-infected individual. Patients who control HBV infection after acute illness still harbour a small number of hepatocytes containing the HBV minichromosome, known as covalently closed circular (cccDNA).
Furthermore, HBsAg, the sum of noninfectious subviral and whole viral particles composed of the three major proteins of the HBV envelope (PreS1/ S2/S), is secreted not only by infected hepatocytes, but, particularly in adults with CHB, by hepatocytes carrying integrated HBV-DNA. Functional cure therefore represents a sustained reduction, rather than complete elimination, of the number of infected hepatocytes and/or those harbouring HBV-DNA integration.3 This can be achieved by compounds that directly target these hepatocytes, or by enhancing the immunological control of HBV, which is known to be defective in patients with CHB.4
TREATMENT PATHWAYS
This was the rationale behind two families of compounds, short interfering RNA (siRNA) and antisense oligonucleotides (ASO), designed to target HBV RNA and thereby reduce both HBV replication (by targeting the pregenomic RNA, the
template for HBV-DNA synthesis) and viral antigen production (principally HBsAg, by targeting the S mRNA originating from either cccDNA or integrated HBV-DNA). The possibility of delivering siRNA and ASO compounds selectively to hepatocytes via GalNAc conjugation made them even more attractive candidates.5
Initial data were promising. Treated patients experienced a steady decline in serum HBsAg; a reduction never observed with nucleotide analogue treatment, which targets HBV-DNA replication but not antigen production. It was quickly recognised, however, that HBsAg reduction reached a plateau after 16–20 weeks of treatment, and complete serum HBsAg clearance was never achieved with siRNA alone. Somewhat better results were obtained with the ASO bepirovirsen, a non-GalNAc-conjugated compound, in which HBsAg negativity was observed in approximately 9% of patients. However, this seroconversion occurred predominantly in patients with CHB who already had low HBsAg levels at treatment initiation.6
What these initial trials also revealed was that the rapid HBsAg reduction achieved with ASO or siRNA compounds was not accompanied by any meaningful recovery of HBV-specific immunity. A reversion of the dysfunctional HBs-specific T and B lymphocytes did not occur. Studies, in both animal models and patients with CHB, clearly showed that HBsAg reduction with siRNA alone does not lead to recovery of HBV-specific T or B cell function.7,8 Antigen reduction may yet prove useful in combination with therapeutic vaccines, but even here, the increased immunogenicity observed in siRNA-treated individuals treated with a therapeutic vaccine did not translate into higher rates of HBsAg seroconversion.8,9
NEW DEVELOPMENTS
Recent data have, however, renewed genuine optimism. Results of the Phase 3 bepirovirsen clinical trial (24 weeks of treatment) show a 20% rate of functional cure (24 weeks after stopping all HBV
treatments) in non-cirrhotic CHB patients (HBsAG lower than 3,000 IU/ml).10 Even though the majority of patients responding have low levels of HBsAg between 1,000 to 3,000 IU/ml) and the incidence of adverse events requiring dose interruption (16% of treated patients, mainly ALT elevation) call for stringent monitoring for the patients (at least every 2 weeks), this rate of functional cure achieved with a single compound is certainly remarkable.10
Also, the combination of siRNA with peginterferon alpha (Peg-IFNα) has been shown to yield HBsAg seroconversion rates of approximately 20–30%, not only in patients with non-cirrhotic CHB with low baseline HBsAg levels, but also in younger HBeAg-positive patients with CHB characterised by high HBsAg levels.11,12 Even more unexpected were the results obtained with siRNA plus Peg-IFNα in patients with CHB who had been vaccinated 2 years earlier with a therapeutic vaccine based on PreS1/S2/S antigens. Among patients who had responded to the vaccine by producing anti-HBs antibodies, the rate of HBsAg seroconversion reached 56% at the end of treatment, and a recent report of 37% of a functional cure 24 weeks after the interruption of every treatment.13,14 Taken together, these results demonstrate that a meaningful proportion of patients with non-cirrhotic CHB can achieve a functional cure when therapies that reduce HBsAg are combined with immunomodulatory agents.15
What mechanisms explain these results? Whether a toll-like receptor (TLR) agonist effect of bepirovirsen, in addition to its ability to suppress HBsAg, contributes to clinical efficacy is a plausible hypothesis and should be tested. It is important to remember that a non-GalNAc-conjugated ASO is, in essence, a single-stranded synthetic nucleic acid molecule that can be sensed not only by hepatocytes but also by myeloid cells (dendritic cells, Kupffer cells) present in the liver. Single-stranded nucleic acids can activate TLR7/8 (if they contain RNA-like features) or TLR9 (if they contain CpG features).
Similarly, we need to understand how Peg-IFN therapy increases the rate of
HBsAg seroconversion, and why does prior vaccination with a therapeutic HBV vaccine, which on its own was essentially ineffective (only one of 77 patients achieved HBsAg seroconversion), produces a striking 56% seroconversion rate when combined with siRNA and Peg-IFNα?8,13
The antiviral effects of Peg-IFNα are well established, but its immunomodulatory actions are likely equally important here. Natural killer cell activation has been proposed as one mechanism, but it is probably not the only one. IFNα induced during viral infection has been shown to potentiate both antiviral B cell and T cell responses.16 In CHB, while T cell dysfunction has received the most attention, B cell biology deserves equal scrutiny: HBs-specific B cell recovery has been demonstrated to correlate with seroconversion following Peg-IFNα therapy, and this arm of the immune response warrants much closer investigation.17
What seems clear is that antigen reduction alone, however dramatic, is insufficient to restore antiviral immunity. Rather, it appears to facilitate a synergistic interaction between the immune activation induced by the TLR-like function of ASO or Peg-IFNα with preexisting natural or vaccine-primed immunity.18 Understanding this interplay mechanistically is the key challenge ahead.
