EMJ Hepatology 12.1 2024

Hepatology

Interview:

Anil Dhawan and Mario Strazzabosco discuss the future of liver transplantation

Prevention of Decompensation in Compensated Cirrhosis: Non-Selective BetaBlockers for Everyone? Feature:

Could PFIC be the hidden cause of cholestasis, or pruritus in your adult patients?

Progressive familial intrahepatic cholestasis (PFIC) is a group of rare, genetic cholestatic disorders characterised by:1

Elevated serum bile acid levels

Progressive liver disease

Debilitating pruritus

While PFIC often affects infants and children, this disorder also occurs in adults.1,2

As a rare disease, PFIC may not immediately be suspected in adults presenting with pruritus and cholestasis1,2

• In one study, 1 in 4 patients with adult-onset cholestatic liver disease had a PFIC-related genotype3

• PFIC may be insidious in adults1

• Left untreated, PFIC can lead to end-stage liver disease 1,2,4

Prompt diagnosis and treatment are key1,2

Consider PFIC as a potential cause of unexplained cholestasis in adults

Check for elevated serum bile acids as part of your differential diagnosis

Utilize genetic testing to confirm the diagnosis

Bylvay (odevixibat) is indicated for the treatment of progressive familial intrahepatic cholestasis (PFIC) in patients aged 6 months or older5

References:

1. Srivastava A. J Clin Exp Hepatol 2014;4(1):25–36. 2. McKiernan P et al. JHEP Rep 2023;6(1):100949. 3. Nayagam JS et al. Hepatol Commun 2022;6(10):2654–2664. 4. Baker A et al. Clin Res Hepatol Gastroenterol 2019;43(1):20–36. 5. Bylvay Summary of Product Characteristics, July 2021. 6. Thompson RJ et al. Lancet Gastroenterol Hepatol 2022;7:830–842. 7. Thompson RJ et al. Poster presented at EASL 2023 Jun 21-24, 2023 Vienna, Austria.

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions to adverse.events@ipsen. com and via the national reporting system as described in section 4.8 of the product prescribing information.

cholestasis, elevated sBA

Bylvay (odevixibat) is the first licensed IBATi approved for PFIC in Europe5

Bylvay is a novel, reversible, potent, selective ileal bile acid transporter (IBAT) inhibitor, that addresses the underlying cause of cholestasis5

Disrupts enterohepatic circulation of bile acids2

Decreases reuptake of bile acids5 Increases clearance of bile acids through the colon5

… to reduce serum bile acid levels and combat intrahepatic cholestasis2,5

Bylvay provides:

• Significant and sustained reduction in serum bile acids5-7

• Clinically meaningful relief from pruritus5,6

• Improvements in parameters linked to liver health (ALT, AST, bilirubin)5,6

Catch up with the latest discussions of adult-onset PFIC in the scientific community

Watch a recording of the Ipsen symposium at EASL 2024

Hear the Professor Thomas Berg (Germany), Dr Palak Trivedi (UK) and Professor Filomena Morisco (Italy) describe best practice in diagnosing and managing PFIC in adults.

VIEW SYMPOSIUM ONLINE NOW

This is a promotional symposium for healthcare professionals only.

Intestine

Faecal excretion of excess bile Impaired

6 Editorial Board

9 Welcome

11 Foreword

Congress Review

12 Review of the European Association for the Study of the Liver (EASL) International Congress 2024, 5th–8th June 2024

Congress Feature

20 The Next Frontier in Metabolic Dysfunction-Associated Steatotic Liver Disease

Ada Enesco

24 Healthy Livers, Healthy Lives

Aleksandra Zurowska

Symposium Review

27 Re-imagining Primary Biliary Cholangitis Care: Patient-Centric, Utilising Biochemistry, Controlling Symptoms

Abstract Reviews

36 Suitability of Non-Invasive Tests in the Evaluation of Liver Fibrosis in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease

Yagüe et al.

38 Gut Dysbiosis is Associated With the Severity of Liver Fibrosis

Assessed by Magnetic Resonance Elastography in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease

Satthawiwat et al.

40 Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide

Interruption in Hepatitis B Virus/HIV Co-Infected Individuals in the USA: Monitoring Practices and Incidence of Hepatitis B Virus

Reactivation or Hepatitis Flare

Dieterich et al.

42 Barriers and Motivators for Implementation of Lifestyle Changes in Metabolic Dysfunction-Associated Steatotic Liver Disease

Veldhuis et al.

44 TGR5 Deficiency in Liver Sinusoidal Endothelial Cells Disrupts Angiocrine Signalling During Liver Regeneration After Partial Hepatectomy

Kaur et al.

46 Abstract Highlights

Congress Interviews

58 Loreta Kondili

63 Sven Francque Interviews

66 Mario Strazzabosco

69 Anil Dhawan Feature

74 Prevention of Decompensation in Compensated Cirrhosis: Non-Selective Beta-Blockers for Everyone?

Sharma and Tripathi

Article

81 Tongue Hyperpigmentation with Peginterferon α-2b Therapy in Hepatitis B: Case Series With Review of Literature Ghosh and Samanta

"A groundbreaking event which promises to continually improve education, advocacy, and policy in hepatology in Europe"

Editorial Board

Editor-in-Chief

Prof Markus Peck-Radosavljevic

Klinikum Klagenfurt am Wörthersee, Austria

Professor of Medicine and Chairman, Department of Gastroenterology and Hepatology, Endocrinology and Nephrology, Klinikum Klagenfurt am Wörthersee, Austria

Dr Ahmed Elsharkawy

University Hospitals Birmingham, UK

Dr Fabio Marra

University of Florence, Italy

Dr Ken Simpson

University of Edinburgh, UK

Prof Ashwani Singal

University of South Dakota

Sanford School of Medicine, USA

Dr Amr Amin

United Arab Emirates University, UAE

Dr Kieron B.L. Lim

Mount Elizabeth Hospital Liver Transplant Program, Singapore

Prof Cecília Rodrigues

University of Lisbon, Portugal

Dr Dhiraj Tripathi

Queen Elizabeth Hospital Birmingham, UK

Aims and Scope

EMJ Hepatology is an open-access, peer-reviewed eJournal committed to helping elevate the quality of liver healthcare globally by informing healthcare professionals on all aspects of liver health and disease.

The journal is published annually, six weeks after the European Association for the Study of the Liver (EASL) Congress, and features highlights from this congress, alongside interviews with experts in the field, reviews of abstracts presented at the congress, as well as in-depth features on congress sessions. 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 publishes 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 doubleblind peer-review process, maintains high standards of copy editing, and ensures timely publication.

EMJ Hepatology focuses on topics that are relevant to healthcare professionals in hepatology. We do not publish veterinary science papers or laboratory studies that are 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 hepatology.

Further details on coverage can be found here: www.emjreviews.com

Editorial Expertise

EMJ is supported by various levels of expertise:

• Guidance from an Editorial Board consisting of leading authorities from a wide variety of disciplines.

• Invited contributors who are recognised authorities in their respective fields.

• Peer review, which is conducted by expert reviewers who are invited by the Editorial team and appointed based on their knowledge of a specific topic.

• An experienced team of editors and technical editors.

Peer Review

On submission, all articles are assessed by the editorial team to determine their suitability for the journal and appropriateness for peer review.

Editorial staff, following consultation with either a member of the Editorial Board or the author(s) if necessary, identify three appropriate reviewers, who are selected based on their specialist knowledge in the relevant area.

All peer review is double blind. Following review, papers are either accepted without modification, returned to the author(s) to incorporate required changes, or rejected.

Editorial staff have final discretion over any proposed amendments.

Submissions

We welcome contributions from professionals, consultants, academics, and industry leaders on relevant and topical subjects. We seek papers with the most current, interesting, and relevant information in each therapeutic area and accept original research, review articles, case reports, and features.

We are always keen to hear from healthcare professionals wishing to discuss potential submissions, please email: editorial.assistant@emjreviews.com

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EMJ is distributed through controlled circulation to healthcare professionals in the relevant fields across Europe.

Indexing and Availability

EMJ is indexed on DOAJ, the Royal Society of Medicine, and Google Scholar®; selected articles are indexed in PubMed Central®

EMJ is available through the websites of our leading partners and collaborating societies. EMJ journals are all available via our website: www.emjreviews.com

Open Access

This is an open-access journal in accordance with the Creative Commons Attribution-Non Commercial 4.0 (CC BY-NC 4.0) license.

Congress Notice

Staff members attend medical congresses as reporters when required.

This Publication

Launch Date: 2012 Frequency: Yearly Online ISSN: 2053-4221

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 2024) and the use of the organisations does not constitute endorsement or media partnership in any form whatsoever. The cover photo is of Milan, Italy, the location of EASL 2024.

Front cover and contents photograph: Milan, Italy © Summit Art Creations / stock.adobe.com

Editor

Evgenia Koutsouki

Editorial Manager

Darcy Richards

Copy Editors

Noémie Fouarge, Katheeja Imani, Jenna Lorge

Editorial Co-ordinator

Abigail Craig

Editorial Assistants

Victoria Antoniou, Helena Bradbury, Ada Enesco, Laith Gergi, Katrina Thornber, Katie Wright, Aleksandra Zurowska

Creative Director

Tim Uden

Design Manager

Stacey Rivers

Senior Designers

Roy Ikoroha, Steven Paul

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Junior Designers

Dillon Benn Grove, Shanjok Gurung

Senior Performance

& Insight Lead

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Dan Healy

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Spencer Gore

Welcome

Dear Readers,

I am delighted to welcome you to the 2024 issue of EMJ Hepatology, covering topical insights from this year’s European Association for the Study of the Liver (EASL) Congress, which took place in Milan, Italy. The event saw a plethora of discussions, with metabolic dysfunction-associated liver disease and patient-centred approaches to managing pruritus emerging as key topics of exploration.

Our Congress features look at the increasing prevalence and future promise for diagnosis and treatment of metabolic dysfunction-associated liver disease. The issue also includes cutting-edge abstract reviews spotlighting research on hepatitis B reactivation, liver regeneration, and fibrosis. Make sure not to miss our exclusive interviews with key opinion leaders from EASL, as well as experts in paediatric hepatology and hepato-oncology.

Amongst our peer-reviewed content is a compelling feature article discussing the use of non-selective beta-blockers for cirrhotic decompensation prevention, and a review of tongue hyperpigmentation secondary to peginterferon α-2b treatment.

I would like to thank our Editorial Board, authors, peer reviewers, and interviewees for their contributions to this issue. I would also like to invite you, our valued readers, to provide feedback on our content via our website. Your insights will be crucial in assisting our commitment to delivering high-quality, timely, and relevant content.

I hope you enjoy this issue of EMJ Hepatology!

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Evgenia Koutsouki Editor

Foreword

It is with great pleasure that I present to you the latest issue of EMJ Hepatology. In this edition, you will find peer-reviewed articles on some of the most exciting topics in the field, interviews with internationally renowned hepatologists, and an extensive review of the European Association for the Study of the Liver (EASL) Congress 2024, which took place in Milan, Italy, from 5th–8th June.

This year’s Congress saw experts from around the world come together to discuss the latest research and developments in the field. Sessions were made up of plenary lectures, abstract presentations, and large-scale symposia, with topics ranging from addressing pruritus in primary biliary cholangitis to the future of treatment for metabolic dysfunction-associated steatotic liver disease (MASLD).

In the following pages of this journal, you will find a summary of the insightful session, ‘Future of Hepatology: The Next Frontier in MASLD’, chaired by renowned experts in the field, Dina Tiniakos, National & Kapodistrian University of Athens, Greece; and Hannes Hagström, Karolinska University Hospital, Stockholm, Sweden. This session explored current and future methods of treating and measuring progression of MASLD, as well as addressing the ever-present question of how AI may one day be applied to treatment. This topic, and many more, are explored throughout this review of EASL.

In addition to insightful Congress coverage, EMJ Hepatology 12.1 features multiple interviews with leading experts in the field, each with a different focus in hepatology, and each doing their part to improve liver care across the globe. From Anil Dhawan, an experienced liver transplant specialist, to Sven Francque, EASL Education Councillor, and Loreta Kondili, EASL Policy and Public Health Committee Member, this issue provides a range of insights into personalised treatment and care. Mario Strazzabosco sheds further light on this topic in his own interview, sharing with us how he works closely with his patients to provide the best care possible, and why he recommends this approach for all hepatologists.

Mario Strazzabosco shares with us how he works closely with his patients to provide the best care

Lastly, I would like to take this opportunity to thank everyone who has contributed to this spectacular issue, including all the authors, peer reviewers, interviewees, and the Editorial Board. I hope you enjoy reading this journal.

Markus Peck-Radosavljevic

Professor of Medicine and Chairman, Department of Gastroenterology and Hepatology, Endocrinology and Nephrology, Klinikum Klagenfurt am Wörthersee, Austria

EASL 2024

A groundbreaking event which promises to continually improve education, advocacy, and policy in hepatology in Europe

Review of the European Association for the Study of the Liver (EASL) International Congress 2024 Congress Review

Location: Paris, France

Date: 5th–8th June 2024

Citation: EMJ Hepatol. 2024;12[1]:12-19. https://doi.org/10.33590/emjhepatol/CEXN5013.

This June, Milan, Italy, became more than the fashion capital of the world; from the 5th–8th June 2024, this historic city housed thousands of the brightest minds in the field of hepatology, coming together to present and discuss the latest developments, innovations, and insights into the future of liver care.

This year’s European Association for the Study of the Liver (EASL) International Congress featured symposia, roundtable discussions, abstract sessions, and many more presentations on all the hottest topics in hepatology today.

Talks surrounded the latest research in treating metabolic dysfunction-associated steatotic liver disease, as well as managing pruritus in primary biliary cholangitis, with insights from experts as well as patients. The Congress shed light on all of the most fascinating research in the world of liver disease today.

The excitement kicked off with an introduction from Aleksander Krag, EASL Secretary General, who welcomed the 7,578 delegates in attendance, before going on to emphasise the goals and importance of this annual congress. Krag highlighted the need for increased educational efforts in hepatology worldwide, and stressed the need for policy interventions and prevention strategies to address the noncommunicable disease (NCD) burden in Europe. Emerging leaders and innovation in healthcare were also discussed, with

a focus on continuous improvement and collaboration to improve treatments for patients everywhere. The need for stakeholders to come together to fight obesity was additionally addressed, with the aim of reducing exposure to risk factors, and therefore decreasing mortality and disability rates.

Krag’s rousing welcome was followed by a talk from Debbie Shawcross, King’s College Hospital, London, UK. Shawcross discussed the prevalence of steatotic liver disease (SLD), which affects over one-third of the global adult population, and introduced a global coalition for Healthy Livers, Healthy

Lives, formed of various societies that focus on improving treatment and research in liver disease. Shawcross called for SLD to be integrated into the World Health Organization (WHO) NCD portfolio, “where it is not yet seen, but where it must belong,” she emphasised. It is SLD that accompanies all of the leading causes of NCD death, and therefore its importance cannot be ignored. Kremlin Wickramasinghe, WHO Regional Office for Europe, Copenhagen, Denmark, followed Shawcross’ plea for the inclusion of SLDs in the WHO portfolio with a deep dive into how cost-effective policies might be implemented to reduce NCDs in the WHO European Region. Jeffrey Lazarus, CUNY Graduate School of Public Health and Health Policy, New York, USA, then expanded on the Healthy Livers, Healthy Lives Global Coalition, which he explained was formed to address the low awareness of liver disease. This coalition, Lazarus explained, seeks to include liver disease on the United Nations agenda for 2025, and aims to work with WHO and the World Health Assembly to address liver health issues.

Increasing awareness and education in liver disease was a recurring topic throughout the introductory session; Vincenza Calvaruso, University of Palermo, Italy, and Francesco Russo, University Hospital Padua, Italy, were welcomed onto the stage to discuss 'Love Your Liver', a series of impact projects in London, UK. The mission of the project, they highlighted, is simply to create a better future for all Europeans when it comes to liver health. The

programme encompasses several activities designed to raise awareness for liver health, promote prevention and early detection of liver diseases, and to support professional development for those in the field.

Calvaruso and Russo laid out before the audience their plans to increase screening, hold interprofessional forums, and organise school visits in order to raise awareness. Last year, they proudly pointed out, EASL screened more than 400 people in Vienna, Austria, with the help of various other organisations. The hope, they emphasised, is to continue increasing these numbers, improving awareness and screening, for better health throughout the continent.

The opening ceremony continued on with awards presented by Krag and Shawcross, for the most influential and impressive emerging leaders in hepatology today. Each speaker, presenter, and award recipient expressed their excitement for the events to come in this year’s Congress, and expressed their hopes for the future of liver disease research. The end of this ceremony marked the true start of EASL 2024, a groundbreaking event which promises to continually improve education, advocacy, and policy in hepatology in Europe.

Read on for highlights from the Congress, as well as some of the most intriguing abstracts and press releases from the event, and make sure to return next year for updates from EASL 2025, taking place in Amsterdam, the Netherlands, from 7th–10th May.

Faecal Microbiota Transplant Reduces Hepatic Encephalopathy Recurrence

A RECENT study explored the effectiveness of faecal microbiota transplant (FMT) in preventing hepatic encephalopathy (HE) recurrence in patients with cirrhosis already on lactulose and rifaximin. The results of this trial were presented at EASL 2024.

The double-blind, placebo-controlled, randomised controlled trial compared two FMT administration routes: oral capsules and enemas. Sixty patients were randomly assigned to four groups: both oral and enema FMT, oral FMT with placebo enema, placebo oral with enema FMT, and both oral and enema placebos. FMT was administered at baseline, with a third oral dose at Day 30. Exclusions included recent infections, other antibiotic use, Model for End-Stage Liver Disease (MELD) scores >22, transplant history, and immunosuppression.

Results showed significantly lower HE recurrence in FMT groups compared to the placebo group

The primary outcome focused on safety, particularly HE recurrence defined as over or equal to Grade 2 on the West-Haven criteria. Secondary outcomes included other adverse events, infection rates, cirrhosis severity, cognitive function (assessed via psychometric hepatic encephalopathy score [PHES] and Stroop tests), and patientreported outcomes measured by the Sickness Impact Profile (SIP). Participants were monitored for 6 months. Six patients dropped out: three died (two from Group 1 and one from Group 2), and three failed to return for follow-up visits. Despite these dropouts, an intent-to-treat analysis was performed. Additionally, five patients missed some visits due to COVID-19 but were followed up remotely. Four infections (spontaneous bacterial peritonitis, cholecystitis, and two cellulitis) were noted but were not related to FMT.

Results showed significantly lower HE recurrence in FMT groups compared to the placebo group: 13% in Group 1, 13% in Group 2, 0% in Group 3, and 40% in Group 4 (placebo), with p=0.03. Secondary outcomes indicated higher liver-related hospitalisations in the placebo group and improvements in SIP scores among FMT recipients. Regression analysis linked HE recurrence to the number of FMT doses, male sex, and physical health impact.

In conclusion, this Phase II randomised controlled trial demonstrated that FMT, whether administered orally or via enema, significantly reduced HE recurrence in patients with cirrhosis compared to placebo, without being affected by the route of administration, donor variability, or dosage range. This suggests that FMT could be an effective strategy for preventing HE in this patient group.

Promising Novel Therapy Targeting Liver Fibrosis

RESEARCHERS at EASL 2024 presented promising findings from the CEC-11/ NAS trial, evaluating the efficacy and safety of ZED1227, a transglutaminase 2 inhibitor, in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and significant fibrosis.

The double-blind, randomised, multi-centre, placebo-controlled Phase II trial aimed to determine the optimal dose of ZED1227 for reducing liver fibrosis. The study involved 186 patients who received either 20, 50, or 100 mg/day of ZED1227 or a placebo for 12 weeks. The primary efficacy endpoint was the relative change in serum levels of PRO-C3, a marker of fibrogenesis. Of the 334 patients screened, 174 received at least one dose of the study drug or placebo, with 168 completing the study. Baseline characteristics were comparable across treatment groups, with an average age of 59.9 years, a mean BMI of 33.8 kg/ m², and 56.3% of participants having Type 2 diabetes mellitus.

In patients with higher baseline PRO-C3 levels, the drug demonstrated a more pronounced and dose-dependent effect

Results indicated a numerical reduction in PRO-C3 levels in the low (20 mg) and high (100 mg) dose groups after 12 weeks of treatment. Specifically, the least squares mean difference from placebo for the 20 mg group was -6.5%, while the 100 mg group showed an -8.1% difference; but these reductions did not achieve statistical significance. No significant effect was observed in the 50 mg group. A subgroup analysis of patients with baseline PRO-C3 levels above the median showed a dosedependent reduction in PRO-C3, with the most substantial decrease in the 100 mg group. Additionally, a dose-dependent decrease in PRO-C6, a cardiovascular disease marker, was noted in this subgroup. Responder analysis revealed that patients who responded to ZED1227 treatment had higher baseline PRO-C3, aspartate

transaminase, and alanine aminotransferase levels compared to non-responders.

Overall, ZED1227 was well-tolerated, with most adverse events being mild or moderate. Three patients discontinued the study due to adverse events, and nine serious adverse events were reported, but none attributed to the study drug. While ZED1227 showed a trend towards reducing PRO-C3 levels in patients with MASLD, the results did not reach statistical significance. However, in patients with higher baseline PRO-C3 levels, the drug demonstrated a more pronounced and dose-dependent effect. These findings suggest that ZED1227 holds the potential for treating liver fibrosis in MASLD, warranting further investigation in larger, more definitive trials.

Intelligent Liver Function Testing: 5 Years On

RESEARCH presented at EASL 2024 by Damien Leith, University of Dundee, Ninewells Hospital, UK, investigated the utilisation and evolution of Intelligent Liver Function Testing (iLFT) at NHS Tayside during the first 5 years of routine use in primary care settings.

This was in response to increasing mortality rates from chronic liver disease and frequent occurrence of abnormal liver function tests (LFT) without appropriate follow-up.

The study observed the use of iLFT in approximately 400,000 patients during the first 5 years of routine use. An automated algorithm combined clinician-entered clinical information with basic LFT results with reflex fibrosis scoring, relevant aetiological testing, and the recommended management outcomes.

