BACKGROUND:Vitamin D deficiency has been implicated in cancer risk across several organ systems, but its role in hepatobiliary malignancy (HBM) remains unclear. We evaluated whether vitamin D supplementation (VDS) was associated with a lower risk of HBM specifically in patients with primary sclerosing cholangitis (PSC). METHODS:Patients enrolled in the PSC registry at our quaternary care and liver transplant (LT) center from 2010 to 2020 were analyzed. The primary exposure was VDS, modeled as a time-dependent variable. The primary outcome was HBM. Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics, and Cox proportional hazards models were employed to estimate marginal hazard ratios (HRs). Cumulative incidence functionsfor HBM were estimated using a competing risks analysis treating death, and LT was as competing events. RESULTS:A total of 160 patients (mean age 42 years; 66% male) were included, of whom 76 (47.5%) reported baseline VDS. Over a median follow-up of 7 years, 15 patients developed HBM, corresponding to an incidence rate of 12.3 per 1000 person-years. VDS was associated with a significantly lower risk of HBM in both conventional (HR 0.16, 95% CI 0.05-0.57) and IPTW (HR 0.15, 95% CI 0.03-0.41) analyses. This association was consistent across baseline vitamin D strata, including <30 ng/mL (HR 0.12, 95% CI 0.02-0.79) and ≥30 ng/mL (HR 0.18, 95% CI 0.05-0.65). Accounting for competing risks, the 5-year cumulative incidence of HBM was 1.1% among patients receiving VDS versus 11.5% without VDS (p<0.01). DISCUSSION:VDS was associated with a significantly lower risk of HBM in this longitudinally followed cohort of patients with PSC. These findings support the consideration of VDS in all patients with PSC and underscore the need for mechanistic and interventional studies to further evaluate this association.

BACKGROUND:Magnetic resonance cholangiopancreatography (MRCP) is used in the diagnosis and management of primary sclerosing cholangitis (PSC). However, MRCP is subjective, and guidelines state that there is insufficient evidence to recommend MRCP as a prognostic tool. EASL-PSC guidelines have identified quantitative MRCP (MRCP+) as having promising utility for risk assessment and prediction of clinical outcomes. We conducted a systematic review to determine the clinical utility of MRCP+ metrics for the management of patients with PSC. METHODS:We systematically searched PubMed and MEDLINE for cohort studies reporting on MRCP+ metrics associated with risk prediction, clinical outcomes, and disease progression published between January 2019 and May 2024. Studies reporting on adults with diagnosed PSC with paired MRCP were selected. There were no limitations on the type of study (retrospective/prospective). Studies reporting on only qualitative assessment of MRCP were excluded. RESULTS:Six manuscripts with 512 subjects met the study criteria. For risk prediction and disease progression, 4 articles reported 21 unique MRCP+ metrics, which were significantly associated with the Amsterdam-Oxford model and the MAYO risk score. MRCP+ metrics had AUC ranging 0.65 to 0.87 and hazard ratios ranging 0.96 to 17.79 for the prediction of adverse outcomes, including liver transplantation, death, hepatic decompensation, biliary complications, and cholangiocarcinoma. Associations between biochemical markers of liver function (alkaline phosphatase, bilirubin, aspartate aminotransferase, gamma glutamyl transferase, and albumin) ranged -0.42≤ R ≤0.48. CONCLUSION:MRCP+ metrics have clinical utility to support patient management alongside addressing key gaps, including standardising MRCP assessment, early detection of disease, and quantification of risk.

Liver Imaging Reporting and Data System (LI-RADS) category 3 (LR-3) observations remain indeterminate and often result in repeated follow-up or biopsy. Prostate-specific membrane antigen (PSMA) is overexpressed in hepatocellular carcinoma (HCC) neovasculature and may serve as a useful imaging biomarker. This study aimed to evaluate whether [68Ga]Ga-PSMA-11 PET/MRI improved characterization of LR-3 observations in patients with cirrhosis compared with MRI alone. Methods: In this prospective study, conducted between March 2022 and June 2024, 19 patients with cirrhosis and 54 LR-3 observations identified on prior MRI underwent [68Ga]Ga-PSMA-11 PET/MRI. An observation was classified as HCC if it demonstrated focal 68Ga-PSMA uptake greater than background liver combined with at least 1 LI-RADS major or ancillary feature. The reference standard was histopathology or a follow-up MRI within 12 mo. Diagnostic metrics were calculated. Univariable logistic regression and decision tree analysis were performed to identify imaging predictors of malignancy. Results: Of the 54 LR-3 observations, 13 (24%) were confirmed as HCC and 41 (76%) as benign. [68Ga]Ga-PSMA-11 PET/MRI correctly identified 12 of 13 HCCs (sensitivity, 92%; 95% CI, 66.7-99.6) and 39 of 41 benign observations (specificity, 95%; 95% CI, 81.9-99.3). Overall diagnostic accuracy was 94%, with a positive predictive value of 86% and negative predictive value of 97%. Diagnostic performance was significantly better than MRI alone (McNemar test, P < 0.001). [68Ga]Ga-PSMA-11 uptake was the only significant imaging predictor of malignancy on univariable analysis (odds ratio, 5.7; P = 0.017). Decision tree analysis identified [68Ga]Ga-PSMA-11 uptake, observation size, and hepatobiliary phase hypointensity as principal discriminators. Conclusion: [68Ga]Ga-PSMA-11 PET/MRI demonstrates high diagnostic accuracy in differentiating malignant from benign LR-3 liver observations in patients with cirrhosis. This technique may reduce unnecessary follow-up imaging and biopsy. These results support further validation of [68Ga]Ga-PSMA-11 PET/MRI as a promising imaging approach for indeterminate liver observations.