CONCLUSION
Crucially, future trials must move beyond virological markers alone. If immune recovery is driving these successes, immunological parameters such as T cell function, HBs-specific B cell responses, and antigen presenting cell activity must be systematically measured and used to guide treatment design.
Fortunately, newer whole-blood assay methods have substantially simplified immunological monitoring, making this feasible even in large multicentre studies.19
We are at the dawn of a new era in HBV treatment. Turning these initial, tantalising
results into a broadly effective therapy will require mechanistic clarity, smarter combination strategies, and a commitment
References
1. Pawlotsky J-M. New hepatitis B drug development disillusions: time to reset? Lancet Gastroenterol Hepatol. 2023;8(2):192-7.
2. Fanning GC et al. Therapeutic strategies for hepatitis B virus infection: towards a cure. Nat Rev Drug Discov. 2019;18(11):827-44.
3. Zoulim F et al. Hepatitis B virus DNA integration: implications for diagnostics, therapy, and outcome. J Hepatol. 2024;81(6):1087-99.
4. Thimme R et al. Decoding HBVspecific adaptive immunity: from natural clearance to cure. Gut. 2025;DOI:10.1136/gutjnl-2025-337129.
5. Iannacone M et al. Targeting HBV with RNA interference: paths to cure. Sci Transl Med. 2025;17(805):eadv3678.
6. Feld JJ et al. New perspectives on development of curative strategies for chronic hepatitis B. Clin Gastroenterol Hepatol. 2023;21(8):2040-50.
7. Fumagalli V et al. Serum HBsAg clearance has minimal impact on CD8+ T cell responses in mouse models of HBV infection. J Exp Med. 2020;217(11):e20200298.
8. Ji Y et al. The impact of hepatitis B surface antigen reduction via small interfering RNA treatment on natural and vaccine (BRII-179)-
to studying the immune response with the same rigour we have long applied to virology.20
induced hepatitis B virus-specific humoral and cellular immune responses. Gastroenterology. 2025;169(1):136-49.
9. Michler T et al. Knockdown of virus antigen expression increases therapeutic vaccine efficacy in high-titer hepatitis B virus carrier mice. Gastroenterology. 2020;158(6):1762-1775.e9.
10. Hou J et al. Phase 3 results of bepirovirsen treatment for chronic hepatitis B virus infection. N Engl J Med. 2026;394(24):2395-406.
11. Hou J et al. Xalnesiran with or without an immunomodulator in chronic hepatitis B. N Engl J Med. 2024;391(22):2098-109.
12. Kennedy PTF et al. Peginterferon alpha-2a add-on to siRNA JNJ73763989 in untreated patients with HBeAg-positive chronic hepatitis B virus (HBV) infection: the phase 2 REEF-IT study. Gut. 2026;75(5):1043-54.
13. Wong GL-H et al. Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial. Nat Med. 2026;32(1):151-9.
14. Wong GL-H et al. LBP-040 functional cure rate in chronic hepatitis B virus infected participants receiving elebsiran and pegylated interferon
alfa: final results from the phase 2 ENSURE study. J Hepatol. 2026;84(Suppl 1):S85-S86.
15. Battistella S et al. Elebsiran and pegylated-IFNα: progress toward a functional cure for chronic hepatitis B. JHEP Rep. 2026;8(4):101741.
16. Le Bon A et al. Cutting Edge: enhancement of antibody responses through direct stimulation of B and T Cells by Type I IFN. J Immunol. 2006;176(4):2074-8.
17. Zhang J-W et al. Varied immune responses of HBV-specific B cells in patients undergoing pegylated interferonalpha treatment for chronic hepatitis B. J Hepatol. 2024;81(6):960-70.
18. Cornberg M. PEG is back: revisiting the role of pegylated interferon alfa and benchmarking its place in HBV cure strategies. Gut. 2026;DOI:10.1136/ gutjnl-2025-337336.
19. Hofmann M, Rehermann B. T cells in a drop: rapid T-cell monitoring in chronic hepatitis B. J Hepatol. 2025;83(6):1247-49.
20. Bertoletti A. The challenges of adopting immunological biomarkers in the management of chronic HBV infection. J Hepatol. 2022;77(2):299-301.
Metabolic Dysfunction-Associated Steatotic Liver Disease in Challenging Care Settings: Clinical Implications from the MENA Region
Authors: *Mahmoud S. Desoky,1,2 Mohamed El-Kassas2,3
1. Internal Medicine Department, Sultan Bin Abdulaziz Humanitarian City (SBAHC), Riyadh, Saudi Arabia
2. Steatotic Liver Disease Study Foundation in the Middle East and North Africa (SLMENA), Cairo, Egypt
3. Endemic Medicine Department, Faculty of Medicine, Capital University, Cairo, Egypt
*Correspondence to mdesoky15@yahoo.com
Disclosure: The authors have declared no conflicts of interest.
