Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and a major risk factor for hepatocellular carcinoma. Compared with viral-related liver cancer, MASLD-associated hepatocellular carcinoma occurs at older age, is often diagnosed at more advanced stages, and may develop in a significant proportion of patients without established cirrhosis. These features profoundly affect surveillance strategies, which have largely been based on cirrhosis-driven eligibility criteria. This review summarizes current evidence on hepatocellular carcinoma risk in MASLD, with a focus on surveillance. We discuss the epidemiology of MASLD-related hepatocellular carcinoma, the clinical relevance of non-cirrhotic disease, and the limitations of current surveillance approaches, particularly in individuals with obesity and hepatic steatosis. Across international guidelines, routine surveillance is recommended for patients with MASLD-related cirrhosis, whereas surveillance in non-cirrhotic MASLD is generally not advised because of the absence of validated selection criteria. Recent epidemiological and real-world data highlight the marked heterogeneity of HCC risk in MASLD populations and the suboptimal performance of ultrasound-based surveillance strategies. Future research should focus on validating risk stratification tools, refining eligibility criteria for surveillance beyond cirrhosis, and evaluating surveillance strategies tailored to individual risk profiles.
CD38 is a highly conserved multifunctional enzyme that regulates intracellular calcium signaling and NAD⁺ metabolism. Although extensively studied in cancer and autoimmune diseases, growing evidence points to a critical role for CD38 in both normal and diseased liver physiology. In hepatic tissue, CD38 is expressed on multiple cell types. Aberrant CD38 activity contributes to increased oxidative stress, inflammation, and diminished tissue repair. Recent studies suggest that CD38 may also promote cellular senescence partly through its regulation of intracellular NAD⁺ and calcium. This review examines the role of CD38 in maintaining hepatic homeostasis and explores its involvement in liver injury, chronic liver diseases, and carcinogenesis. We also highlight the contribution of CD38-mediated signaling to hepatic fibrogenesis and end-stage liver failure as well as its potential role in liver transplantation, particularly post-transplant related conditions including ischemic injury and acute cellular rejection. Given its impact on multiple intracellular processes, CD38 has emerged as a promising therapeutic target. New findings describe how CD38 inhibition preserves NAD⁺ levels, supports tissue recovery, and mitigates disease progression in the liver. Finally, we outline new frontiers for CD38 in liver biology and the advancement of CD38-targeted therapeutic strategies.
INTRODUCTION AND OBJECTIVES:Psychometric hepatic encephalopathy score (PHES) is the gold standard for minimal hepatic encephalopathy (MHE), predicts overt HE (OHE), but remains cumbersome for routine care. Point-of-care (POC) tests such as Stroop (EncephalApp) and Animal Naming Test (ANT) are simpler but assess narrower cognitive domains. We evaluated whether integrating POC domains into a composite score could improve the prediction of incident OHE. PATIENTS AND METHODS:153 outpatients underwent PHES, Stroop, and ANT. The primary endpoint was incident OHE within 180 days; death and liver transplantation were competing events. Cognitive predictors were analysed using Fine-Gray competing-risks regression with MELD and prior OHE as prespecified covariates. A composite cognitive risk score (CCRS) was derived from the principal component of standardized Stroop and ANT scores and rescaled from 0 to 10 RESULTS: MHE was present in 48.4% of cases. During follow-up, 29 (18.9%) developed incident OHE. In univariable models, PHES, Stroop time, and the CCRS were associated with incident OHE, whereas ANT was not. In multivariable models adjusted for MELD and prior OHE, PHES was the strongest predictor of incident OHE (sHR 0.77; 95% CI 0.66-0.90; p=0.001).Stroop (per 10-second prolongation) independently predicted OHE (sHR 1.05; 95% CI 1.03-1.07; p < 0.001). CCRS independently predicted OHE (sHR 1.37; 95% CI 1.04-1.82; p = 0.028) and pragmatically stratified patients into risk-based strata. CONCLUSIONS:In a competing-risks framework, PHES best predicts incident OHE. Among POC tests, Stroop outperformed ANT. A novel CCRS predicts OHE, risk-stratifies, but does not approximate PHES performance.