Results showed that 26,459 iLFT tests were performed between August 2018–August 2023. Of these, 60.9% cascaded to a full aetiology screen, 7.4% to a partial aetiology screen, and 31.7% required no further testing. Over the past year, the demand has stabilised at an average of 860 requests per month, with 48% cascading to additional tests. iLFT’s generated 20,895 outcomes from the cascaded tests. The most frequent outcome was isolated abnormal alanine aminotransferase without fibrosis (23.7%), primarily linked to metabolic dysfunction that is associated with steatotic liver disease (MASLD). Another notable outcome was probable alcohol-related liver disease (15.0%) and MASLD (11.9%). Additionally, iLFT identified cases of MetALD (657; patients who meet both MASLD and alcohol-related fatty liver disease criteria), alpha-1 antitrypsin phenotypes associated with chronic liver disease (529), possible haemochromatosis (470), possible autoimmune conditions (230), active hepatitis C infections (87), and active

The study observed the use of iLFT in approximately 400,000 patients during the first 5 years of routine use

hepatitis B infections (19). Biochemical evidence of significant fibrosis was present in 20.0% of all requests, with 69.9% of outcomes indicating that patients could be safely managed in primary care.

iLFT has shown significant adaptability, evolving in response to clinical needs. In July 2020, Enhanced Liver Fibrosis (ELF) testing was introduced for patients with intermediate FIB-4 or NAFLD Fibrosis Scores in response to increasing secondary care hepatology clinic waiting times. This reduced secondary care referrals by around one-third. In addition, new outcomes were developed to address emerging clinical evidence, such as highlighting the risk of malignancy in patients with elevated alkaline phosphatase and thrombocytosis. Existing outcomes have also been updated to align with new guidance, including the steatotic liver disease nomenclature.

iLFT has become an integral part of liver disease investigation at NHS Tayside, 5 years since its inception. Its high usage is reflected in its wide acceptance in primary care settings. The platform has proven to be robust and adaptable, effectively responding to the challenges of the COVID-19 pandemic, new clinical evidence, and changes in disease nomenclature. Future work will focus on refining the algorithm and supporting the national rollout of this tool.

CHANCE Study Shows Current Graft Allocation Policies Fail

Patients With Acute-on-Chronic Liver Failure

SIGNIFICANT shortcomings in current graft allocation policies for patients with severe acute-on-chronic liver failure (ACLF) on the liver transplant waiting list were outlined in a report presented at EASL 2024 by Thierry Gustot, Liver Transplant Unit, HUB Hospital Erasme, Université Libre de Bruxelles, Belgium.

The global CHANCE study analysed data from 823 patients across 62 liver transplant centres in Asia, Europe, and Latin and North America. It aimed to assess the clinical outcomes of patients with ACLF Grades 2 and 3 (ACLF 2,3) undergoing liver transplantation in the current allocation systems.

ACLF is characterised by an increased risk of short-term mortality proportional to the number of organ failures. Although liver transplantations improve the survival of these patients, current organ allocation systems, primarily based on the Model for End-Stage Liver Disease (MELD) scores, do not adequately account for the risk of death due to extrahepatic organ failures. As a result, a significant number of patients with ACLF die while on the waiting list. The interim report analysed the mortality rates of patients on the waiting list.

The study analysed data from 823 patients, divided into three groups; Group 1: 376 patients with ACLF 2,3 listed for liver transplantation; Group 2: 313 patients with ACLF 0,1 and MELD >20 listed for liver transplantation; and Group 3: 134 patients with ACLF 2,3 referred for evaluation but

not listed. ACLF was defined by using the EASL Chronic Liver Failure (CLIF) criteria. The study examined rates of delisting and death according to ACLF grade, MELD-sodium score at inclusion, and geographical distribution.

ACLF is characterised by an increased risk of short-term mortality proportional to the number of organ failures

Results showed that delisting or death while on the waiting list occurred in 28% of patients in Group 1, compared to 16% in patients in Group 2, and 85% of non-listed patients in Group 3 died. The majority of patients who received liver transplants were in Groups 1 and 2 (68% and 79%, respectively; p <0.001). The time to death or delisting was significantly shorter at 38.5 days compared to the time to liver transplant at 14 days (p <0.001). Additionally, there were some geographic disparities with delisting or death rates varying significantly across continents: Asia (13%), Europe (18%), Latin America (40%), and North America (20%). While the higher rate of delisting or death for patients with ACLF 2,3 was consistent across all MELDsodium ranges compared to those without severe ACLF.

The interim results show that the current global organ allocation systems are inadequate for patients with ACLF 2,3, which leads to excessively high mortality rates on the waiting list. The findings advocate for a review and update of the organ allocation protocols to better address the needs of patients.

Cirrhosis Treatment Breakthrough: LPCN 1148

INTERVENTION with oral LPCN 1148 improves sarcopenia and hepatic encephalopathy (HE) in patients with cirrhosis, reports a recent study presented at EASL 2024. Sarcopenia, characterised by progressive and generalised muscle loss, is common in patients with cirrhosis and is linked to poor clinical outcomes, including HE.

Androgens have potential therapeutic benefits for these conditions; however, the safety and efficacy of these multimodal hormones in patients with cirrhosis have not been well researched. This study investigated the impact of LPCN 1148, an oral prodrug of testosterone, on sarcopenia and HE in patients with cirrhosis awaiting liver transplant.

In the Phase II, multicentre trial, 29 men (mean age=59±8 years; BMI=29±7 kg/m²) with cirrhosis and sarcopenia from eight centres were randomised in a 1:1 ratio to receive either LPCN 1148 (n=15) or a placebo (n=14) for 24 weeks. Following this, all participants received LPCN 1148 during a 28-week open-label extension. Participants maintained their usual diet, exercise routines, and background therapies, including rifaximin or lactulose. CT scans were conducted at 12, 24, 36, and 52 weeks to measure changes in the skeletal muscle index (SMI) at the third lumbar spine level (L3-SMI), the primary endpoint. Secondary endpoints included the frequency and severity of overt HE (OHE) events.

Baseline characteristics of the participants were similar, with a mean Model for EndStage Liver Disease score of 17 and 76% having a history of HE. At 24 weeks, participants receiving LPCN 1148 exhibited a significant increase in L3-SMI compared to the placebo group (Δ4.1±0.9 cm²/ m² versus Δ-0.6±1.2 cm²/m²; p=0.006), corresponding to a 9.9% placebo-adjusted increase with LPCN 1148. This increase was sustained through Week 52. Six participants switched from placebo to LPCN 1148 at the Week 24, all of which showed a notable SMI increase by Week 52 (Δ8.1±1.7 cm²/ m², an increase of 16.7%). During Stage 1, OHE rates were significantly lower in the LPCN 1148 group compared to the placebo

Participants receiving LPCN 1148 exhibited a significant increase in L3-SMI compared to the placebo group

group (two versus six events, respectively; p<0.050), with a longer average time to first OHE recurrence (114 versus 35 days, respectively). Adverse event rates were comparable between groups, with no new cases of drug-induced liver injury or thrombosis. There were three deaths: two in the placebo group and one in the LPCN 1148 group.

LPCN 1148 is the first treatment shown to improve sarcopenia and reduce OHE episodes in men with cirrhosis awaiting liver transplant. It was well tolerated over 52 weeks, supporting its potential for effectively treating sarcopenia and preventing HE recurrence in advanced cirrhosis.

Author:

The Next Frontier in Metabolic Dysfunction-Associated Steatotic Liver Disease

Ada Enesco, EMJ, London, UK

Citation: EMJ Hepatol. 2024;12[1]:20-23. https://doi.org/10.33590/emjhepatol/OKRX2930.

THE FUTURE of metabolic-dysfunction associated liver disease (MASLD) was discussed in an insightful session chaired by Hannes Hagström, Karolinska Institutet, Stockholm, Sweden; and Dina Tiniakos, National and Kapodistrian University of Athens, Greece, during the European Association for the Study of the Liver (EASL) Congress 2024, held in Milan, Italy from the 5ᵗʰ–8ᵗʰ June. Hot topics included the evolving role of hepatologists, novel treatments and biomarkers for MASLD, and the promise of AI in the field.

CLINICAL PATHWAYS IN 2030: WHAT, WHO, AND WHERE?

“What will the role of the hepatologist be in 2030?” Opening the session, Ian Rowe, Leeds Institute for Medical Research, UK, emphasised the importance of simplifying testing and risk prediction for MASLD. Standard routine liver ultrasound has low specificity, with the probability of steatosis remaining at almost 30% after a negative test. Recently, the LiverRisk score, developed by the LiverScreen consortium to predict liver stiffness using blood parameters, showed good performance in prediction of liver-related events; however, there is still potential for further improvement.

The role of the hepatologist will return towards management of those with most severe disease

Rowe noted that, when developing new diagnostic pathways, a low risk of false negatives cannot be balanced with a sufficient risk to justify cost and burden of treatment. For 2030, he outlined a more simplified pathway for MASLD, with no need for confirmation of steatosis in at-risk

patients; a straightforward, individualised risk prediction for management decisions; and risk thresholds for treatment defined by effectiveness, notably costeffectiveness, of treatment. With many people with MASLD already receiving likely effective treatment (e.g., glucagon‐like peptide‐1 [GLP-1] receptor agonists) from primary care, the role of the hepatologist will return towards management of those with most severe disease. However, clinicians should not stop advocating for population-level interventions.

BREAKING THE BARRIER WITH MASLD TREATMENT

Elizabetta Bugianesi, University of Torino, Italy, reminded the audience that, in order to gain provisional drug approval, resolution of metabolic dysfunction-associated steatohepatitis (MASH) with no worsening of liver fibrosis, and/or fibrosis improvement ≥1 stage, need to be demonstrated. However, full approval would be based on long-term outcomes of randomised clinical trials, involving 4–5 years of follow-up.

Bugianesi outlined the key mechanisms involved in the pathophysiology of MASLD and MASH: lipolysis and de novo

lipogenesis, leading to overflow of fatty acids, which causes formation of lipotoxic species and hepatocyte injury through mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis. These pathways serve as potential targets for the development of new treatments.

GLP-1 receptor agonists, a very successful class of drugs for MASLD, decrease hepatic glucose production, increase hepatic insulin sensitivity, and reduce de novo lipogenesis, subsequently reducing steatosis. They also offer nephroprotection and cardiovascular protection.

Further treatment options have been explored in recent trials. In a Phase IIb trial, semaglutide 0.4 mg led to resolution of MASH with no worsening of liver fibrosis in 60% of patients, and no serious adverse events reported.1 Bugianesi also spoke about twincretins, a potential therapeutic for the management of MASLD, which couple the effects of GLP-1 with those of glucagon and gastric inhibitory polypeptide (GIP). The addition of the glucagon effect enhances liver function, with increase in lipid oxidation and decrease in lipid synthesis; increases thermogenesis in brown adipose tissue; and improves cardiomyocyte survival in the heart. The addition of GIP increases the potency of GLP-1 effects. In a recent Phase IIb trial assessing the dual GIP receptor/GLP-1 receptor agonist tirzepatide in MASH, the percentage of patients showing resolution

of MASH with no worsening of liver fibrosis 48 weeks after treatment (primary endpoint) increased with tirzepatide dose (5, 10, or 15 mg), to reach almost 74% resolution with tirzepatide 15 mg.2 The same was observed for dual GCG receptor/GLP1 receptor agonist survodutide in MASH, with 83% of patients on survodutide 4.8 mg achieving the primary endpoint compared to 19.2% of the placebo group.

Resmetirom, a thyroid hormone receptor-β agonist approved for treatment of MASH F2–F3, has also been found to lower liver fat, resolve non-alcoholic steatohepatitis, and lower low-density lipoprotein cholesterol and triglycerides. In a Phase III trial, continued Bugianesi, resmetirom 100 mg led to MASH resolution in 29.9% of patients, compared to 9.7% of the placebo group; as well as a 25.9% fibrosis improvement ≥1, compared to 14.2% placebo.4

Another drug currently in clinical development, lanifibranor, a pan-peroxisome proliferator-activated receptor agonist, carries anti-inflammatory and anti-fibrotic properties, beyond lowering steatosis. A Phase IIb trial showed that 1,200 mg of lanifibranor reduced MASH in 49% of patients, and improved fibrosis in 42% of patients, with only mild side effects.5

Finally, fibroblast growth factor 21 (FGF21), an endogenous metabolic hormone with pleiotropic effects, reduces fatty acid

oxidation and lipogenesis, while also reducing inflammation and oxidative stress in the heart. However, native FGF21 has a short half-life (<2 hours). Long-acting fusion protein, pegozafermin, and longacting FGF21 analogue, efruxifermin, were recently tested in Phase IIb trials, with promising results of NASH resolution and fibrosis improvement.

Moving onto comorbidities for liver disease, Bugianesi stressed that, while weight loss is important in disease management, key lessons should be learned from bariatric surgery outcomes. For instance, a study showed that a range of 20–25% body weight loss led to the highest response rate of NASH regression without worsening of fibrosis. Moreover, after 1 year of bariatric surgery, the percentage of patients with fibrosis decreased to 66%, but after 5 years, this number fell drastically to 36.5%. Bugianesi added that the liver should be considered as a component of the cardiorenal-metabolic system. MASLD/MASH can worsen the detrimental effects of metabolic syndrome, leading to interrelated diseases such as Type 2 diabetes, cardiovascular disease, and chronic kidney disease. She concluded that interdisciplinary management is key: “All these organs belong to the same body.”

BIOMARKERS FOR MEASURING MASLD PROGRESSION

“Is liver biopsy suitable to monitor disease progression/therapeutic response in clinical practice?” was the question addressed by Raluca Pais, Pitié Salpetriere Hospital,

Paris, France. Pais explained that, while liver biopsy has long been the ‘gold standard’ and a ‘reasonably likely’ surrogate endpoint for accelerated approval in MASH clinical trials, it is now recognised as an imperfect tool, and unsuited for use in real-life clinical practice. Several challenges are currently associated with liver biopsy, especially regarding inter-observer variability in liver fibrosis assessments, and the complexity of ballooned hepatocyte feature recognition, which is a significant issue as ballooned hepatocytes are essential for the diagnosis of MASH.

Pais stated that non-invasive tests (NIT) are having a growing role in clinical practice to replace liver biopsies. A recent study showed that simple NITs like liver stiffness and the fibrosis-4 index (FIB-4) performed as well as histology in predicting clinical outcomes in patients with MASLD. Furthermore, changes in FIB-4 have been associated with risk of severe liver disease; however, more studies will be required to assess if FIB-4 can predict response to treatment. According to Pais, direct fibrosis biomarkers, which reflect the balance between fibrogenesis and fibrolysis, are probably more suitable than a simple fibrosis marker to assess disease progression. Enhanced Liver Fibrosis (ELF) score and hepatic collagen have been associated with a risk of progression to cirrhosis. Liver stiffness thresholds may also be useful for risk stratification of patients with NASH in clinical practice. Patients who progressed to a liver stiffness threshold ≥10 kPa had an almost four-fold increase in the risk of liver-related events.6

Pais emphasised that NITs should become ‘reasonably accepted’ tools to monitor disease progression and treatment response, with several levels of evidence required to select an NIT for clinical practice. These should include context of use, disease severity, drug mechanism of action, and availability of NITs in real-life setting. She also noted that a panel of NITs should be preferred to a single biomarker.

AI IN MASLD: PROMISE OR HYPE?

“Are we as physicians ready to apply AI to our patient data?” asked Jörn Schattenberg, Saarland University Medical Center, Homburg, Germany.

While AI can be harnessed to support research models for detection and risk stratification based on big data, it is only limited to the data that are available, and could be missing crucial data points, which is a significant challenge for using AI in a clinical research setting. In a recent study, Schattenberg and colleagues aimed to separate NASH versus non-NASH cases using the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) dataset. The AI Light Gradient Boosting Model identified a 14-parameter algorithm to identify NASH versus non-NASH, which could prove useful in the clinic to predict at-risk patients.7 However, he emphasised that clinicians may not always have ready access to the 14 parameters required by the AI system. “What we really need,” continued Schattenberg, “is prospective data, to collect the data points that are really important.” He highlighted the significance

References

1. Novo Nordisk. Investigation of efficacy and safety of three dose levels of subcutaneous semaglutide once daily versus placebo in subjects with non-alcoholic steatohepatitis. NCT02970942. https://clinicaltrials. gov/study/NCT02970942.

2. Eli Lilly and Company. A study of tirzepatide (LY3298176) in participants with nonalcoholic steatohepatitis (NASH) (SYNERGY-NASH). NCT04166773. https://clinicaltrials. gov/study/NCT04166773.

of prospective studies, where data points that are actually of interest to clinicians can be integrated, therefore gaining more reliability.

Schattenberg explained that, while AI can be used to refine imaging technology, like ultrasound, and detect the degree of steatosis with high precision and recall, this is very dependent on the operator. If the operator does not give AI the right angle or liver section, precision will be lost. He also added that liver histology is an attractive area where AI can be used to identify different histological features, reduce challenges with the reference standard, and even generate new fibrosis categories and markers of regression and progression.

What we really need is prospective data, to collect the data points that are really important

Schattenberg also noted that AI-language models could be used to empower patients and support education; for instance, ChatGPT can help translate and customise answers for patients who have questions about management of their MASLD. He concluded the session by highlighting the importance of harmonising data, and adopting a data security standard. For physicians, AI can help overcome issues like low awareness and expertise, but he stressed that “AI must be explainable”. Before basing any decisions for patients on the results of an algorithm, physicians must first understand it.

3. Boehringer Ingelheim. A study to test safety and efficacy of BI456906 in adults with non-alcoholic steatohepatitis (NASH) and fibrosis (F1-F3). NCT04771273. https:// clinicaltrials.gov/study/NCT04771273.

4. Madrigal Pharmaceuticals, Inc. A Phase 3 study to evaluate the efficacy and safety of MGL-3196 (Resmetirom) in patients with NASH and fibrosis (MAESTRO-NASH). NCT03900429. https://clinicaltrials.gov/study/ NCT03900429.

5. Inventiva Pharma. Phase 2b study in NASH to assess IVA337 (NATIVE). NCT03008070. https://clinicaltrials. gov/study/NCT03008070.

6. Indian University. Trial of anakinra (plus zinc) or prednisone in patients with severe alcoholic hepatitis (AlcHepNet). NCT04072822. https:// clinicaltrials.gov/study/NCT04072822.

7. Schattenberg JM et al. NASHmap: clinical utility of a machine learning model to identify patients at risk of NASH in real-world settings. Sci Rep. 2023;13(1):5573.

Healthy Livers, Healthy Lives

Author: Aleksandra Zurowska, EMJ, London, UK

Citation: EMJ Hepatol. 2024;12[1]:24-26. https://doi.org/10.33590/emjhepatol/AEMS2949.

NON-COMMUNICABLE diseases (NCD) represent a major global health challenge, with significant mortality and morbidity. Among these, metabolic-associated steatotic liver disease (MASLD) and its more severe form, metabolic-associated steatohepatitis (MASH), have emerged as critical, but often under-recognised, public health threats. At this year’s European Association for the Study of the Liver (EASL) Congress, experts delivered insightful presentations on the topic.

THE ‘WHO’ PERSPECTIVE ON MULTIMORBIDITY IN NON-COMMUNICABLE DISEASES

Kremlin Wickramasinghe, Regional Adviser for Nutrition, Physical Activity, and Obesity for the World Health Organization (WHO), began his talk by highlighting the rising issue of multimorbidity in NCDs, and the collective goal among research groups to reduce the disease burden. He referenced the WHO Global Health Estimates to illustrate the significant impact of NCDs in the European region, noting that nearly 90% of deaths are related to NCDs, with higher mortality rates in Eastern Europe. He emphasised the importance of international cooperation to address health inequalities.

Europe has the highest alcohol consumption per capita globally

Key risk factors contributing to the disease burden in Europe include tobacco and alcohol use, dietary risks, high BMI, and low physical activity. Wickramasinghe introduced the WHO Global Action Plan for NCD prevention and control (2013–2030), which targets a 10% reduction in insufficient physical activity, harmful alcohol use, and halting the rise of diabetes and obesity.

Looking to the future, Wickramasinghe stressed the need for countries to monitor progress against WHO targets using indicators for premature mortality and risk factors. He highlighted that Europe has the highest alcohol consumption per capita globally, linking it to liver diseases such as fatty liver disease, hepatitis, fibrosis, cirrhosis, and liver cancer. The exponential dose-response relationship between alcohol and liver disease underlines the need for targeted interventions.

Wickramasinghe also discussed the European framework for action on alcohol (2022–2025), focusing on pricing, availability, marketing, health information, health services response, and community action to combat alcohol-related harm. Additionally, the WHO European Regional Obesity Report 2022 aims to halt the rise of obesity, another significant risk factor for NCD.

Wickramasinghe concluded his talk by calling for increased efforts to implement WHO recommendations to combat high-risk factors for NCDs, including rising tobacco consumption. He highlighted the WHO’s role in providing tools for better intersectoral engagement, which can support comprehensive regulations and policies to limit harmful industry practices, and promote transparency and accountability.

Enhanced collaboration and engagement are crucial for the effective prevention and control of NCDs.

GLOBAL RECOGNITION OF MASLD/MASH AND NAFLD AS PUBLIC HEALTH THREATS

Jeffrey Lazarus, CUNY Graduate School of Public Health & Health Policy, New York, USA, highlighted the under-recognised public health threats of MASLD and MASH, alongside non-alcoholic fatty liver disease (NAFLD), which he believes should be acknowledged as another NCD. Lazarus emphasised the importance of patient and community perspectives in advancing this agenda, alongside clinical societies. MASLD, affecting over 30% of the global adult population, presents significant health, economic, and social challenges that require interdisciplinary and cross-sector collaboration to be addressed effectively.

Lazarus noted the lack of attention MASLD has received from policy makers and the public health community. He discussed his own study, which offers recommendations for improving models of care for MASLD and MASH.1 The study emphasises the importance of non-invasive screening and testing, developing patient-centred pathways according to disease stage, preventing disease progression, and tailoring treatment strategies. It also advocates for co-locating services to treat NAFLD and its common comorbidities, aiming to integrate care across the healthcare system and define the roles of a multidisciplinary team responsible for managing NAFLD patients.1

Lazarus recommended liver health checks for all individuals with Type 2 diabetes and improved referral models to hepatology. He outlined risk factors for MASLD and MASH progression, including obesity, alcohol use, drug use, old age, lifestyle, diabetes, iron overload, male sex, and genetic modifiers. Lazarus stressed the importance of shifting from disease-centred to people-centred care, focusing on comorbidities and health-related quality of life.

He also discussed the need for a paradigm shift in gastroenterology and hepatology to address obesity and steatotic liver disease, expanding the emerging steatotic liver disease community of practice. Lazarus highlighted two of his studies, which identified 28 research priorities,2 and 29 action priorities,3 to tackle steatotic liver disease globally. In another recent study, Lazarus et al.4 developed a fatty liver disease Sustainable Development Goal country score for 195 countries and territories, providing insights into countrylevel preparedness to address fatty liver disease through a whole-of-society approach. Higher scores indicate better preparedness, with significant variation observed between countries.4

Lazarus concluded by stressing the need for action ahead of the fourth High-Level Meeting of the United Nations (UN) General Assembly on the prevention and control of NCDs in September 2025. He also highlighted the relevance of his findings for policy makers, public health professionals, and advocates, and the necessity for multisectoral collaborations to address fatty liver disease and NCDs overall.

