Trending Topics in Gastroenterology | GastroAGI

Primary Sclerosing Cholangitis: Evolving Risk Stratification and Emerging Therapies: Clinics in Liver Disease | June 2026

* Primary sclerosing cholangitis (PSC) remains one of the leading indications for liver transplantation despite being a relatively rare disease. * The incidence and prevalence of PSC continue to rise in Europe and North America, suggesting factors beyond inflammatory bowel disease alone contribute to disease development. * Approximately 60%–80% of patients with PSC develop inflammatory bowel disease, most commonly ulcerative colitis, while 5%–21% of IBD patients develop biliary abnormalities. * PSC-associated IBD differs from classical ulcerative colitis, often demonstrating extensive pancolitis with prominent right-sided involvement and a higher colorectal cancer risk. * Most patients are asymptomatic at diagnosis, with PSC often detected incidentally through abnormal cholestatic liver biochemistry during IBD surveillance. * Young patients frequently present with elevated transaminases and may initially resemble autoimmune hepatitis before evolving into classical PSC. * The natural history of PSC is highly variable, ranging from stable disease over decades to rapid progression requiring transplantation. * Women generally experience a more favorable clinical course, while younger age at diagnosis is associated with a greater burden of PSC-related complications over time. * Hepatopancreatobiliary malignancies remain a major cause of mortality in PSC. * PSC substantially increases the risk of: * Cholangiocarcinoma * Hepatocellular carcinoma * Gallbladder cancer * Pancreatic cancer * PSC-associated IBD also carries a markedly increased risk of colorectal neoplasia, necessitating intensive colonoscopic surveillance. * Risk stratification is rapidly evolving with advances in: * MRI and MRCP imaging * Liver stiffness measurement * Serum biomarkers * Fibrosis assessment tools * Emerging molecular markers * No single risk model currently captures the full complexity of PSC, and multimodal approaches are increasingly favored. * There remains no approved disease-modifying therapy proven to improve transplant-free survival. * Management currently focuses on: * Monitoring disease progression * Managing dominant strictures * Cancer surveillance * Optimizing IBD control * Timely transplant referral * Ursodeoxycholic acid remains widely used in selected patients, although its role continues to be debated. * Several promising therapeutic strategies are under investigation, including: * Norursodeoxycholic acid (norUDCA) * Bile acid receptor modulators * Antifibrotic therapies * Microbiome-targeted approaches * Immune-modulating therapies * Increasing evidence suggests that intestinal inflammation may directly influence PSC progression, reinforcing the importance of achieving deep IBD control. * Future PSC management is expected to move toward precision medicine with individualized risk prediction and targeted therapeutic approaches. Bottom line: PSC remains a challenging cholestatic liver disease with high risks of transplantation and hepatopancreatobiliary malignancy. Advances in imaging, biomarkers, and emerging therapies are improving risk stratification, but effective disease-modifying treatment remains the major unmet need.

Denosumab Shows Safer Osteoporosis Control in PBC : Hepatology Communications | Nov 2025

