Hepatology

Background and AimsMetabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), lead to significant morbidity and mortality in adults with type 2 diabetes (T2D) and obesity. This study evaluated whether participation in an individualized, nutrition-focused telemedicine care model emphasizing carbohydrate reduction (Virta Individualized Nutrition Therapy, VINT) was associated with reduced onset of MASLD, MASH, and advanced liver disease. Approach and ResultsAdults with T2D, prediabetes, overweight, or obesity who enrolled in VINT (2015-2024) were identified in the Komodo Healthcare Map and matched 1:1 to usual care (UC) controls (n = 5,031 per group). Using three complementary analytic approaches, incidence and time-to-event analyses were performed for new-onset liver disease. Across all strategies, VINT participants consistently showed lower incidence of any liver-related diagnosis (27.8 vs 42.8 per 1,000 person-years; HR = 0.61, p < 0.001), MASH and beyond (4.2 vs 10.7; HR = 0.38, p < 0.001), advanced liver disease (2.8 vs 8.7; HR = 0.33, p < 0.001) and any liver complications (2.0 vs 7.7; HR = 0.25, p < 0.001). VINT participants who lost [&ge;]15% body weight was at lower risk of new-onset liver disease (21.2 vs 31.8 per 1,000 person-years; HR = 0.66, p = 0.02) compared to VINT participants who lost less weight. ConclusionsParticipation in individualized nutrition-focused telemedicine care was associated with significantly lower incidence and risk of new-onset MASLD, MASH, and advanced liver disease. These findings support lifestyle-first interventions that is potentially scalable to reduce liver disease burden in adults with T2D and obesity. Infographic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/25338753v2_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@4233fdorg.highwire.dtl.DTLVardef@633589org.highwire.dtl.DTLVardef@14fd55eorg.highwire.dtl.DTLVardef@414142_HPS_FORMAT_FIGEXP M_FIG C_FIG Plain Language SummaryPeople with type 2 diabetes and obesity are more likely to develop liver conditions such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), which can progress to cirrhosis, decompensation or liver cancer. This study examined whether a nutrition-focused remote care program could help prevent these liver diseases. The Virta Individualized Nutrition Therapy (VINT) program uses telemedicine and personalized, carbohydrate-reduced nutrition to support long-term weight loss and metabolic health. Using health claims data, researchers compared more than 5,000 participants in the VINT program with matched individuals receiving standard of care. Those in the VINT group had significantly fewer new cases of MASLD, MASH, and advanced liver disease. Participants who lost 15% or more of their body weight were especially protected. These findings suggest that individualized, nutrition-based remote care can help prevent liver disease in people with type 2 diabetes and obesity.

Liver cirrhosis and chronic liver diseases impose a substantial and growing health burden globally, with sub-Saharan Africa (SSA) disproportionately affected. Leveraging Global Burden of Disease 2021 data and Bayesian hierarchical models, we quantified mortality and disability trends in SSA from 1990 to 2021 and projected disease burden through 2035, incorporating scenarios for hepatitis B vaccination scale-up. In 2021, liver cirrhosis accounted for an estimated 181,311 deaths in SSA, despite a 29% decline in age-standardized death rates (ASDR) since 1990. Absolute deaths increased by 65%, predominantly driven by hepatitis B (37%), hepatitis C (28%), and alcohol-related cirrhosis (17%). Disability-adjusted life years (DALYs) surged by 76%, from approximately 1.05 million in 1990 to 1.85 million in 2021, highlighting rising absolute disability alongside a 29% reduction in age-standardized DALYs. Mortality and disability burdens were highest in Somalia, Central African Republic, and Guinea-Bissau. Males bore nearly twice the burden of females. While death rates declined across all socio-demographic strata, absolute deaths rose by 55-86%. Projections to 2035 suggest further potential reductions in mortality from hepatitis B (up to 21.5%), hepatitis C (up to 18.7%), and alcohol-related cirrhosis, while the burden of non-alcoholic fatty liver disease is expected to remain stable or increase slightly. Scaling up hepatitis B vaccination could further avert 27% of related deaths by 2035. These findings reveal persistent and widening disparities in cirrhosis burden across SSA, underscoring the urgent need for integrated, context-specific interventions combining viral hepatitis control with metabolic liver disease management to improve equitable liver health outcomes.