THE ECONOMIC BURDEN OF MASLD AND MASH

Zobair Younossi, Chairman of the Global NASH Council and Professor at Inova Health System, Virginia, USA, highlighted the significant economic burden of MASLD and MASH in his presentation. He noted that the global prevalence of MASLD and MASH stands at 38% and 5%, respectively. While health providers often focus on clinical outcomes and quality of life, Younossi emphasised the need to address the economic burdens, as this will ultimately provide the resources necessary to combat these diseases.

Younossi introduced the use of a Markov model to estimate the economic burden of MASLD and MASH. This model can assess MASH-related direct costs, societal costs, and health outcomes for both existing and new cases in the USA. The model requires data on age-specific prevalence rates,

incidence rates, age-adjusted causespecific mortality rates, transition rates between states of liver disease, direct healthcare costs, societal costs, and quality of life scores for MASH patients at different stages. He shared his ongoing project for the Global NASH Council, which estimated MASH prevalence in five countries by averaging data from multiple sources. He stressed the importance of having accurate data for each disease stage, and recommended obtaining incidence rates from sources like the Global Burden of Disease (GBD) study and the International Diabetes Federation (IDF).

Younossi also mentioned his study on transition probabilities between different states of NASH.5 He detailed the MASHdirected costs in the USA, where a combination of micro-costing and grosscosting methods was used to estimate direct medical costs for each health state based on 2020 Medicare reimbursement rates. This approach allows for a detailed assessment of individual-level costs and broader healthcare system expenses. Additionally, Younossi calculated work productivity impairment using data from MASH patients in the USA and Europe. This

References

1. Lazarus JV et al. Defining comprehensive models of care for NAFLD. Nat Rev Gastroenterol Hepatol. 2021;18:717-29.

2. Lazarus JV et al. A global research priority agenda to advance public health responses to fatty liver disease. J Hepatol. 2023;79(3):618-34.

helped estimate productivity costs for each stage of MASLD and MASH.5

He then highlighted the clinical burden of MASH in the USA, Germany, and Japan from 2020–2040, noting increases in MASH, diabetes, obesity rates, advanced fibrosis, and mortality. By 2040, the direct healthcare cost in the USA is projected to exceed 60 billion USD, with productivity loss costs nearing 250 billion USD.

Younossi concluded the presentation by stressing that the clinical and economic burden of MASH is expected to grow substantially over the next two decades. Without intervention, the societal costs of MASH will be enormous. These data underscore the urgent need for policymakers to invest in addressing both the clinical and economic aspects of MASH.

The clinical and economic burden of MASH is expected to grow substantially over the next two decades

CONCLUSION

The growing prevalence and impact of MASLD and MASH highlight an urgent need for increased recognition and action from policy makers. Experts emphasise the necessity for interdisciplinary collaboration, comprehensive care models, and robust policy measures to address both the clinical and economic burdens of these diseases.

3. Lazarus JV et al. A global action agenda for turning the tide on fatty liver disease. Hepatol. 2024;79(2):50223.

4. Lazarus JV et al. The global fatty liver disease Sustainable Development Goal country score for 195 countries and territories. Hepatol. 2023;78(3):911-28.

5. Younossi ZM et al. Global NASH Council. Clinical and patient-reported outcomes from patients with nonalcoholic fatty liver disease across the world: data from the global nonalcoholic steatohepatitis (NASH)/ nonalcoholic fatty liver disease (NAFLD) registry. Clin Gastroenterol Hepatol. 2022;20(10):2296-2306.

Re-imagining Primary Biliary Cholangitis Care: PatientCentric, Utilising Biochemistry, Controlling Symptoms

This industry-sponsored symposium took place during the European Association for the Study of the Liver Congress in Milan, Italy, 5th−8th June 2024

Chairperson: Gideon Hirschfield1

Speakers: Mo Christie,2 Andreas Kremer,3 Maria Londoño,4 David Jones5

1. Toronto Centre for Liver Disease, University Health Network, Canada

2. PBC Foundation, Dunfermline, UK

3. Department of Gastroenterology and Hepatology, University Hospital Zürich, Switzerland

4. Hospital Clinic of Barcelona, Spain

5. Newcastle Hospitals NHS, Foundation Trust, Newcastle upon Tyne, UK

Disclosure: Hirschfield declares consultancy, education, and trial involvement with Chemomab, Escient, Gilead/CymaBay, GSK, Intercept, Ipsen, Kowa, Mirum, and Pliant. Christie is a full-time employee of the PBC Foundation. Kremer declares they are a consultant/advisor for AbbVie, Advanz, Alentis, AlphaSigma, AstraZeneca, Avior, Bayer, CymaBay, Escient, Falk, Gilead, GSK, Guidepoint, Intercept, Ipsen, Mirum, MSD, Myr, Roche, Takeda, and Viofor; a speaker for AbbVie, Advanz, AOP Orphan, Bayer, BMS, CMS, CymaBay, Eisai, Falk, Gilead, GSK, Intercept, Ipsen, Medscape, Mirum, MSD, Newbridge, Novartis, Roche, Vertex, Viofor, and Zambon; and has received research grants from Gilead and Intercept. Londoño has no disclosures. Jones disclosures grant funding, consultancy and lecture fees from Intercept, consultancy fees from GSK, lecture fees from Abbott, Falk, and Ipsen, and is an author of the PBC-40 assessment tool.

Acknowledgements: Medical writing assistance was provided by Eleanor Roberts, Beeline Science Communications, Ltd, UK.

Disclaimer The symposium content and views expressed herein are those of the speakers and not necessarily of the company.

Keywords: Biochemistry, cholestatic pruritus, fatigue, health-related quality of life (HRQoL), liver disease, patient testimony, personalised care.

Citation: EMJ Hepatol. 2024;12[1]:27-35. https://doi.org/10.33590/emjhepatol/PGQP6795.

Support: The publication of this article was supported by GSK.

Summary

For patients with the chronic progressive liver disease primary biliary cholangitis (PBC), personalised treatment is key to both preserving liver function and retaining health-related quality of life (HRQoL). This symposium at the 2024 European Association for the Study of the Liver (EASL) congress reimagined ‘PBC’ as standing for a ‘personalised’ approach, managing ‘biochemistry’, and gaining symptom ‘control’ as well as for ‘providing better care’. The symposium started with personal testimony from Mo Christie, a person with PBC, recounting how PBC symptoms, most notably cholestatic pruritus, had severely impacted her HRQoL. This was backed by myriad other patient testimonies collected by the PBC Foundation, of which she is Head of Patient Services. According to symposium chair Gideon Hirshfield, such symptoms necessitate a patient-centric approach to PBC symptom management. While standard treatment for PBC is ursodeoxycholic acid (UDCA), personalised management can help elucidate if, and when, additional therapies are needed to aid disease control. Andreas Kremer and Maria Londoño discussed that this may also take into account risk factors such as liver stiffness, age, and levels of bilirubin and alkaline phosphatase (ALP), all of which may influence progression-free survival rates. David Jones discussed how cholestatic pruritus and/or fatigue can occur in the majority of patients with PBC to some extent and can severely impact HRQoL. Both symptoms need to be discussed and assessed at every visit to a healthcare professional (HCP), with the need for treatment guided by the patient.

INTRODUCTION

Gradual destruction of intrahepatic bile ducts is the key characteristic of the chronic, progressive, liver disease PBC.1 This immune-mediated condition occurs predominantly in middle age and has been shown by a number of studies to be 1.6−13.0 times more common in females.2

According to Gideon Hirshfield, “PBC is a disease of great unmet need where real people’s lives are changed and shortened, and their quality of life is reduced.” With this in mind, at the 2024 EASL conference, Hirschfield and the other presenters centred their discussions on how the ‘P’ in PBC should be about taking a ‘personalised,’ patient-centric approach, with the ‘B’ highlighting management of ‘biochemistry’, and the ‘C’ to be for the goal of ‘controlling’ symptoms.

A PATIENT-CENTRIC APPROACH TO TREATING PBC

The Importance of Patient Testimony

According to Mo Christie, a patient’s journey to diagnosis and treatment can vary greatly, with each patient’s experience of PBC being different and complex. As a patient herself, Christie provided personal testimony while also highlighting the experience of fellow patients. She started by showing some of the words patients use to describe feelings related to their symptoms (Figure 1).

“Symptoms can be debilitating and have a huge impact on quality of life,” said Christie, “yet so many patients tell us that they are not asked about their symptoms at clinic appointments.” This is important because, with regard to a symptom like fatigue, for example, “patients often struggle to share the impact that this has on their quality of life. The words ‘I’m tired’ don’t really come close to describing just how exhausted and debilitated they feel.” Christie also described how another symptom, cholestatic pruritus, “can be extremely difficult for patients to deal with.

The extent and impact of this is often not fully understood. A patient once told me that her itch was so bad that she wanted to walk out into the ocean and keep going.”

Christie also shared her own story of how she endured 6 years of different treatments for cholestatic pruritus without success. By this time, she said, “I barely recognised the person I’d become and I rarely left the house. My daughter was then seven and I felt like her childhood was just passing me by.” Eventually, Christie was given two liver transplants, as the first led to complications, and she described how this restored her life.

Christie concluded by discussing how “we need to inform, educate, and empower patients to be involved in their own care journey. Signpost patients to patient organisations (such as the PBC Foundation) where we can help inform, educate, and empower them to be involved in their own care.” Christie finished by appealing to HCPs “to please consider your patient’s individual needs and circumstances. Ask about their symptoms to understand how their quality of life is impacted.”

Moving to Patient-Centric Treatment

The current treatment paradigm for PBC is for all patients to be prescribed 13−15 mg/ kg/day UDCA for life. Optimal outcomes of such therapy are normalisation of laboratory parameters and a very low risk of disease progression.1,4 Studies show that with UDCA, 10-year cumulative liver transplantation survival is lower compared to patients not treated with UDCA, even if the response is not complete.5 Of note though, in patients treated with an adequate dose of UDCA for at least 2 years, the likelihood of response is lower in younger patients, males, and those with higher bilirubin and ALP levels.6

Current treatment paradigms typically recommend that initial treatment response is assessed at 6−12 months, at which point, second-line therapy and symptom management are added as required (Figure 2).1,4 This is after ruling out other reasons for liver test abnormalities, such as alcohol consumption, drug-induced liver injury, autoimmune hepatitis, steatotic

liver disease, and biliary obstruction.7 Of note though, this recommendation means that second-line treatment is only given if, and when, UDCA treatment fails. A new paradigm suggests more personalised care that assesses baseline risk and then utilises all available therapies from treatment start according to individual results of liver tests, liver fibrosis, symptoms, and risk factors (Figure 2).8 Hirschfield stressed how this patient-centric approach, where symptoms are readily addressed and managed in addition to starting disease-modifying therapy, could make a difference to HRQoL.

ASSESSING BIOCHEMISTRY AND CONTROLLING SYMPTOMS

Risk stratification for PBC progression can depend on a number of factors including age, sex, symptoms, fibrosis, and biochemical and serological results.1,4 The latter may include increased ALP and bilirubin, decreased albumin, and the presence of anti-gp210.9 Maria Londoño and Andreas Kremer discussed how risk stratification and biochemistry measurements can help guide patient treatment. Risk stratification is important, said Londoño, “because during follow-up, it will help us to make decisions to improve the treatment and care of patients.”

With regard to fibrosis, worse clinical outcomes are typically shown in patients where liver stiffness measurement (LSM) is higher.10 However, variables in outcome according to LSM may also depend on other accompanying factors. A recent study examined the interaction between LSM, ALP, and age in a cohort of 1,047 patients with PBC deemed to have an adequate UDCA response 12 months after initiation. As expected, this study found that 10-year complication-free survival rate was higher for patients with normal ALP levels at study entry (85.7%; 95% CI: 77.5%, 91.0%) compared to those with a higher ALP at this timepoint (73.2%; 95% CI: 61.5%, 81.9%), especially where LSM was ≥10 kPa at study entry (indicating advanced fibrosis).11

With regard to who benefitted most from UDCA therapy, subgroup analysis found

Figure 1: Words patients have used to explain how primary biliary cholangitis symptoms make them feel.3

2: Current versus new treatment paradigms.8

Figure

PBC: primary biliary cholangitis; UDCA: ursodeoxycholic acid.

that in patients with normal ALP at study entry, the greatest gain in complication-free survival was in the 7.3% of patients who, at study entry, had LSM values ≥10 kPa and were ≤62 years old, with some gains if just one age/LSM value-related condition was met. However, gains were not significant in the 40.7% of participants who, at study entry, were >62 years old and had an LSM value <10 kPa (indicating nonadvanced fibrosis). As such, the authors suggested that "additional therapeutic efforts should be considered in UDCA-treated PBC patients with persistent ALP elevations, particularly in those with advanced disease and/or sufficiently young age."11

There is also a relationship between ALP and bilirubin levels. For example, an investigation that included over 2,000 patients with PBC showed that, when the cohort was taken as a whole, bilirubin >0.6 times the upper limit of normal (ULN) was predictive of progression to liver transplantation or death. Decreasing bilirubin with UDCA to ≤0.6 x ULN in the first year was associated with a 10.5% improvement in 10-year survival. Of note, if a patient’s ALP levels were normal, survival where bilirubin >0.6 x ULN was similar to when bilirubin was ≤0.6 x ULN. For ALP, 10-year survival was 93.2% where it was ≤1.0 x ULN and 86.1% where it was 1.0−1.67 x ULN. However, in patients with bilirubin >0.6 x ULN, survival for those with ALP 1.0−1.67 x ULN was lower, at 74.2%.12

These results highlight why guidelines suggest that in patients where response to UDCA is inadequate, as shown by ALP >1.67 x ULN or increased bilirubin, there is a high risk of disease progression, and second-line therapy should be considered. This includes obeticholic acid (5 mg/day, increasing to 10 mg/day after 6 months if needed).1,4 Notably, in a recent audit of PBC management in the UK, which included data for 8,968 patients, while 87.7% were receiving first-line treatment with UDCA, 26.7% taking UDCA for ≥12 months had an inadequate response, 48.9% of which were not prescribed second-line therapy, despite guidelines to do so. Other actions that fell short of guidelines included adequate symptom and osteoporosis risk

assessments; hepatocellular carcinoma surveillance in patients with cirrhosis; biopsy for PBC/autoimmune hepatitis overlap; and referral and discussion around the possibility of a transplant.13

While treatment in the two scenarios of optimal management or inadequate response is fairly clear-cut, Kremer explained that what is less clear-cut is how to manage patients with an adequate, but not optimal, response (e.g., slightly elevated aspartate transaminase but normal bilirubin), who may be at low-to-moderate risk for disease progression, but may have additional risk factors such as advanced fibrosis, age <50 years old, and be antigp210 positive.9,11 As such, with regard to disease management and progression, Kremer stressed how “risk stratification is essential not only at the beginning but also after 1 year of therapy to optimise PBC care. Keep in mind,” he continued, “age and signs of advanced fibrosis as being very important additional factors.”

Kremer concluded that “the decision for additional therapies should not only be based on the biochemical response but on other parameters, age in particular.” However, he cautioned to “always consider a risk-benefit for additional therapies.”

ADDRESSING CHOLESTATIC PRURITUS AND FATIGUE IN PBC

By assessing symptoms that may be overlooked in patients with PBC, most notably cholestatic pruritus and fatigue, Hirschfield stressed how “there’s more opportunity to change what happens to our patients than just how long they live.”

Cholestatic Pruritus

In one USA-based survey, cholestatic pruritus was found to be experienced by 80.5% of 211 patients, of which 37.1% experienced pruritus to a clinically significant degree.14 However, David Jones said, “the symptom of itch is never a symptom in isolation, it is at the epicentre of a whole range of things that really impact people.” Hirschfield added that “when we

start off with itch and then broaden it out to the consequences including fatigue, we need to recognise what that means for sleep quality, daytime somnolence, energy, willingness and ability to do physical activity, and impacts on family, jobs, and mood.”

Indeed, in the above-mentioned USA survey, pruritus impacts were shown on several HRQoL domains including emotional, social, educational, domestic, and cognitive factors, as well as on levels of fatigue.14 The latter may be linked to findings that cholestatic pruritus can interfere with sleep, as reported by 74.1% of 162 patients with PBC in another USA survey.15 This is of interest as one meta-analysis investigating the sequelae of low sleep quality in people with multiple underlying medical conditions found significant correlation with occurrences of depression and anxiety, along with worse disease-specific HRQoL scores.16 These relationships are illustrated in Figure 3

“What we find though,” said Jones, “is that clinicians don’t talk about itch nearly as much as patients perceive it to be a problem.” Indeed, a UK-based survey of 633 patients found that 44.2% were not asked about itch at their last HCP visit,19 with the above USA survey showing that 69.8% of 149 patients said their doctor did not evaluate pruritus occurrence. Of those who were evaluated, this was primarily through questioning only, with very few being formally assessed.15

Such measures include a simple numerical rating scale or visual analogue scale, where a patient is asked to rate their pruritus from absent (0) to worse possible itch (10);20 the Patient Global Impression of Severity Scale-Itch, which rates pruritus from absent to severe;21 and tracker applications for pruritus occurrence and severity that can be noted on paper, or used on a computer or a phone. These, Jones suggested, can also be used to evaluate treatment response. Additionally, he stressed, “don’t just ask for severity, look at the impact on day-to-day life. Is the itch bad enough for you to want to have treatment for it? Are you getting itch at night that is disturbing your sleep?

Leave the treatment decision in the hands of the patient,” he also suggested, “if they feel it needs treating, then it needs treating.”

Jones continued by saying that “itch may not be the commonest symptom in PBC, that’s fatigue, but it’s the one that we can make the biggest impact on. If you can treat the itch effectively, and reduce sleep impairment, you will have impacts on all these other symptoms (Figure 3), it’s the key to unlocking the door of symptom control.”

Despite the knowledge of pruritus being a symptom of PBC,14 and that UDCA does not necessarily alleviate cholestatic pruritus,22 one of the USA surveys above found that of those with clinically significant pruritus, one-third never received treatment aimed at this symptom.14 According to EASL and American Association for the Study of Liver Diseases (ASLD) guidelines, firstline treatment for pruritus is bile acid sequestrants. However, Jones cautioned that patients may not tolerate this therapy, as confirmed by Christie. Where pruritus is refractory, rifampicin may be tried as second-line treatment, followed by oral opioid antagonists, then selective serotonin reuptake inhibitors. For those where pruritus is still refractory, clinical trial entry or liver transplantation may be considered.1,23

“My advice,” said Jones, ”is to work through these therapies in a systematic way and make sure you don’t discard therapies before you’ve adequately tried them.” He stressed that a few weeks may be needed for some therapies before response can be fully ascertained. With all treatments, there is a need for a balance between treatment benefits and safety.

However, even with these guidelines,1,23 the USA study showed that only 25.0% of patients with clinically significant pruritus were currently receiving bile acid sequestrants and only 45.2% had ever received this treatment. Respective figures for antihistamines, which have not been proven to reduce cholestatic pruritus, were 65.6% and 64.3%.14 In a UK-based study, 73.5% of 2,194 patients

3: Relationships between cholestatic pruritus, fatigue, and health-related quality of life.14-18

HRQoL: health-related quality of life.

experienced pruritus. Of the 759 where this was persistent, 37.4% were treated with cholestyramine, 11.1% with rifampicin, and 4.5% with naltrexone. Corresponding figures for the 257 patients with severe pruritus were higher, at 50.2%, 23.0%, and 9.0%, but notably did not include everyone with this level of pruritus.20

Other recommendations for patients with cholestatic pruritus include applying moisturisers and appropriate topical agents; bathing with tepid water or using ice packs or wet cooling, moist wraps; avoiding tight or sticky clothing and hot environments; having controlled ultraviolet exposure and trimming nails. Additionally, behavioural measures and relaxation techniques may help stop the itch-scratch-itch cycle.24

Jones concluded that it is important that pruritus is discussed at every visit so that patients know that what they are experiencing may be related to PBC. The discussion should include assessment of whether the pruritus is PBC-related, how severe the pruritus is, how often it occurs, and how pruritus impacts HRQoL.

Fatigue

Another symptom experienced with PBC is mild−severe fatigue, experienced by 93% of patients in one study.25 This symptom can impact a patient’s HRQoL (Figure 3) in domains such as job performance, family and social life, physical activity, mood, sleep, and daytime somnolence.14,17,18,26 Where fatigue is present and includes cognitive deficits, there may be a higher degree of HRQoL impairment compared to patients with fatigue but without cognitive impairment, or those with no or mild fatigue.27

Interviews with patients with PBC and fatigue reflect these findings. They include one person who reported how “I felt I had ‘dumbed down’ and no longer expected so much of myself,” and explained how “my social life deteriorated” and that “I did not like to plan ahead, as I was never sure how much I would be able to manage.” This patient also reported that, while they often mentioned fatigue to their hospital doctors, some were sympathetic but did not offer any treatment, while others “felt I should pull myself together” and that, “as my liver function tests were quite good, this could

Figure

not really be a problem related to my liver disease.”28 This last point highlights how the degree of fatigue does not necessarily correlate with disease severity. As such, fatigue should be regularly measured in all patients with PBC to properly assess disease-related burden.1,23,29

Indeed, Jones discussed how, even though a patient may feel uncomfortable discussing fatigue, it needs to be assessed at every visit and the patient reassured that many people with PBC experience the same symptom. Support and empathy are key.17 Discussion can include how it is impacting a person’s daily life, in terms of asking questions such as “what do you struggle with?” and the relative severity of fatigue over time. Jones also suggested to emphasise how it was important for patients to maintain social structure and ensure that they left the consultation feeling positive, “even if this is just about them taking ownership of their problems.” He additionally discussed how in his practice, “we have a specialist nurse who spends a lot of time talking to people about this; this is about giving people control of their destiny.”

Fatigue may be rated by both patients and HCPs using a variety of instruments, such as visual analogue scales,30 the Fatigue Assessment Instrument,31 and the fatigue domain of the PBC-40 assessment tool. In the latter, patients are asked to rate how often statements such as ‘I had to force myself to get out of bed,’ ‘I had to have a sleep during the day,’ and ‘fatigue interfered with my daily routine,’ applied to them in the last 4 weeks.32

References

1. European Association for the Study of the Liver (EASL). EASL Clinical Practice Guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017;67(1):145-72.

2. Lleo A et al. Evolving trends in female to male incidence and male mortality of primary biliary cholangitis. Sci Rep 2016;6:25906.