Introduction Primary Biliary Cholangitis is frequently complicated by osteoporosis due to chronic cholestasis, systemic inflammation, malabsorption and altered bone metabolism. Skeletal fragility substantially increases morbidity in PBC, yet evidence-based treatment strategies specific to this population remain limited. Problem Statement Although bisphosphonates are commonly used in cholestatic liver disease–associated osteoporosis, comparative prospective data evaluating newer antiresorptive therapies in patients with PBC are scarce. Summary The multicenter DELTA trial directly compared Denosumab with Zoledronic Acid in Japanese patients with PBC-associated osteoporosis. This randomized open-label study demonstrated that denosumab achieved non-inferior improvement in lumbar spine bone mineral density compared with zoledronic acid over 12 months. Lumbar spine BMD increased substantially in both treatment groups, confirming the effectiveness of antiresorptive therapy in this high-risk population. Notably, denosumab showed numerically greater improvement in total hip BMD, suggesting potentially stronger effects at cortical bone sites, although predefined statistical non-inferiority criteria were not fully met for this endpoint. Both therapies significantly reduced bone turnover markers and improved biochemical indicators of bone remodeling, reflecting effective suppression of osteoclastic activity. A particularly important finding was the superior tolerability profile of denosumab. Adverse events occurred substantially less frequently compared with zoledronic acid, highlighting a clinically meaningful safety advantage in patients with chronic liver disease who often have multiple comorbidities and frailty. These results are highly relevant because osteoporosis management in PBC differs mechanistically from postmenopausal osteoporosis alone. Chronic cholestasis contributes to impaired osteoblast function, vitamin deficiencies, sarcopenia and altered calcium metabolism, creating a complex skeletal phenotype. The study also reinforces the increasingly recognized burden of hepatic osteodystrophy in chronic cholestatic liver disease. Fractures in PBC are associated with significant functional decline, impaired quality of life and increased healthcare utilization. From a practical standpoint, denosumab offers several advantages in PBC populations. Subcutaneous administration every six months may improve adherence compared with intravenous bisphosphonate strategies, particularly in older or frail patients. The findings additionally raise important considerations regarding individualized bone management in chronic liver disease. Patients with renal dysfunction, gastrointestinal intolerance or poor bisphosphonate tolerance may particularly benefit from denosumab-based approaches. Importantly, no major hepatic safety concerns emerged during the study. This is clinically reassuring given the frequent polypharmacy and metabolic vulnerability observed in advanced cholestatic disease. The trial also underscores the need for proactive bone health surveillance in hepatology practice. Osteoporosis remains underdiagnosed and undertreated in PBC despite its major impact on long-term morbidity. Broader implications extend beyond PBC alone. As survival improves across chronic liver diseases, management of extrahepatic complications including sarcopenia, frailty and osteoporosis is becoming increasingly central to comprehensive hepatology care. Nevertheless, several limitations remain. The study was relatively small, limited to a Japanese population and evaluated surrogate bone density outcomes rather than fracture reduction. Longer-term data regarding fracture prevention, durability of response and sequential treatment strategies following denosumab discontinuation will be important for future practice guidance. Overall, the DELTA study supports denosumab as a safe and effective therapeutic option for osteoporosis in patients with PBC, demonstrating robust bone mineral density improvement alongside a favorable tolerability profile compared with zoledronic acid.

Practical Nutrition Strategies Improve Cirrhosis Care : Frontline Gastroenterology | May 2026