Received: 06.05.26
Accepted: 10.06.26
Keywords: Challenging care settings, glucagon-like peptide-1 (GLP-1) receptor agonists, implementation science, metabolic dysfunction-associated steatotic liver disease (MASLD), Middle East and North Africa (MENA), multidisciplinary care, non-invasive diagnostics, resource-variable healthcare.
Recently, the global response to hepatitis C virus infection has shown that major liver disease challenges can be reshaped through coordinated clinical, public health, and policy action.1
Yet, as the burden of viral hepatitis declines in many settings, a broader and more complex challenge has moved to the foreground. Metabolic dysfunctionassociated steatotic liver disease (MASLD) now affects approximately one in three adults worldwide and has become one of the defining liver diseases of modern hepatology.2 The clinical and system-level challenges of MASLD are not confined to any single region. They are increasingly shared across health systems with different resources, infrastructures, and models of care.3 For this reason, the experience of the
Middle East and North Africa (MENA) region is not only regionally relevant, but also instructive for clinicians and policymakers in Europe and beyond.
The MENA region provides a relevant example of how MASLD care is being shaped under conditions of high disease burden, variable resources, and uneven health system infrastructure. Rather than presenting these challenges as regionspecific, this article uses the MENA experience as a practical lens through which to examine implementation problems that are increasingly familiar to European clinicians. The authors focus on four key pillars: awareness and education gaps, diagnostic access and risk stratification, pharmacotherapy affordability and access, and care coordination across fragmented health systems (Figure 1).
Figure 1: Four implementation pillars for MASLD management in challenging care settings: MENA and European perspectives.
MENA REALITY
Knowledge deficits documented among primary care providers in Egypt, Saudi Arabia, and Türkiye; MASLD frequently diagnosed incidentally at advanced fibrosis stage; no unified Arabic medical terminology across the region.
Advanced diagnostic tools (VCTE, MRE, MRI-PDFF) confined to tertiary centers; clinicians rely on abdominal ultrasound and FIB-4 as daily operational necessity where fibroscan is unavailable.
PILLAR
Awareness and education gaps
Diagnostic access and risk stratification
Resmetirom (~47,400 USD/year) inaccessible for most MENA health systems; GLP-1 receptor agonists restricted to T2D indications rather than liver-directed therapy; cost a primary barrier.
Patients with obesity, T2D, and MASLD managed separately across specialty clinics; no unified multidisciplinary care plan; MASLD not integrated as hepatic manifestation of metabolic disease.
Pharmacotherapy affordability and access
Care coordination and system fragmentation
EUROPEAN MIRROR
Identical gaps in primary care physician preparedness documented across European health systems; guidelines exist but implementation at point of first contact remains consistently poor.
NIT-first pathways (FIB-4 as first-line tool) becoming the standard approach; liver biopsy increasingly reserved for selected cases; same practical triage challenge at population scale.
Reimbursement decisions vary substantially across European national health systems; a drug can be licensed, guideline-endorsed, and still unreachable for patients.
Structurally identical fragmentation documented in European primary care; MDT models recommended but rarely implemented; primary-led pathways remain aspirational in most settings.
Four implementation pillars for MASLD management in challenging care settings, comparing clinical realities in the MENA region with parallel challenges in European health systems. Each pillar represents a domain where resource-variable experience from MENA offers directly transferable lessons for European primary care.
FIB-4: fibrosis-4 index; GLP-1: glucagon-like peptide-1; MASLD: metabolic dysfunction-associated steatotic liver disease; MDT: multidisciplinary team; MENA: Middle East and North Africa; MRE: magnetic resonance elastography; MRI-PDFF: MRI-derived proton density fat fraction; NIT: non-invasive test; T2D: type 2 diabetes; VCTE: vibration-controlled transient elastography.
THE MENA BURDEN
MASLD prevalence in the MENA region is among the highest reported globally. Prevalence rates vary between studies according to the diagnostic methods, study population, and disease definition, but consistently range from approximately 36–46%, with the highest rate recorded in Egypt (45%), Kuwait (45.4%), and Qatar (44.4%), countries with highest burden of obesity and Type 2 diabetes.4
The clinical picture in MENA is shaped not only by the prevalence figures but also by a characteristic metabolic phenotype. Patients presented with hepatic fibrosis at earlier stages and progression from MASLD to metabolic dysfunction-associated
steatohepatitis (MASH) with advanced fibrosis occurred at a younger age.4 This acceleration is attributed to dense clustering of metabolic risk factors, such as obesity, insulin resistance, dyslipidaemia, and Type 2 diabetes, which are highly prevalent between patients. Rapid dietary transitions and lifestyle urbanisation over the past two to three decades have participated in this.
