Fenofibrate has shown biochemical benefit in primary biliary cholangitis (PBC) patients with a suboptimal response to ursodeoxycholic acid (UDCA), but its long-term efficacy on survival remains unknown. In this retrospective-prospective cohort study, we enrolled 160 PBC patients with a suboptimal response to UDCA and followed up on these patients to obtain laboratory results and adverse events. Finally, we evaluated long-term survivals analyzed with Kaplan-Meier plotting and log-rank test. The fenofibrate add-on therapy group showed more significant improvements in alkaline phosphatase (ALP) and gamma-glutamyl transferase levels compared with UDCA monotherapy group after 1 year of treatment, resulting in a normalization rate of 60.9% for ALP and 45.3% for both ALP and total bilirubin. Importantly, compared with UDCA monotherapy group, the fenofibrate add-on therapy group had a better transplant-free survivals of 5 (89.7 vs 75.3%) and 10 years (87.0 vs 47.6%), with a hazard ratio of 0.3282 (95% confidence interval: 0.1334-0.8073, P < 0.05). Twenty-one cases (25.6%) developed adverse events, with liver injury being the most frequent one (17.1%). Fenofibrate add-on therapy improved not only biochemical responses but also long-term transplant-free survival in PBC patients with suboptimal response to UDCA. However, liver injury needs to be closely monitored and properly managed.

Steatotic liver disease (SLD) is becoming increasingly prevalent, leading to a higher frequency of primary biliary cholangitis (PBC) cases coexisting with SLD. However, data on its impact in patients with PBC remain scarce. The aim is to assess the impact of SLD on treatment response and prognosis in patients with PBC receiving ursodeoxycholic acid (UDCA). A retrospective, multicenter cohort study including patients diagnosed with PBC enrolled in the Spanish ColHai registry. A total of 469 patients with available data required for the study were included. Among them, 158 (33.7%) had SLD, and 124 (78.5%) met the diagnostic criteria for MASLD. Patients with PBC and SLD had lower baseline levels of alkaline phosphatase and higher liver stiffness at diagnosis. Regarding treatment response, no significant differences were observed across the different response criteria (Paris II, GLOBE, UK-PBC, deep response and complete normalization). Additionally, the presence of SLD was not associated with UDCA response at 1-year (Paris II: OR 1.04 [0.69-1.56]; GLOBE: OR 0.91 [0.58-1.44]; deep response: OR 1.08 [0.72-1.63]; complete normalization: OR 0.82 [0.52-1.30]). Baseline SLD was not associated with an increased risk of liver related-events in either the univariate analysis (HR 1.19, 95% CI 0.71-2.02) or in the different multivariate models evaluated. After inverse probability of treatment weighting (IPTW) using propensity scores, SLD still showed no significant impact on hepatic event development (HR 1.62; 95% CI 0.92-2.83). Although SLD is frequently observed in PBC, it does not appear to adversely affect UDCA response or long-term hepatic outcomes.

Self-assembling gardenia pectin gel for cholestatic liver injury: Dual mechanisms of hepatoprotection via PPARα activation and gut microbial modulation.

Rapid weight loss following Metabolic bariatric surgery (MBS) is associated with an increased risk of developing de novo gallstone formation. We aimed to evaluate the efficacy of prophylactic ursodeoxycholic acid (UDCA) in preventing gallstone formation and reducing gallstone-related outcomes after MBS. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) following the PRISMA guidelines through PubMed/MEDLINE, Cochrane, Embase, Scopus, Google Scholar, and clinicaltrials.gov. The primary outcome was gallstone formation at 12-24 months, while symptomatic gallstones and cholecystectomy incidence were secondary outcomes. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using random-effects models. Subgroup analysis was conducted according to UDCA dose, duration of administration, and the type of operation. Meta-regression was performed to assess the effect of age and baseline BMI on gallstone formation. I2 and Cochrane Q p-value were used to assess the heterogeneity of the studies. Ten RCTs, including 3,575 participants, were included. Prophylactic UDCA reduced the incidence of gallstone formation by 67% at 12-24 months, and 73% at 6 months, while symptomatic gallstones were reduced by 70%. No statistically significant difference was found in the cholecystectomy rates. Subgroup analysis showed that UDCA doses of 500-600mg daily administered for 6-12 months were effective, with no significant differences in gallstone formation between surgical procedures. Meta-regression analysis showed a slight increase in gallstone risk with age and a slight decrease with higher BMI, although neither relationship reached statistical significance. Prophylactic UDCA may be an effective preventive measure for gallstone formation in MBS patients, however additional studies are needed to assess its effect on cholecystectomy. The systematic review was registered in PROSPERO under registration number CRD420251004594.