BACKGROUND AND AIMS:Statins have been investigated for their potential to reduce liver-related complications in chronic liver diseases, but evidence in primary biliary cholangitis (PBC) remains limited. This study aimed to assess the association between statin use and the risk of hepatic decompensation using a target trial emulation (TTE) design. APPROACH AND RESULTS:We performed a sequential TTE using 2 electronic health record databases: Mass General Brigham (MGB, Boston, USA) and Asan Medical Center (AMC, Seoul, Korea). Adults diagnosed with PBC between 2001 and 2024 were eligible. Statin use was defined as a cumulative duration of ≥90 days. In each monthly trial, statin initiators were matched 1:2 to non-users using propensity score matching. The primary outcome was hepatic decompensation; the secondary outcome was a composite major adverse liver outcome (MALO), including decompensation, hepatocellular carcinoma, and liver transplantation. Among 2889 eligible patients, 443 statin users were matched to 886 non-users. Over a median follow-up of 3.8 years, hepatic decompensation occurred in 24 statin users (5.4%) and in 67 non-users (7.6%) [hazard ratio (HR), 0.61; 95% confidence interval (CI): 0.38-0.97]. Statin use was also associated with a reduced risk of MALO (HR, 0.58; 95% CI: 0.38-0.89). Sensitivity analyses stratified by data source (MGB, HR 0.65; AMC, HR 0.60) and cirrhosis status (HR 0.70 for cirrhosis; HR 0.57 for without) showed similar directional trends. CONCLUSIONS:Statin use was consistently associated with a lower risk of hepatic decompensation and major liver events in patients with PBC, supporting a potential protective effect.

Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by inflammation and progressive fibrosis of the biliary tree. PSC pathogenesis remains poorly understood, and there are no effective therapies. Previous studies have observed associations between colonic and biliary microbiome alterations and PSC. We aimed to determine whether bacterial isolates cultured from PSC patient bile induce disease-associated phenotypes in cells, specifically cell death, epithelial permeability, inflammation, and changes in host-protective pathways. Bile was collected from PSC patients by endoscopic retrograde cholangiography and from non-PSC controls undergoing cholecystectomies. Biliary bacteria were cultured anaerobically, and 50 colonies per sample were identified by 16S sequencing. No bacteria were isolated from non-PSC controls, while bacteria were cultured from most PSC patients. The PSC bile microbiomes exhibited reduced diversity compared to the gut or oral cavity, with one or two species predominating. The effects of supernatants from seven PSC-associated bacterial isolates on cellular phenotypes were characterized using human colonic (Caco-2), hepatic (HepG2), and biliary (EGI-1) cells. Overall, PSC-associated bacteria produced factors cytotoxic to hepatic and biliary cells. An Enterococcus faecalis isolate, and to a lesser extent a Veillonella parvula isolate, induced epithelial permeability, while Escherichia coli, Fusobacterium necrophorum, and Klebsiella pneumoniae isolates induced inflammatory cytokines in biliary cells. Our data suggest that bacteria cultured from PSC bile induce cellular changes characteristic of PSC pathogenesis, with different isolates inducing distinct cellular responses. Our work provides a starting point for future research into bacterial contributions to PSC with the eventual goal of developing therapies for this disease.IMPORTANCEPrimary sclerosing cholangitis (PSC) is a chronic liver disease in which inflammation and scarring of the bile ducts cause bile to build up in the liver, leading to liver damage and eventually liver failure. The causes of this disease are poorly understood, and the only current treatment is a liver transplant. To develop new treatments, we must first better understand what leads to this disease. We examined whether bacteria isolated from PSC patient bile can cause disease-related responses in human biliary, liver, and intestinal cells. We observed that different PSC-associated bacteria can induce distinct disease-related cellular changes, including inflammation and cell death. These data suggest that the microbial community in PSC patients may indeed be linked to disease development. Our findings provide new starting points for further exploration into the poorly understood origins of PSC.