Introduction and Objectives : Primary biliary cholangitis (PBC) is associated with impaired quality of life and symptoms such as fatigue, pruritus, and sleep disturbances. However, the relationship between sleep disorders, disease severity, and patient outcomes is not well understood. This study evaluated the prevalence of sleep disorders in patients with PBC and their association with symptoms and clinical outcomes. Patients and Methods : Adult patients with PBC enrolled in a prospective autoimmune liver disease registry between 2018 and 2024 were included. Sleep disturbances, fatigue, pruritus, and self-rated health were assessed using the PBC-40 and Chronic Liver Disease Questionnaire (CLDQ). Clinical characteristics, laboratory values, and treatment response were compared between patients with and without sleep disorders. Logistic regression was used to identify factors associated with sleep disturbances. Results : Among 104 patients with PBC, 33% reported sleep disorders. Patients with sleep disorders had higher ALP (p = 0.003) and AST levels (p = 0.018), reported more fatigue (p = 0.016), and had poorer self-rated health (p < 0.001). They were also less likely to meet Paris II response criteria (44% vs. 94%, p < 0.001). In multivariable analysis, higher ALP levels, non-response to UDCA, and poorer self-rated health were independently associated with sleep disorders. Conclusions : Sleep disorders are prevalent among patients with PBC and are associated with greater symptom burden, lower rates of response to UDCA, and poorer self-rated health. Recognition of sleep complaints may help identify patients with a greater disease burden.
INTRODUCTION AND OBJECTIVES:Risk stratification is important in the management of metabolic dysfunction-associated steatotic liver disease (MASLD) to prioritize monitoring and treatment resources. We evaluated whether non-invasive tests (NITs) can predict major adverse liver outcomes (MALOs) and diagnose advanced fibrosis in patients with MASLD. PATIENTS AND METHODS:A prospective cohort of 270 patients with MASLD (median age 56 years; 44% female; 41% type 2 diabetes) was evaluated using nine NITs: FIB-4, LSM, Agile3+, Agile4, FAST, ADAPT, ELF, PRO-C3, and C1M. Cox proportional hazards models and ROC analyses were used to assess prognostic performance for MALOs and diagnosis of advanced fibrosis, respectively. RESULTS:Over a four-year follow-up period, 25 patients experienced MALOs. All NITs were associated with MALOs, though confidence intervals were wide given the limited number of events. Most NITs demonstrated positive associations with risk (HR range 1.82-5.39; p < 0.05), whereas C1M was inversely associated (HR 0.63, 95% CI 0.49-0.82; p < 0.001), indicating reduced risk. As a secondary objective, we evaluated whether each NIT could diagnose advanced fibrosis. FIB-4 and LSM effectively ruled out advanced fibrosis, while ELF and the Agile scores showed the strongest overall discriminative performance. For confirming advanced fibrosis, ELF (81%/76%) and Agile3+ (85%/79%) achieved the best sensitivity-specificity balance. CONCLUSIONS:Our findings suggest that NITs may hold both diagnostic and prognostic value, helping to identify advanced fibrosis and stratify future risk of MALOs in MASLD which is a clinically heterogenous but clinically relevant outcome. Additional research is needed to evaluate their performance in primary care settings. IMPACT AND IMPLICATIONS:In MASLD, NITs have the potential for identification of at-risk patients. Identifying NITs that predict beneficial as well as detrimental outcomes could also add value to monitoring strategies although further evidence is needed to evaluate this potential.
Chronic liver diseases are an increasing cause of morbidity and mortality in Latin America, driven by the convergence of alcohol and metabolic-associated steatotic liver disease, and viral hepatitis. The region faces structural barriers including fragmented data systems, delayed diagnosis, disparities in access, and limited research capacity. Although artificial intelligence has shown clinical utility across hepatology, evidence supporting its implementation in Latin America remains limited. We reviewed the AI applications most relevant to regional hepatology, the barriers to adoption, and priorities for safe implementation.We conducted a narrative review based on iterative appraisal of peer-reviewed studies, regional epidemiological reports, and digital health policy documents identified through March 2026. Priority was given to evidence reporting external validation, pragmatic clinical testing, or direct relevance to implementation in regional health systems.Discriminative AI is most mature in fibrosis risk stratification, digital pathology for MASH trials, and opportunistic case finding using electrocardiogram-based screening. In a pragmatic cluster-randomized trial of 15,596 adults, AI-enabled electrocardiography doubled the detection of previously undiagnosed advanced chronic liver disease in primary care. Retrieval-augmented generation improves the accuracy of large language models for hepatitis C guideline interpretation, but generative systems still pose hallucination risk. Adoption in Latin America is limited by uneven digital maturity, weak interoperability, scarce local validation, regulatory fragmentation, and insufficient workforce preparation.AI may help address major challenges in Latin American hepatology, but implementation should be phased: first infrastructure and governance, then locally validated discriminative tools, and finally supervised generative AI.