Introduction Cirrhosis is increasingly prevalent worldwide and is associated with major metabolic, nutritional and functional derangements. Malnutrition and sarcopenia are highly prevalent across all stages of cirrhosis and substantially contribute to decompensation, hospitalization and mortality. Problem Statement Despite strong evidence supporting nutritional intervention in cirrhosis, practical nutrition management remains inconsistently implemented in routine care, particularly among non-hepatologists who increasingly manage these patients. Summary This practical review provides a clinically focused framework for integrating nutrition into everyday cirrhosis management across compensated and decompensated disease stages. The authors emphasize that nutritional intervention should be viewed as a core therapeutic component rather than supportive adjunctive care. Malnutrition and sarcopenia are strongly associated with hepatic encephalopathy, ascites severity, variceal bleeding, prolonged hospitalization and reduced survival. A central physiologic concept highlighted is the accelerated starvation state observed in cirrhosis. Patients rapidly transition into catabolism during fasting because of impaired hepatic glycogen storage, resulting in increased muscle breakdown and worsening sarcopenia. To counter this metabolic shift, the review strongly advocates frequent meal intake with three to five meals daily alongside a late evening carbohydrate-protein snack. Avoidance of prolonged fasting is presented as a key practical intervention to preserve muscle mass and metabolic stability. Importantly, the article reinforces that protein restriction should generally be avoided. Contrary to historical practice, high-protein intake is now recognized as protective against Hepatic Encephalopathy and essential for maintaining skeletal muscle ammonia metabolism. The review additionally highlights the importance of routine sarcopenia assessment, recognizing skeletal muscle dysfunction as a major prognostic determinant in cirrhosis. Muscle depletion increasingly functions as both a metabolic and immunologic vulnerability factor in advanced liver disease. Micronutrient deficiency screening is another major practical focus. Deficiencies involving vitamin D, zinc, thiamine and other nutrients are common and frequently underrecognized, particularly in alcohol-related liver disease and advanced decompensation. The article also provides nuanced guidance regarding sodium restriction in ascites management. While low-salt diets remain important, excessive restriction that compromises caloric intake may worsen malnutrition. The authors support individualized dietary liberalization when nutritional intake becomes inadequate, provided diuretics are appropriately adjusted. Bone health is emphasized as another neglected aspect of cirrhosis care. Osteoporosis and fragility fractures are common yet often overlooked complications, supporting low-threshold screening and early intervention strategies. A major strength of the review is its practical accessibility for non-specialists. Rather than focusing solely on detailed guideline statements, the article translates nutritional principles into clinically actionable bedside strategies relevant to general physicians, gastroenterologists and multidisciplinary teams. The review also reflects the growing recognition that nutritional status directly influences transplant outcomes, procedural tolerance, infection risk and overall frailty trajectories in cirrhosis. From a broader perspective, the article reinforces the paradigm shift toward holistic metabolic management in chronic liver disease. Nutrition, exercise, frailty assessment and muscle preservation are increasingly central components of modern hepatology practice. Importantly, many of the proposed interventions are low-cost, scalable and immediately implementable, making them particularly valuable in routine clinical settings with limited specialist dietetic access. Overall, this review provides a highly practical framework for nutritional management in cirrhosis, emphasizing early recognition of malnutrition and sarcopenia, avoidance of prolonged fasting, maintenance of adequate protein intake and individualized metabolic support as key strategies to improve patient outcomes.

ISHEN Consensus Standardizes Ammonia Testing in Cirrhosis : J Hepatol | May 2026

Introduction Hepatic Encephalopathy is a major complication of Cirrhosis and is closely linked to ammonia metabolism. Despite ammonia’s central pathogenic role, the clinical value of blood ammonia measurement has remained controversial because of inconsistent sampling methods, laboratory variability and uncertainty regarding interpretation in routine practice. Problem Statement Lack of standardized guidance regarding ammonia measurement has resulted in major variability in clinical practice, limiting its reliable use in diagnosis, prognostication, therapeutic monitoring and research in cirrhosis and hepatic encephalopathy. Summary This International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus represents the first structured international effort to standardize the role of ammonia measurement in cirrhosis care using a formal evidence-based Delphi methodology. The recommendations were developed through a rigorous multinational multidisciplinary consensus process involving expert hepatologists and researchers with specific expertise in hepatic encephalopathy and ammonia metabolism. The panel addressed 25 clinically relevant PICO questions spanning diagnostic utility, prognostication, therapeutic monitoring and technical aspects of ammonia measurement. A major contribution of the document is its emphasis on preanalytical standardization. The consensus highlights that ammonia measurements are highly susceptible to methodological error, including delays in processing, improper sample handling and variability in collection techniques. Standardized acquisition and processing protocols are therefore essential for clinically interpretable results. The panel supports the clinical relevance of ammonia measurement in selected settings rather than indiscriminate routine use. Elevated ammonia levels were recognized as useful in supporting the diagnosis of overt hepatic encephalopathy, particularly when diagnostic uncertainty exists, while acknowledging that ammonia alone cannot definitively establish or exclude the diagnosis. Importantly, the consensus also emphasizes ammonia’s prognostic role. Elevated levels may help identify patients at higher risk of developing overt hepatic encephalopathy and other liver-related complications, supporting incorporation into risk stratification frameworks for both inpatient and outpatient management. The recommendations additionally address therapeutic monitoring. Serial ammonia assessment may provide supportive information regarding response to ammonia-lowering therapies, although clinical evaluation remains the cornerstone of management decisions. A particularly valuable aspect of the document is its balanced interpretation of ammonia biology. The panel acknowledges that hepatic encephalopathy is multifactorial and not solely ammonia-dependent, explaining why some patients with elevated ammonia remain clinically asymptomatic while others develop encephalopathy despite lower concentrations. The consensus also identifies several important research priorities. These include development of reliable point-of-care ammonia testing, validation of ammonia-based predictive models and improved understanding of non-hyperammonemic encephalopathy phenotypes. Clinically, the document may substantially improve harmonization of practice across centers and trials. Standardized ammonia measurement protocols are especially important for multicenter hepatic encephalopathy studies, biomarker development and emerging therapeutic trials targeting ammonia metabolism. The work additionally reinforces the growing movement toward precision phenotyping in cirrhosis. Rather than viewing ammonia as a binary diagnostic marker, the consensus frames ammonia as a dynamic biologic variable integrated within broader clinical, inflammatory and metabolic contexts. From a translational perspective, the document is also highly relevant for drug development. Reliable ammonia measurement frameworks will likely become increasingly important as novel therapies targeting nitrogen metabolism, microbiome modulation and skeletal muscle ammonia handling continue to emerge. Overall, this ISHEN Delphi consensus establishes the first evidence-based international framework for ammonia measurement in cirrhosis. The recommendations provide practical guidance for clinicians, standardize best practices for sampling and interpretation, and reinforce ammonia’s evolving role in diagnosis, risk stratification and management of hepatic encephalopathy.