Background: The natural history of primary sclerosing cholangitis (PSC) among African Americans (AA) is not well understood. Methods: Transplant-free survival and hepatic decompensation-free survival were assessed using a retrospective research registry from 16 centers throughout North America. Patients with PSC alive without liver transplantation after 2008 were included. Diagnostic delay was defined from the first abnormal liver test to the first abnormal cholangiogram/liver biopsy. Socioeconomic status was imputed by the Zip code. Results: Among 850 patients, 661 (77.8%) were non-Hispanic Whites (NHWs), and 85 (10.0%) were AA. There were no significant differences by race in age at diagnosis, sex, or PSC type. Inflammatory bowel disease was more common in NHWs (75.8% vs. 51.8% p=0.0001). The baseline (median, IQR) Amsterdam-Oxford Model score was lower in NHWs (14.3, 13.4-15.2 vs. 15.1, 14.1-15.7, p=0.002), but Mayo risk score (0.03, -0.8 to 1.1 vs. 0.02, -0.7 to 1.0, p=0.83), Model for End-stage Liver Disease (5.9, 2.8-10.7 vs. 6.4, 2.6-10.4, p=0.95), and cirrhosis (27.4% vs. 27.1%, p=0.95) did not differ. Race was not associated with hepatic decompensation, and after adjusting for clinical variables, neither race nor socioeconomic status was associated with transplant-free survival. Variables independently associated with death/liver transplant (HR, 95% CI) included age at diagnosis (1.04, 1.02-1.06, p<0.0001), total bilirubin (1.06, 1.04-1.08, p<0.0001), and albumin (0.44, 0.33-0.61, p<0.0001). AA race did not affect the performance of prognostic models. Conclusions: AA patients with PSC have a lower rate of inflammatory bowel disease but similar progression to hepatic decompensation and liver transplant/death compared to NHWs.

BACKGROUND & AIMS:Recurrent primary biliary cholangitis (rPBC) develops in approximately 30% of patients and negatively impacts graft and overall patient survival after liver transplantation (LT). There is a lack of data regarding the response rate to ursodeoxycholic acid (UDCA) in rPBC. We evaluated a large, international, multi-center cohort to assess the performance of PBC scores in predicting the risk of graft and overall survival after LT in patients with rPBC. METHODS:A total of 332 patients with rPBC after LT were evaluated from 28 centers across Europe, North and South America. The median age at the time of rPBC was 58.0 years [IQR 53.2-62.6], and 298 patients (90%) were female. The biochemical response was measured with serum levels of alkaline phosphatase (ALP) and bilirubin, and Paris-2, GLOBE and UK-PBC scores at 1 year after UDCA initiation. RESULTS:During a median follow-up of 8.7 years [IQR 4.3-12.9] after rPBC diagnosis, 52 patients (16%) had graft loss and 103 (31%) died. After 1 year of UDCA initiation the histological stage at rPBC (hazard ratio [HR] 3.97, 95% CI 1.36-11.55, p = 0.01), use of prednisone (HR 3.18, 95% CI 1.04-9.73, p = 0.04), ALP xULN (HR 1.59, 95% CI 1.26-2.01, p <0.001), Paris-2 criteria (HR 4.14, 95% CI 1.57-10.92, p = 0.004), GLOBE score (HR 2.82, 95% CI 1.71-4.66, p <0.001), and the UK-PBC score (HR 1.06, 95% CI 1.03-1.09, p <0.001) were associated with graft survival in the multivariate analysis. Similar results were observed for overall survival. CONCLUSION:Patients with rPBC and disease activity, as indicated by standard PBC risk scores, have impaired outcomes, supporting efforts to treat recurrent disease in similar ways to pre-transplant PBC. IMPACT AND IMPLICATIONS:One in three people who undergo liver transplantation for primary biliary cholangitis develop recurrent disease in their new liver. Patients with recurrent primary biliary cholangitis and incomplete response to ursodeoxycholic acid, according to conventional prognostic scores, have worse clinical outcomes, with higher risk of graft loss and mortality in similar ways to the disease before liver transplantation. Our results supportsupport efforts to treat recurrent disease in similar ways to pre-transplant primary biliary cholangitis.