Introduction and objectives Dutch guidelines for hepatocellular carcinoma (HCC) are based on the European Association for the Study of the Liver (EASL) guideline. With the emergence of novel therapies, this study aimed to describe real-world first-line treatment practices in the Netherlands and assess their alignment with the EASL 2018 and 2025 recommendations. Methods Between 2019 and 2024, treatment-naive patients with HCC were prospectively enrolled across six Dutch tertiary referral centres as part of a cohort study paired with a biobank. Staging was in accordance with the Barcelona Clinic Liver Cancer (BCLC) 2022 classification. Results A total of 619 patients (79% male; median age 71 years) were included. Cirrhosis was registered in 65%. BCLC stage distribution was 11% BCLC-0, 53% BCLC-A, 14% BCLC-B, 18% BCLC-C, 2.9% BCLC-D, and 1.1% missing data. First-line therapy was most commonly thermal ablation (TA) in BCLC-0/A (48%), transarterial chemoembolization (TACE) in BCLC-B (46%), and systemic therapy in BCLC-C (41%). Adherence to first-line treatment recommendations was 46% per EASL 2018 and 63% per EASL 2025 guidelines. TACE, transarterial radioembolization and atezolizumab + bevacizumab were applied across all stages, ahead of guideline integration. One-year overall survival was 97% (BCLC-0), 91% (BCLC-A), 79% (BCLC-B), 70% (BCLC-C), and 33% (BCLC-D). Conclusion Treatment practices in the Netherlands adapt in response to emerging evidence. Guideline-adherent first-line treatment was observed in 46% of patients according to the EASL 2018 guidelines and 63% according to the EASL 2025 guidelines. Although guidelines remain the foundational framework for clinical decision-making, treatment decisions in real-world practice often extend beyond guideline recommendations.
INTRODUCTION AND OBJECTIVES:Despite non-selective beta-blockers (NSBBs), patients with cirrhosis and portal hypertension (PH) remain at substantial risk of death. Statins may improve intrahepatic microcirculation and potentially complement NSBB effects. MATERIALS AND METHODS:We searched PubMed, Web of Science, Embase, Cochrane Library, and ClinicalTrials.gov from inception to October 2025 for randomized controlled trials (RCTs) comparing NSBB-based therapy plus statins versus NSBB-based therapy alone. Rare events were synthesized using fixed-effect Peto odds ratios; other outcomes were pooled with random-effects models, with prediction intervals (PI) reported. Prespecified subgroup and sensitivity analyses were performed. RESULTS:Seven RCTs (n = 954) were included. Statin add-on therapy was not clearly associated with fewer PH-related complications, including variceal bleeding (RR = 0.79, P = 0.10), new or worsening ascites (RR = 0.81, P = 0.13), or hepatic encephalopathy (RR = 0.41, P = 0.06). However, it was associated with a lower risk of all-cause mortality (RR = 0.46, 95% CI: 0.32-0.65, 95% PI: 0.28-0.76, P < 0.001, I2 = 0). Adding statins also resulted in greater hepatic venous pressure gradient (HVPG) reductions and a higher proportion of patients achieving a ≥ 20% HVPG decrease. Aches and transaminase elevations occurred more often with statins. In subgroup analyses, the mortality association was observed in Child-Pugh A/B patients. CONCLUSIONS:In cirrhosis with PH, statin add-on therapy is associated with improved portal hemodynamics and lower all-cause mortality, whereas associations with PH-related complications remain uncertain. PROSPERO REGISTRATION NUMBER:CRD420251172719.
INTRODUCTION AND OBJECTIVES:Despite low alcohol consumption across most MENA countries, the burden and management challenges of alcohol-associated liver disease (ALD) remain poorly characterized. This study assessed healthcare providers' perceptions, clinical experiences, and barriers to ALD care in the region. PATIENTS AND METHODS:A cross-sectional survey was distributed to clinicians involved in liver disease management in MENA. The survey explored perceived ALD prevalence, diagnosis patterns, clinical practices, access to services, and sociocultural barriers. Selected variables were compared across three subregions (Gulf, North Africa, and Levant & Turkey). RESULTS:A total of 286 providers from 16 MENA countries participated. ALD prevalence was perceived as low or moderate by most respondents, and 52.1% reported an increase in ALD case numbers over the past five years. ALD was commonly diagnosed during routine assessments or at advanced stages. Only 12.9% reported existing national ALD guidelines, and 28.3% had access to specialized clinics. Medical management and nutritional support were widely available, whereas liver transplantation was accessible to 54.5%. Stigma (76.6%) and limited treatment facilities (46.9%) were major barriers. CONCLUSION:This region-wide assessment highlights major gaps in ALD recognition, clinical pathways, and policy infrastructure. Reducing stigma, strengthening provider training, and developing region-specific guidelines are essential to improve ALD care in culturally sensitive settings.