Of note, use of the PROMIS® fatigue instrument33 in one study confirmed that mean fatigue scores increase with pruritus intensity.14

Fatigue may not be alleviated with UDCA22 and Jones concluded by saying that while “at this moment, we do not have a pharmacological treatment that will improve fatigue; that doesn’t mean we can’t help patients. In particular, we can help them to understand the symptoms and to live the best life they can with it; it’s about helping people to cope.”

CONCLUSION

In conclusion, this symposium underlined how disparities in access to high-quality, patient-centred care for people with PBC need to be addressed. Treatment paradigms should be based on a personalised approach, with individual risks assessed at baseline. They should aspire to both normalise liver function and prevent endstage liver disease, as well as to address HRQoL. Above all, with symptoms such as fatigue and pruritus, it is important that the patient feels believed and that their concerns are taken seriously. Hirschfield concluded by saying that opportunities for the future for people with PBC are rooted in ‘providing better care’. He urged that, although care has excelled in recent years, the journey isn’t finished. There is a need to continue to improve and strive, and keep changing the focus as more options for patients arise that can be utilised to help optimise as many aspects of PBC-related care as possible.

3. Hirschfield G. Reimanging PBC care: how do we change the focus. European Association for the Study of the Liver Congress; 5-8 June, 2024.

4. Hirschfield GM et al. The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines. Gut. 2018;67(9):1568-94.

5. Harms MH et al. Ursodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis. J Hepatol. 2019;71(2):35765.

6. Carbone M et al. Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. Gastroenterology. 2013;144(3):560-9. e7;quiz e513-64.

7. Younossi ZM et al. Diagnosis and management of primary biliary cholangitis. Am J Gastroenterol. 2019;114(1):48-63.

8. Levy C et al. New treatment paradigms in primary biliary cholangitis. Clin Gastroenterol Hepatol. 2023;21(8):2076-87.

9. Haldar D et al. Antibodies to gp210

and understanding risk in patients with primary biliary cholangitis. Liver Int. 2021;41(3):535-44.

10. Corpechot C et al. Liver stiffness measurement by vibration-controlled transient elastography improves outcome prediction in primary biliary cholangitis. J Hepatol. 2022;77(6):1545-53.

11. Corpechot C et al. Adequate versus deep response to ursodeoxycholic acid in primary biliary cholangitis: To what extent and under what conditions is normal alkaline phosphatase level associated with complication-free survival gain? Hepatology. 2024;79(1):39-48.

12. Murillo Perez CF et al. 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.

13. Abbas N et al. Critical shortfalls in the management of PBC: results of a UK-wide, population-based evaluation of care delivery. JHEP Rep 2024;6(1):100931.

14. Mayo MJ et al. Impact of pruritus on quality of life and current treatment patterns in patients with primary biliary cholangitis. Dig Dis Sci. 2023;68(3):995-1005.

15. Rishe E et al. Itch in primary biliary cirrhosis: a patients’ perspective. Acta Derm Venereol 2008;88(1):34-7.

16. Bonder A et al. Sleep disturbance due to pruritus is associated with

anxiety, depression, and worse quality of life: evidence for management of pruritus and sleep in chronic liver disease. Abstract THU-181. J Hepatol 2024;80:S340. Available at: DOI: https://doi.org/10.1016/S01688278(24)01149-8. Last accessed: 26 June 2024.

17. Khanna A et al. Management of fatigue in primary biliary cholangitis. Curr Hepatol Rep 2019;18(2):127-33.

18. Cauch-Dudek K et al. Fatigue in primary biliary cirrhosis. Gut 1998;43(5):705-10.

19. Leighton J et al. Patient ownership of primary biliary cholangitis long-term management. Frontline Gastroenterol. 2021;12(5):370-3.

20. Hegade VS et al. Pruritus is common and undertreated in patients with primary biliary cholangitis in the United Kingdom. Clin Gastroenterol Hepatol 2019;17(7):1379-87.e3.

21. Martin ML et al. Development and adaptation of patient-reported outcome measures for patients who experience itch associated with primary biliary cholangitis. J Patient Rep Outcomes 2019;3(1):2.

22. Rudic JS et al. Ursodeoxycholic acid for primary biliary cirrhosis. Cochrane Database Syst Rev 2012;12(12):CD000551.

23. Lindor KD et al. Primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019;69(1):394-419.

24. Weisshaar E et al. European S2k guideline on chronic pruritus. Acta Derm Venereol 2019;99(5):469-506.

25. Al-Harthy N et al. The specificity of fatigue in primary biliary cirrhosis: evaluation of a large clinic practice. Hepatology. 2010;52(2):562-70.

26. Montagnese S et al. Sleep-Wake profiles in patients with primary biliary cirrhosis. Liver Int. 2013;33(2):203-9.

27. Phaw NA et al. Understanding fatigue in primary biliary cholangitis. Dig Dis Sci 2021;66(7):2380-6.

28. Hale M et al. Fatigue in primary biliary cirrhosis. BMJ. 2012;345:e7004.

29. Younossi ZM et al. Assessment of fatigue and its impact in chronic liver disease. J Hepatol 2024;DOI:10.1016/j. jhep.2024.04.008.

30. Lee KA et al. Validity and reliability of a scale to assess fatigue. Psychiatry Res 1991;36(3):291-8.

31. Schwartz JE et al. The measurement of fatigue: a new instrument. J Psychosom Res 1993;37(7):753-62.

32. UK-PBC. PBC-40. 2022. Available at: http://www.uk-pbc.com/wp-content/ uploads/2015/12/blank-PBC-40.pdf. Last accessed:26 June 2024..

33. HealthMeasures. User manual and scoring instructions: PROMIS fatigue. 2023. Available at: https://www. healthmeasures.net/images/PROMIS/ manuals/Scoring_Manual_Only/ PROMIS_Fatigue_User_Manual_and_ Scoring_Instructions_02202023.pdf. Last accessed: 26 June 2024.

Abstract Reviews

Explore the latest developments in hepatology with novel abstracts presented by experts in the field at the European Association for the Study of the Liver (EASL) Congress 2024. Read on for their fascinating insights.

Suitability of Non-Invasive Tests in the Evaluation of Liver Fibrosis in Patients With Metabolic DysfunctionAssociated Steatotic Liver Disease

Authors: *Álvaro Yagüe,1 Andrés Castañeda,1 Rocío Calvo,1 Agustina González,1 Andrés Varela,1 Marta Morán,1 Michelle Casanova,1 Benjamín Polo1

1. Gastroenterology and Hepatology Department, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain *Correspondence to alvaro.yague@quironsalud.es

Disclosure: The authors have declared no conflicts of interest.

Acknowledgements: The authors would like to thank Hospital Universitario Fundación Jiménez Díaz for providing the resources to do this study.

Keywords: Hepatic steatosis, liver fibrosis, metabolic dysfunction-associated steatotic liver disease (MASLD), non-invasive tests.

Citation: EMJ Hepatol. 2024;12[1]:36-38. https://doi.org/10.33590/emjhepatol/UPIH9690.

BACKGROUND

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the main cause of liver disease, and its incidence is rising due to the outbreak of metabolic syndrome and obesity. The spectrum ranges from simple steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma, having become a common reason for liver transplantation.1,2

It is essential to stratify patients with MASLD according to the degree of liver fibrosis since its presence and progression determines the prognosis of

the disease.2 Liver biopsy has traditionally been considered the gold standard for the diagnosis of cirrhosis and staging of fibrosis.1-3 However, it is an invasive procedure, carrying a risk of rare but potentially life-threatening complications.2,3 Therefore, a number of non-invasive markers have been developed over the past decade for the evaluation of liver fibrosis.1-3

AIM

This study aimed to analyse the usefulness of FibroScan, non-alcoholic fatty liver disease fibrosis score (NFS), aspartate aminotransferase to platelet ratio index (APRI), and fibrosis-4 index (FIB-4) indexes in evaluating the presence and severity of liver fibrosis in MASLD, using liver biopsy as the reference standard.

METHOD

The case records of 210 patients who underwent liver biopsy from March 2019–January 2023 were retrospectively reviewed, and for this investigation, those who had undergone FibroScan measurements and blood samples simultaneously or with a maximum difference of 3 months from liver biopsy were selected. Patients without histological confirmation of hepatic steatosis (defined as a liver fat content ≥5% on biopsy) were

later excluded. NFS, FIB-4, and APRI were calculated. In all markers, indeterminate results were discarded. Liver fibrosis stage was determined using the meta-analysis of Histological Data in Viral Hepatitis (METAVIR) system.

RESULTS

A total of 194 patients were initially examined, and the presence of hepatic steatosis on biopsy was detected in 44.3% of those selected for the study. These patients had a mean age of 54.5±10.6 years, with 76.7% being females. FibroScan

liver stiffness results ranged from 2.6–45.0 kPa (mean: 8.6 kPa). Serological marker values ranged from -5.2–1.3 kPa (mean: -2.1 kPa) for NFS, from 0.2–9.3 kPa (mean: 1.8 kPa) for FIB-4, and from 0.1–6.1 kPa (mean: 0.9 kPa) for APRI. In liver biopsy, 73.3% of the patients presented F0-1, while mild fibrosis (F≥2) was found in the remaining 26.8%. For advanced fibrosis (F3–F4), FibroScan showed a sensitivity of 64.3% and a specificity of 87.3%, with a positive predictive value of 50% and a negative predictive value of 92.5%. Its degree of concordance with the biopsy was moderate (kappa index [κ]: 0.46). NFS showed low sensitivity (25%) and high

FibroScan*Biopsy: 0.463

NFS*Biopsy: 0.303

FIB-4*Biopsy: 0.552

APRI*Biopsy: 0.364

APRI: aspartate aminotransferase to platelet ratio index; FIB-4: fibrosis-4 index; NFS: non-alcoholic fatty liver disease fibrosis score.

Figure 1: Suitability of non-invasive tests in the evaluation of liver fibrosis in patients with metabolic dysfunctionassociated steatotic liver disease.

Cohen's Kappa coefficient

specificity (98.2%), having a weak degree of concordance with the biopsy (κ: 0.3). Regarding FIB-4 and APRI, both showed high sensitivity (85.7% for FIB-4 and 75% for APRI) and specificity (86.1% for FIB-4 and 81.2% for APRI), with a κ of 0.55 and 0.36, respectively (Figure 1).

References

1. European Association for the Study of the Liver (EASL) et al. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388-402.

2. Anstee QM et al. Noninvasive tests accurately identify advanced fibrosis due to NASH: baseline data from the STELLAR trials. Hepatology.

CONCLUSION

The authors concluded that FibroScan and FIB-4 are comparable to liver biopsy with a moderate degree of agreement, being useful tools for the non-invasive detection of advanced fibrosis among patients with MASLD.

2019;70(5):1521-30.

3. Xiao G et al. Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: a meta- analysis. Hepatology. 2017;66(5):1486-501.

Gut Dysbiosis is Associated With the Severity of Liver Fibrosis Assessed by Magnetic Resonance Elastography in Patients With Metabolic DysfunctionAssociated Steatotic Liver Disease

Authors: Nantawat Satthawiwat,1 Natthaya Chuaypen,1 *Pisit Tangkijvanich1

1. Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

*Correspondence to pisittkvn@yahoo.com

Disclosure: The authors recieved a grant from the Program Management Unit for Human Resources & Institutional Development, Research and Innovation (PMU-B, grant number B36G660010).

Acknowledgements: The authors would like to thank National Science Research Fund (NSRF) via the Program Management Unit for Human Resources & Institutional Development, Research and Innovation.

Keywords: Gut microbiota, liver fibrosis, magnetic resonance elastography, metabolic dysfunction-associated steatotic liver disease (MASLD), single nucleotide polymorphisms.

Citation: EMJ Hepatol. 2024;12[1]:38-40. https:// doi.org/10.33590/emjhepatol/HWDA3400.

BACKGROUND AND AIMS

The gut microbiome might affect the severity of metabolic dysfunctionassociated steatotic liver disease (MASLD);1 3 however, data regarding their association in Asian populations is limited. The authors analysed the differences in the gut microbial composition of Thai patients with MASLD, according to the severity of liver fibrosis assessed by MRI.

METHOD

This cross-sectional study included 156 patients with MASLD (51% male, mean age: 56±10 years). Liver steatosis grades ≥1 were identified by MR-proton density fat fraction ≥5.2%. Based on MR-elastography (MRE) at the cut-off of 2.97 kPa, there were 131 patients with mild fibrosis (F01) and 25 patients with significant fibrosis (F234). The single nucleotide polymorphisms of PNPLA3, TM6SF2, and HSD17B13 were assessed by allelic discrimination assays. Faecal specimens were sequenced

targeting the V4 region of the 16S rRNA gene and analysed using the nf-core ampliseq bioinformatics pipeline. Differential analysis of individual taxa between two groups was conducted through linear discriminant analysis effect size (LEFSe), employing a cut-off of LEFSe >2 and a significance level of p<0.05.

RESULTS

There was no significant difference in alpha-diversities (Chao1, Shannon, and Simpson indices) between patients with F01 and F234. However, the beta diversity significantly differed between the two groups (p=0.012). High abundances of Fusobacterium and Escherichia-Shigella, pathogenic bacteria, contributing to the inflammatory process and carcinogenesis, were significantly detected in the faecal samples of patients with F234 compared

to those in the F01 group (odds ratio: 3.31; 95% CI: 1.30–8.42; p=0.012). Additionally, enriched Fusobacterium significantly correlated with MRE (Pearson correlation coefficient: 0.235; p=0.003). In contrast, the abundance of Lachnospira, a shortchain fatty acid-producing bacterium, was significantly lower in patients with F234 compared to the F01 group (odds ratio: 0.38; 95% CI: 0.15–0.93; p=0.033). The enrichment of Lachnospira was also negatively correlated with MRE (Pearson correlation coefficient:-0.206; p=0.010).

Using the random forest classifier, the gut microbial signature of three genera could differentiate the groups with high diagnostic accuracy (area under the curve: 0.93). The bacterial genera, PNPLA3 polymorphisms, old age, and diabetes were independently associated with advanced fibrosis in multivariable analyses (Figure 1).

Genus level

Agathobacter

Anaerostipes

Bacteroides

Bifidobacterium

Blautia

Collinsella

Dorea

Escherichia Shigella

Faecalibacterium

Fusicatenibacter

Lachnoclostridium

Megamonas

Not Assigned

Phascolarctobacterium

Prevotella 9

Roseburia

Ruminococcus

Ruminococcus gnavus group

Ruminococcus torques group

Subdoligranulum

Figure 1: The top 20 relative bacterial compositions at the genus level in the F01 and F234 groups.

CONCLUSION

In an analysis of the gut microbiome of Thai patients with MASLD, the authors found that gut dysbiosis was correlated with the severity of liver disease. Specifically, greater abundance of bacterial genera involving inflammatory processes and lower enrichment of beneficial bacteria were significantly associated with fibrosis severity in patients with MASLD. These results indicated that the imbalance of enriched pathogenic genera and decreased beneficial bacteria, in association with

several clinical and genetic factors, were potential contributors to the pathogenesis and progression of MASLD.

References

1. Rinella ME et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023;79(6):1542-56.

2. Tilg H et al. Gut microbiome and liver diseases. Gut. 2016;65(12):2035-44.

3. Jayakumar S, Loomba R. Review article: emerging role of the gut microbiome in the progression of nonalcoholic fatty liver disease and potential therapeutic implications. Aliment Pharmacol Ther. 2019;50(2):144-58.

Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide Interruption in Hepatitis B Virus/HIV

Co-Infected Individuals in the USA: Monitoring Practices and Incidence of Hepatitis B Virus

Reactivation or Hepatitis Flare

Authors: Douglas T. Dieterich,1 *Laurence Brunet,2 Ricky K. Hsu,3 Karam Mounzer,4 Gerald Pierone,5 Michael B. Wohlfeiler,6 Jennifer S. Fusco,2 Megan S. Dunbar,7 Joshua Gruber,7 Leland J. Yee,8 Catherine Frenette,9 Gregory P. Fusco2

1. Institute for Liver Medicine, Mount Sinai Health System, Icahn School of Medicine at Mount Sinai, New York, USA

2. Epividian, Raleigh, North Carolina, USA

3. AIDS Healthcare Foundation, NYU Langone Medical Center, New York, USA

4. Philadelphia FIGHT, Pennsylvania, USA

5. Whole Family Health Center, Vero Beach, Florida, USA

6. AIDS Healthcare Foundation, Miami, Florida, USA

7. HIV Global Medical Affairs, Gilead Sciences, Foster City, California, USA

8. Gilead Sciences, Foster City, California, USA

9. Global Medical Affairs, Liver Diseases, Gilead Sciences, Foster City, California, USA

*Correspondence to laurence.brunet@epividian.com

Disclosure: Dieterich has received consulting and speaking fees from Gilead, and consulting fees from VIR; Brunet has received a grant from Gilead Sciences for the current project through payments to Epividian, grants from AIDS Healthcare Foundation, EMD Serono, Gilead Sciences, Janssen Scientific Affairs,

Merck & Co., Theratechnologies Inc., and ViiV Healthcare through payments to Epividian; Hsu received grants from Speaker honoraria from ViiV Healthcare, Merck, Gilead Sciences, and Janssen, and advisory board participation with ViiV Healthcare, Gilead Sciences, Janssen, and Epividian; Mounzer has received a grant from Gilead Sciences for the current project through payments to Epividian; Mounzer has received grants from Gilead Sciences and Epividian through payments to Philadelphia FIGHT; Pierone has received grants from GSK, ViiV Healthcase, and Abbvie through payments through the institution; Wohlfeiler has received grant from ViiV Healthcare and Epividian for being the Principal Investigator on ViiV Healthcare clinical trials, and has received personal fees for being on the Epividian Epidemiology and Clinical Advisory Board for Epividian; Fusco has received a grant from Gilead Sciences for the current project through payments to Epividian, and has received research funding from AIDS Healthcare Foundation, EMD Serono, Gilead Sciences, Janssen Scientific Affairs, Merck & Co., Theratechnologies Inc., and ViiV Healthcare; Dunbar is an employee and owns stock at Gilead Sciences; Yee is an employee and owns stock at Gilead Sciences; Frenette is an employee and owns stock at Gilead Sciences; Fusco has received research funding from AIDS Healthcare Foundation, EMD Serono, Gilead Sciences, Janssen Scientific Affairs, Merck & Co., Theratechnologies Inc., and ViiV Healthcare with payments made to Epividian. This research was

sponsored by Gilead Sciences and the authors have declared no conflict of interest.

Acknowledgements: The authors would like to thank Robin Beckerman (SAS programming), Michael Stagner (QA), Bernie Stooks (IT/data management), Lisa Lutzi and Nicole Shaw (data architecture), and Judy Johnson (medical terminology classification). This research would not be possible without the generosity of people living with HIV/HBV and their OPERA caregivers.

Keywords: Hepatitis B, hepatitis flare, HIV, monitoring, reactivation, tenofovir alafenamide, tenofovir disoproxil fumarate, treatment interruption.

Citation: EMJ Hepatol. 2024;12[1]:40-42. https:// doi.org/10.33590/emjhepatol/SVUV5256.

BACKGROUND AND AIMS

Among hepatitis B virus (HBV) core antibody positive (cAb+) people with HIV, suppressive HBV treatment, including either tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF), is recommended to prevent HBV reactivation and possibly fulminant or fatal hepatitis.1,2 The risk of HBV resistance is high if lamivudine is used without TDF or TAF, whereas the risk of HIV resistance is high if entecavir is used without TDF or TAF. The authors describe TDF/TAF interruptions and HBV monitoring practices in the USA, as well as assess the incidence of HBV reactivation and hepatitis flares during TDF/ TAF interruptions in the OPERA cohort.

METHOD

The OPERA cohort includes electronic health records from >142,000 people with HIV receiving routine clinical care in the USA (96 clinics, 22 states, 1 USA territory), representing approximately 13% of people with diagnosed HIV infection in the USA at the time of this study.3 All TDF/TAF interruptions among HBV surface antigen positive (sAg+) and/or cAb+ people with HIV were categorised by risk of reactivation (high: sAg+; moderate: sAg-/cAb+/HBV surface antibody negative [sAb-]; low: sAg-/ cAb+/sAb+).The presence of HBV DNA, sAg, and alanine transaminase (ALT) testing was assessed before (within ≤12 months)

and during the interruption. The incidence of HBV reactivation and hepatitis flares (American Association for the Study of Liver Diseases definitions) was assessed with Poisson regression.

RESULTS

Of 30,549 people co-infected with HBV/ HIV, 5,343 (17%) had ≥1 interruption, for a total of 6,252 interruptions (11% high, 19% moderate, 70% low-risk) and the median duration was 23 months (interquartile range: 4–53). There were no DNA tests before (high: 56%; moderate: 94%; low: 92%) or during interruptions (high: 48%; moderate: 91%; low: 95%). There was no sAg test in 75% of high, 69% of moderate, and 72% of low-risk interruptions. HBV reactivation occurred in 117 high-risk interruptions (17% overall, 32% of those with DNA tests) for an incidence rate [IR] of 9.92 per 100 person-years (95% CI: 8.28, 11.89). Reactivation occurred in 24 moderaterisk interruptions (2% overall, 6% of those with DNA and/or sAg tests), with an IR of 0.67 (95% CI: 0.45, 1.00). Only 10 low-risk interruptions resulted in HBV reactivation (<1% overall; <1% of those with DNA and/or sAg tests), with an IR of 0.08 (95% CI: 0.04, 0.15). ALT tests were available before (high: 91%; moderate: 91%; low: 93%) and during interruptions (high: 99%; moderate: >99%; low: >99%). Hepatitis flares occurred in 68 (10%) high-risk interruptions (IR per 100 person-years: 5.53; 95% CI: 4.36, 7.01), 59 (5%) moderate-risk interruptions (IR: 1.74; 95% CI: 1.35,2.24), and 162 (4%) low-risk interruptions (IR: 1.31; 95% CI: 1.13, 1.53).

CONCLUSION

In this large USA cohort of sAg+ and/ or cAb+ people with HIV receiving care in primary or HIV care clinics, TDF/TAF interruptions were common and lengthy, and HBV lab monitoring was sub-optimal, suggesting that primary and HIV care providers tend to be unaware of HBV status or overlook HBV monitoring and management in people with co-infection. While sAg+ individuals had the highest HBV reactivation and hepatitis flare risk, all

were at risk regardless of serology. Given infrequent testing, many reactivations were likely missed. Primary and HIV care providers need to incorporate HBV monitoring in their standard of care and proceed with caution if considering a TDF/ TAF interruption for people with HBV/HIV co-infection.

References

1. Terrault NA et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B:

AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560-99.