Conflict of interest Yes, Full disclosures sent separately. Introduction and Objectives Seladelpar reduces biochemical markers of cholestasis and pruritus in patients with primary biliary cholangitis. ASSURE (NCT03301506) is an ongoing, open-label, long-term Phase 3 trial of seladelpar in patients rolling over from Phase 3 RESPONSE (NCT04620733) or legacy studies (NCT03602560, NCT02955602, NCT03301506, and NCT04950764). We report interim 2-year efficacy and safety results. Patients / Materials and Methods Patients with insufficient response/intolerance to ursodeoxycholic acid could enroll in ASSURE. Key endpoints were composite biochemical response (alkaline phosphatase [ALP] <1.67 × upper limit of normal [ULN], ALP decrease ≥15%, and total bilirubin ≤ULN) and ALP normalization. Pruritus was measured using numerical rating scale (NRS; 0–10). For patients enrolling from RESPONSE, baseline was entry to RESPONSE and analyzed as continuous seladelpar or crossover from placebo; legacy patients were analyzed separately with baseline defined as entry to ASSURE. Results and Discussion As of 01/2024, 158 RESPONSE and 179 legacy patients received seladelpar 10 mg daily for up to 155 weeks. In RESPONSE, 61.7% of patients met the endpoint at 12 months (M) vs 20% for placebo. In ASSURE, 61.8% (6M) and 72.4% (12M) met the composite endpoint; 75% (6M) and 93.8% (12M) of placebo crossover patients met the endpoint. In RESPONSE, ALP normalized in 25% of seladelpar and 0 placebo patients at 12M. With continued treatment, 33.3% (6M) and 17.2% (12M) had ALP normalization; 26.9% (6M) and 50% (12M) of crossover patients had ALP normalization. In ASSURE, 6-month change from baseline in pruritus NRS was similar to RESPONSE: −3.8 and −3.7 in continuous and crossover patients, respectively. At 12M and 24M, 73.2% and 69.7% of legacy patients met the endpoint in ASSURE; 42.1% and 42.4% achieved ALP normalization, and reduction in pruritus NRS was −3.8 and −3.1, respectively. There were no treatment-related serious adverse events. Conclusions Seladelpar treatment led to improvements in biochemical markers and pruritus, and was well tolerated with long-term use.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing cause of morbidity with limited treatment options. Thus, accurate in vitro systems to test new therapies are indispensable. While recently, human liver organoid models have emerged to assess steatotic liver disease, a systematic evaluation of their translational potential is still missing. Here, we evaluated human liver organoid models of MASLD, comparatively testing disease induction in three conditions: oleic acid, palmitic acid, and TGF-β1. Through single-cell analyses, we find that all three models induce inflammatory signatures, but only TGF-β1 promotes collagen production, fibrosis, and hepatic stellate cell expansion. In striking contrast, oleic acid ameliorates fibrotic signatures and reduces the hepatic stellate cell population. Linking data from each model to gene expression signatures associated with MASLD disease progression further demonstrates that palmitic acid and TGF-β1 more robustly model inflammation and fibrosis. Our findings highlight the importance of stratifying MASLD organoid models by signatures of clinical disease progression, provide a single-cell reference to benchmark future organoid injury models, and allow us to study evolving steatohepatitis, fibrosis, and HSC susceptibility to injury in a dynamic, multi-lineage human in vitro system.

Background: Genome-wide association studies (GWAS) have identified 30 risk loci for primary sclerosing cholangitis (PSC). Variants within these loci are found predominantly in noncoding regions of DNA making their mechanisms of conferring risk hard to define. Epigenomic studies have shown noncoding variants broadly impact regulatory element activity. The possible association of noncoding PSC variants with regulatory element activity has not been studied. We aimed to (1) determine if the noncoding risk variants in PSC impact regulatory element function and (2) if so, assess the role these regulatory elements have in explaining the genetic risk for PSC. Methods: Available epigenomic datasets were integrated to build a comprehensive atlas of cell type–specific regulatory elements, emphasizing PSC-relevant cell types. RNA-seq and ATAC-seq were performed on peripheral CD4 + T cells from 10 PSC patients and 11 healthy controls. Computational techniques were used to (1) study the enrichment of PSC-risk variants within regulatory elements, (2) correlate risk genotype with differences in regulatory element activity, and (3) identify regulatory elements differentially active and genes differentially expressed between PSC patients and controls. Results: Noncoding PSC-risk variants are strongly enriched within immune-specific enhancers, particularly ones involved in T-cell response to antigenic stimulation. In total, 250 genes and >10,000 regulatory elements were identified that are differentially active between patients and controls. Conclusions: Mechanistic effects are proposed for variants at 6 PSC-risk loci where genotype was linked with differential T-cell regulatory element activity. Regulatory elements are shown to play a key role in PSC pathophysiology.

Export {"href":"Single Video Player","role":"media-player-id","content-type":"play-in-place","position":"float","orientation":"portrait","label":"","caption":"","object-id":[{"pub-id-type":"doi","id":""},{"pub-id-type":"other","content-type":"media-stream-id","id":"1_5zesudt2"},{"pub-id-type":"other","content-type":"media-source","id":"Kaltura"}]}