Intrahepatic cholestasis of pregnancy (ICP) requires timely diagnosis to guide management, including initiation of ursodeoxycholic acid (UDCA) and delivery planning. LC-MS/MS provides fractionated bile acid profiles but has a turnaround time (TAT) of approximately 1 week, delaying treatment. Enzymatic total bile acid (TBA) assays offer faster results but measure all bile acids collectively, which some have reported can be impacted by UDCA treatment. We validated the Diazyme enzymatic TBA assay on a Roche Cobas analyzer, assessing analytical measurement range, reference interval, precision, and accuracy vs LC-MS/MS. The comparison cohort included samples from 100 pregnant patients (median age 31 years; gestational age 34 weeks) presenting with pruritus and suspected of ICP. A secondary analysis examined UDCA and tauroursodeoxycholic acid in a UDCA-detectable subset. TAT was evaluated retrospectively in 971 specimens. We verified the assay's analytical measurement range of 1 to 180 µmol/L and reference interval of <10 µmol/L. Precision was <10%, and method comparison revealed minimal bias, with 98% clinical concordance. In the UDCA subset (n = 19), UDCA and tauroursodeoxycholic acid represented minor fractions of total TBA. Operationally, the enzymatic assay provided rapid results, with a median TAT of 5.6 h from collection (range 0.6-36.8) and 0.5 h from receipt (range 0.2-22.3); delays were mainly due to transport. The Diazyme enzymatic TBA assay on Roche Cobas demonstrates robust performance and rapid turnaround, supporting timely ICP diagnosis and management. LC-MS/MS remains useful for fractionated profiling but is limited by longer TAT.

Primary Biliary Cholangitis (PBC) is an autoimmune hepatic disorder characterized by the progressive destruction of intrahepatic bile ducts. Ursodeoxycholic acid (UDCA) remains the primary treatment modality; however, a subset of patients exhibits non-responsiveness to UDCA therapy. The objective of this study is to investigate the association between the Prognostic Nutritional Index (PNI) and UDCA treatment non-responsiveness in individuals diagnosed with PBC. This retrospective study encompassed PBC patients who received UDCA therapy (13-15mg/kg) from June 1, 2014, to December 31, 2021. The criterion for UDCA non-response was defined as an alkaline phosphatase (ALP) level exceeding 1.67 times the upper limit of normal (ULN) after 12 months of UDCA therapy. Logistic regression analysis was utilized to examine the relationship between baseline PNI and response to UDCA. The stableness of the findings was assessed through both unadjusted and adjusted models. The study included 241 patients with PBC (mean age 55.80 ± 11.694 years; 210 (87.1%) females). During the 12-month clinical follow-up, 83 patients exhibited non-responsiveness to UDCA, corresponding to a non-response rate of 34.44%. Univariate binary logistic regression analysis indicated that factors such as alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), total bile acid, total cholesterol, neutrophils, and PNI were associated with UDCA non-responsiveness (p < 0.05). Multivariate regression analysis showed that lower baseline PNI was associated with UDCA non-response (odds ratio [OR]: 0.882, 95% confidence interval [CI]: 0.825-0.943, p < 0.001). PNI showed modest discriminatory ability for UDCA non-response, with an AUROC of 0.664 in the overall cohort and 0.676 in non-cirrhotic patients. Based on the Youden index, the optimal PNI cut-off value was 49.03. Lower baseline PNI was associated with inadequate biochemical response to UDCA in patients with PBC and may serve as a supportive risk stratification marker. However, its modest discriminatory performance and retrospective design limit its standalone clinical application. Further prospective validation is needed.