INTRODUCTION AND OBJECTIVES:Stem cell therapies have shown potential in treating liver cirrhosis and acute-on-chronic liver failure by promoting liver regeneration. However, their efficacy and safety remain uncertain due to inconsistent results. This systematic review and meta-analysis aimed to evaluate efficacy and safety of stem cell therapies in patients with liver cirrhosis and acute-on-chronic liver failure, compared to standard of care or placebo. MATERIALS AND METHODS:We conducted a systematic review and meta-analysis following PRISMA guidelines. Randomized controlled trials (RCTs) comparing stem cell therapies to standard medical care or placebo for patient important outcomes were included. Risk of bias was assessed using Cochrane RoB 2 tool, and quality of evidence was evaluated with GRADE framework. RESULTS:A total of 19 studies were included. Meta-analysis of 15 RCTs (n = 925) provided very low-certainty evidence regarding effects of stem cell therapy on overall mortality. The pooled risk ratio (RR) for mortality was 0.63 (95% CI 0.43 to 0.91; I² = 60%). Ten RCTs (n = 250) assessed effect of stem cell therapy on Model for End-Stage Liver Disease (MELD) scores. The pooled mean difference (MD) was -1.22 (95% CI -2.25 to -0.19; I² = 51%). The certainty in evidence was rated down for risk of bias and imprecision for most outcomes. CONCLUSIONS:This systematic review and meta-analysis provides very low-certainty evidence regarding efficacy of stem cell therapies for liver cirrhosis and acute-on-chronic liver failure. Further high-quality research is necessary to clarify role of stem cells in treating liver diseases and to ensure safety and efficacy.
INTRODUCTION AND OBJECTIVES:Treatment response of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) is assessed after 12 months by Paris II criteria. In the German PBC registry, individuals were stratified into adequate and inadequate Paris II responders. We analyzed the concordance between clinical judgement and formal Paris II classification. PATIENTS AND METHODS:Physician-assessed UDCA treatment response was compared to formal Paris II criteria (alkaline phosphatase (ALP) or aspartate-aminotransferase (AST) >1.5 x ULN or bilirubin >1 mg/dL). RESULTS:10/130 (8%) cases were misclassified as inadequate UDCA responders, 44/253 (17%) as adequate responders despite not meeting Paris II criteria. Incorrectly classified responders occurred in 26% versus 13% of individuals at secondary and tertiary centers (p = 0.0141). At secondary centers, 86% of misclassified responders had ALP >1.5 × ULN and 5% had bilirubin >1 mg/dL, compared with 32% and 27% at tertiary centers. ALP levels >1.5 x ULN occurred significantly more often at secondary centers (p = 0.0005). At secondary centers, ALP levels at diagnosis were higher in misclassified versus correctly classified responders (3.6 ± 3.0 x ULN vs. 1.7 ± 0.9 x ULN, p < 0.001) and remained higher after 12 months of therapy (2.3 ± 1.2 vs. 0.9 ± 0.3 × ULN, p < 0.001). CONCLUSIONS:Clinical judgement and Paris II classification differ in 20% of patients. Higher baseline ALP levels and kinetics may lead to misclassification. This may result in withholding of second line treatments in these patients.
INTRODUCTION AND OBJECTIVES:Ascites is the most frequent complication in patients with cirrhosis. Although guidelines propose diuretic treatment monitoring through measuring spot urine sodium, data on its application in clinical care as well as its independent prognostic information are surprisingly scarce. We therefore aimed to evaluate the role of spot urine parameters in patients with cirrhosis and ascites. PATIENTS AND METHODS:We analysed patients managed at the Medical University of Vienna between 2011 and 2024. Data on urine spot analyses were obtained within 30 days of first ascites development and longitudinally thereafter. The prognostic implication for predicting recurrent ascites within 180 days was evaluated. RESULTS:One-hundred and ten patients (61% male, main aetiology alcohol-related liver disease in 61%) were included. Median spot urine sodium was significantly different according to ascites severity and diuretic therapy (grade II + diuretics: 119.0 vs. grade III + diuretics: 54.5 mmol/L; grade II + no diuretics: 60.0 vs. grade III + no diuretics: 16.0 mmol/L). However, neither baseline nor longitudinal spot urine sodium provided independent prognostic information for the development of recurrent ascites within 180 days after adjustment for liver disease severity. Similarly, the spot urine sodium/potassium ratio, analysed continuously or using established cut-offs, was not independently associated with recurrent ascites. These findings remained consistent in sensitivity analyses considering recurrent ascites within 90 days and after accounting for diuretic therapy. CONCLUSIONS:Spot urine analyses around index ascites decompensation were not associated with the development of recurrent ascites in the current study.