Impaired VO₂ Recovery Highlights Frailty Physiology in Cirrhosis : Liver Transpl | May 2026

Introduction Frailty and reduced functional capacity are increasingly recognized as major prognostic determinants in patients with Cirrhosis awaiting Liver Transplantation. The Six-Minute Walk Test is widely used to assess exercise tolerance and frailty in cirrhosis, yet the physiologic mechanisms underlying impaired performance remain incompletely characterized. Understanding cardiovascular, metabolic and muscular responses during functional testing may help refine prehabilitation strategies and exercise prescription in transplant candidates. Problem Statement Although patients with cirrhosis demonstrate markedly reduced aerobic capacity, the dynamic physiologic abnormalities during exercise and recovery that contribute to impaired functional performance are poorly understood, particularly among frail and pre-frail transplant candidates. Summary This physiologic study evaluated real-time cardiopulmonary and skeletal muscle responses during six-minute walk testing in frail/pre-frail cirrhotic patients awaiting transplantation compared with age-matched controls. Investigators continuously measured heart rate, oxygen consumption and calf muscle oxygenation before, during and after exercise using portable metabolic monitoring and near-infrared spectroscopy. Patients with cirrhosis demonstrated profound impairment in functional capacity, walking substantially shorter distances than controls during the six-minute walk test. At baseline, cirrhotic participants already exhibited elevated resting heart rates and reduced calf muscle oxygenation, suggesting underlying circulatory and peripheral tissue abnormalities even before exertion began. During exercise, patients with cirrhosis displayed blunted physiologic responses characterized by lower peak heart rate, reduced oxygen consumption and diminished tissue deoxygenation compared with controls. These findings suggest impaired aerobic reserve and reduced skeletal muscle oxygen extraction during exertion, likely reflecting the combined effects of sarcopenia, mitochondrial dysfunction, autonomic dysregulation and cirrhotic cardiomyopathy. One of the most important observations involved delayed recovery kinetics after exercise. Although heart rate and muscle oxygenation recovery were relatively preserved, recovery of oxygen consumption remained significantly prolonged in cirrhotic patients. This delayed VO₂ recovery likely reflects impaired oxidative metabolism and delayed restoration of aerobic homeostasis following exertion. The physiologic pattern observed resembles impaired metabolic flexibility seen in advanced heart failure and severe frailty syndromes. Reduced mitochondrial efficiency, skeletal muscle dysfunction and altered peripheral oxygen utilization may collectively contribute to the slowed recovery phenotype identified in these transplant candidates. Clinically, the findings provide mechanistic support for structured prehabilitation programs in cirrhosis. Importantly, the study suggests that exercise training protocols may need modification in this population, particularly by incorporating longer recovery intervals between exercise bouts because of delayed oxygen consumption normalization. The work also reinforces that frailty in cirrhosis is not simply deconditioning but rather a complex multisystem physiologic disorder involving cardiovascular, muscular and metabolic impairment. Functional limitation appears to arise not only from reduced exercise tolerance itself but also from impaired post-exercise recovery dynamics. These findings may have important implications for transplant assessment and longitudinal frailty monitoring. Recovery physiology — particularly delayed VO₂ normalization — may eventually emerge as a more sensitive marker of physiologic reserve than walk distance alone. Overall, this study demonstrates that frail/pre-frail cirrhotic patients awaiting transplantation exhibit markedly impaired aerobic endurance and delayed metabolic recovery after exercise. The findings strengthen the rationale for individualized prehabilitation strategies and suggest that recovery kinetics may represent an important physiologic target in exercise-based interventions for advanced liver disease.