Background & AimsIron corrected T1 (cT1) is an MRI derived biomarker of liver disease activity. Emerging data suggest a change in cT1 of [&ge;] 80 ms reflects histological improvement. We aimed to validate the association between the [&ge;] 80 ms decline in cT1 and histological improvement, specifically the resolution of MASH. MethodsA retrospective analysis of study participants from three interventional clinical trials with histologically confirmed MASH (n = 150) who underwent multi-parametric MRI to measure cT1 (LiverMultiScan(R)) and biopsies at baseline and end of study. Histological responders were defined using the four criteria: (1) a decrease in NAFLD Activity score (NAS) [&ge;] 2 with no worsening in fibrosis, (2) a decrease in fibrosis [&ge;] 1 stage with no worsening in NAS, (3) both a NAS decrease [&ge;] 2 and a fibrosis decrease [&ge;] 1, and (4) MASH resolution with no worsening in fibrosis. Difference in the magnitude of change in cT1 between responders and non-responders was assessed. ResultsSignificant decreases in cT1 were observed in responders for all the histological criteria. The largest decrease was observed for those achieving MASH resolution, and was 119ms, compared to 43ms for non-responders. The optimal reduction in cT1 for separating responders from non-responders for MASH resolution was -74ms (64ms-73ms for the other criteria), in close agreement with the previously predefined threshold of -80ms. Those achieving an [&ge;] 80 ms reduction in cT1 were substantially more likely to achieve histological response with odds ratios ranging from 2.7 to 6.3. ConclusionsThese results demonstrate that a reduction in cT1 of 80 ms was associated with histological response supporting the utility of cT1 to predict clinical improvement in patients undergoing therapeutic intervention.

Background and aimsThe prevalence and etiology of liver fibrosis vary over time and impact racial/ethnic groups unevenly. This study measured time-trends and identified factors associated with advanced liver fibrosis in the U.S. MethodsStandardized methods were used to analyze data on 47,422 participants ([&ge;] 20 years) in the National Health and Nutrition Examination Survey (1999-2018). Advanced liver fibrosis was defined as Fibrosis-4 [&ge;]2.67 and/or Forns Index [&ge;]6.9 and elevated ALT. ResultsThe estimated number of people with advanced liver fibrosis increased from 1.3 million (95% CI, 0.8-1.9) to 3.5 million (95% CI, 2.8-4.2), a nearly 3-fold increase. Prevalence was higher in non-Hispanic Black and Mexican American persons than in non-Hispanic White persons. In multivariable logistic regression analysis, cadmium was an independent risk factor in all racial/ethnic groups. Smoking and current excessive alcohol use were risk factors in most. Importantly, non-Hispanic Black persons had a distinctive set of risk factors compared to non-Hispanic White persons that included poverty (OR = 2.09; 95%CI, 1.44-3.03), and susceptibility to lead exposure (OR = 3.25; 95%CI, 1.95-5.43), but did not include diabetes (OR = 0.88; 95% CI, 0.61-1.27, P =0.52). Non-Hispanic Black persons were more likely to have high exposure to lead, cadmium, polychlorinated biphenyls, and poverty than Non-Hispanic White persons. ConclusionsThe number of people with advanced liver fibrosis has increased, creating a need to expand the liver care workforce. The risk factors for advanced fibrosis varied by racial/ethnicity. These variations provide useful information for the design of screening programs. Poverty and toxic exposures were associated with the high prevalence of advanced liver fibrosis in non-Hispanic Black persons and need to be addressed. Lay summaryBecause liver disease often produces few warning signs, simple and inexpensive screening tests that can be performed by non-specialists are needed to allow timely detection and linkage to care. This study shows that non-Hispanic Black persons have a distinctive set of risk factors that need to be taken into account when designing liver disease screening tests. Exposure to exogenous toxins may be especially important risk factors for advanced liver fibrosis in non-Hispanic Black persons.

ObjectiveIn sub-Saharan Africa, hepatitis B is the principal cause of liver disease. Non-invasive biomarkers of liver fibrosis are needed to identify patients requiring antiviral treatment. We assessed aspartate aminotransferase-to-platelet ratio index (APRI), gamma-glutamyl transferase-to-platelet ratio (GPR) and FIB-4 to diagnose significant fibrosis and cirrhosis in an individual patient data (IPD) meta-analysis. DesignIn total, 3,549 patients from 12 cohorts of HBsAg positive individuals in 8 sub-Saharan African countries were included. Transient elastography was used as a reference test for cirrhosis (>12.2 kPa), excluding patients who were pregnant, had hepatitis C, D, or HIV co-infection, were on hepatitis B therapy, or had acute hepatitis. A bivariate Bayesian IPD model was fitted with patient-level covariates and study-level random effects. ResultsAPRI and GPR had the best discriminant performance (area under receiver operating curve 0.81 and 0.82) relative to FIB-4 (0.77) for cirrhosis. The World Health Organization (WHO) recommended APRI threshold of [&ge;]2.0 was associated with a sensitivity and specificity (95% credible interval) of 16.5% (12.5-20.5) and 99.5% (99.2-99.7) for cirrhosis. For APRI, we identified an optimised rule-in threshold for cirrhosis (cut-off 0.65) with a sensitivity and specificity of 56.2% (50.5-62.2) and 90.0% (89.0-91.0), and an optimised rule-out threshold (cut-off 0.36) with a sensitivity and specificity of 80.6% (76.1-85.1) and 64.3% (62.8-65.8). ConclusionsThe WHO recommended APRI threshold of 2.0 is too high to diagnose cirrhosis in sub-Saharan Africa. We identified new and optimised rule-in and rule-out thresholds for cirrhosis, with direct consequences for treatment guidelines in this setting.