INTRODUCTION AND OBJECTIVES:Impaired muscle strength is increasingly recognized as an integrative marker of metabolic dysfunction and adverse prognosis. This study aimed to examine the associations between grip strength and cause-specific mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). PATIENTS AND METHODS:This cohort study included 92,263 individuals with MASLD from the UK Biobank. Grip strength was categorized into sex-specific tertiles. We used Cox proportional hazards models and restricted cubic splines to assess associations between grip strength and the risks of mortality, including all-cause mortality and cause-specific mortality (cardiovascular, extrahepatic cancer, liver, and diabetes-related mortality). RESULTS:During a median follow-up of 13.3 years, 9923 deaths were documented. Restricted cubic splines indicated that grip strength showed linear associations with both all-cause mortality and cause-specific mortality. Compared to high grip strength, low grip strength was associated with increased risks of all-cause mortality (HR=1.36, 95% CI 1.28-1.43), cardiovascular-related mortality (HR=1.54, 95% CI 1.28-1.87), cancer-related mortality (HR=1.25, 95% CI 1.14-1.38), liver-related mortality (HR=1.76, 95% CI 1.08-2.87) and diabetes-related mortality (HR=2.40, 95% CI 1.36-4.23). These associations were generally consistent across age and sex subgroups. Notably, the protective association between high grip strength and reduced risk of cardiovascular mortality was more pronounced in participants aged ≥60 years (HR=0.86, 95% CI 0.82-0.91) compared to those <60 years (HR=0.96, 95% CI 0.88-1.04). CONCLUSIONS:Lower grip strength was associated with increased risks of all-cause mortality and cause-specific mortality in patients with MASLD. Muscle strength management may be considered as part of the care strategy for MASLD patients.
INTRODUCTION AND OBJECTIVES:Spontaneous bacterial peritonitis (SBP1) is a common complication of cirrhosis. In the United States, inconsistent norfloxacin availability has shifted secondary SBP prophylaxis toward ciprofloxacin or trimethoprim-sulfamethoxazole (TMP-SMX2), but these agents have not been robustly compared head-to-head. We compared clinical outcomes among patients receiving TMP-SMX versus ciprofloxacin for secondary SBP prophylaxis. MATERIALS AND METHODS:We conducted a multicenter retrospective cohort study using the TriNetX de-identified electronic health record network. Adults with cirrhosis (ICD-10 K74.6) and SBP (ICD-10 K65.2) from January 2013 to July 2021 were included. Index date was the first prescription for TMP-SMX (RxNorm 10,829/10180) or ciprofloxacin (RxNorm 2551), with follow-up through July 11, 2024. Exclusions included prior exposure to the alternative agent, liver transplant, or end-stage renal disease. We performed 1:1 greedy nearest-neighbor propensity score matching (caliper 0.1) on demographics, comorbidities, and hepatic/renal laboratory variables. Primary outcomes were SBP recurrence and all-cause mortality; secondary outcomes included all-cause hospitalization, variceal bleeding, hepatic encephalopathy, and ascites. Cox proportional hazards models estimated hazard ratios (HRs). RESULTS:Among 31,011 patients (TMP-SMX 11,166; ciprofloxacin 19,845), 11,140 well-balanced matched pairs were analyzed. TMP-SMX was associated with lower SBP recurrence (HR 0.75, 95% CI 0.72-0.79) and all-cause mortality (HR 0.84, 95% CI 0.80-0.87; both p < 0.0001). TMP-SMX also reduced risks of variceal bleeding (HR 0.81), hepatic encephalopathy (HR 0.79), and ascites (HR 0.86), while hospitalization was not significantly different. CONCLUSIONS:TMP-SMX was associated with significantly lower SBP recurrence and mortality than ciprofloxacin, supporting TMP-SMX as a potentially more effective secondary prophylaxis option pending randomized confirmation.