Background and AimsPrimary sclerosing cholangitis (PSC) increases the risk of developing cholangiocarcinoma (CCA), which is the leading cause of premature death in these patients. Current diagnostic methods for early detection of either condition remain largely suboptimal. This study investigates serum metabolites as potential non-invasive diagnostic biomarkers.MethodsThis multicenter international study analyzed 459 serum samples from 13 international centers, including patients with PSC (n = 216), PSC who developed CCA during follow-up (PSC to CCA; n = 24), PSC with concomitant CCA (PSC-CCA; n = 88), ulcerative colitis (UC; n = 14), and healthy individuals (n = 79). Serum metabolomics was evaluated by ultra‐high‐performance liquid chromatography‐mass spectrometry (UHPLC-MS) and the accuracy of the single candidate metabolite biomarkers was further assessed. Machine learning was used to generate the best diagnostic and predictive algorithms.ResultsFifty-two serum metabolites were identified as markers of PSC, independent of age, biological sex, cirrhosis, UC, or ursodeoxycholic acid (UDCA) treatment. A diagnostic model based on only six lipids distinguished PSC patients from healthy controls with high accuracy (AUC 0.952 discovery, 0.918 validation), independently of the levels of transaminases or cholestasis markers (i.e., GGT, AP, bilirubin) in blood. Subgroup analyses were performed in PSC patients with and without inflammatory bowel disease (IBD), confirming the model’s consistent performance across both subgroups when compared with their respective control groups – UC and healthy controls (AUC 0.959 and 0.939, respectively). The PSC model also confirmed its diagnostic performance in patients with established PSC-CCA or progression to CCA within 2 years, when compared to UC and healthy controls, showing AUC values ranging from 0.911 to 0.976.Additionally, 20 metabolites were significantly altered in PSC patients with CCA (PSC-CCA), regardless of demographics, cirrhosis, UDCA treatment, IBD status, or CCA subtype, and independently of serum transaminases and cholestatic markers levels. A model incorporating six lipids accurately identified PSC-CCA cases compared to PSC patients (AUC = 0.912 discovery; 0.896 validation), showing excellent performance in early-stage tumor detection (AUC 0.921) and outperforming CA19-9 (AUC 0.708). Importantly, the model retained high accuracy even in CCA patients with low CA19-9 levels (AUC 0.905) and in PSC patients who developed CCA within a year of clinical diagnosis (AUC 0.792).ConclusionThe PSC and PSC-CCA blood tests provide a non-invasive approach for diagnosing PSC and PSC-CCA, addressing an important need in this population. Their integration into clinical practice could enhance risk stratification, early detection, personalized surveillance, and treatment decision-making in PSC patients.

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are chronic cholestatic liver diseases characterized by bile duct injury that may progress to fibrosis, cirrhosis, liver failure, and malignancy and ultimately require liver transplantation. Although these diseases share several clinical features, they differ substantially in pathogenesis, clinical course, and therapeutic approaches. Ursodeoxycholic acid remains the standard first-line therapy for PBC; patients with an inadequate biochemical response may be treated with second-line agents such as seladelpar, elafibranor, or fibrates. In contrast, no approved therapy has been shown to slow disease progression in PSC. Emerging therapies primarily target symptom and complication management, and overall management focuses on surveillance and timely referral for liver transplantation. This review summarizes current approaches to risk assessment, treatment, symptom management, monitoring, and transplantation decision-making in both conditions.

The increasing availability and decreasing costs of DNA sequencing have resulted in the re-grouping of rare, severe paediatric cases of progressive familial intrahepatic cholestasis (PFIC) with more frequent, later-onset cases of cholestasis (eg, intrahepatic cholestasis of pregnancy, benign recurrent intrahepatic cholestasis, low phospholipid-associated cholelithiasis) under the umbrella of genetic cholestasis. The common denominator is the presence of functional variants in the PFIC-associated genes, predominantly in ABCB4, ABCB11 and ATP8B1, which cause PFIC types 1-3. Several other congenital diseases such as Alagille syndrome and alpha1-antitrypsin deficiency comprise cholestatic pruritus as frequent symptoms.With the availability of intestinal bile acid transporter inhibitors (IBATi) as new and efficacious therapeutics for pruritus, the most debilitating symptom of PFIC, it is essential to envision their usefulness for patients with later-onset cholestatic liver disease suffering from pruritus.In this review, we summarise published studies on the genetic makeup of patients with paediatric, juvenile and adult-onset cholestasis, and discuss their findings with respect to genotype-specific treatment with IBATi, ursodeoxycholic acid, or alternative drugs. The aim is to provide an overview of the genetic variants likely to be encountered in future sequencing investigations of patients with cholestatic liver diseases, and how to translate this genetic information into personalised treatment recommendations.