2. Clinicalinfo. Panel on Antiretroviral Guidelines for Adults and Adolescents, Department of Health and Human Services. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV 2024. Available at: https://clinicalinfo.hiv. gov/en/guidelines/hiv-clinical-guidelines-adultand-adolescent-arv/whats-new. Last accessed: 14 June 2024

3. Centers for Disease Control and Prevention (CDC). HIV Surveillance Report, 2021. 2023. Available at: https://stacks.cdc.gov/view/cdc/149071. Last accessed: 31 May 2023.

Barriers and Motivators for Implementation of Lifestyle Changes in a Large Population With Metabolic Dysfunction-Associated Steatotic Liver Disease

Authors: *Sharon Oude Veldhuis,1,2 Stans Drossaert,2 Marjolein den Ouden,1,3 Lisette Van Gemert-Pijnen,2 Maureen Guichelaar4

1. Saxion University of Applied Sciences, Enschede, the Netherlands

2. University of Twente, Enschede, the Netherlands

3. Regional Community College of Twente, Hengelo, the Netherlands

4. Medisch Spectrum Twente, Enschede, the Netherlands

*Correspondence to l.s.derksen@saxion.nl

Disclosure: The authors declare no conflicts of interest.

Acknowledgements: The authors would like to thank Henrik ten Berge for his assistance in the data collection.

Keywords: Barriers, lifestyle, metabolic dysfunction-associated steatotic liver disease (MASLD), motivators.

Citation: EMJ Hepatol. 2024;12[1]:42-43. https://doi.org/10.33590/emjhepatol/DFOF9828.

BACKGROUND AND AIMS

Patients with metabolic dysfunctionassociated steatotic liver disease (MASLD) experience difficulties in complying with required lifestyle changes. In particular, long-term improvements have shown to be difficult.1 This study explored the barriers

and motivators in patients with MASLD to implement long-term lifestyle changes.

MATERIALS AND METHODS

A quantitative survey with some openended questions was distributed via two Dutch patient organisations. The survey included questions about comorbidities, attempts to change lifestyle, motivators and barriers for lifestyle changes, and information provision and information needs. The data was analysed using descriptive statistics.

RESULTS

The survey was completed by 449 patients with MASLD (81% female; mean±standard deviation age: 56±11 years; BMI: 30±5 kg/m2). Sixty-three percent of patients (n=283) self-reported their stage of disease; of which, 16% reported fibrosis/ cirrhosis. Patients experienced a high rate of comorbidities, including diabetes mellitus (n=98, 22%), and cardiovascular disease (n=83, 19%). Almost half of the patients (n=210, 47%) experienced joint problems.

The majority of patients attempted one or more lifestyle changes (n=364, 81%),

including dietary changes to support weight loss. A low percentage of participants succeeded in permanently changing their diet (n=174, 39%), exercise pattern (n=159, 35%), and permanent weight reduction (n=91, 20%). Most frequently mentioned motivators for lifestyle changes were symptoms of MASLD and/or comorbidities (n=92, 20%), desire to live a long and healthy life (n=76, 17%), and discomfort from being overweight (n=65, 14%). Barriers to implement lifestyle changes were insufficient knowledge about MASLD-related topics (n=177, 39%), stress (n=153, 34%), and lack of practical advice (n= 40, 31%) (Figure 1).

Information about MASLD was mainly provided by a gastroenterologist (n=210, 47%) or general practitioner (n=123, 27%). Only less than 20% of participants indicated that they had received sufficient information about a broad range of MASLD-related topics. Approximately 72–90% of patients would like to receive more information on almost all MASLD-related topics, including disease specifics and self-management options. Patients were least interested in the topic ‘contact with other patients with MASLD’ (37%).

CONCLUSION

Key reasons to attempt lifestyle changes, in a large population of patients with MASLD, included motivation to improve discomfort and comorbidities related to MASLD and obesity. Although the majority of respondents attempted lifestyle changes, only a minority of them were able to sustain long-term improvements (approximately 20% sustained permanent weight loss). Lack of knowledge about MASLD and stress were key barriers to improving lifestyle in the long term. The authors’ study supports ongoing efforts to increase patients’ knowledge about MASLD and its treatment in order to sustain long-term lifestyle changes.

References

1. Tincopa MA et al. Patient disease knowledge, attitudes and behaviours related to non-alcoholic fatty liver disease: a qualitative study. BMJ Open Gastroenterol. 2021;8(1):e000634.

Symptoms of MASLD and/or comorbidities

Desire to live a long and healthy life

Discomfort from being overweight

Preventing/improving advanced MASLD stages

Feeling fit and energetic

Concerns regarding consequences of MASLD

Insufficient knowledge about MASLD Stress

Lack of motivation

Lack of practical advice

Insufficient knowledge about lifestyle

Lack of time

Motivators Barriers

Figure 1: Motivators (n=302) and barriers (n=449).

TGR5 Deficiency in Liver Sinusoidal Endothelial Cells Disrupts Angiocrine Signalling During Liver Regeneration After Partial Hepatectomy

Authors: Impreet Kaur,1 Pinky Juneja,1 Ashwini

Vasudevan,1,2 Michael Trauner,3 Mlitz Veronika,3

Shiv K. Sarin,1 Dinesh M. Tripathi,1 *Savneet Kaur1

1. Institute of Liver and Biliary Sciences, New Delhi, India

2. Amity University, Noida, India

3. Medical University of Vienna, Austria

*Correspondence to savykaur@gmail.com

Disclosure: The authors have declared no conflicts of interest.

Acknowledgements: The authors would like to thank Jaswinder Singh Maras and Prabhjyoti Pahwa for assisting with bile acid analysis.

Keywords: Angiocrine factors, bile acid receptors, liver regeneration, partial hepatectomy.

Citation: EMJ Hepatol. 2024;12[1]:44-45. https://doi.org/10.33590/emjhepatol/TTVV7775.

BACKGROUND AND AIMS

Bile acid (BA) receptors like farnesoid X receptor (FXR) and TGR5 have been implicated in liver regeneration.1,2

Mechanisms underlying FXR-mediated cell proliferation and liver regeneration are well-studied but those of TGR5 in liver regeneration remain largely elusive. Given the fact that TGR5 is highly expressed in liver sinusoidal endothelial cells (LSEC), the authors have investigated the role of BA-activated TGR5 in LSECs during liver regeneration in rat models of 70% partial hepatectomy (PHx).

MATERIALS AND METHODS

The authors have developed PHx and sham rat models and studied the endpoints at Day 2 and Day 5 post-PHx. Primary hepatocytes, LSECs, and hepatic stellate cells have been isolated by collagenase perfusion.3 The gene expression of FXR and TGR5 in liver tissues and LSECs has been studied. BA profiling of portal and

peripheral serum in PHx rat models using liquid chromatography-mass spectrometry has been performed. In vitro, the effects of specific BA have been investigated on angiocrine factors4 and pathways released by LSECs in presence of and absence of TGR5-small interfering RNA (siRNA). In vivo effects of TGR5 deficiency on LSECs have been evaluated in TGR5 knockout mice. Co-cultures of LSECs and hepatocytes have been performed under different study conditions. To validate their findings, the authors have also studied BA profile and angiocrine factors in the serum of human liver donors (n=5) undergoing hepatectomy for living donor liver transplantation.

RESULTS

The authors show that, in liver tissues and LSECs, TGR5 gene expression is substantially increased at Day 2 postPHx in comparison to sham. BA profiling clearly demonstrated that secondary BA, such as lithocholic acid (LCA) and deoxycholic acid, are enhanced in PHx compared to sham at Day 2. An inhibition of TGR5 receptor by siRNA in LSECs significantly reduces gene expression of the master regulator of angiocrine factors, inhibitor of differentiation-1 (Id1), and also the expression of angiocrine factors, hepatocyte growth factor (HGF), and wingless-related integration site (WNT2) The gene expression data is also validated by ELISA assays that showed reduced release of HGF and WNT2 in cell soups compared to controls. Also, compared to cell soups obtained from TGR5-siRNA treated LSECs, cell soups obtained from LCA treated LSECs significantly enhanced the proliferation of hepatocytes in both 2D and 3D cultures. Mechanistically, TGR5siRNA-treated LSECs showed a decrease in the expression of phospho-AKT. In TGR5 knockout mice, LSECs show reduced gene expression of Id1, HGF, and WNT2, compared to wild-type mice. Human donors

undergoing hepatectomy with remnant liver volume to total liver volume between 35–40% also have an increased ratio of serum secondary to primary BA with a specific increase of LCA and deoxycholic acid along with WNT2 and HGF levels at Day 2 post-hepatectomy.

CONCLUSION

The authors provided a novel link between secondary BA-dependent TGR5 activation and angiocrine signalling in LSECs. Deficiency of TGR5 in LSECs disrupts the Id1 angiocrine signalling pathway, reducing the release of HGF and WNT2 and hence hepatocyte proliferation after PHx. LCA-

TGR5 constitutes a key upstream signal activating the Id1-PI3-AKT pathway in LSECs during early liver regeneration.

References

1. van de Laarschot LFM et al. The role of bile salts in liver regeneration. Hepatol Int. 2016;10(5):733.

2. Kaur I et al. Bile acids as metabolic inducers of hepatocyte proliferation and liver regeneration. Regen Eng Transl Med. 2022;8(6):200-9.

3. Tripathi DM et al. Immunonano-lipocarriermediated liver sinusoidal endothelial cell-specific RUNX1 inhibition impedes immune cell infiltration and hepatic inflammation in murine model of NASH. Int J Mol Sci. 2021;22(16):8489.

4. Ding B et al. Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature. 2010;468(7321):310-5.

Abstract Highlights

Citation: EMJ Hepatol. 2024;12[1]:46-57. https://doi.org/10.33590/emjhepatol/ZHNU8747.

The following highlights spotlight the latest research in hepatology, featuring studies presented at this year’s European Association for the Study of the Liver (EASL) Congress. Ranging from a deep dive into clinical trial eligibility amongst steatotic liver disease patients, to complication predictors after biopsy, these highlights demonstrate the latest cutting edge developments and most talked-about topics in the field today.

Cirrhosis and Bacterial Infections: A Deadly Duo

DECOMPENSATED cirrhosis poses a major public health issue in Latin America, with bacterial infections potentially worsening both morbidity and mortality rates according to a study presented at the 2024 EASL Congress.

The presence of multidrug-resistant (MDR) bacteria complicates the management and prognosis of these infections. This study’s objective was to examine the current epidemiology and prognostic significance of MDR bacterial infections in patients with cirrhosis throughout Latin America.

The presence of multidrugresistant (MDR) bacteria complicates the management and prognosis of these infections

A multicentre prospective study was conducted between 2018–2020, involving 1,274 non-elective hospitalised patients with acutely decompensated cirrhosis. The study spanned 44 centres across seven Latin American countries: Argentina, Brazil, Chile, Colombia, Mexico, Peru, and Paraguay.

Among the 1,274 patients, 524 (41.1%) experienced a total of 619 bacterial infections, with 41.7% of these being culture-positive. Acute-on-chronic liver failure (ACLF) developed in 47.1% of cases, and septic shock occurred in 26.9%. Higher rates of both conditions were observed in Mexico (ACLF: 62.5%; septic shock: 45.7%) and Peru (ACLF: 53.3%; septic shock: 37.8%), with respective p-values of 0.042 and <0.001. Gram-negative bacteria were the most commonly isolated (67.8%; Escherichia coli: 34.8%). MDR bacteria were found in 29.4% of culturepositive infections, with higher rates in Mexico (41.7%), Argentina (35.1%), and Peru (33.3%). Extended spectrum beta-

lactamases (ESBL)-producing Escherichia coli was the most prevalent MDR strain (27.6%). There were notable differences in MDR bacteria types among countries. ESBLand Amp-C producing Enterobacteriaceae were most common in Mexico (36.1%), followed by Colombia and Paraguay (25% each), Peru (22.2%), Chile (18.2%), Argentina (16.2%), and Brazil (12.1%).

Methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci were mainly found in Argentina (5.4% and 2.7%, respectively). Carbapenem-resistant Klebsiella pneumoniae was prevalent in Argentina (5.4%), and Carbapenemresistant Pseudomonas was prevalent in Brazil (2%). MDR infections were more frequently linked to septic shock (40%) and ACLF (57.4%). The 28-day mortality rate for infected patients was 29.4%, with a higher rate in Mexico (47.1%; p<0.001). This rate increased to 47.8% for patients infected with MDR, with no significant difference between countries.

The study concludes that MDR bacterial infections are common and linked to poor outcomes in patients with decompensated cirrhosis in Latin America. The predominant resistant strains differ significantly between countries.

The Key to Tailored Hepatocellular Carcinoma Treatment

THE VESSELS that encapsulate tumour (VETC) phenotype is predictive of the effectiveness of anti-angiogenic drugs in patients with advanced hepatocellular carcinoma (HCC).

VETC, a distinctive vascular feature associated with a worse prognosis for patients with HCC, has previously shown promise in predicting responses to chemoembolisation and sorafenib. A new study, presented at the EASL Congress 2024, aimed to assess VETC's predictive value for patients undergoing systemic treatment for advanced HCC.

The research was conducted utilising a retrospective, mono-institutional analysis of 81 patients with advanced HCC (the study cohort), which was later validated in an external, retrospective series of 83 patients (the validation cohort). Each patient's VETC status was determined from liver biopsy samples taken just before initiating systemic treatment. Results from both the study and validation cohorts indicated that patients

Identifying patients who are VETC-positive can guide clinicians in selecting the most effective systemic therapies

with the positive VETC phenotype exhibited a significantly better response to antiangiogenic therapies, including tyrosine kinase inhibitors (TKI) and bevacizumab. In the combined total of 163 patients, those with the positive VETC phenotype treated with TKI or bevacizumab demonstrated a notably longer overall survival (OS) compared to those receiving immune checkpoint inhibitors (ICI). Specifically, the OS for patients treated with TKI and/or bevacizumab was 19.2 months versus 10.2 months for those treated with ICIs (hazard ratio: 0.4; 95% CI: 0.24–0.70; P=0.0012).

Similar trends were observed for patients treated with sorafenib versus ICIs, with OS of 16.3 months compared to 8.7 months, respectively (hazard ratio: 0.4; 95% CI: 0.25–0.93; P=0.03). Conversely, no significant benefit from anti-angiogenic drugs was observed in patients negative for the VETC phenotype.

The findings underscore the importance of the VETC phenotype as a predictive marker for treatment response in patients with advanced HCC. Identifying patients who are VETC-positive can guide clinicians in selecting the most effective systemic therapies, potentially improving patient outcomes. This study highlights the potential for tailored treatment strategies based on individual tumour characteristics, marking a significant step forward in the personalised treatment of HCC.

Patients with the positive VETC phenotype exhibited a significantly better response to antiangiogenic therapies

Inadequate Organ Allocation in Acute-on-Chronic Liver Failure

LIVER transplantation (LT) improves survival of patients with acuteon-chronic liver failure (ACLF), which is characterised by a high risk of short-term mortality. However, current worldwide organ allocation systems are primarily based on the model for end-stage liver disease (MELD) scores, or its variations.

They do not consider risk of death due to failure of extrahepatic organs. Because of this, many patients die on the waiting list.

A study presented at the 2024 EASL Congress aimed to assess the clinical outcomes of patients with ACLF Grade 2 or 3 undergoing LT in the current allocation systems. Among 823 patients (80% of the overall study cohort), 376 patients with ACLF Grade 2 or 3 were listed for LT (Group 1), 313 patients with ACLF Grade 0 or 1 and MELD>20 were listed for LT (Group 2), and 134 patients with ACLF Grade 2 or 3 were referred to the waiting list evaluation but not listed (Group 3). Patients were recruited from 62 liver transplant centres across Asia, Europe, Latin America, and North America between July 2021–October 2023. ACLF was defined by the EASL-Chronic Liver Failure (CLIF) criteria. The rate of delisting/death was presented according to ACLF Grade and MELD-sodium at study inclusion, and by geographical distribution.

Delisting/death on the waiting list occurred in 28% of patients in Group 1, compared with 16% in Group 2

Delisting/death on the waiting list occurred in 28% of patients in Group 1, compared with 16% in Group 2 (P<0.001); while 85% of non-listed patients (Group 3) died. For Groups 1 and 2, 68% and 79% received LT (P<0.001), respectively, and time to death/ delisting was 38.5 days (interquartile range [IQR]: 13–85), while time to LT was 14 days (IQR: 5–47; P<0.001). Significant differences in death/delisting on the waiting list were observed across continents (Asia: 13%; Europe: 18%; Latin America: 40%; North America: 20%), which were associated with significantly greater time (in days) on the waiting list for Latin America, compared to Asia (47.5 [19–68]); Europe (10 [4–30]); Latin America (50 [10–79]); and North America (10 [4–22]); P<0.001. The higher rate of delisting/death for patients with ACLF Grade 2 or 3 was observed across all MELD-sodium ranges (<25 [50%], 25–29 [35%], 30–34 [22%], >35 [29%]) compared to patients without ACLF 2 or 3 (<25 [12%], 25–29 [19%], 30–34 [15%], >35 [17%]; P<0.001).

These findings suggest that current worldwide allocation systems are inadequate for patients with ACLF Grade 2 or 3, leading to an excess of waiting list mortality. The authors strongly argue for a change in the organ allocation system for patients with ACLF, given the efficacy of LT.

The authors strongly argue for a change in the organ allocation system for patients with ACLF

Steatotic Liver Disease Severity Predicts Mortality

and Cardiovascular Disease

NEW findings presented at EASL 2024 showed that the severity of steatotic liver disease (SLD) is associated with increased all-cause mortality and cardiovascular disease (CVD) events, most pronounced in individuals aged 50+ years.

SLD, the most common chronic liver disease worldwide, has been linked to heightened mortality in patients. A recent longitudinal cohort study conducted as part of the Busselton Health Study in Western Australia examined the relationship between hepatic steatosis severity and subsequent mortality and CVD events.

Analysis revealed a nonlinear association between FLI and all-cause mortality, evident in both sexes

The study included 4,382 participants (56% female) with a mean age of 51 years. Participants were followed for up to 20 years, from the survey dates in 1994–1995 until death or the end of the study period in 2014. The study utilized the fatty liver index (FLI) to diagnose SLD, calculated based on body mass index (BMI), waist circumference, serum triglycerides, and gamma-glutamyl transferase levels. Cox proportional hazards models explored the relationships between FLI and A) all-cause mortality, B) CVD mortality, and C) CVDrelated events. Nonlinear relationships between FLI and outcomes were analyzed using restricted cubic splines.

The study underscores the importance of monitoring hepatic steatosis severity in older adults to mitigate mortality and long-term health risks

Over the follow-up period, there were 974 deaths (22.2%), 408 CVD-related deaths (9.3%), and 1,018 CVD events (23.2%).

Analysis revealed a nonlinear association between FLI and all-cause mortality, evident in both sexes. After adjusting for multiple variables, participants in the lowest FLI quintile had a 28% lower risk of all-cause mortality compared to those in the highest quintile (hazard ratio [HR]: 0.72; 95% CI: 0.55–0.94). CVD deaths and events initially increased with higher FLI in Model A, though this association weakened after further adjustments in Models B and C. No significant association was observed between FLI and mortality or CVD outcome

in participants younger than 50 years. Conversely, in individuals aged 50+ years, there was a notable increase in all-cause mortality in the third and fourth FLI quintiles (HR: 1.30 and HR: 1.26, respectively) and an increased risk of CVD-related events in the third quintile (HR: 1.29).

The study underscores the importance of monitoring hepatic steatosis severity in older adults to mitigate mortality and long-term health risks. Further research is warranted to explore interventions that could reduce these risks.

Early Pain Predicts Complications after Percutaneous Liver Biopsy

MONITORING of patients after an ultrasound-guided percutaneous liver biopsy (US-PLB) can be safely discontinued if no pain develops within the first hour post-procedure, according to findings presented at EASL 2024.

This research, conducted in three tertiary centres in Lombardia, Italy, analysed complications associated with the procedure and identified pain within 1 hour as the sole significant predictor of major issues.

The study retrospectively assessed 1,838 patients who underwent either parenchymal or lesion-targeted PLB between January 2018–December 2023. The cohort had an average age of 55.1 years, with 46.1% females and a mean body mass index of 25.1 kg/m². Notably, 13.7% of the biopsies were performed on patients with previous liver transplants. The patients had a mean platelet count of 209.7±80.74 x10³/mm³ and a mean Prothrombin Time International Normalized Ratio value of 1.04±0.12. Needle aspiration was the predominant technique used (92%), mostly employing 18G (59.5%) and 16G (22.1%) needles. The study also considered various clinical, biochemical, and procedural features, including the use of anticoagulant/antiplatelet therapy, which was relatively rare (4.2%/16.2%).

Future guidelines could consider these results to streamline post-procedure care

Over an average observation period of 5.4±2.0 hours, pain was reported in 7.4% of patients. Major complications were infrequent, occurring in only 1.4% of cases, with transient hypotension being the most common (0.8%). Bleeding events were observed in 0.5% of patients, typically within the first hour. Hospitalisation was required in 0.7% of cases, primarily for managing bleeding, although most cases resolved spontaneously. Pain, especially within the first hour post-procedure, was significantly associated with major complications. However, no other baseline or procedural variables, such as heart rate, mean arterial pressure, or haemoglobin values, were linked to severe outcomes.

The findings suggest that if pain does not develop within 1 hour after a USPLB, patient monitoring can be safely discontinued, reducing the need for prolonged hospital stays and repeated blood counts. Future guidelines could consider these results to streamline post-procedure care, emphasising the importance of immediate pain assessment to identify patients at risk for complications. Further studies could help refine these recommendations to improve patient management and resource allocation in clinical settings.

Machine Learning Advances Liver Fibrosis Prediction

METABOLIC dysfunction-associated steatotic liver disease (MASLD) impacts around 30% of the global adult population.

It significantly increases the risk of disease progression, especially in those with moderate to advanced fibrosis (Stage 2–3). Following the FDA's approval of resmetirom for treating metabolic dysfunctionassociated steatohepatitis (MASH) at these fibrosis stages, a surrogate marker is needed to enhance the selection process for liver biopsy candidates. The ALADDIN study, presented at the 2024 EASL Congress, has introduced an innovative web-based calculator, employing machine learning, to estimate the likelihood of Stage ≥2 fibrosis in patients with MASLD using routine laboratory parameters, both with and without vibration-controlled transient elastography (VCTE).

A total of 3,708 patients from six global centres with biopsy-confirmed MASLD were split evenly into derivation and internal validation cohorts. Additionally, 1,289 patients from nine centres were included for external validation. The ALADDIN models were created to assess moderate fibrosis (Stage ≥F2).