The knowledge gap represents an additional contributing factor. A survey of 584 physicians across Saudi Arabia, Egypt, and Türkiye found a significant deficit in MASLD identification, diagnosis, and management, which was most pronounced among primary care physicians, and the guidelines adherence rate was only
38–51%.5 Clinical infrastructure for identifying, staging, and managing MASLD remains uneven across the MENA region. This variability reflects what the authors define here as a challenging care setting: a clinical environment in which MASLD care is limited by structural barriers rather than by disease biology alone. These barriers may include fragmented referral pathways, limited preparedness of primary care to recognise and risk stratify MASLD, restricted access to advanced diagnostic tools outside tertiary centres, delayed staging of liver fibrosis, inequitable access to emerging pharmacotherapies, and insufficient multidisciplinary coordination.6
Importantly, this concept is not restricted to the MENA region. Similar barriers may arise in any health system when metabolic disease burden increases faster than the capacity of primary care, hepatology services, diagnostic infrastructure, and reimbursement pathways. For European clinicians, the relevance is therefore practical rather than purely comparative. The MENA experience provides a lens through which to examine four shared implementation challenges: awareness and education gaps, diagnostic access and risk stratification, pharmacotherapy affordability and access, and care coordination across fragmented health systems.
PILLAR 1: AWARENESS AND EDUCATION GAPS
Awareness gaps in MASLD present at both healthcare providers and public levels, and both matter clinically. At the physicians level, the gap begins in medical education curricula, which allocate minimal time to MASLD, leaving primary care providers (the frontline of disease detection) inadequately prepared to identify, stage, or manage the disease systematically.7 A regional survey confirmed knowledge deficit among health care professionals in Egypt, Saudi Arabia, and Türkiye,5 and in most cases, MASLD was diagnosed accidentally during imaging or blood tests orders for other reasons, frequently at advanced fibrosis stage.7 At the public level, knowledge and understanding of disease prevalence, risk
of progression, and complications remain a major misconception. At both levels, unified Arabic terminology across the MENA region has been a longlisting challenge, and in response, a consensus on Arabic medical terminology for steatotic liver disease was established.8
Europe is not exempt; identical gaps in primary care physician preparedness have been reported across the European healthcare system. Guidelines exist, but implementation at first point of contact remains behind.
PILLAR 2: DIAGNOSTIC ACCESS AND RISK STRATIFICATION
Advanced diagnostic tools, such as vibration-controlled transient elastography, magnetic resonance elastography, and MRI derived proton density fat fraction, remain largely confined to tertiary centres across MENA. In real clinical settings, most clinicians depend on abdominal ultrasound as a screening method in patients with documented history of metabolic diseases (obesity, Type 2 diabetes, hyperlipidaemia) and with palpable hepatomegaly, despite ultrasound’s limited sensitivity for mild steatosis and early fibrosis.7 New guidelines, and global and local consensus documents, have positioned the Fibrosis-4 Index (FIB-4) score as mandatory first-line risk stratification tool, with a score below 1.3 enabling management at the primary care setting, while higher scores should be referred to a hepatologist.9 This practice represents a daily operational necessity when fibroscan access is unavailable. European clinicians face the same practical dilemma, and the use of non-invasive tests becomes the foundational first step for MASLD evaluation across European primary care.
PILLAR 3: PHARMACOTHERAPY AFFORDABILITY AND ACCESS
The approval of the first liver directed pharmacotherapies for MASH has changed the therapeutic landscape, but it has also introduced a new implementation challenge.
Resmetirom received accelerated FDA approval in March 2024 for adults with noncirrhotic MASH and moderate-toadvanced fibrosis, consistent with fibrosis stages F2–F3, to be used alongside diet and exercise.10 Semaglutide 2.4 mg was subsequently granted accelerated FDA approval in August 2025 for adults with noncirrhotic MASH with moderate-toadvanced fibrosis, becoming the first glucagon-like peptide-1 receptor agonist approved for this indication.11
These approvals mark an important transition from lifestyle-based management alone to disease-targeted therapy.6,9 However, access is likely to be highly uneven. Even when liver-directed therapies are approved, their availability in routine practice may be constrained by cost, reimbursement policies, health system capacity, and the absence of clearly defined treatment pathways. This is particularly relevant for many MENA health systems and for other reimbursementconstrained settings elsewhere.12 In addition, glucagon-like peptide-1 receptor agonists remain primarily accessed through diabetes and obesity indications in many countries, rather than through liver-directed treatment pathways. Without mechanisms such as differential pricing, reimbursement reform, local access agreements, and integration of MASLD pharmacotherapy into broader noncommunicable disease programmes, approved therapies may remain available only to a small proportion of eligible patients.7,12 This concern is not unique to MENA. European clinicians may face a parallel challenge in which a drug can be licensed, supported by evidence, and incorporated into clinical guidance, yet remains difficult to access because of cost, reimbursement restrictions, or service capacity.3
PILLAR 4: CARE COORDINATION AND SYSTEM FRAGMENTATION
Patients with Type 2 diabetes, hyperlipidaemia, obesity, and MASLD are typically managed separately for each condition in the corresponding specialty clinic, with no unified multidisciplinary care plan coordinating their treatment.12 Addressing MASLD as the hepatic
manifestation of metabolic disease has not been adopted in routine clinical practice; this is fragmented care in its most recognisable form, leaving patients with no clear structured care plan and no clear referral pathway. European primary care is not structurally different in this regard. Both settings therefore need the same structural solution: a primary care physician initiates MASLD screening and diagnostic pathway in at-risk patients and coordinates with the relevant specialties from that point forward.9
SHARED CHALLENGES, TRANSFERABLE LESSONS
The rising burden of metabolic diseases (obesity and Type 2 diabetes) across Southern and Eastern Europe mirrors the metabolic trajectory that previously preceded MASLD surge in the MENA region. Primary care system gaps and unpreparedness must be addressed, and routine metabolic screening protocols should be implemented to translate guidelines into active clinical practice. The patients are already there, and infrastructure must be ready for them.