Hepatocytes (HCs), which share a developmental origin with cholangiocytes (CCs), have the capacity to undergo reparative reprogramming into CCs in response to liver injury and, under specific conditions, can also transform malignantly into cholangiocarcinoma (CCA). However, the molecular mechanisms governing HC plasticity in liver diseases remain poorly understood. In this study, we investigated the role of Spalt Like Transcription Factor 4 (SALL4), an oncofetal transcription factor, in both malignant and regenerative HC fate transitions toward the biliary lineage. Using Sleeping Beauty hydrodynamic tail vein injection-mediated murine liver cancer models, we explored HC-to-CCA transformation, while the DDC diet-induced cholestasis model was used to investigate regenerative HC-to-CC reprogramming. Our findings reveal that SALL4 is specifically required for myristoylated Akt (myrAkt)-YAP1S127A (AY)-driven HC-to-CCA transformation, as its loss significantly suppressed malignant reprogramming and clonal expansion. Surprisingly, SALL4 overexpression also prevented AY-driven CCA development while promoting the expansion of liver progenitor cell (LPC)-like fatty HCs. Mechanistically, we propose Bmi1 as a key downstream effector of SALL4 in YAP1-dependent HC- to-CCA transformation. Additionally, in the DDC-fed cholestasis model, Sall4 deletion enhanced HC-to-LPC activation while impairing LPC differentiation into mature CCs. These findings establish SALL4 as a critical regulator of HC plasticity in both malignant and regenerative contexts and highlight its potential as a therapeutic target for specific liver cancer subtypes. SIGNIFICANCEHepatocyte plasticity supports repair but can drive malignancy, acting as a double-edged sword. We identify SALL4 as regulator of YAP1-driven hepatocyte-to-cholangiocyte reprogramming, revealing the YAP1-SALL4- BMI1 axis as a therapeutic target for cholangiocarcinoma.

Background & AimsHepatocellular carcinoma (HCC) is the third top cause of cancer death globally, often arising on a background of cirrhosis. Here, we aimed to establish novel genetic drivers of HCC across ancestries at a population level through a large meta-analysis of all-cause HCC. Approach & ResultsWe included 15 cohorts comprising 17,329 HCC cases and 2,424,298 controls in this meta-analysis. We found 15 genome-wide significant (P < 5x10-8) germline loci, 6 novel in/near GCKR, MTTP, ADH5, MYC, MAP3K9, and GABPB2. MAP3K9, TERT, and GABPB2 variants act independently of cirrhosis on both co-localisation analysis and sensitivity analyses. There was significant ancestral heterogeneity in 6 loci including variants in the HLA locus that had divergent effects on HCC risk between East Asian and European ancestries. Fine-mapping identified 11 potentially causal coding variants, including p.Leu446Pro in GCKR and p.Asp418Glu in MEN1. MEN1, MYC, and TERT are all involved in the beta-catenin pathway transactivation complex. Transcriptome-wide analysis identified enrichment of germline-encoded DHRS1 in HCC. Regulome-wide analysis replicated the germline signal for EPHA2 and found a novel chromatin accessible region containing genes ZNF367 and HABP4. Finally, we demonstrated that population-level genetic architecture for HCC overlaps with steatotic and viral liver disease, and individuals with genetic risk for lower BMI have higher risk of HCC. ConclusionsGenetic risk for HCC is determined by germline susceptibility to beta-catenin pathway activation and cirrhosis. HCC is driven by both heterogenous and homogenous genetic factors across ancestries, which require further ancestral diversity in liver GWAS to fully dissect.

Background and AimsThe newly proposed nomenclature for steatotic liver diseases (SLD) aims to reduce the stigma associated with "non-alcoholic fatty liver disease" (NAFLD), increase awareness, and provide a framework for delineating pathogenic pathways. Approach and ResultsWe projected the new nomenclatures diagnostic scheme onto National Health and Nutrition Examination Survey (NHANES) data and determined SLD prevalence, fibrosis risk factors, subtypes, and consistency with previous classifications. Steatosis grade and fibrosis stage were estimated from vibration controlled transient elastography (VCTE). At a threshold of 240 dB/m, 62.1% [95% confidence interval (CI), 59.8-64.3%] of adults ([&ge;] 20 years) and 30.5% (95% CI, 27.1-34.0%) of adolescents (12-19 years) had SLD. By American Gastroenterological Association criteria, 19.3 million (95% CI, 15.8-22.8) adults with SLD qualify for hepatology referral. Over 98% of adults but only 85% of adolescents with NAFLD met criteria for definite MASLD. Significant fibrosis ([&ge;] 8.6 kPa) occurred in 13.5 million (95% CI, 10.9-16.2) adults with MASLD; risk factors varied by race and ethnicity. Significant fibrosis occurred in over 1.5 million adults without any identified LD and was associated with lead (Pb) exposure, odds ratio = 3.89 (95% CI, 2.00-7.56). ConclusionsThe overarching term, SLD, changes the diagnostic algorithm and creates an umbrella classification that highlights the extraordinary prevalence of liver steatosis. The more precise nomenclature establishes a valuable patient-centric platform for research and clinical care, clarifying risk groups and risk factors, including adolescents with NAFLD but without definite MASLD and adults without SLD in whom toxic exposures may increase fibrosis risk.