In external validation, the VCTE model achieved an area under the curve (AUC) of 0.800 (95% CI: 0.773–0.827), significantly surpassing the FAST (AUC: 0.707; 95% CI: 0.674–0.739; p<0.0001) and Agile-3 (AUC: 0.764; 95% CI: 0.735–0.793; p=0.001) models. The model using only routine laboratory parameters, without VCTE, achieved an AUC of 0.757 (95% CI: 0.730–0.783), performing comparably to FAST and Agile-3. Additionally, the VCTE model

demonstrated superior results in decision curve analysis, calibration, and classification accuracy using a dual cut-off approach, and outperformed existing models in predicting moderate fibrosis.

The researchers conclude that the ALADDIN study, through an international consortium, has successfully developed and externally validated machine learning models with high accuracy for predicting moderate fibrosis. The authors’ VCTE model has shown statistical superiority, while the model using routine laboratory parameters without VCTE has demonstrated comparable performance to traditional models such as Agile-3 and FAST. These algorithms will aid in the targeted selection of patients for liver biopsy, aligning with the recent FDA approval of resmetirom treatment.

It significantly increases the risk of disease progression, especially in those with moderate to advanced fibrosis (Stage 2–3)

Classification of Steatotic Liver Disease and Clinical Trial Eligibility

IN NEW research presented at EASL Congress 2024, a team based in Denmark has found that the highly dynamic classification of steatotic liver disease (SLD) impacts eligibility for clinical trials and subclassspecific interventions.

SLD includes several subclasses including metabolic-dysfunction associated steatotic liver disease (MASLD), metabolic and alcohol-related liver disease (MetALD), and alcohol-related liver disease (ALD). Classification is based on the presences of hepatic steatosis, cardiometabolic risk factors (CMRF) and current alcohol use. However, these criteria may be sensitive to spontaneous changes in lifestyle, making the SLD diagnoses dynamic.

The team concluded that SLD and its subclassification are highly dynamic

The team conducted a prospective cohort study among individuals from the general population and individuals at risk of SLD (obesity, Type 2 diabetes or, a history of excessive alcohol use). Presence of steatosis was defined as controlled attenuation parameter (CAP) >275 dB/m and presence of advanced fibrosis as transient elastography (TE) >12 kPa. Subclassification of SLD was based on the presence of at least one CMRF and self-reported current alcohol use (MASLD <20/30 (female/male) g/day; MetALD 20–50 / 30–60 (female/male) g/day; ALD >50/60 (female/male) g/day). The SLD classification was assessed at baseline and after 2 years follow-up. In total, 994 patients were included (mean age: 57 years; 64% male). Of this group, 54 had advanced fibrosis.

At baseline, 551 (55%) patients had SLD (CAP >275 dB/m and/or TE >12 kPa) while 443 (45%) did not have SLD. Among the patients with SLD, 337 (61%) met the criteria for MASLD, 133 (24%) for MetALD, 79 (14%) for ALD, and two (0.4%) were classified as cryptogenic SLD. Median time between baseline and follow up visit was 25 months (IQR: 25–31). At follow-up, 382 (38%) of the 994 participants were reclassified. Among the 443 participants that did not have SLD at baseline, 113 (26%) met the criteria for SLD at follow-up. Among the 551 participants classified as having SLD at baseline, 269 (49%) were reclassified, of which 186 (69%) did not meet the criteria for SLD at follow up and 83 (31%) changed SLD subclass. For the 382 participants reclassified, 299 (78%) were due to changes in steatosis, 83 (22%) due to changes in alcohol use, and zero due to changes in presences of CMRFs.

The team concluded that SLD and its subclassification are highly dynamic, especially driven by changes in alcohol use and steatosis. This in turn affects eligibility

for clinical trials, and the team reported that patients with SLD should be reassessed regularly to ensure correct subclass diagnosis and management.

Congress Interviews

The following interviews highlight the latest developments in hepatology covered at the European Association for the Study of the Liver (EASL) Congress 2024, held in Milan, Italy, from 5ᵗʰ–8ᵗʰ

June. Loreta Kondili, EASL Policy and Public Health Committee Member, discusses inequities in liver cancer, and Sven Francque, EASL Educational Councillor, elaborates on the ways in which young hepatologists can learn more through EASL.

Loreta Kondili

EASL Policy and Public Health Committee Member

The implementation of chronic liver disease policies across Europe will only be possible with valuable data that guides policy changes

Citation: EMJ Hepatol. 2024;12[1]:58-62. https://doi.org/10.33590/emjhepatol/PVAV6427.

Q1

What originally led you to a career in gastroenterology and hepatology, specifically focusing on digestive endoscopy?

I first graduated from the Faculty of Medicine at the University of Tirana in Albania. My career started with my thesis, which studied the clinical and epidemiological profile of chronic liver disease in Albania compared to other neighbouring countries like Italy and Greece. Following my degree in Medicine and Surgery, I earned a scholarship at Istituto Superiore di Sanità (Italy's National Institute of Public Health), one of the most important research institutes in Italy. This was the time when hepatitis C infection was discovered; there was a lot of fascinating research work like the detection of the virus in different populations, including those with chronic liver disease of unknown aetiology and paediatric populations, as well as virus genotyping and sequencing. Working in the field of hepatitis viruses, and trying to interpret the virological data on different clinical contexts and implications,

served as the main driver for my decision to specialise in gastroenterology and digestive endoscopy, with the main focus on chronic liver diseases.

Q2

You are the Principal Investigator of the Italian Platform for the Study of Viral Hepatitis Therapies (PITER), and work with many other international networks. What do these positions mean for your own work, and how do you use them to further hepatological research?

The PITER is a structured network that benefits from an integrated endeavour involving Istituto Superiore di Sanità, the Italian Society for the Study of the Liver (AISF), the Italian Society for Infectious Diseases (SIMIT), and their affiliated clinical centres. PITER represents a collaborative effort to improve the understanding and management of viral hepatitis in Italy, aiming to reduce the disease burden and improve patient care.

Being the principal investigator of PITER gave me the great opportunity to collaborate with

medical doctors and researchers of around 100 clinical centres all over Italy. I also coordinate the work of a fantastic team at the Center for Global Health of Istituto Superiore di Sanità, comprising dedicated researchers from different specialties like epidemiologists, biostatisticians, biologists, data managers, and several members of the administrative staff. The idea of creating a network for chronic liver disease treatment was first put in place with the arrival of drugs with direct antiviral action against chronic hepatitis C infection. In Italy, there was a great need for them because the prevalence of hepatitis C, and mortality due to hepatitis C, were the highest in Europe. The evidence produced by PITER served as an extremely helpful tool for the policy-making process for the universal treatment of patients with chronic hepatitis C, and hepatitis C virus mass screening, which are health policies put

in place in Italy to achieve the World Health Organization’s (WHO) target of eliminating viral hepatitis as a public health threat by 2030. PITER expanded its work also on hepatitis B and Delta in 2019, and the well-established network is fostering a successful collaboration in the field of metabolic disfunction-associated liver disease, which is becoming a new epidemic disease worldwide.

I am very proud of this nationwide experience, which is also recognised at the international level, thanks to over 100 highlevel research publications mainly in the public health field. I am also lucky because I have the possibility to extend the benefit of this experience at the European Association for the Study of Liver Diseases (EASL) as a member of the EASL Policy, Public Health and Advocacy Committee (PPHAC) since 2022.

Q3 What are the current priorities for the EASL Policy and Public Health Committee?

One of the main EASL missions is fostering a unified approach towards tackling chronic liver disease and those which are preventable on a global scale. To reach this goal, EASL has built collaborative initiatives through the PPHAC, bringing together stakeholders from various sectors to address chronic liver disease comprehensively and holistically. This work will be continuously improved by engaging different stakeholders, and working with coalitions and partnerships. There are several priorities for the committee, like focusing on a wide range of public health and advocacy work, promoting public health initiatives across Europe. The work of the committee is focused on both policy influence and public health improvement. Key aspects of its mission include

advocacy for liver health policies that support liver disease prevention, diagnosis, treatment, and research at the international and national levels, collaborating with several main stakeholders. The committee also works in public health promotion through awareness campaigns and prevention programmes. Another important field of work for the committee is research, education, and training through wide network collaboration.

Q4

How do you hope to see EASL’s policy and public affairs improving in the future?

I strongly believe that the work of the committee will be reflected in the new health policies of the European Union (EU) countries. Hopefully, the work of the committee, which addresses increasing awareness about chronic liver disease, inequities in chronic liver disease and liver cancer care, actions against harmful alcohol use and for a healthy liver, actions focused on migrants' health, and reducing stigma and discrimination in people affected by liver diseases, will be prioritised and reflected in the EU and national health policies, prioritising specific evidence-based policy actions.

Q5 Your own policy and advocacy efforts revolve around improving evidence-based health policies for reducing the chronic liver disease burden. Can you tell our readers more about this, and how you hope EASL may further this goal?

I think it is important to produce evidence through thorough, welldesigned research conducted in specific areas of chronic liver disease focused on answering policy questions. It is important to ask for policy changes, but

also to establish evidence-based recommendations for prevention, diagnosis, and treatment. It is necessary to produce data which shows that the required policy actions will produce real-life public health benefits. The implementation of chronic liver disease policies across Europe will only be possible with valuable data that guides policy changes. Case investment in the context of chronic liver disease, in terms of the comprehensive allocation of resources towards the management and care of patients with chronic liver conditions, should be promoted, and presented to the attention of different stakeholders at the EU and national level. It is also

important to produce evidence on various aspects of healthcare, aiming to improve patient outcomes, enhance quality of life, and reduce the overall burden of chronic liver disease on the healthcare system at national and EU levels.

Through this vision, EASL will significantly impact liver health policies, advocating for comprehensive, evidence-based approaches to prevent and manage viral hepatitis, and harmful alcohol use-related metabolic dysfunctionassociated liver disease, ultimately aiming to reduce the global burden of liver disease.

Q6

You also work with the Italian Ministry of Health on eradicating hepatitis in a costeffective way. What developments in this area have you found particularly impactful?

A strong political commitment has been put in place since the arrival of drugs that eradicate viral hepatitis C in Italy. Thanks to the real-life PITER data, we evaluated the cost-effectiveness of the universal therapy of chronic hepatitis C with direct-acting antiviral drugs. This evidence served policymakers to approve the universal treatment at the beginning of 2017. Treatment with direct-acting antiviral drugs was made available not only for patients with advanced liver disease but for all the diagnosed patients with chronic hepatitis C infection regardless of the disease severity.

To achieve the WHO hepatitis C elimination targets in 2030, the screening of hepatitis C infection has been approved by law in Italy with dedicated, specific funds. This was made possible thanks to the political commitment supported by several evidences produced by the collaboration of PITER with the Polaris Observatory of the Center for Diseases Analysis Foundation, Colorado, USA, and the Center for Economic and International Studies (CEIS) of the Tor Vergata University of Rome, Italy. I am proud to have contributed, as senior clinical researcher and principal investigator, to producing this important evidence that helped the Italian Medicines Agency and the Ministry of Health to implement important public health policies aimed at elimination of hepatitis C as a public health threat in Italy.

Q7 At EASL, you chaired a session on inequities in liver cancer, and later gave a talk on the same topic. Could you expand a little on the inequities in liver cancer today?

Addressing health inequities is at the top of indications of the EASLLancet Commission on liver health in Europe, which indicates steps for the prevention, case-finding, and early diagnosis to reduce liverrelated mortality.

Between 1990–2015, liver cancer incidence increased by 75% worldwide, and is expected to grow dramatically by 55% over the next 20 years if prevention strategies are not promoted. Inequities in liver cancer are determined by social determinants of health (SDoH). SDoHs have an interacting role in each step of the liver cancer pathway, impacting its development and the whole care cascade from the distribution of risk factors to incidence rates, as well as medical care, survival, and

mortality. In particular, vulnerable and marginalised populations with a low socioeconomic and educational level are the most affected by liver cancer risk factors. Reasons for this include varied access to hepatitis B virus vaccination, limited access to viral hepatitis B and C screening, harm reduction, and treatment. Alcohol-related liver disease remains highly prevalent among individuals with low education, insecure employment, economic instability, migrants, and deprived populations. Significant variation exists across Europe in the proportion of adults with steatotic liver disease, overweight/ obesity, and diabetes based on geographical area, gender, socioeconomic, and educational background, and density of ultraprocessed food outlets.

Liver disease care worsens in the most socioeconomically disadvantaged regions. Insufficient healthcare access for key populations with primary

It is also important to promote and advocate for preventive measures, and raise public awareness about liver cancer risk factors

liver cancer is influenced by complex healthcare systems, stigmatisation, discrimination, low education, language barriers, and fear of disclosure.

Activities essential for the integration of social needs into liver cancer health policy are awareness, adjustment activities aimed at tailoring care to overcome social barriers, and activities of assistance at the individual level. These include connecting patients to social care resources outside of the healthcare system and

community-level interventions, organising social care assets to facilitate synergies and advocacy, and working with social care organisations to promote new policies. It is also important to promote and advocate for preventive measures, and raise public awareness about liver cancer risk factors, empowering individuals with knowledge and encouraging healthy behaviours.

Liver health should be part of a general health policy that considers the role of SDoH.

Future studies are needed to explore the different SDoHinterlinked effects on liver cancer incidence and outcomes in the European countries. The ultimate goal is to develop evidence-based multilevel public health interventions that reduce the SDoH impact on precipitating and perpetuating the disproportionate burden of liver cancer in specific populations.

Sven Francque

EASL Educational Councillor; Chair of the Department of Gastroenterology and Hepatology, Antwerp University Hospital, University of Antwerp, Belgium

And that's the role of the Educational Committee, to oversee and develop tools to educate health care professionals

Citation: EMJ Hepatol. 2024;12[1]:63-65. https://doi.org/10.33590/emjhepatol/RLRC3633.

Q1

What initially led you to hepatology and, more specifically, metabolic dysfunction associated steatotic liver disease (MASLD)?

During my studies, I was most fascinated by the mechanisms behind diseases. That was what always triggered my interest, as well as trying to link the mechanisms of the diseases and how you treat them. And I must say, I was first more interested in cardiology, because of all the physiology behind it; how you influence cardiac function was very, very interesting. However, I found the clinical daily practice less interesting. I then got in touch with a liver specialist, and I realised how complex the liver was in terms of pathophysiology and this switched my interest. My research looks into the vascular mechanisms, but it's that complexity of pathophysiology, and the link with the treatment of the diseases that has always triggered my interest in the liver; it being such a complex organ with such a huge impact on whole body metabolism.

Q2 Can you describe the role of the EASL Educational Committee for our readers?

The aim is, in the end, to provide the best treatment for the patient, and that's what we are here for. But to deliver that you must have the right knowledge and know how to apply it to make sure that, in the end, the care is delivered to the highest quality possible. And that's the role of the Educational Committee, to oversee and develop tools to educate health care professionals. It is important that scientists, nurses, liver doctors, and doctors of different specialities, as well as people living with liver disease, have access to high-quality information. There is also the training aspect, because people need to know, of course, a lot of things to be able to help the patients, but they also need to have the right skills; they need to know how to perform certain techniques, and handle patients. That is the mission of the Education Committee.

If you look at all the activities that we are doing, you will see that the portfolio is very diverse with a lot of training designed for different target groups. We develop different resources for individuals in different stages of their clinical or scientific career. We have e-learning courses, accessible guidelines, journal clubs, schools, and organise oneto-one mentorships.

Q3 How have you aimed to improve EASL’s educational strategy throughout your time as Educational Councillor?

It's now the end of my first of 4 years, so I still have a way to go. One of the big projects I am particularly trying to do is to develop a kind of core curriculum in hepatology training. We already have a lot of stuff for the training of a gastroenterologist, including a chapter on hepatology in the European board’s blue book. But hepatology is not always done by gastroenterologists; it's different from one country to another. Also, what a general gastroenterologist needs to know is different from the knowledge of somebody who qualifies as a specialist in liver diseases. So, the aim is to start working on a standardised core curriculum for what somebody qualified as a specialist in liver diseases should know. Subsequently, once we have that as a kind of international standard, we can see what educational material fits with it and if there are gaps that we need to fill. And then of course, it's also trying to develop something that is not just for specialised physicians, but also to see how we can assist other types of healthcare providers, such as nurses, to take care of patients with liver disease.

Q4 What areas of hepatology do you think remain underrepresented in liver education worldwide?

There are some fields that are in development, of course. We have the different disease areas, which I think are well covered, though they are probably working

a little bit too much in silos. The transition from paediatric to adult care is for sure something that could be improved. I think the field of rare liver diseases has improved a lot because the European Union is now supporting reference networks for rare diseases, and there's one for liver diseases. So, progress has been made in rare liver diseases, but still, it's an area that deserves to be highlighted. There have also been many developments in the field, including the increased use of endoscopy and the use of ultrasound, which is very different from one country to another but adds a lot of value to hepatology clinics.

Q5 How can EASL and the Educational Committee help young healthcare professionals entering the world of hepatology today?

First of all, we have a lot of offerings they can utilise in their education, and a lot of opportunities for them to participate in different activities. The second thing is, of course, all the material that is available on the EASL Campus, and we now have a very user-friendly app with easy access to the guidelines. We are making it easy to have access to high-quality education, and some of that education is also Continuing Medical Educationaccredited so they can use it to get the necessary credits. But I

We had a strong focus on what is needed to better understand how we can work with non-invasive tests

think one of the other important things is that with meetings like EASL’s Liver Congress, they can get in touch with colleagues and build a network amongst young people and those more experienced. I think that is something that we also see with the activities that we do with the Educational Committee. For example, an EASL school has 25 young people who go to a specific institution for a few days and receive dedicated training on a specific topic from the team there. That's the training, but they also come to know each other as a result. They come to know the experts, and those connections are there to stay. That network is useful for them in their development for years to come; not just in the hepatology clinic, but also in terms of scientific meetings at conferences. It's really about building a community that helps develop skills and technology, but also helps each other, which is invaluable for people. I experienced it myself, and I now hear it from the other colleagues, because unfortunately, I'm not that young anymore. But that's a big added value of the educational activities that we do.

Q6

Earlier this week, you chaired a session on the rapidly changing landscape of metabolic dysfunction-associated steatotic liver disease. Was there anything that surprised you during the discussion, and what was your key takeaway?

Nothing really surprised me, but the discussion was very interesting because it, first of all, confirmed that the field is really moving. With the first drug approved, it creates some excitement, but we should be realistic. Just because there is now a drug approved, it does not mean that all our problems are solved. In the session, we highlighted a few important points about finding the right place for the liver biopsy, and we had a strong focus on what is needed to better understand how we can work with non-invasive tests for monitoring disease evolution and treatment response. Everybody agrees that we have already done quite a lot of work, but in terms of monitoring patients over time, there's still a lot more to be done. There is still a lot of room for progress in treating patients with more advanced disease stages, and patients with cirrhosis.

Q7 What has been your highlight of EASL 2024?

For me, one of the highlights was the new guideline, which we have been working on for more than a year with three different societies. We were able to finalise it for the Congress, so we could launch it and incorporate it immediately into the app. We launched the EASL guidelines app this year, but being able to immediately incorporate the big new guidelines on metabolic dysfunction-associated steatotic liver disease (MASLD) was a standout highlight. Besides that, there were a lot of very interesting scientific communications on new drug treatments in MASLD. It was very impressive to see several oral presentations with high-level results of Phase II trials, really showing that, as with the session you were alluding to earlier, the field is moving.

Interviews

This year, EMJ is thrilled to introduce key opinion leaders Anil Dhawan, King's College London, UK; and Mario Strazzabosco, Yale School of Medicine, New Haven, Connecticut, USA, whose interviews explore the most important topics in the field today. From innovation in liver transplantation to the importance of personalised patient care, the following interviews spotlight various vital discussions taking place amongst experts.

Mario Strazzabosco Professor of Medicine, Co-Director, Liver Center, Yale School of Medicine; Director and Clinical Program Leader of the Smilow Liver Cancer Program, New Haven, Connecticut, USA

More efforts need to be spent on prevention, as most liver diseases are preventable

Citation: EMJ Hepatol. 2024;12[1]:66-68. https://doi.org/10.33590/emjhepatol/TYEM6621.

Q1

How has liver cancer treatment changed throughout your career?

The management of liver cancer has changed dramatically during the 4 decades since I started as an internal medicine speciality fellow. The changes are too many to list, but I would like to highlight the increase in the incidence of hepatocellular carcinoma (HCC) due to epidemiological factors, but also to the prolonged survival of patients with advanced liver disease; the establishment of an oncologic screening protocol and of a staging system that is accepted by all the major western liver societies; the advent of liver transplantation as a curative treatment; and the progress in locoregional treatments and radiation treatments (both local and stereotactic body radiotherapy). A tremendous advance in systemic treatment started around 15 years ago, and this now is exponentially increasing with combination treatments and immune-oncology. These advances have significantly increased the prognosis for patients affected by HCC. But the

war is not won yet because, as science and its implementation progress, the disease changes, the epidemiology morphs and now that we have defected hepatitis C virus and controlled hepatitis B virus, other risk factors like metabolic liver disease emerge. More efforts need to be spent on prevention as most liver diseases are preventable. Furthermore, the cost-effectiveness of the treatments and related technologies has not been assessed yet. Last, but not least, for a vast number of patients with difficult access to care, these improvements are not present, rather they lay in an unlikely and unevenly distributed future.

Q2 You have spoken in the past about forming lasting relationships with your patients after treatment. What benefits do you think this brings to both the patient and practice?

Around 60–70% of patients with liver cancer experience recurrence. How to prevent this is still unclear. There are ongoing clinical trials aiming to demonstrate the efficacy

of adjuvant medical treatment after surgery or locoregional treatments, but the main approach remains to continue a longitudinal, years-long monitoring of liver imaging, liver function, and biomarkers, along with addressing and treating the main risk factors. Some risk factors are related to lifestyle changes and therefore are very difficult to implement unless there is a strong bond between the hepatologist and the patient. In addition, many of our patients have unfavourable social determinants of health and these need to be addressed, with the help of social services.

Q3 Would you recommend this personalised approach to others, especially those just starting out in their careers?

Yes, patients need to feel that you are there for them. They need to feel your empathy, that you are working with them and through them to improve their health in the broader definition of health.

Q4

What does the Smilow Liver Cancer Program at Yale do differently compared to other liver cancer treatment centres to ensure patients are receiving the best care possible?

The Smilow Liver Cancer Program has many strengths, and we have phenomenal providers who master all the available techniques and are all involved in the program even if they belong to different departments. Another strength is our tumour board dedicated to HCC, where all decisions are discussed and shared; because every treatment is available at Smilow, our decisions are focused on what is best for the patient, without being limited by local availability. The other point of strength is the continuous involvement of hepatologists being able to follow longitudinally the patient and to help preserve the function of their livers and address the risk factors.

Q5 You are not only a clinician, but a researcher and professor as well. How does teaching and research aid your clinical practice, and vice versa?