Working within limited and variable resources, MENA clinicians have built practical MASLD care pathways. Point-of-care ultrasound screening combined with FIB-4 scoring, followed by selective referral for further evaluation, represents a resource adapted experience that is transferable and can be recognised and adopted by European primary care settings facing the same constraints.
MENA is a cornerstone in the global MASLD story, and it offers an early signal to healthcare systems worldwide. The clinical and strategic lessons from hepatitis C virus elimination experience are directly applicable to the ongoing MASLD challenge and represent a learning opportunity that deserves to be studied and globally adapted. For European health systems facing the same disease, the same patients, and the same challenges, MENA’s experience is now documented and its lessons are available. What was learned under pressure in MENA, Europe can build on and adapt to its own context (Figure 2).
Figure 2: Proposed MASLD care pathway for challenging care settings: from primary care screening to multidisciplinary management.
1. Primary care identification of at-risk patients
Patients with ≥1 cardiometabolic risk factor: obesity, Type 2 diabetes, hypertension, dyslipidaemia, or unexplained elevated liver enzymes.
Applicable in all settings regardless of resource level.
POCUS to detect hepatic steatosis combined with FIB-4 index calculation (age × AST / [platelet count × √ALT]). Both tools are low-cost, widely available, and validated for primary care use.
FIB-4 <1.3
Low risk for advanced fibrosis
FIB-4 1.3–2.67 FIB-4 >2.67
Indeterminatesecond-line NIT High risk: refer to hepatologist
PRIMARY CARE SETTING
LOW RISK: FIB-4 <1.3
HIGH RISK: FIB-4 ≥2.67
Primary Care Management Second-Line NIT/ Specialist Referral
3. Hepatology: comprehensive risk stratification
stratification
Advanced NIT assessment (VCTE, ELF, MRE where available).
Confirmation of fibrosis stage.
Identification of at-risk MASH.
Consider liver biopsy only when non-invasive tests are indeterminate or alternative diagnoses suspected.
4. Multidisciplinary management plan
Coordinated input from hepatology, endocrinology, nutrition, and health psychology.
Pharmacotherapy where indicated (resmetirom for F2-F3 MASH; GLP-1 receptor agonists for eligible patients). Regular follow-up with primary care as the coordinating hub.
PRIMARY CARE SETTING
Lifestyle counselling, metabolic risk factor optimisation, repeat FIB-4 every 1-2 years. Patient remains within primary care setting.
VCTE (fibroscan) where available, or direct referral to hepatologist.
FIB-4 >2.67 warrants direct specialist referral without delay.
HEPATOLOGY/ GASTROENTEROLOGY
MULTIDISCIPLINARY TEAM
Proposed MASLD screening and management pathway for primary care-led implementation in challenging care settings. The pathway is designed to function across resource-variable contexts using non-invasive, widely available tools.
The challenges documented across MENA and European care settings will not be resolved through guidelines alone. MASLD requires coordinated action at the clinical, health system, and policy levels. Clinically, immediate priorities include improving physician and public awareness, strengthening medical education, and embedding non-invasive risk stratification into routine metabolic care. At the health system level, care pathways should be reorganised to support early identification, structured referral, access to appropriate diagnostic tools, multidisciplinary management, and equitable access to approved therapies. At the policy level, MASLD should be integrated more clearly
into national non-communicable disease strategies, with governments and health ministries prioritising national screening approaches, locally adapted clinical guidance, implementation research, and sustainable access to pharmacotherapy.
MASLD is a global disease shaped by local health system realities. The MENA region, as one of the most affected areas worldwide, illustrates how high disease burden, variable resources, and fragmented care can expose the implementation gaps that many European systems are also beginning to face. The central task is no longer only to define MASLD, but to identify patients earlier, stage risk more consistently, and build care pathways that reach patients before advanced liver disease develops.
2. POCUS + FIB-4 score calculation
References
1. World Health Organization (WHO). Global hepatitis report 2024: action for access in low- and middleincome countries. 2024. Available at: https://www.who.int/publications/i/ item/9789240091672. Last accessed: 15 June 2026.
2. Miao L et al. Current status and future trends of the global burden of MASLD. Trends Endocrinol Metab. 2024;35(8):697-707.
3. European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASDEASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol. 2024;81(3):492-542.
4. Younossi ZM et al. Prevalence of metabolic dysfunction-associated steatotic liver disease in the Middle East and North Africa. Liver Int. 2024;44(4):1061-70.
5. Alqahtani SA et al. Knowledge about metabolic dysfunction-associated steatotic liver disease among medical professionals from countries in the MENA region. Ann Hepatol. 2025;30:101569.
6. El-Kassas M et al.; Steatotic Liver Disease Study Foundation in Middle East and North Africa (SLMENA) Collaborators. Mapping metabolic dysfunction-associated steatotic liver disease models of care across 17 Middle East and North Africa countries: insights into guidelines, infrastructure, and referral systems. J Clin Transl Hepatol. 2025;13(10):791-808.
7. Abdelhamed W et al. Metabolic dysfunction-associated steatotic liver disease in Egypt. World J Gastroenterol. 2025;31(45):111643.