Background and AimsHighly aggressive hepatobiliary tumours include gallbladder cancer (GBC), hepatocellular carcinoma (HCC), intrahepatic and extrahepatic cholangiocarcinoma (iCCA, eCCA) and ampulla of Vater cancer (AoV). We aimed to identify plasma biomarkers for the early diagnosis of hepatobiliary cancer by leveraging the metabolomic signatures of established clinical risk factors. MethodBased on 273,190 participants from the UK Biobank, we (1) identified metabolites associated with gallstone-related conditions (e.g. cholecystitis), primary sclerosing cholangitis (PSC) and metabolic liver diseases (e.g. cirrhosis), and (2) evaluated the relationship between the identified metabolites and the risk of GBC, HCC, iCCA, eCCA and AoV. Findings were validated in an independent group of 227,809 participants from the UK Biobank. We also derived metabolomic scores summarizing the three risk-factor signatures and evaluated their ability to stratify cancer risk. ResultsWe identified 27 metabolites associated with gallstone-related conditions, 11 with PSC, and 34 with metabolic liver diseases, some of which showed associations with inconsistent directions across risk factors, suggesting distinct pathogenic processes. Several metabolites were associated with cancer risk in both the discovery and validation datasets, independently of established risk factors, predominantly for HCC (16 signals) and for iCCA (4), with one for GBC and none for eCCA and AoV. Metabolomic scores clearly distinguished individuals at high risk for HCC and iCCA. ConclusionThe preselection of plasma metabolites associated with established risk factors facilitated the subsequent identification and validation of biomarkers for early cancer detection. The identified metabolites suggest specific pathogenic pathways for each type of hepatobiliary cancer. Wider replication is urgently needed to advance toward clinical implementation. What you need to knowO_ST_ABSBACKGROUND AND CONTEXTC_ST_ABSClinical risk factors for hepatobiliary cancers often progress silently, making early identification of high-risk individuals difficult and highlighting the need for biological markers detectable before clinical diagnosis. NEW FINDINGSRisk-factor-based serum metabolomic profiling identified circulating metabolites that predict specific hepatobiliary cancers years before diagnosis, with strongest and most consistent signals for hepatocellular and intrahepatic cholangiocarcinoma. LIMITATIONSClinical risk factors were assumed to be frequently underdiagnosed in UK Biobank, and event numbers were relatively small for some cancers, which may have reduced power and attenuated associations for less common endpoints. CLINICAL RESEARCH RELEVANCEThis study shows that serum metabolic profiles can identify individuals at increased risk for hepatobiliary cancers long before symptoms appear, particularly for hepatocellular and intrahepatic cholangiocarcinoma. These findings support the development of precision risk-stratification strategies that may ultimately enable earlier surveillance. BASIC RESEARCH RELEVANCEBy first identifying metabolites linked to specific liver and biliary clinical conditions, the study clarifies which metabolites are indirectly associated with hepatobiliary cancers through known disease pathways. Testing these metabolites again while adjusting for diagnoses of those conditions then reveals which ones also show direct, pathway-independent associations with individual hepatobiliary cancers, providing clearer insight into cancer-specific metabolic mechanisms.

BackgroundMetabolic dysfunction-associated steatotic liver disease (MASLD) and hypertension frequently coexist in adults across the Americas, yet evidence to guide pharmacologic management in individuals with both conditions remains limited. Antihypertensive medications may influence liver outcomes, but comparative data across drug classes are sparse. MethodsWe performed a cross-sectional analysis using pooled data from the US National Health and Nutrition Examination Survey (1999 to 2018), linked to mortality records through 2019. Hepatic steatosis was assessed using the US Fatty Liver Index (US-FLI), Fatty Liver Index (FLI), and Hepatic Steatosis Index (HSI). Fibrosis was assessed using noninvasive scores. Antihypertensive exposure, identified through prescription records, included ACE inhibitors, ARBs, beta blockers, calcium channel blockers (CCBs), and diuretics. Associations with liver fibrosis were estimated using logistic regression. All cause and cardiovascular mortality were assessed using Cox proportional hazards models with inverse probability of treatment weighting. FindingsAmong 2,909 adults with MASLD receiving monotherapy antihypertensive treatment, use of ACEIs and ARBs was associated with lower odds of liver fibrosis compared with CCBs. In adjusted models, ACEIs were associated with reduced all-cause mortality (adjusted hazard ratio 0.30; 95% CI 0.11-0.82), as were ARBs (0.25; 95% CI 0.07-0.94). No significant differences were observed for cardiovascular mortality across medication classes. InterpretationUse of angiotensin converting enzyme inhibitors and angiotensin receptor blockers was associated with lower fibrosis burden and improved survival in individuals with metabolic dysfunction associated steatotic liver disease. These findings are hypothesis generating and warrant confirmation in prospective studies. FundingNo Funding.