Teaching, practice, and research are like a trinity; they exist and happen together, and cannot be separated. Practice and research are two faces of the same reality: there is research in patient care and patient care in research. I often use the image of the yin and yang, except that research and practice are not opposite, but are rather complementary forces. All our ‘basic’ research is inspired by clinical observation and ultimately is done for the potential benefit of our patients. As for teaching, forming future leaders in our profession is not only a duty but also an enormous benefit for the teacher. I usually learn from our bright young colleagues more than I transmit. What we teach may be new to them, but the perspective of our junior colleagues is always different and fresh.

Teaching, practice, and research are like a trinity; they exist and happen together, and cannot be separated

Q6

Much of your research focuses on damage to the bile ducts, as well as cholangiocarcinoma (CCA), a cancer which starts in the bile ducts. What key discoveries have you been involved in within this field?

I would say that together with a handful of colleagues, we changed the approach to study the pathophysiology of diseases, the biliary tree, and how the liver reacts to their damage. We were able to generate cellular models that enabled the application of cellular, molecular, and physiology techniques to understand the pathobiology of biliary cells. These cells were considered mere conduits for the bile, but now we know they modify the bile, they participate in the repair of the liver, they are the cells that instruct the inflammatory

microenvironment, and so on. New observations are made daily. Recently our group has generated compelling evidence for the role of gut dysbiosis in determining the biliary damage in cystic fibrosis. This is a paradigmshifting observation. Now that we can use human cellular models, the future seems more optimistic.

Q7

What developments in liver transplantation and CCA do you hope to see shortly?

Our interest in CCA was initially motivated by its desmoplastic nature. We were interested in understanding the relationships between cholangiocyte proliferation and fibrosis deposition. This led us to investigate the microenvironment of CCA (its tumour-reactive stroma) and its multiple cellular components. We investigated

the role of cancer-associated fibroblasts and their cross-talk with neoplastic cholangiocytes and lymphatics endothelial via signalling like platelet-derived growth factors, vascular endothelial growth factors, leukaemia inhibitory factors, etc. We also investigated the role of CCA microenvironment in the spreading of the tumour and response to therapy. This turned out to be a rewarding field of study that is now continuing with powerful single-cell transcriptomic approaches. It is too early to say whether this will lead to better medical treatments or to more transplants performed for CCA, but I sure would like to see more transplants done in patients with intrahepatic CCAs and in patients with sclerosing cholangitis, a disease that carries a sizable risk of developing a CCA.

Anil Dhawan Professor of Paediatric Hepatology, King's College London, UK

When I left India, there were no transplants happening there, but the UK was doing very well

Citation: EMJ Hepatol. 2024;12[1]:69-73. https://doi.org/10.33590/emjhepatol/VIFN1921.

Q1

You have had an extensive and impressive career in hepatology to date, particularly with regard to paediatric hepatology. What was it that led you to specialise in this field in particular?

I started in paediatric hepatology in 1992, when I got a placement at King's College Hospital, London, UK. I graduated in India as a medical student, and then did my postgrad in paediatrics at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. After that, I was exposed to the field of liver disease in that hospital in India. Then I arrived at King’s College Hospital, which was, and continues to be, one of the premier level disease centres in the world, for children particularly, as there are very few children’s liver centres in the world, even today. The UK is also the only country in the world that specialises exclusively in liver disease in children; other countries have gastroenterology and hepatology as one training programme.

When I started here, I realised that was the field which

was progressing, as liver transplantation had just started in the late 1980s. I really embraced hepatology, and realised that this is where the innovations were happening, or would happen in the future. I was also very lucky to have been welcomed by people at Kings, and so, the rest is history.

Q2 How has paediatric liver transplantation changed over the course of your career, both in terms of the treatment itself, and the attitudes around it in hospitals today?

In the 1960s, Thomas Starzl started doing liver transplantation in Denver, Colorado, USA. He was successful, technically, but unfortunately, some of the patients did not survive, so there was a pause. However, in 1984, liver transplantation was accepted by the National Institute of Health (NIH) as a clinical treatment. The problem that children faced before, when transplantation had just started, was that they could only receive whole livers as grafts. This meant that a lot of children died while on the waiting list, as they could not get the right size graft. So, when the techniques to reduce the whole liver to fit in a child, and

Now, you can perform a transplant without opening up the patient’s abdomen

subsequently splitting one liver for two patients got established, that made a big difference in reducing wait list mortality.

At the same time, we began to consider who needed a transplant. Previously, we were only doing transplants for children who were going to die in a few months’ time, but as a result of the improved transplantation survival rates, we became more liberal. Quality of life became one of the factors when we started deciding who qualified for liver transplantation. If the child was suffering from extreme itch, or if medicines were not helping the child, then they were accepted for transplantation. Then, as we gained more experience, we became even more liberal;

previously, we excluded children at high risk, for example, if they had a cardiac problem. Afterwards, even those at high risk could get a liver transplantation. However, the big breakthrough was for children with liver cancer. Previously, the mortality rate for children with liver cancer was >90%. After transplantation was introduced, the survival rate became >90%. We introduced transplantation because chemotherapy was not enough in itself in eradicating the tumour, or making the tumour resectable.

We then started offering liver transplantations for conditions that are not life-threatening in the short-term, but where treating them could improve the patients’ quality of life. We also started

looking at conditions that are not liver-based, but where a problem in the liver causes problems somewhere else. These patients have a liver that looks normal if you do liver tests, but treatment can protect the brain, or protect the kidneys. For example, in conditions like Crigler–Najjar syndrome, patients have to lie under the lights for 12–18 hours per day, sometimes more. Can you imagine the effect of that on somebody’s quality of life? Maybe for a young child, you can leave them, but if they are 10, 15, or 20 years old, what is going to happen? So, that became an indication for liver transplantation. Transplantation over the last 10–15 years has become a very ‘well accepted’ procedure.

Other innovations have come in as well, like using living donor transplantation. If you look at the countries where organ donation is not very well established, for either logistical or religious reasons, such as in Japan, Korea, China, or India, living donation is the most common mode for transplantation.

For some time, I called liver transplant a ‘disease’ in itself and not a ‘cure’. What we do is we change one disease into another. We take a life-threatening or lifelimiting condition; or a condition that is interfering with quality of life, such as itching, or yellow discoloration of the eyes; and we give patients a transplant. But transplantation comes with its own set of problems, the biggest being a lifelong commitment for immunosuppressive medication, because we do not have enough data to show that you can stop it safely. These medications also come with their own side effects. So, the liver transplant recipient is a patient forever again, and I believe we have to support these people with their day-to-day

living. A lot of these adults and young adults do not like taking their medicine. They will stop taking it, or not take it every day, and then they have to go for retransplantation. We also find that some patients develop mental health problems contributing to poor adherence to medication. If we know their needs, I think we will be in a much better position to assist them.

Q3 You qualified as a doctor in India, and have since worked in the USA and the UK. What are some of the main differences you have noticed in liver transplantation between the places you have worked?

When I left India, there were no transplants happening there, but the UK was doing very well. When I went to Nebraska, in the USA, I was exposed to a new culture, and different ways of practising medicine. However, in terms of surgical techniques, I would not say there is much difference. Healthcare professionals speak to

each other formally and informally to deliver the best care possible.

The advantage in the USA is that they have a better donor pool, they have twice the number of paediatric donors compared to the UK per million population. The number of donors on every level overall is higher, and donation consent is twice the UK number. Unfortunately, paediatric deaths are also slightly higher than in the UK.

In India, as I said, there was no transplantation, but I can take some pride in the fact that I was part of the group that helped starting liver transplantation in India. Now, India’s transplant programme is really one of the biggest in the world, and the results are very good too. The majority of liver transplant procedures are from living donors, but outcomes are no different than in the UK. I visit India regularly, I teach online, and I attend meetings. As part of continued education, I have

hosted a lot of doctors, not only from India, but also from China, South America, the Middle East, and Africa, to provide training into new aspects of liver disease management and transplantation.

Q4

Tell us a little about the Dhawan Lab at King’s College London, how it started, and the work that goes on there

My mentor, who helped me to establish my career, believed that we, as clinicians, need to be researchers and academicians, and we need to understand mechanisms of disease. When I came back from the USA, I had been exposed to a treatment that was just emerging in Nebraska: hepatocyte transplantation where you do not replace the whole liver, but you replace the cells of the liver, like a building is made of millions of bricks. A liver is made of billions of cells, so the functional unit of the liver is a little cell. It does all the work; it synthesises proteins and detoxifies toxins. The hypothesis was that, if we could

replace the cells, rather than the whole liver, we could get away with many problems of whole liver replacement.

We started the Dhawan Lab in 2000. We were awarded a grant by the National Lottery Charities Board and the Children’s Liver Disease Foundation of UK, which allowed us to start research into hepatocyte isolation and transplantation. We succeeded in setting up the lab, and in treating certain metabolic conditions, but the problem we faced was that the treatment we were giving was not lasting long enough. It was lasting 16–18 months, likely because these cells were being destroyed by the immune system despite immune suppression, and these people would then opt for liver transplantation. We were not alone with this problem. Other centres in Pittsburgh, Pennsylvania, USA; Valencia, Spain; Hannover, Germany; and Brussels, Belgium, all realised that longevity of hepatocytes was the problem. We went back to the lab, where we

looked at animal experiments, and found a protein we used called ɑ-1 antitrypsin, which can improve the quality and engraftment of hepatocytes. Clinical trials will inform us if it will be of clinical benefit. Another life-threatening liver condition is acute liver failure, where only proven treatment is liver transplant. Our lab developed a novel treatment for the first time in the world to treat children with acute liver failure. The treatment involves embedding liver cells and coating them with alginate, an algae product that is available for medicinal use. We set all of that up in our lab, did all the work that we needed to, got the approvals, and then used it in patients. Essentially, the lab is looking at treating diseases, and at the same time looking at the mechanistic side of liver disease.

Q5

Could you briefly explain to our readers a little bit about the process of hepatocyte transplantation, and the benefits of using this method instead of liver transplantation?

As I mentioned earlier, the hepatocyte is a single functional unit of the liver, and there are billions of them. We are using hepatocyte transplantation for conditions that are single gene defects in the liver. Currently, the liver cells we are getting are from livers that are either not used, or are only partly used for liver transplant. Sometimes, even though the liver is not suitable, we can use the liver for cell isolation, and sometimes it is reduced to suit the patient’s liver size, and some is left over. Unfortunately, some newborn babies pass away, and their livers are not suitable for transplantation because their vessels are very small. We evaluated these cells in the lab, which proved that the cells isolated from a newborn baby’s liver are very effective in terms of quality and durability.

Essentially, hepatocyte transplantation can be used for conditions that currently require liver transplantation. Then, you indirectly expand the donor pool, as one liver used for cell isolation can be used in two or three patients, or more. Otherwise, one liver goes to one or two patients. That is definitely a benefit. Another benefit would be that it is less invasive. Additionally, hepatocyte transplantation is futuristic because, if the gene therapy were to become available tomorrow, then these patients could still have it. Otherwise, if you have a liver transplant, then you would not be able to have gene therapy for many liver based conditions. We are looking to the future, rather than only the immediate effects. I think that, once you have taken off the initial establishment costs, it will be a lot less expensive, as well as a lot less invasive.

Q6

What do you think are the most exciting developments happening in the world of hepatology at the moment?

Developments in hepatology can be divided into many subgroups: diagnostic hepatology, therapeutic hepatology, and surgical hepatology. In terms of diagnosis, we are moving away from liver biopsy, and going more towards liquid biopsies. Previously, we did biopsies for most patients, now, not so many. The second is small molecules. Previously, to improve quality of life, we gave patients liver transplantation for

cholestatic disorders, but now we have medication that can help with itching so dramatically that we avoid liver transplantation. New antiviral medications have changed the outcomes of viral hepatitis C and B patients.

Moreover, robotic surgery has made a big difference. Now, you can perform a transplant without opening up the patient’s abdomen and without leaving a big scar. Some centres are even looking at whether they can implant a liver with a robotic arm, and those who have undergone this surgery report less pain, shorter hospital stays, and a much smaller

scar size. Things are moving and developing all the time. A lot of work is also being done in immunosuppression and the ways to avoid it.

Future understanding of AI will help early diagnosis and management of liver diseases, like all other health conditions.

And finally, as stated by Thomas Starzl: “History of medicine is such that what was inconceivable yesterday becomes a routine tomorrow.”

Prevention of Decompensation in Compensated Cirrhosis: Non-Selective Beta-Blockers for Everyone?

Authors: Sanchit Sharma,1 *Dhiraj Tripathi1,2

1. Liver Unit, University Hospital Birmingham, NHS Foundation Trust, UK

2. Institute of Immunology and Immunotherapy, University of Birmingham, UK

*Correspondence to d.tripathi@bham.ac.uk

Disclosure: Sharma and Tripathi are both investigators in the BOPPP trial of nonselective beta-blockers in cirrhosis. Tripathi received the National Institute of Health and Care Research grant for the CALIBRE trial from the University of Birmingham, paid to the institution. The authors have declared no conflicts of interest.

Received: 12.04.24

Accepted: 13.06.24

Keywords: Clinically significant portal hypertension, compensated cirrhosis, hepatic decompensation, hepatic venous pressure gradient, non-invasive tools, varices, non-selective beta-blockers.

Citation: EMJ Hepatol. 2024;12[1]:74-80. https://doi.org/10.33590/emjhepatol/AWYU7333.

INTRODUCTION

Portal hypertension is the major determinant of outcomes in patients with cirrhosis, defined as the presence of a hepatic venous pressure gradient (HVPG) of more than 5 mmHg. Mild portal hypertension is defined as HVPG of 6–10 mmHg. The major determinant of mild portal hypertension is hepatic fibrosis with little systemic contribution.1 On the other hand, clinically significant portal hypertension (CSPH) is defined as an HVPG ≥10 mmHg. The development of CSPH is regarded as an important event in the natural history of patients with cirrhosis. Physiologically, this heralds the onset of hyperdynamic circulation, sympathetic overactivation, splanchnic vasodilatation, and bacterial translocation, making CSPH a systemic condition unlike mild portal hypertension.2 Clinically, this stage is associated with the development of gastro-oesophageal varices, increased risk of decompensation, and mortality

due to hepatic decompensation.3 Patients with compensated cirrhosis with CSPH (especially those with established varices) decompensate more frequently than those with mild portal hypertension.4,5 The gold standard for the diagnosis of CSPH is HVPG estimation. Clinically, gastro-oesophageal varices and abdominal collaterals signify CSPH as an HVPG of 10 mmHg or more is required for their formation.6 Liver stiffness measurement (LSM) is a marker of liver fibrosis and inflammatory activity and correlates precisely with HVPG in patients with mild portal hypertension. After the onset of CSPH, this correlation becomes less precise.7 LSM cut-offs using vibrationcontrolled transient elastography (a bedside tool) with or without platelet count can rule in or rule out CSPH, at least in viral, alcohol-related, and non-obese metabolic dysfunction-associated steatotic liver disease (MASLD).8 Baveno VII consensus has laid down risk prediction rules to detect CSPH by non-invasive estimation (Rule of 5; Figure 1).1

Figure 1: Conceptual flow diagram showing the role of non-selective beta-blockers in patients with different stages of portal hypertension.

Splanchnic vasodilatation and hyperdynamic circulation

Rule in CSPH

• HVPG 10 mmHg

• LSM 15 20 kPa and platelet count <110109/L

• LSM 20 kPa and platelets 150109/L

• LSM 25 kPa

Rule out CSPH

• HVPG 0 mmHg

• LSM 15 kPa and platelet 150109/L

CSPH: clinically significant portal hypertension; HVPG: hepatic venous pressure gradient; LSM: liver stiffness measurement; NIT: non-invasive test; NSBB: non-selective beta-blocker.

Splenic stiffness measurement is a marker of portal blood flow and is emerging as a more accurate marker of CSPH than LSM.9 It can be a useful adjunct to improve the accuracy of LSM to detect CSPH, particularly in patients stratified in the grey zone with LSM.10 Novel biomarkers such as von-Willebrand factor and serum metabolomics, when used alone or in combination with Baveno VII risk prediction rules, are also being assessed to detect CSPH non-invasively and predict the risk of hepatic decompensation.11,12

NON-SELECTIVE BETA-BLOCKERS IN CLINICALLY SIGNIFICANT PORTAL HYPERTENSION: ESTABLISHED INDICATIONS

Over four decades ago, an increased understanding of portal circulation physiology laid down the foundation for non-selective beta-blockers (NSBB) in the management of portal hypertension in selected patients.13 NSBBs dampen the hyperdynamic circulation and splanchnic vasodilatation, the two self-perpetuating mechanisms of CSPH. Therefore, their role in the absence of CSPH and the hyperdynamic circulation is not defined.2 The indications for NSBB have been refined over this time. These were originally used for the prevention of variceal bleeding in patients with large varices or red signs. With the recognition of ascites rather than

NSBB No

variceal bleeding as the most common decompensating event in the natural history of liver disease, and the fact that 25% of patients with CSPH decompensate with ascites over 2 years, a paradigm shift of using NSBB beyond prophylaxis against variceal bleeding emerged recently. 3,14

Early signs of this shift became apparent 2 decades ago in a randomised placebocontrolled trial of timolol to prevent the formation of varices in compensated cirrhosis.15 In this trial, NSBB did not prevent the onset of varices or reduce the incidence of hepatic decompensation. The trial included all patients with compensated cirrhosis and portal hypertension (HVPG >5 mmHg). Post-hoc analysis of this trial showed that patients with HVPG ≥10 mmHg decompensated more frequently than those with HVPG <10 mmHg over 4 years of follow up (30% versus 10%).16 This trial quantified the concept of CSPH and identified the subgroup with higher rates of decompensation and more likely to benefit from portal pressure-lowering therapies. The critical threshold in stratifying these patients was HVPG ≥10 mmHg. The most reliable surrogate marker of HVPG ≥10 mmHg is the presence of varices irrespective of size and radiological collaterals.1 The shift in the role of NSBB from bleed prophylaxis to prevention of all-cause decompensation became more apparent after the PREDESCI trial. This trial randomised patients with compensated cirrhosis and CSPH based on HVPG estimation to NSBB (carvedilol or propranolol) and placebo for each corresponding NSBB.4 NSBB reduced the incidence of hepatic decompensation compared to placebo (16% versus 27%; hazard ratio [HR]: 0.51; 95% CI: 0.26–0.97; p=0.041) primarily by reducing the incidence of ascites (HR: 0.44; 95% CI: 0.20–0.97; p=0.0297). This pivotal trial laid down the concept of treating CSPH to prevent allcause decompensation. However, subgroup analysis of this trial showed the net benefit of this strategy to be restricted to those with varices on endoscopy. This was subsequently validated by an individual patient meta-analysis showing the benefits of NSBB in those with compensated cirrhosis with varices irrespective of their size.17 The ongoing UK-based multicentre

pragmatic randomised trial conducted in patients with cirrhosis and small varices (BOPPP, ISRCTN10324656) will give more information in this regard.18 This trial, which includes both compensated and decompensated patients, was initially designed to study the role of NSBB for variceal bleed prophylaxis but was later modified to evaluate all-cause decompensation as its primary endpoint. As of now, there is increasing evidence for treating patients with compensated cirrhosis with any varices with NSBB to prevent the first decompensation. This strategy has been endorsed by the Baveno VII consensus and the American Association for the Study of Liver Diseases (AASLD).1,19 The BOPPP trial, with over 700 participants already randomised, will provide further valuable evidence in a contemporary cohort of patients resulting in more generalisable findings.18

NON-SELECTIVE BETA-BLOCKERS IN CLINICALLY SIGNIFICANT PORTAL HYPERTENSION: PROPOSED INDICATIONS

Overall, the evidence for treating CSPH only exists when it is confirmed using HVPG or stratified by the presence of varices. The bulk of discussion and controversy of NSBB in patients with compensated cirrhosis is centred around their role in patients who do not have clinical signs of CSPH. As discussed earlier, while HVPG is helpful in this condition, its invasive nature limits its application in clinical practice. While rates of decompensation in this sub-group (HVPG ≥10, no varices) are lower than in those with established varices, it is still around 25–30% in 2 years, especially in aetiologies like alcohol-related liver disease with ongoing consumption.16

Patients with compensated cirrhosis and non-invasive surrogates of CSPH but without varices represent a unique subgroup as there is a lack of evidence of NSBB to improve outcomes in this state. While recent data suggests that noninvasive risk prediction rules predict distinct decompensation, there is no data to support their utility alone in starting NSBB

in the absence of varices (Table 1).20-25 The concept of starting NSBB in patients with compensated cirrhosis with only non-invasive criteria of CSPH (i.e., without varices/HVPG estimation) is extrapolated from the PREDESCI trial.4 However, there are significant drawbacks to this proposed extrapolation. First, the efficacy of NSBB was significantly lower in patients with CSPH but without varices in the PRESDESCI trial. The benefits of NSBB were restricted to only patients with varices, which constituted 56% of the trial population and hence impacted the overall study results. Unlike HVPG, LSM

Jachs et al.20

N=420

Non-invasive (LSM ≥10 kPa, VITRO, platelet count, BMI, ANTICIPATE±NASH)

Invasive (HVPG)

Dajti et al.21

N=195 (114 from validation cohort analysed)

Non-invasive (LSM ≥10 mmHg, SSM, platelets)

Retrospective

did not have the same discriminatory ability to predict decompensation in this trial. Second, the overall event rate in this trial was low, with only a moderate effect size. Third, the predominant aetiology of liver disease in the PREDESCI trial was hepatitis C virus.

Since the advent of direct-acting antivirals, treatment of hepatitis C has drastically changed. There is emerging data that shows that NSBB may not be needed in patients with compensated viral cirrhosis who achieve virological suppression/cure as

Retrospective, two centres in Italy

Median follow-up: 42 months

ARLD: 20.5%

MASLD: 18.6%

119 patients had control or cure of aetiological factor

Viral: 57.9%

ARLD: 12.3%

MASLD: 36.0%

All had compensated CSPH

Predictors of decompensation at 1 year (AUROC): HVPG: 0.739; VITRO: 0.811; ANTICIPATE±NASH CSPH probability: 0.683; LSM to PLT ratio: 0.699.

AASLD CSPH criteria were used.

