Cirrhosis Liver

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.

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.

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.

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.