Although viral hepatocellular carcinoma (HCC) is declining, non-viral HCC, which often is the end-stage of non-alcoholic or alcoholic steatohepatitis (NASH, ASH), is on an upward trajectory. Immune checkpoint inhibitors (ICI) that block the T cell inhibitory receptor PD-1 were approved for treatment of all HCC types. However, only a small portion of HCC patients show a robust and sustained response to PD-1 blockade, calling for improved understanding of factors that negatively impact response rate and duration and the discovery of new adjuvant treatments that enhance ICI responsiveness. Using a mouse model of NASH-driven HCC, we identified peritumoral fibrosis as a potential obstacle to T cell mediated tumor regression and postulated that anti-fibrotic medications may increase ICI responsiveness. We now show that the angiotensin II receptor inhibitor losartan, a commonly prescribed and safe antihypertensive drug, reduced liver and peritumoral fibrosis and substantially enhanced anti-PD-1 induced tumor regression. Although losartan did not potentiate T cell reinvigoration, it substantially enhanced HCC infiltration by effector CD8+ T cells compared to PD-1 blockade alone. The beneficial effects of losartan correlated with inhibition of TGF-{beta} receptor signaling, collagen deposition and depletion of immunosuppressive fibroblasts. SignificanceImmune checkpoint inhibitors are used in HCC treatment but overall response rates for single agent PD-1/PD-L1 blockers have remained stubbornly low. Using a mouse model of NASH-driven HCC, we show that co-treatment with the safe and inexpensive angiotensin II receptor inhibitor losartan substantially enhanced anti-PD-1 triggered HCC regression. Although losartan did not influence the reinvigoration of exhausted CD8+ T cells it considerably enhanced their intratumoral invasion, which we postulated to be compromised by peritumoral fibrosis. Indeed, the beneficial effect of losartan correlated with inhibition of TGF-{beta} signaling and collagen deposition, and depletion of immunosuppressive fibroblasts. Losartan should be evaluated for its adjuvant activity in HCC patients undergoing PD-1/PD-L1 blocking therapy.

Background & Aims: ACLF is defined differently by APASL (acute hepatic dysfunction) and by organ failure-based frameworks including EASL-CLIF and the recently developed A-TANGO score. Whether these definitions identify competing populations or sequential stages of the same syndrome remains unresolved, with direct implications for the timing of intervention. We tested whether APASL-defined ACLF can be integrated into the A-TANGO framework to identify a clinically actionable patient population. Methods: 4,024 patients hospitalised with acute decompensation of cirrhosis in a multicentre cohort were classified simultaneously by APASL and A-TANGO criteria. Mortality, progression to A-TANGO ACLF among A-TANGO-negative patients, and reversal of ACLF were assessed using Fine-Gray competing-risk models with death as a competing event. EASL-CLIF analyses were performed as sensitivity analyses. Results: A-TANGO-negative/APASL-positive patients comprised 8.7% of the cohort and had higher 90-day mortality than A-TANGO-negative/APASL-negative patients (22.3% vs 14.4%, p=0.001), despite similar 28-day mortality. Once A-TANGO ACLF was established, 28-day mortality was high irrespective of APASL status (45.4% in APASL-positive and 56.0% in APASL-negative patients). Among A-TANGO-negative patients, 53.5% of APASL-positive vs 27.9% of APASL-negative patients progressed to A-TANGO ACLF within 28 days, with APASL positivity independently predicting progression (adjusted sHR: 2.30, 95%CI: 1.90-2.77). Within A-TANGO-negative/APASL-negative patients an A-TANGO OF score [&ge;]8 independently enriched for progression (52% vs 19%). A-TANGO reversal occurred in 17.1% and was independently reduced by APASL positivity (adjusted sHR: 0.756, 95%CI: 0.586-0.975), while APASL reversal was rare (4.0%). EASL-CLIF sensitivity analyses were directionally consistent. Conclusions: APASL-defined ACLF does not compete with A-TANGO; it occupies an upstream position on the same disease trajectory. A-TANGO-negative/APASL-positive patients and A-TANGO-negative/APASL-negative patients with A-TANGO OF [&ge;]8 represent complementary pre-ACLF populations suitable for prevention trials and enrichment strategies.