Wilson Disease Remains a Single-Gene Disorder : JHEP Reports | May 2026

Introduction Wilson disease (WD) is an autosomal recessive copper metabolism disorder caused by pathogenic variants in the ATP7B gene. Although genetic confirmation is increasingly incorporated into diagnostic algorithms, up to 20% of clinically diagnosed patients in historical cohorts remained genetically unresolved despite strong clinical evidence of WD. This multicenter international study evaluated whether modern genomic and functional approaches could clarify the molecular basis of these unresolved cases and determine whether WD truly represents a single-gene disorder. Problem Statement Conventional sequencing strategies, including hotspot analysis and Sanger sequencing, frequently fail to identify all pathogenic ATP7B variants. This diagnostic gap has generated speculation regarding alternative genetic causes, modifier genes or genetically heterogeneous Wilson-like syndromes. Uncertainty in unresolved cases complicates diagnostic confidence, family screening and genetic counselling, particularly when clinical Leipzig scores strongly support WD despite incomplete molecular confirmation. Summary This international multicenter study analyzed 761 clinically confirmed WD patients from tertiary referral centers in Germany, USA, Spain and Denmark. Among the cohort, only 44 patients (5.8%) had zero or one previously identified pathogenic ATP7B variant despite definite clinical WD. A comprehensive five-step diagnostic strategy incorporating whole genome sequencing (WGS), expanded gene panel analysis, long-read sequencing and ATP7B peptide quantification was applied to these unresolved cases. Reanalysis of ATP7B alone resolved 52% of previously unexplained cases. Seven patients were solved through reinterpretation of previously reported variants of uncertain significance, while 16 additional patients were diagnosed after WGS identified previously undetected ATP7B variants, including intronic, structural and complex rearrangements missed by earlier sequencing methodologies. Overall, 11 novel ATP7B variants were identified. Functional ATP7B peptide analysis further confirmed protein dysfunction in additional unresolved patients, increasing the diagnostic confirmation rate to 66% within the genetically unresolved subgroup and to 98% across the entire WD cohort. Importantly, extensive screening of 97 copper metabolism-related genes and more than 4,300 genes associated with hepatic or neurological disorders failed to identify alternative monogenic causes of disease. Even advanced long-read sequencing approaches did not reveal non-ATP7B pathogenic mechanisms. These findings strongly reinforce the concept that WD is fundamentally a single-gene disorder caused by ATP7B dysfunction rather than a genetically heterogeneous syndrome. The study has major clinical implications. It demonstrates that many historically “genetically negative” WD cases reflect limitations of older sequencing technologies or outdated variant classification rather than alternative disease biology. The authors advocate routine re-evaluation of unresolved WD cases using contemporary WGS, comprehensive ATP7B analysis and functional peptide assays before considering alternative diagnoses. This strategy can substantially improve diagnostic certainty, cascade family testing and personalized clinical management in WD.