8. El-Kassas M et al. Establishing consensuson Arabic medical terminology for steatotic liver disease: a mixed-methods approach. Arab J Gastroenterol. 2025;26(2):143-8.
9. Younossi ZM et al. Global consensus recommendations for metabolic
dysfunction-associated steatotic liver disease and steatohepatitis. Gastroenterology. 2025;169(5): 1017-1032.e2.
10. Keam SJ. Resmetirom: first approval. Drugs. 2024;84(6):729-35.
11. U.S. Food and Drug Administration (FDA). FDA approves treatment for serious liver disease known as ‘MASH’. 2025. Available at: https://www.fda. gov/drugs/news-events-human-drugs/ fda-approvestreatment-serious-liverdisease-known-mash. Last accessed: 15 June 2026.
12. AlNaamani KM et al. Making metabolic dysfunction-associated steatotic liver disease medicines affordable: lessons from hepatitis C. Ann Hepatol. 2026;31(2):102213.
Clinical Outcomes of Cross-Sectional Imaging to Investigate Hepatic Focal Fatty Sparing in Patients with Advanced Chronic Liver Disease
Background: Focal fatty sparing (FFS) is a benign, localised absence of hepatic fat in an otherwise steatotic liver, frequently identified on surveillance liver ultrasound in patients with advanced chronic liver disease (ACLD). However, FFS can mimic hepatocellular carcinoma (HCC), and may prompt clinicians to further investigate with cross-sectional imaging, such as CT or MRI.
Aim: This study aimed to assess the incidence of HCC in patients with ACLD with newly identified FFS on surveillance ultrasound, evaluate radiographic concordance between ultrasound and cross-sectional imaging, and describe associated demographic and metabolic characteristics.
Methods: The authors retrospectively identified 53 patients with ACLD with new FFS detected during routine liver ultrasound, under a nurse-led HCC surveillance programme, between January 2016–December 2024. Inclusion criteria included liver stiffness measurement ≥10 kPa or nodular liver contour on ultrasound. Clinical data, ACLD aetiology, metabolic risk factors, alpha fetoprotein (AFP) levels, and follow-up imaging (CT/MRI) were analysed.
Results: A total of 445 patients were screened, and 53 patients were identified for analysis. The median age was 60 years (range: 37–83 years), 67.9% were male, and most had MASLD (41.5%) or mixed aetiologies (43.4%). The median AFP was 3.3 IU/mL (range: 0–10), and the median BMI was 31.7 kg/m2. Type 2 diabetes, dyslipidaemia, and hypertension were present in 28 (52.8%), 27 (50.9%), and 22 (41.5%) patients, respectively. Multiple liver-related risk
factors were observed in 37 (69.8%) patients. Cross-sectional imaging was performed in 38 (71.7%) patients, with concordant FFS findings in eight (21.1%; 95% CI: 9.6–37.3). No HCC cases were diagnosed. Fifteen patients did not undergo subsequent crosssectional imaging as per clinician’s decision. Instead, they resumed routine 6-monthly HCC surveillance with a median follow-up duration of 25 months (range: 7–112 months) and no HCC cases were diagnosed.
Conclusion: New FFS on surveillance ultrasound in patients with ACLD was not associated with increased risk of HCC. Routine escalation to CT or MRI imaging may be more appropriate in the presence of high-risk features such as lesion size ≥10 mm, nodularity, or elevated AFP. This approach could reduce patient harm through radiation exposure and reduce healthcare costs, emphasising the need for a standardised diagnostic pathway.
Key Points
1. In patients with advanced chronic liver disease undergoing hepatocellular carcinoma (HCC) surveillance, newly detected focal fatty sparing (FFS) on ultrasound often prompts escalation to cross-sectional imaging. These findings show that FFS was not associated with HCC, challenging the assumption that new FFS invariably warrants cross-sectional imaging.
2. In a single-centre retrospective cohort of 53 patients with advanced chronic liver disease and newly detected FFS on surveillance ultrasound, 71.7% underwent CT or MRI. Concordant FFS was confirmed in only 21.1% of cases, and no HCC diagnoses were made during a median follow-up of 25 months.
3. These data support a risk-stratified approach, reserving CT or MRI for high-risk lesions, such as lesions ≥10 mm in size, with suspicious morphology or elevated alpha fetoprotein, in line with international guidance. Selective imaging may minimise unnecessary radiation exposure, contrast risk, incidental findings, and healthcare costs, while maintaining safe HCC surveillance in this high-risk population.
INTRODUCTION
Focal fatty sparing (FFS) is characterised by localised regions within the liver with an absence of fat infiltration, appearing as hypoechoic or isoattenuating areas on imaging amidst a diffusely steatotic liver.1,2 It typically occurs in predictable anatomical locations such as the gallbladder and hepatic hilum, influenced by directed splanchnic venous supply to the liver other than portal venous flow.3
Although benign, FFS can mimic true focal liver lesions, raising concern for hepatocellular carcinoma (HCC) or metastasis. The differentiation of such focal spared areas from true tumours has been a diagnostic challenge, as ultrasound alone cannot always reliably distinguish FFS from a tumour.
The distinction is clinically significant in patients with advanced chronic liver disease (ACLD), where the annual HCC risk is approximately 2.4%.4 Surveillance for HCC in ACLD commonly relies on liver ultrasound and serum alpha fetoprotein (AFP) every 6 months.5 Newly detected FFS may prompt clinicians to further investigate with cross-sectional imaging, such as liver multiphase CT or liver MRI. However, this practice poses risks of radiation exposure, contrast-related risks, incidental findings, and healthcare resource utilisation.