Background and ObjectivesBariatric surgery is a highly effective obesity treatment, yet it may predispose individuals to alcohol-related liver injury. While altered ethanol metabolism following procedures like Roux-en-Y gastric bypass (RYGB) is well described, the long-term hepatic consequences, particularly the risk of portal hypertension in patients who develop alcohol-related hepatitis (AH,) remain poorly defined. MethodsUsing the TriNetX US Collaborative Network, we identified adult patients diagnosed with AH or alcohol-related cirrhosis. We compared outcomes between patients with a history of RYGB or sleeve gastrectomy (SG) who subsequently developed AH (Bariatric+AH group) and those with AH and no history of bariatric surgery (AH-only group). Propensity score matching was performed on over 44 demographic, clinical, and laboratory variables. Cox proportional hazards models and Kaplan-Meier survival curves were used to estimate the risk of clinically significant portal hypertension (PH) events, liver transplantation, and all-cause mortality at three-, five-, and seven-year follow-ups. ResultsAfter matching, 772 patients were included in each cohort. At 7 years post-index event, the Bariatric + AH group exhibited a significantly higher risk of PH-related complications compared to the AH-only group (HR 1.519; 95% CI, 1.15-2.005; p = 0.003). No significant differences were observed in liver transplantation (HR 1.412; 95% CI, 0.850-2.346; p = 0.181) or all-cause mortality (HR 1.085; 95% CI, 0.904-1.303; p = 0.381). These findings were consistent across all follow-up intervals. ConclusionBariatric surgery is associated with an increased long-term risk of portal hypertension in patients who develop alcohol-related hepatitis despite similar mortality and transplantation rates. These findings underscore the need for targeted postoperative counseling, liver-focused surveillance strategies, and integration of hepatologic risk assessment into metabolic surgery care pathways.

Background: Focal liver lesions (FLLs) encompass a wide spectrum of benign and malignant pathologies, and accurate diagnosis is essential for appropriate management. Although advances in imaging have improved lesion characterization, histopathologic assessment remains the diagnostic gold standard for indeterminate lesions. Data on the histopathologic spectrum and diagnostic utility of ultrasound-guided percutaneous liver biopsy (US-PLB) in sub-Saharan Africa (SSA) are limited. This study aimed to characterize the histopathologic findings of US-PLB performed for FLLs at a tertiary referral center in SSA and to identify factors associated with hepatocellular carcinoma (HCC). Methods: We conducted a retrospective observational study of adult patients ([&ge;]18 years) who underwent US-PLB for FLL between January 2021 and December 2024 at Adera Medical and Surgical Center. Patients with indeterminate pathology results, incomplete records, biopsies performed for diffuse liver disease, or lesions classified as LI-RADS 1, 2, or 5 were excluded. Demographic, clinical, laboratory, imaging, histopathologic, and outcome data were extracted from medical records. Descriptive statistics were used to summarize patient characteristics and histopathologic diagnoses. Logistic regression analysis was performed to identify factors associated with HCC. Results: A total of 119 were included in the final analysis. The median age was 56 years (IQR 45-65), and 59.7% were male. No major biopsy-related complications were reported. HCC was the most common histopathologic diagnosis, accounting for 42.9% of cases, followed by secondary metastatic tumors (15.9%) and regenerative nodules (15.9%). Other diagnoses included chronic hepatitis (8.4%), cholangiocarcinoma (5.9%), and hepatic abscess (3.4%). Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections were present in 14.3% and 12.4% of patients, respectively. On multivariate analysis, HBV infection (AOR 7.85, 95% CI 1.45-42.60; p=0.017), HCV infection (AOR 9.03, 95% CI 1.41-57.76; p=0.020), and larger tumor size (AOR 1.27, 95% CI 1.11-1.46; p<0.01) were significantly associated with HCC. Conclusion: Ultrasound-guided percutaneous liver biopsy demonstrated a favorable safety profile for the evaluation of FLL. HCC was the predominant histopathologic diagnosis, reflecting the substantial burden of primary liver cancer in this setting. Chronic viral hepatitis and larger tumor size were significantly associated with HCC. These findings support the continued role of US-PLB in the diagnostic evaluation of indeterminate focal liver lesions and underscores the importance of viral hepatitis prevention, surveillance, and early detection strategies in sub-Saharan Africa.

Background and AimsAcute-on-chronic liver failure (ACLF) is associated with high short-term mortality, but substantial heterogeneity among existing diagnostic and prognostic models results in inconsistent patient identification and risk assessment. We conducted a systematic head-to-head comparison of major ACLF diagnostic and prognostic models to evaluate concordance, short-term mortality prediction and clinical utility, with the goal of informing harmonization of ACLF assessment. MethodsWe analysed 3,370 patients with acute decompensation of cirrhosis in the COSSH cohort, with external validation in an independent Ambi-Spective cohort from India (n=2,055). Five ACLF diagnostic models were evaluated for identification of patients at risk of 28-day mortality. Reclassification was assessed using net reclassification improvement. Prognostic scores were compared using concordance index, integrated discrimination improvement, calibration, and decision-curve analysis. ResultsDiagnostic frameworks identified markedly different proportions of ACLF. A-TANGO and COSSH-ACLF classified the largest high-risk populations while maintaining substantial short-term mortality and balanced sensitivity-specificity profiles. Compared with COSSH-ACLF, A-TANGO improved net reclassification by 7.7%, with further gains versus EASL-CLIF (11.8%), APASL-ACLF (36.4%), and NACSELD-ACLF (45.9%). In the external cohort, A-TANGO and COSSH-ACLF showed similar discrimination and identified comparable proportions of patients. Combined application of the two models delineated three clinically meaningful strata, identifying a discordant intermediate-risk group with approximately 11% 28-day mortality. Among prognostic scores, COSSH-ACLF II and A-TANGO OF scores demonstrated strong and complementary performance across cohorts. ConclusionsOutcome-anchored ACLF definitions converge in identifying patients at highest short-term risk across diverse populations. Alignment between A-TANGO and COSSH-ACLF, together with identification of an intermediate-risk phenotype, supports a data-driven framework for improving consistency and advancing global harmonization of ACLF diagnosis and risk stratification.