Tacrolimus Shows Promise in Refractory Paediatric AIH : Frontline Gastroenterol | May 2026

Introduction Autoimmune hepatitis (AIH) in children is typically managed with corticosteroids and azathioprine, achieving remission in most patients. However, a subset of paediatric patients remain refractory to standard therapy or develop significant treatment intolerance, creating a major therapeutic challenge with risk of progressive fibrosis and liver failure. Problem Statement Evidence supporting second-line immunosuppressive therapy in difficult-to-treat paediatric AIH remains limited, particularly regarding long-term efficacy and safety of tacrolimus. Optimal management strategies for children with incomplete response or intolerance to conventional therapy are not well established. Summary This single-centre retrospective study evaluated tacrolimus as rescue immunosuppression in children with refractory or treatment-intolerant autoimmune hepatitis. Most patients received tacrolimus because of inadequate biochemical response to standard therapy, while a smaller proportion required escalation because of medication intolerance. Notably, many children already demonstrated progression of hepatic fibrosis at the time tacrolimus was initiated, underscoring the aggressive nature of difficult-to-control paediatric AIH. Tacrolimus induced complete biochemical remission in approximately two-thirds of patients, with remission often achieved rapidly after treatment initiation. Importantly, even patients who failed to achieve full remission demonstrated significant biochemical improvement, suggesting clinically meaningful disease control despite persistent low-grade activity. The treatment was well tolerated overall, with no major adverse effects or treatment discontinuations observed during follow-up. These findings support tacrolimus as a viable second-line or third-line immunosuppressive strategy in carefully selected paediatric AIH patients managed within specialized hepatology centres. The study also reinforces the importance of early recognition of treatment-refractory disease, as ongoing inflammatory activity may contribute to progressive fibrosis despite conventional therapy. Although limited by retrospective design and small cohort size, the findings add important real-world evidence supporting calcineurin inhibitor–based rescue therapy in paediatric AIH and highlight the need for prospective multicentre studies to better define long-term outcomes, optimal therapeutic timing and predictors of response.

Delisting for Clinical Improvement Emerges as a Practical Marker of Cirrhosis Recompensation : Liver Transpl | April 2026

Introduction The concept of recompensated cirrhosis has gained increasing importance with the advent of effective disease-modifying therapies for chronic liver disease, including antiviral treatment and sustained alcohol abstinence. As more patients experience meaningful clinical recovery, reassessing transplant candidacy and determining when liver transplantation may no longer be necessary have become major clinical challenges. Problem Statement Although recompensation is increasingly recognized as a relevant therapeutic endpoint, standardized real-world markers for durable clinical improvement remain poorly defined. Delisting for clinical improvement (DCI) from the liver transplant waitlist has been proposed as a potential surrogate for recompensation, but the durability of improvement and risk of subsequent clinical deterioration remain uncertain. Summary This large national cohort study demonstrates that delisting for clinical improvement occurs in a meaningful subset of liver transplant waitlist patients and may serve as a practical surrogate marker for recompensated cirrhosis. Rates of DCI varied substantially according to liver disease etiology, with the highest frequencies observed in hepatitis B, alcohol-associated liver disease and autoimmune hepatitis, reflecting the greater reversibility of these conditions under effective therapy or sustained disease control. Importantly, the study shows that true durable recompensation is not fully captured by MELD improvement alone. Patients achieving both MELD reduction and improvement in Child–Turcotte–Pugh class had the lowest risk of relisting, suggesting that combined biochemical and clinical recovery better defines stable recompensation. Notably, many patients delisted for improvement still retained significant underlying liver dysfunction, as fewer than half normalized to Child–Turcotte–Pugh class A. Relisting remained relatively uncommon overall but was frequently driven by hepatocellular carcinoma, emphasizing the continued oncologic vulnerability of cirrhotic patients despite hepatic improvement. Additional predictors of relapse included hypoalbuminemia, male sex and underlying disease etiology. Overall, the study supports a more nuanced and multidimensional approach to defining recompensated cirrhosis and provides important real-world evidence that integrated clinical improvement metrics may help guide safer liver transplant delisting decisions.