Despite the clinical relevance of FFS in HCC surveillance, there is a lack of literature evaluating the outcomes of FFS detection in patients with ACLD undergoing surveillance. To the authors’ knowledge, this represents the first study to systematically examine the incidence of HCC and the diagnostic utility of cross-sectional imaging following newly identified FFS in a dedicated HCC
surveillance cohort. This evidence gap has growing relevance in contemporary hepatology practice given the rising prevalence of metabolic liver disease.
This study aimed to evaluate the incidence of HCC in patients with ACLD with new FFS detected on surveillance ultrasound, assess concordance with cross-sectional imaging findings, and describe associated demographic and metabolic characteristics of this population.
METHODS
A retrospective observational cohort study was conducted at Gold Coast University Hospital, Queensland, Australia. The Gold Coast Hospital and Health Service Research Office deemed the study as not requiring HREC review. For publication purposes, the HREC reference is EX/2024/QGC/114893.
Patients with ACLD enrolled in a nurseled HCC surveillance programme from January 2016–December 2024 were screened. Eligibility criteria included newly detected FFS on routine surveillance liver ultrasound in patients with confirmed ACLD. Exclusion criteria included patients under the age of 18 years, those without a confirmed diagnosis of ACLD, preexisting or previously diagnosed HCC, and prior liver transplantation. ACLD was defined according to the Baveno VII consensus guidelines, using a liver stiffness measurement (LSM) ≥10 kPa on Fibroscan or nodular liver contour on ultrasound where LSM was inconclusive.6,7 ACLD aetiologies were classified in accordance with current nomenclature guidelines as alcohol-related liver disease, MASLD, chronic viral hepatitis B or C, or mixed aetiology. Mixed aetiology was defined as the co-existence of two or more contributing aetiologies, most notably MASLD combined with alcohol-related liver disease or chronic hepatitis.
FFS was defined as a hypoechoic, solid, avascular focus within a background of diffusely hyperechoic liver parenchyma irrespective of hepatic location. Lesion size was not included as the sizing was inconsistently stated across reports.
Ultrasound findings were retrospectively documented from imaging reports. Demographic data, ACLD aetiology, metabolic risk factors (Type 2 diabetes, dyslipidaemia, hypertension), serum AFP, LSM values, and ultrasound findings were retrospectively extracted from electronic medical records. CT or MRI performed after FFS detection was reviewed for concordance and presence of HCC. The primary outcome was the diagnosis of HCC following newly detected FFS on ultrasound. The secondary outcome was HCC detection on longitudinal follow up until July 2025 among patients who did not undergo crosssectional imaging. Continuous variables are reported as median with range. Categorical variables are expressed as frequencies and proportions. The primary outcome is reported with 95% CI using the frequentist framework method. Given the observational nature of the study and the sample size of 53 patients, no formal power calculation was performed.
RESULTS
Of 445 screened patients, 53 met inclusion criteria. Median age was 60 years (range: 37–83 years), with 36 males (67.9%). The majority had MASLD (41.5%) or mixed aetiology (43.4%). Median LSM was 13.6 kPa, median AFP was 3.3 IU/mL, and median BMI was 31.7 kg/m². Two patients did not have an LSM recorded but met inclusion criteria due to presence of a nodular liver contour on liver ultrasound. Metabolic comorbidities were frequent, including Type 2 diabetes (52.8%), dyslipidaemia (50.9%), and hypertension (41.5%). Nearly 70% had two or more of the listed metabolic risk factors for liver disease. Cross-sectional imaging was performed in 38 (71.7%) patients. Concordant FFS findings on CT or MRI were identified in eight (21.1%; 95% CI: 9.6–37.3) cases. No patients were diagnosed with HCC during the study period. Of the 38 patients who underwent cross-sectional imaging, five had incidental findings that required further investigations. The 15 patients who did not undergo further imaging continued routine 6-monthly ultrasound surveillance without detection of a focal liver lesion. These patients were
followed longitudinally until July 2025, with a median follow-up duration of 25 months (range: 7–112 months). No HCC diagnoses were made in this subgroup during followup (Table 1).
Table 1: Patient demographics and imaging data.
DISCUSSION
Newly detected FFS on ultrasound can mimic a true focal mass and may raise concern for HCC in patients with ACLD.8,9 In the authors’ cohort, 71.7% of newly detected FFS lesions were further investigated with cross-sectional imaging,
Patients 53
Gender
Male
36/53 (67.9%)
Female 17/53 (32.1%)
Median age (range), y 60 (37–83)
Chronic liver disease aetiology
MASLD
22/53 (41.5%)
Cured hepatitis C 6/53 (11.3%)
Alcohol 2/53 (3.8%)
Mixed aetiology
Liver stiffness measurements (of 51/53 patients)
Median LSM (range), kPa
23/53 (43.4%)
13.6 (7.1–61.8)
LSM ≥10 kPa 47/51 (92.2%)
Median AFP (range), IU/mL
Median BMI (range), kg/m²
Metabolic risk factors
Diabetes
Dyslipidaemia
Hypertension
Multiple risk factors
Cross-sectional imaging
Yes
3.3 (0–10)
31.7 (19.2–53)
28/53 (52.8%)
27/53 (50.9%)
22/53 (41.5%)
37/53 (69.8%)
38/53 (71.7%)
Liver CT multiphase 33/38 (86.8%)
Liver MRI+contrast 5/38 (13.2%)
No 15/53 (28.3%)
Concordance of FFS on cross-sectional imaging 8/38 (21.1%; 95% CI: 9.6–37.3)
reflecting a common clinical practice to escalate to CT or MRI when faced with indeterminate findings on ultrasound. In this healthcare setting, there were no barriers to accessing cross sectional imaging when clinically indicated.