Background & AimsDilutional hyponatremia and sarcopenia (SP) are prognostic factors linked to portal hypertension (PHT) in chronic liver disease (CLD). Because skeletal muscle functions as the bodys largest intracellular water reservoir, early Na decline may reflect impaired muscular buffering rather than renal Na loss. This MRIbased study investigated the relationship between serum Na, SP, and PHT. MethodsWe retrospectively analyzed 880 CLD patients who underwent MR elastography. SP was defined as low muscle mass by MRI. Patients were categorized into five Na strata (<135, 135-136, 137-138, 139-140, [&ge;]141 mEq/L). Individuals with Na <139 mEq/L were further stratified by ALBI score and SP to construct the liver-muscle phenotype (LMP) classification. ResultsSP prevalence was 28% and increased stepwise with decreasing Na levels. In non-HCC patients, Na <139 mEq/L optimally identified both SP and PHT. Liver stiffness increased progressively across SP, Na <139, and PHT (3.3[-&gt;]4.6 kPa, all P<0.01). Decision-tree analysis identified ALBI score (cutoff -2.16) and SP as major determinants of Na <139, producing four LMP types with graded Na decline (P<0.01). Among advanced CLD patients without ascites, worsening LMP predicted higher incidence of new-onset ascites (P<0.01). In Cox models, LMP4 (ALBI [&ge;]-2.16 with SP) independently predicted poor prognosis (HR 3.87, P<0.01). ConclusionsFunctional hyponatremia (Na <139) reflects early hemodynamic stress associated with asymptomatic PHT. Given its central role in systemic water handling, distinct from the hepato-renal axis, SP may represent a modifiable target for early intervention before overt decompensation. Key PointsO_ST_ABSSignificant findings of the studyC_ST_ABSO_LIFunctional hyponatremia (Na <139 mEq/L) and sarcopenia emerge at nearly identical liver stiffness thresholds, preceding classical portal hypertension. C_LIO_LIThe novel Liver-Muscle Phenotype (LMP) classification identifies a high-risk group (LMP4) for fluid retention that is often underestimated by conventional MELD scores. C_LI What this study addsO_LIEarly sodium dilution and muscle loss reflect impaired buffering by skeletal muscle--the bodys largest intracellular water reservoir--within the liver-muscle-fluid axis. C_LIO_LISarcopenia defines a reversible therapeutic window in which targeted nutrition and rehabilitation may restore fluid balance before overt retention develops. C_LI

Background & AimsThe metabolic interplay between obesity and myopenia (MP) in chronic liver disease (CLD) remains poorly understood. We investigated whether progressive liver dysfunction mediates an obesity-MASLD (metabolic dysfunction{square}associated steatotic liver disease)-MP cascade and assessed the prognostic impact of MP and myopenic obesity (MO) in advanced CLD (ACLD). MethodsWe analyzed 859 CLD patients cross{square}sectionally and 169 obese patients longitudinally (median 38{square}months), using multimodal MRI to measure liver stiffness (LS), proton{square}density fat fraction (PDFF), and body composition. Temporal relationships between changes ({Delta}) in adiposity, muscle mass, and liver injury markers were assessed. Prognosis in ACLD (n=328) was evaluated using Cox regression. ResultsMP and MO were present in 29% and 8% of patients, respectively. In the longitudinal cohort, MO prevalence increased significantly from 15% to 23% (P{square}<{square}0.01). In fibrosis stages F0-2, {Delta}visceral adipose tissue significantly correlated with {Delta}PDFF, {Delta}ALT, and {Delta}LS (all P{square}<{square}0.01), whereas {Delta}muscle mass decreased, likely from weight loss. In F3-4, {Delta}ALBI score and {Delta}PDFF (hepatic fat "burning{square}out") independently correlated with {Delta}muscle mass (both P{square}<{square}0.01). In ACLD, MP--but not obesity itself--was an independent predictor of liver{square}related death (HR{square}2.27, 95%{square}CI{square}1.08-4.78, P{square}={square}0.025). ConclusionsOur findings suggest an obesity-MASLD-MP cascade driven by a liver-centered metabolic paradox: preserved hepatic function promotes harmful fat accumulation, whereas hepatic dysfunction leads to fat depletion (energy deficiency) and muscle loss. Recognition of this dynamic loop highlights the need for stage-specific strategies: fat reduction initially, followed by aggressive muscle preservation and energy repletion in ACLD.