Integrating Portal Hypertension and HCC into a Unified Stage-Based Cirrhosis Model : Nat Rev Gastroenterol Hepatol | May 2026

Introduction Cirrhosis and hepatocellular carcinoma (HCC) represent closely interconnected consequences of chronic liver disease, with portal hypertension serving as a central driver of hepatic decompensation and a major determinant of prognosis. Despite this biologic overlap, clinical management frameworks have traditionally approached portal hypertension and HCC as separate entities. Problem Statement Current guidelines frequently fail to integrate cirrhosis stage, clinically significant portal hypertension (CSPH) and HCC stage into a unified prognostic model. This separation may lead to suboptimal treatment selection, inaccurate risk stratification and inadequate personalization of therapy, particularly when determining candidacy for curative interventions such as hepatic resection or transplantation. Summary This review proposes a clinically integrated, stage-based framework that combines cirrhosis severity, portal hypertension status and HCC stage to guide prognostication and therapeutic decision-making. The authors emphasize that CSPH represents a critical biologic and clinical milestone in compensated cirrhosis, strongly influencing risk of decompensation, survival and eligibility for curative HCC therapies. Importantly, the review highlights the transition from invasive hepatic venous pressure gradient measurement toward non-invasive assessment using liver stiffness and platelet-based tools, with emerging evidence suggesting these methods may soon become standard even in patients with HCC. The article further argues that management strategies should differ substantially according to the interaction between cirrhosis stage and tumor burden rather than relying on tumor stage alone. In compensated cirrhosis without CSPH, aggressive curative approaches may remain feasible, whereas decompensated disease substantially limits therapeutic tolerance and prognosis independent of tumor stage. The authors also call for future HCC clinical trials to incorporate cirrhosis stage and portal hypertension stratification into study design and outcome analysis. Overall, this review advances an important conceptual shift toward fully integrated hepatology-oncology care, where liver function, portal hypertension and tumor biology are evaluated simultaneously to optimize individualized management in cirrhosis-associated HCC.

Semaglutide Reduces Heavy Drinking in Alcohol Use Disorder with Obesity | The Lancet

Introduction Alcohol use disorder (AUD) remains a major global health challenge with limited pharmacologic treatment options and persistently high relapse rates. Although behavioural therapies remain foundational, currently approved medications offer modest efficacy, creating a substantial need for more effective therapeutic strategies. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used in obesity and diabetes, have emerged as promising candidates owing to their effects on reward signalling, appetite regulation and addictive behaviours. Problem Statement Effective pharmacotherapy for AUD remains limited, particularly in patients with coexisting obesity, a phenotype increasingly recognized to share overlapping neurobiological and metabolic pathways with addictive behaviour. While preclinical and early human data have suggested that GLP-1RAs may reduce alcohol consumption, robust randomized evidence in treatment-seeking patients with clinically significant AUD has been lacking. Summary This randomized, placebo-controlled trial demonstrates that once-weekly semaglutide significantly reduces heavy drinking in treatment-seeking patients with moderate-to-severe AUD and comorbid obesity. Over 26 weeks, semaglutide produced greater reductions in heavy drinking days, total alcohol intake, alcohol craving and WHO drinking risk levels compared with placebo, while also improving several objective alcohol-related biomarkers. These benefits were accompanied by substantial reductions in body weight, waist circumference and glycated hemoglobin, supporting a broader metabolic benefit in this high-risk population. The treatment was generally well tolerated, with predominantly mild-to-moderate gastrointestinal adverse effects consistent with the known safety profile of semaglutide. Importantly, this is the first randomized trial to show clinically meaningful reductions in alcohol consumption with semaglutide in treatment-seeking individuals, supporting GLP-1 receptor agonism as a promising therapeutic strategy for AUD. Although larger and more diverse studies are needed before routine clinical adoption, these findings position semaglutide as a potentially important dual-purpose intervention for patients with coexisting alcohol use disorder and obesity.