Imaging concordance between ultrasound and cross-sectional imaging was limited, with FFS confirmed in 21.1% (95% CI: 9.6–37.3%) of cases. However, this should not be interpreted as evidence of poor ultrasound sensitivity or diagnostic inaccuracy. The two imaging modalities detect hepatic fat through different physical principles. Ultrasound identifies FFS as a relative hypoechogenicity against a hyperechoic steatotic background, whereas cross-sectional imaging relies on attenuation differences for CT or chemicalshift signal dropout for MRI.10 Therefore, FFS that is sonographically apparent may not meet quantitative thresholds for detection on cross-sectional imaging, particularly when background steatosis is mild. Discordance between modalities likely reflects differences in the technique sensitivity for detecting subtle parenchymal fat variation rather than ultrasound inaccuracy. The possibility that some nonconcordant cases represented genuine FFS below the detection threshold of CT or MRI cannot therefore be excluded.
In the authors’ cohort, no HCC diagnoses were made, suggesting that routine escalation to CT or MRI in the absence of high-risk features may not always be warranted. This is consistent with current American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) guidance, which recommend diagnostic CT or MRI for any new nodule ≥10 mm, nodules with suspicious morphology, or when accompanied by an elevated or rising AFP, while lesions <10 mm without high-risk features are typically managed with short interval repeat ultrasound.5,11 However, this must be interpreted with caution, given the retrospective single-centre design, small sample size, and absence of a comparator group.
The decision to pursue to cross-sectional imaging, while invaluable for diagnosis, exposes patients to ionising radiation and carries risks of contrast-related adverse events for CT, whereas MRI avoids radiation but remains costly and may still pose contrast-related risks.12 Cross-sectional imaging may reveal incidental findings that can trigger a cascade effect of care. In the authors’ study, five incidental findings were identified, none of which resulted in a new clinically significant diagnosis, yet each prompted further imaging and potentially invasive investigations. This illustrates how incidental findings can lead to increased healthcare costs and a considerable psychological burden for patients, without improving outcomes.13
Several limitations warrant acknowledgement. The retrospective design introduced selection and ascertainment bias. Patients were included only if FFS was identified and reported, and the decision to proceed with cross-sectional imaging was clinician dependent rather than protocol driven. Patients who did not undergo crosssectional imaging may have represented a clinically lower-risk subgroup, and the absence of HCC in this group should be interpreted in that context. Ultrasound detection of FFS is further influenced by degree of background steatosis, operator experience, equipment quality, and patient habitus, suggesting the true prevalence of FFS in ACLD surveillance populations is likely underestimated.14,15
Although limited by its retrospective single-centre design and small sample size, this study represents the first focused investigation of FFS in a cohort with ACLD undergoing HCC surveillance. It provides valuable clinical insights into the frequency of cross-sectional imaging escalation, the complexity of intermodality concordance on imaging, and the consequences of incidental findings. This study offers a foundation upon which prospective, multicentre studies can be designed to better define the optimal HCC surveillance and investigation pathway for this population.
In this cohort of patients with ACLD undergoing HCC surveillance, no HCC was diagnosed following newly detected FFS on liver ultrasound, and concordance with cross-sectional imaging was limited. These findings support a more selective, riskstratified imaging strategy consistent with currently AASLD and EASL guidance, with the potential to reduce radiation exposure, contrast-related risks, and healthcare resource use. To the authors’ knowledge,
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6. de Franchis R et al. Baveno VII Faculty. Baveno VII - renewing consensus in portal hypertension. J Hep. 2022;76(4):959-74.
this is the first study to systematically examine HCC incidence and cross-sectional imaging utility following newly detected FFS in a dedicated HCC surveillance cohort. Prospective multicentre studies with standardised imaging protocols and longer follow-up are needed before definitive recommendations can be made.
7. Barr RG et al. Update to the Society of Radiologists in Ultrasound liver elastography consensus statement. Radiology. 2020;296(2):263-74.
8. Fu R et al. Nodular focal fat sparing of liver mimicking hepatocellular carcinoma in contrast-enhanced ultrasound: a case report. Medicine (Baltimore). 2019;98(22):e15431.
10. Starekova J et al. Quantification of liver fat content with CT and MRI: state of the art. Radiology. 2021;301(2):250-62.
11. Singal AG et al. AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. 2023;78(6):1922-65.
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a comprehensive review. iRADIOLOGY. 2024;2(5):430-68.
13. Ganguli I et al. Cascades of care after incidental findings in a US national survey of physicians. JAMA Netw Open. 2019;2(10):e1913325.
14. Yang S-LD et al. Grading fatty liver and detecting liver pathological features - is there consensus between sonographers and radiologists? Ultrasound MedBiol. 2019;45:S33.
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