Existing drug therapies for hepatocellular carcinoma (HCC), including sorafenib, extend patient survival by only three months. We sought to identify novel druggable targets for use in combination with sorafenib to increase its efficacy. We implemented an in vivo genetic screening paradigm utilizing a library of 43 genes-of-interest expressed in the context of repopulation of the injured livers of Fumarylacetoacetate Hydrolase-deficient (Fah-/-) mice, which led to highly penetrant HCC. We then treated mice with vehicle or sorafenib to discover genetic determinants of sensitivity and resistance. Liver X Receptor alpha (LXR) emerged as a potential target. To examine LXR agonism in combination with sorafenib treatment, we added varying concentrations of sorafenib and LXR agonist drugs to HCC cell lines. We performed transcriptomic analysis to elucidate the mechanisms of HCC death. Fah-/- mice injected with the screening library developed HCC tumor clones containing Myc cDNA plus various other cDNAs. Treatment with sorafenib resulted in sorafenib-resistant HCCs that were significantly depleted in Nr1h3 cDNA, encoding LXR, suggesting that LXR activation is incompatible with tumor growth in the presence of sorafenib treatment in vivo. The combination of sorafenib and LXR agonism led to enhanced cell death as compared to monotherapy in multiple HCC cell lines, due to reduced expression of cell cycle regulators and increased expression of genes associated with apoptosis. Combination therapy also enhanced cell death in a sorafenib-resistant primary human HCC cell line. Our novel in vivo screen led to the discovery that LXR agonist drugs potentiate the efficacy of sorafenib in treating HCC.

Background & AimsA cholestatic pattern of liver enzymes is associated with progressive liver disease and major adverse liver-related outcomes (MALO) among patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). We aimed to authenticate the efficacy of a newly formulated liver function test (LFT) score for distinguishing patients with cholestatic vs. hepatocellular patterns and to evaluate its prognostic utility in MASLD patients. MethodsA retrospective longitudinal study on a dataset of over 250,000 individuals diagnosed with MASLD and/or obesity with cardiovascular risk factors. Patients were categorized into cholestatic (C), mixed (M), or hepatocellular (H) patterns according to the LFT score, or the well-known R score. Long-term MALO, major adverse cardiovascular events (MACE), and all-cause mortality were tracked. ResultsThe LFT score excelled in differentiating patients into C, M, or H groups accurately. While about two-thirds of our cohort initially showed a low FIB4 (<1.3), patients in the C category experienced a higher incidence of MALO and MACE compared to those in the H category (0.5% vs. 0.2% and 7.1% vs. 3.6%, respectively) over the span of 10 years post-diagnosis. Additionally, the 15-year overall survival rate was notably lower for C patients compared to their H counterparts (63% vs. 77%, p<0.0001). The LFT score was more effective than the R score in distinguishing between H and C patients for prognostic purposes, and a baseline cholestatic pattern indicates poorer outcomes regardless of subsequent LFT changes. ConclusionsThe LFT score accurately categorizes cholestatic MASLD patients and may serve as a useful prognostic tool.

BackgroundHBsAg can be derived from intrahepatic cccDNA and integrated HBV DNA (iDNA). We examined the iDNA from liver tissues of 24 HBeAg(+) and 32 HBeAg(-) treatment-naive CHB participants. MethodsLiver tissues were obtained from the North American Hepatitis B Research Network (HBRN). For cccDNA analysis, DNA was heat-denatured and digested by plasmid-safe ATP-dependent DNase to remove rcDNA and iDNA prior to qPCR. For iDNA detection, total DNA was subjected to HBV hybridization-targeted next generation sequencing (HBV-NGS) assay. The HBV-host junction sequences were identified by ChimericSeq. Comparison of HBV cccDNA and iDNA with serum and intrahepatic virological parameters were assessed. ResultsIntrahepatic cccDNA, serum HBV DNA, HBV RNA, HBcrAg and qHBsAg were higher among the HBeAg(+) participants. Among the HBeAg(+) samples, 87% had positive intrahepatic HBcAg staining compared to 13% of HBeAg(-) samples (p<0.0001). HBsAg staining, in contrast, was present in over 85% of both HBeAg(+) and (-) livers. 23 (95.8%) HBeAg(+) participants had [&le;]50% iDNA of total HBV DNA whereas 25 (78.1%) HBeAg(-) participants had >50% iDNA in their livers. The iDNA junction-breakpoint distributions for the HBeAg(+) group were random with 15.9% localized to the DR2-DR1 region. In contrast, 52.4% of the iDNA were clustered at DR2-DR1 region among the HBeAg(-) participants. Microhomology-mediated end joining (MMEJ) patterns of dslDNA HBV integration was more frequent in HBeAg (+) livers. ConclusionSerum RNA and HBcrAg reflect the intrahepatic cccDNA concentrations. HBeAg(-) CHB participants had high levels of intrahepatic iDNA and HBsAg despite lower cccDNA levels suggesting that iDNA is the primary source of HBsAg in HBeAg(-) CHB.