16% decompensation over median follow-up (1.6 [0.5–3.8] years)

Higher decompensation in ARLD versus MASLD (3 years 35.5% versus 14.9%)

First decompensation rate (Baveno VII, Baveno VIII sequential SSM, and Baveno VIII-SSM combined models)

Rule in group (12.5%, 15.4%, 16.1%, respectively)

Rule out group (0 in all models)

Grey zone (9.7%, 4.4%, 0%, respectively)

Combined Baveno VIISSM model had the greatest precision in CSPH diagnosis compared to Baveno VII model and Baveno VII sequential SSM Model with only 15% in the grey zone with NPV and PPV >90% for ruling in an out CSPH

Shearer et al.22

N=3,028

Non-invasive (LSM ≥10 kPa, FIB-4, ALBI) Retrospective using electronic health records at two centres

ARLD: 11%

NAFLD: 28%

43% were missing data

Median follow-up: 3.1 years

All had cACLD

Baseline LSM and 5-year decompensation risk (% [95% CI]): <15 kPa: 3.7 (2.7–5.1); 15–25 kPa: 8.6 (6.4–11.1); >25: 19.0 (15.8–22.4).

ALBI score (per unit increase): 2.4 (1.80–3.18)

7.1% of patients developed varices prior to decompensation/HCC

74% of patients not known to have varices at time of decompensation.

Patients with ARLD had highest risk of decompensation (19.2% at 5 years)

Table 1: Key studies based on non-invasive criteria to predict the risk of decompensation.

Table 1: Continued.

Study Design

Wong et al.23

N=1,159

~Non-invasive (LSM)

Song et al.24

N=1,966

Non-invasive (LSM ≥10 kPa)

Retrospective, four centres

Median follow-up: 40 months

Lin et al.25

N=2,763 with cACLD (Baveno VII criteria: low risk (35.6%), grey zone (44.9%), and high risk (19.4%).

Non-invasive (LSM, ALBI, SSM [n=179])

Retrospective, single centre

Median follow-up: 3.06 (IQR 1.03–6.00) years

Aetiology

HCV: 56.1%

HBV: 21.3%

ARLD: 9.1%

NASH: 102 (8.8)

All patients had compensated disease (CSPH [LSM ≥25 kPa, 36.8%], grey zone [51.1%], CSPH excluded [LSM < 15 kPa, 12.1%])

Viral: 62.60% (majority on HBV antivirals and almost all had HCV SVR)

NAFLD: 18.10%

Alcohol: 15.97%

All had cACLD

Prediction of clinical events Comments

Predictors of decompensation (sHR [95% CI]): CSPH: 2.48 (1.35–4.55); Non-viral aetiology: 3.25 ( 1.83–5.76); INR >1.1: 2.08 (1.14–6.25); Albumin <7 g/L: 3.38 (1.83–6.25); LSM ≥25 kPA: 8.8 (2.9–26.7).

During follow up 7.2% developed decompensation (lower in grey zone [2.6%] versus CSPH [13.8%])

Non-viral aetiology had the highest rate of decompensation (up to 25.5% in the CSPH group)

Prospective, three centres

Median follow-up: 7.2 years

ARLD: 16.20%

MASLD: 31.16%

HCV: 6.36%

HBV: 42.60%

35.60% were on antiviral therapy

Decompensation risk in grey zone (sHR [95% CI]): ARLD: 3.49 (1.65–7.37); Low albumin: 0.41 (0.25–0.67); Lower platelet: 0.99 (0.98–1.00); Higher LSM: (1.14 [1.07–1.22]).

Decompensation risk

CSPH: 22% at 3 years (27% in NAFLD, 37% in ARLD)

Grey zone high probability: 12% (17% in NAFLD, 31% in ARLD)

Grey zone low probability): 3.3% (0% in NAFLD, 10% in ARLD)

CSPH excluded: 1.4% (2.2% in NAFLD, 7.4% in ARLD)

CSPH had higher proportion of ARLD.

Predictors of decompensation in grey zone (SHR [95% CI]): ARLD: 2.05 (1.05–3.99); ALBI: 1.8 (1.06–3.04); ALP: 1.6 (1.09–2.32).

Five-year incidence of decompensation was 0.3%, 4.2%, and 11.4% in low risk, grey zone, and high risk, respectively

Combination of Baveno VII and spleen stiffness reduced classified in grey zone (12.8%)

ALBI: albumin-bilirubin; ARLD: alcohol-related liver disease; AUROC: area under the receiver operating characteristic curve; cACLD: compensated advanced chronic liver disease; CSPH: clinically significant portal hypertension; FIB-4: fibrosis index based on four factors; HBV: hepatitis B; HCV: hepatitis C; HVPG: hepatic venous pressure gradient; IQR: interquartile range; LSM: liver stiffness measurement; MASLD: metabolic dysfunction-associated steatotic liver disease; NAFLD: non-alcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; NPV: net present value; PLT: platelet count; SSM: spleen stiffness measurement; SVR: sustained virologic response; VITRO: von Willebrand Factor antigen to platelet ratio.

the rate of decompensation is significantly reduced.26,27 The predominant aetiology of liver disease in current pragmatic trials of NSBB in CSPH is alcohol (unpublished data from BOPPP and CALIBRE) and MASLD, which have higher rates of decompensation.18,28 Patients with MASLD can even decompensate before the HVPG threshold of 10 mmHg.29 Fourth, the positive predictive value of non-invasive criteria depends upon the baseline prevalence of CSPH and is likely to be different in different cohorts.30 This has resulted in inconsistent demonstration of the benefit of these noninvasive criteria in validation studies for CSPH.31,32 Due to differences in effect size, different aetiology of liver disease, and more importantly, a different method of CSPH estimation (HVPG versus LSM estimation), extrapolation of evidence of treating CSPH from PREDESCI cannot be applied to patients only satisfying non-invasive diagnosis of CSPH without concomitant HVPG estimation or demonstration of varices. To change clinical practice the evidence for this non-invasive test-based strategy must be generated.

DOWNSIDE OF NON-SELECTIVE BETA-BLOCKERS FOR ALL

NSBB have numerous side effects. Around 10% of patients have contraindications to NSBB, and 15% of patients discontinue NSBB due to adverse effects.33 In the timolol study, the incidence of serious

References

1. de Franchis R et al. Baveno VII - Renewing consensus in portal hypertension. J Hepatol. 2022;76(4):959-74.

2. Villanueva C et al. Development of hyperdynamic circulation and response to β-blockers in compensated cirrhosis with portal. Hepatology. 2016;63(1):197-206.

3. D’Amico G et al. Clinical states of cirrhosis and competing risks. J Hepatol. 2018;68(3):563-76.

adverse effects in NSBB arm was 18% compared to 6% with placebo.15 Data on the impact of NSBB on quality of life is not known. With an uncertain benefit of NSBB in those with non-invasive CSPH estimation and listed side effects, unknown impact on quality of life, and indefinite treatment, the practice of NSBB for all is an oversimplified extrapolation of evidence with a concerning risk of lowering net benefit of these drugs (with more patients being treated with this strategy who do not decompensate irrespective of being on NSBB).

SUMMARY

In summary, we have limited drugs to treat portal hypertension, and NSBB are among the most important agents when used in highly selected patients. There is now an established role for NSBB to prevent decompensation in patients with CSPH detected either on HVPG estimation or by the presence of varices. However, there is no evidence to initiate NSBB to reduce decompensation based on noninvasive estimates of CSPH exclusively in the absence of varices and HVPG <10 mmHg/unavailable HVPG. In the absence of prospective data from randomised trials, the strategy of NSBB for all based only on non-invasive risk tools should be strongly discouraged as NSBB are likely to lose their net benefit with intervening adverse effects if their prolonged use is expanded without evidence (Figure 1).

4. Villanueva C et al. β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebocontrolled, multicentre trial. Lancet. 2019;393(10181):1597-608.

5. D’Amico G et al. Competing risks and prognostic stages of cirrhosis: a 25year inception cohort study of 494 patients. Aliment Pharmacol Ther. 2014;39(10):1180-93.

6. Berzigotti A et al. New abdominal collaterals at ultrasound: a clue of progression of portal hypertension. Dig Liver Dis. 2008;40(1):62-7.

7. Kumar A et al. Correlation of transient elastography with hepatic venous pressure gradient in patients with cirrhotic portal hypertension: a study of 326 patients from India. World J Gastroenterol. 2017;23(4):687-96.

8. Pons M et al. Noninvasive diagnosis of portal hypertension in patients with compensated advanced chronic liver disease. Am J Gastroenterol. 2021;116(4):723-32.

9. Reiberger T. The value of liver and spleen stiffness for evaluation of portal hypertension in compensated cirrhosis. Hepatol Commun. 2022;6(5):950-64.

10. Dajti E et al. A combined Baveno VII and spleen stiffness algorithm to improve the noninvasive diagnosis of clinically significant portal hypertension in patients with compensated advanced chronic liver disease. Am J Gastroenterol. 2022;117(11):1825-33.

11. Jachs M et al. The sequential application of Baveno VII criteria and VITRO Score improves diagnosis

of clinically significant portal hypertension. Clin Gastroenterol Hepatol. 2023;21(7):1854-63.e10.

12. Nicoară-Farcău O et al. Metabolomics as a tool to predict the risk of decompensation or liver-related death in patients with compensated cirrhosis. Hepatology. 2023;77(6):2052-62.

13. Lebrec et al. Propranolol - a medical treatment for portal hypertension? Lancet. 1980;2(8187):180-2.

14. Hernández-Gea V et al. Development of ascites in compensated cirrhosis with severe portal hypertension treated with β-blockers. Am J Gastroenterol. 2012;107(3):418-27.

15. Groszmann RJ et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med. 2005;353(21):2254-61.

16. Ripoll C et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology. 2007;133(2):481-8.

17. Villanueva C et al. Carvedilol reduces the risk of decompensation and mortality in patients with compensated cirrhosis in a competing-risk metaanalysis. J Hepatol. 2022;77(4):101425.

18. Patel VC et al. Beta-blockers or Placebo for Primary Prophylaxis (BOPPP) of oesophageal varices: study protocol for a randomised controlled trial. Trials. 2024;25(1):265.

19. Kaplan DE et al. AASLD Practice Guidance on risk stratification and management of portal hypertension

and varices in cirrhosis. Hepatology. 2024;79(5):1180.

20. Jachs M et al. Prognostic performance of non-invasive tests for portal hypertension is comparable to that of hepatic venous pressure gradient. J Hepatol. 2024;80(5):744-52.

21. Hui VWK et al. Baveno VII criteria for recompensation predict transplantfree survival in patients with hepatitis B-related decompensated cirrhosis. JHEP Rep. 2023;5(9):100814.

22. Shearer JE et al. The natural history of advanced chronic liver disease defined by transient elastography. Clin Gastroenterol Hepatol. 2023;21(3):694-703.e8.

23. Wong YJ et al. Baveno-VII criteria to predict decompensation and initiate non-selective beta-blocker in compensated advanced chronic liver disease patients. Clin Mol Hepatol. 2023:29(1):135-45.

24. Song BG et al. Validation of noninvasive diagnosis of CSPH in patients with compensated advanced chronic liver disease according to Baveno VII. Liver Int. 2023;43(9):1966-74.

25. Lin H et al. Risk and predictors of hepatic decompensation in grey zone patients by the Baveno VII criteria: a competing risk analysis. Aliment Pharmacol Ther. 2023;58(9):920-8.

26. Tosetti G et al. Decompensation in direct-acting antiviral cured hepatitis c virus compensated patients with clinically significant portal hypertension: too rare to warrant universal Β-blocker therapy. Am J Gastroenterol. 2021;116(6):1342-4.

27. Wang B et al. Carvedilol plus NUC for patients with HBV-compensated cirrhosis under virological suppression: a randomized open-label trial. Am J Gastroenterol. 2024;119(4):700-11.

28. Tripathi D et al. Study protocol for a randomised controlled trial of carvedilol versus variceal band ligation in primary prevention of variceal bleeding in liver cirrhosis (CALIBRE trial). BMJ Open Gastroenterol. 2019;6(1):e000290.

29. Bassegoda O et al. Decompensation in advanced nonalcoholic fatty liver disease may occur at lower hepatic venous pressure gradient levels than in patients with viral disease. Clin Gastroenterol Hepatol. 2022;20(10):2276-86.e6.

30. Sharma et al. Noninvasive diagnosis of clinically significant portal hypertension in patients with compensated liver disease: whom and how to screen? Am J Gastroenterol. 2021;116(5):1096-7.

31. Jindal A et al. Assessment of the performance of non-invasive criteria for the evaluation of clinically significant portal hypertension in patients with compensated advanced chronic liver disease. Dig Dis Sci. 2023;68(5):2149-57.

32. Podrug K et al. Validation of the new diagnostic criteria for clinically significant portal hypertension by platelets and elastography. Dig Dis Sci. 2022;67(7):3327-32.

33. Albillos A, Krag A. Beta-blockers in the era of precision medicine in patients with cirrhosis. J Hepatol. 2023;78(4):866-72.

Tongue Hyperpigmentation with Peginterferon α-2b Therapy in Hepatitis B: Case Series With Review of Literature

Authors: *Saubhik Ghosh,1 Tryambak Samanta1

1. Department of Medical Gastroenterology, Medical College and Hospital, Kolkata, India *Correspondence to souvikpgi@gmail.com

Disclosure: The authors have declared no conflict of interest.

Received: 19.01.24

Accepted: 05.03.24

Keywords: Hepatitis B, peginterferon α-2b (Peg IFNα-2b), tongue hyperpigmentation.

Citation: EMJ Hepatol. 2024;12[1]:81-85. https://doi.org/10.33590/emjhepatol/JKZU1421.

Abstract

Peginterferon α-2b (Peg IFNα-2b) continues to be used for treating a selected subset of patients with hepatitis B, in the era of direct-acting antivirals for hepatitis C infection. The authors hereby report four cases of tongue pigmentation among 21 patients with hepatitis B, whom they treated in the last 5 years, where at least 48 weeks of Peg IFN were administered. The lesions were mostly self-limiting, having no temporal relation with response to treatment. To the best of the authors’ knowledge, this is the first case series of Peg IFN-induced lingual hyperpigmentation in patients with hepatitis B, which clinicians should be aware of.

Key Points

1. Tongue hyperpigmentation may be an underreported, but a not so uncommon, adverse effect of Peg IFN therapy.

2. This adverse effect has some cosmetic effect, but subsides when therapy is stopped.

3. Physicians should be aware of this adverse effect, and its reversibility.

INTRODUCTION

Peginterferon α-2b (Peg IFNα-2b), which inhibits viral replication in infected cells, suppresses cell proliferation, induces apoptosis, and exerts an anti-angiogenic effect, is a conventionally used treatment for hepatitis B and C infection. However, with the availability of direct-acting antivirals for hepatitis C, Peg IFNα-2b is used for treating hepatitis B in specific scenarios.1,2 Various dermatological side effects of Peg IFN therapy, including dry skin, alopecia, and exacerbation of autoimmune skin diseases, such as psoriasis and lichen planus, have been reported.3,4 There are also some case reports and series of lingual hyperpigmentation with Peg IFN and ribavirin therapy in patients with hepatitis C519 (Table 1). The authors communicate their

experience with this rare side effect for the first time, during routine use of Peg IFN in patients with hepatitis B.

CASE 1

A 31-year-old female with hepatitis B presented with transaminasemia, e-negative viral load, genotype A and hepatitis B virus DNA of 103 copies/mL, no features suggestive of portal hypertension, and liver stiffness measurement of 7 kPa. The patient was non-hypertensive, non-diabetic, nonalcoholic, and a non-smoker. After initial routine work-up, the authors started her on Peg IFNα-2b 80 μg subcutaneously, weekly. They continued her Peg IFN for 48 weeks, as she met all the criteria of response to therapy. She developed hyperpigmentation at the dorsal and lateral surface of the tongue after 36 weeks of therapy (Figure 1A). She had no other diseases that may cause hyperpigmentation, such as McCune–Albright syndrome, Addison’s disease, nutritional deficiencies, Peutz–Jeghers syndrome, heavy metal exposure, malignant melanoma, neurofibromatosis, etc. She had not received any medication that may lead to hyperpigmentation (e.g., oral contraceptives, bismuth salt, etc). The authors followed the patient at regular intervals off-treatment of Peg-IFN. This hyperpigmentation disappeared gradually after a follow-up period of 36 weeks.

CASE 2

A 46-year-old female with incidental detection of chronic hepatitis B with moderate transaminasemia (alanine transaminases [ALT] more than 3 times the norm), genotype A, e-negative disease, viral load of 103 copies/mL, and liver stiffness measurement of 8 kPa, received 48 weeks of Peg IFNα-2b therapy. She had no addiction and no other comorbidities. She too developed tongue hyperpigmentation, albeit on the dorsal surface of the tongue, at 33 weeks of treatment (Figure 1B). The authors regularly followed this patient up to 30 weeks, and the pigmentation faded away. Like in the first case, she had no diseases, and had not received any medication that may cause tongue pigmentation.

CASE 3

A 32-year-old male with chronic hepatitis B, ALT more than five times the norm, e-negative disease, genotype A, viral load of 103 copies/mL, no feature suggestive of portal hypertension, and liver stiffness measurement of 7 kPa, was started on Peg IFNα-2b therapy. He took alcohol occasionally, but had no other addiction or chronic disease. After 46 weeks of therapy, he developed lingual hyperpigmentation at the dorsal surface (Figure 2A). All confounding factor causes of pigmentation were also excluded. Hyperpigmentation gradually vanished after 29 weeks of offtreatment follow-up.

Figure 1: First two documented cases.

Table 1: Previous documentation.

References

Torres et al.5 1 6 weeks of starting therapy Not mentioned White Soreness of tongue

Dell’Isola et al.6 1 Not mentioned 1 White Not mentioned

Mlika et al.7 1 4 weeks 1

Ghosh et al.8 1 40 weeks 4

Willems et al.9 2 36 and 40 weeks 5 and 2

Radha Krishna et al.10 1 36 weeks 6

Non-White Tongue pain

Non-White No symptoms

Both are nonWhite No symptoms

Non-White No symptoms

Gurguta et al.11 5 4–40 weeks 2, 4, 1, 1, 4 All are nonWhite Not mentioned

Sood et al.12 2 8 and 16 weeks 3, 1 Both non-White Not mentioned

Fernandéz et al.13 1 12 weeks 4 White Tongue pain

Farshidi et al.14 1 16 weeks Not mentioned White Soreness of tongue

Karabay et al.15 1 8 weeks Not mentioned Non-White Dysgeusia

de Moraes et al.16 1 32 weeks Not mentioned Non-White No symptoms

Aguayo-Leiva et al.17 1 16 weeks 1 White No symptoms

Tsilika et al.18 7 Not mentioned Not mentioned 3 non-White, 4 White One had minor tongue pain

Alyouzbaki et al.19 1 8 weeks 1

CASE 4

A 37-year-old female with chronic hepatitis B and e-negative disease, genotype A with low viral load (102 copies/mL), transaminases of more than two times the norm, with liver stiffness around 10 kPa, was started on Peg IFNα-2b therapy. The patient was asymptomatic, and had no other chronic disease. She noticed tongue hyperpigmentation around 31 weeks of therapy, which completely disappeared 27 weeks after completion of therapy (Figure 2B). Other factors causing hyperpigmentation were excluded in this patient too.

Non-White No symptoms

DISCUSSION

The treatment option for hepatitis B consists of oral antivirals in most cases. In limited scenarios, Peg IFN can be used in patients with low initial viral load (<103/ mL), younger age, high ALT, low level of fibrosis in the liver, and genotype A and B.20 Retrospectively, the authors have observed the side effects of routine use of Peg IFN therapy in patients with hepatitis B. They had treated only 21 patients with Peg IFN who met the criteria in the last 5 years. All had e-negative disease and genotype A. Among 21 patients with chronic hepatitis B, the authors came across four cases (19%)

of lingual hyperpigmentation. Pigmentation commonly found in tongue can have varied aetiologies, from physiological changes, to oral manifestations of systemic diseases and malignancies.21 The pathophysiology behind this lingual pigmentation is mostly due to deposition of either endogenous (e.g., haemoglobin, haemosiderin, melanin) or exogenous (lead, mercury, bismuth, arsenic, etc.) pigments.21 The presentations can vary from blue/purple vascular lesions, and brown melanotic or haeme-associated lesions, to grey/black pigmentations.21 Considering the temporal association with Peg IFN therapy and appearances, disappearances of lesions, and exclusion of other causes, confirmed the side effect. As past publications were reviewed, to the best of the authors’ knowledge, 28 cases of tongue hyperpigmentation were anecdotally reported, including one by the author of this article, with IFN therapy in patients with hepatitis C.5-19 However, all authors considered it a rare side effect of IFN therapy. These reports suggest female (65%) preponderance, and that populations with dark skin (66.6%) were predisposed.19 To the authors’ knowledge, they are the first to report their experiences in hepatitis B.

In the authors’ series, where they treated a non-White Indian population infected with chronic hepatitis B, three of the cases of tongue hyperpigmentation (75%) were females, and all were dark skinned. As they searched the literature, they noted Willems et al.9 documented that dark-

skinned patients receiving interferon therapy showed higher plasma levels of α-melanocyte-stimulating hormone.9 One hypothetic mechanism of these deposits may be that receptors of this hormone up regulation at melanocytes because of interferon, which ultimately increases the melanin production, and causes tongue hyperpigmentation. One study did the biopsy of the tongue in a White patient co-infected with hepatis C and HIV, treated with Peg IFN. They showed an increased number of melanocytes in the basal layer of the epithelium.5 Where normal keratinocyte and melanocyte ratio is 10:1, it was 5:1 in that particular patient. Biopsy was not done in any of the cases, as they were asymptomatic, and the authors had previous experience of this benign selflimiting side effect in hepatitis C.8 Gurguta et al.11 described five cases of similar tongue hyperpigmentation with chronic hepatitis C therapy. All of them were non-White, and infected with various genotypes of hepatitis C infections. Appearance of pigmentation occurred among them between 4–40 weeks of therapy, as in the authors’ cases.

The authors only had patients of genotype A, simply due to selection bias of choosing patients for Peg IFNα2b treatment. Nevertheless, the same findings theoretically should hold true for all genotypes of hepatitis B. The duration between the start of the treatment and the appearance of the pigment spots ranges from 4–40 weeks, as in the authors’ cases.19

Figure 2: Last two documented cases.

Surprisingly, the sites of involvement were varied, which is a subject of study of interest. As previously described, no dysgeusia or tongue pain, including soreness and burning, were reported by the patients. Gradual improvement of the lesions has been noted in all cases with discontinuation of treatment, which denotes it is a self-limiting side effect. Additionally, the authors need to mention that, although previous reports considered the skin condition of lingual hyperpigmentation a rare side effect, their experience suggests that a good number of patients may have the side effect, which gastroenterologists have to be aware of. As it is a cosmetic effect, this may add to the psychological

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CONCLUSION

Therefore, the authors can come to a conclusion that tongue hyperpigmentation is an important adverse effect of IFN treatment, irrespective of viral aetiology, that can add psychological stress for patients treated with Peg IFN. Further observation with a higher number of patients on Peg IFN therapy may highlight the exact frequency of this underreported, but possibly not uncommon, side effect.

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