Interferon-gamma-inducible protein-10 is associated to increased primary bile acids and fibrosis in primary sclerosing cholangitis.

Although ursodeoxycholic acid (UDCA) is commonly prescribed for primary sclerosing cholangitis (PSC), a beneficial long-term effect on solid clinical endpoints has not yet been established. This study evaluated the efficacy of UDCA on long-term transplant-free survival in a longitudinal population-based cohort. We conducted a retro/prospective study between January 2008 and August 2020, using data from the Dutch population-based EpiPSC2 cohort. Medication use was collected through medical chart review, periodic questionnaires, and the national pharmacy prescription database. The effect of UDCA use was assessed as time-dependent variable using a Cox proportional hazards model. Sex, age at diagnosis, PSC type, IBD status, transplant center inclusion, and PSC diagnosis year were considered as covariates. Medication data were available for 739 cases. Individuals with uncertain use of UDCA were excluded, resulting in a study population of 527. No discernable effect of UDCA use was observed on the endpoints liver transplantation (LT)/all-cause mortality [adjusted HR 1.13 (95%CI 0.76-1.67)] nor LT/PSC-related death/occurrence of hepatobiliary malignancy [adjusted HR 1.07 (95%CI 0.71-1.60)]. The HR of UDCA use was numerically reduced for hepatobiliary malignancy [0.68 (95%CI 0.34-1.37)]. Our study failed to demonstrate that UDCA use impacts long-term outcomes in patients with PSC.

To investigate the association between cholangitis and portal hypertension (PH) risk, and the efficacy of UDCA in native liver survivors after successful Kasai portoenterostomy (KPE). A multicenter, retrospective cross-sectional study was conducted at nine Chinese pediatric centers. Patient grouping was based on cumulative cholangitis episodes and UDCA regimens. After a median follow-up of 56 months, the overall incidence of PH was 23.63% (198/838). Recurrent cholangitis (≥ 3 episodes) was an independent risk factor for PH (OR = 4.25, 95% CI 2.61-6.92, P < 0.001), associated with poorer liver function recovery, greater spleen thickness, and lower peak velocity of the main portal vein. Continuous UDCA therapy significantly attenuated the PH risk induced by recurrent cholangitis (RERI: - 7.66). Among this high-risk subgroup, low-dose UDCA (≤ 10mg/kg/day) constituted an independent protective factor (OR = 0.17, 95%CI 0.04-0.67, P = 0.015) and showed superior efficacy in reducing total bilirubin. These benefits were evident in children under 48 months, but no clear advantage observed beyond this age. Among native liver survivors with jaundice clearance, recurrent cholangitis (≥ 3 episodes) warrants long-term monitoring for PH. Continuous low-dose UDCA until 48 months is recommended for high-risk patients to improve outcomes.

The emerging role of PPARs in primary biliary cholangitis.

Estimation of histological cirrhosis on diagnosis is useful for predicting prognosis in patients with primary biliary cholangitis (PBC). The pretreatment GLOBE score is associated with survival, but its relationship with histological cirrhosis remains unknown. We retrospectively investigated the pretreatment GLOBE score in PBC patients who had undergone liver biopsy. We analyzed the association between pretreatment GLOBE score and clinical findings, including histological cirrhosis and liver transplant (LT)-free survival rate. Among 183 patients with PBC, the pretreatment GLOBE score increased significantly with histological stage. The pretreatment GLOBE score demonstrated a high AUROC (0.868) than other noninvasive tools, with a cutoff value of 1.265 (95% CI: 1.195-1.585) for predicting histological cirrhosis. Patients with a pretreatment GLOBE score of < 1.265 had a significantly higher LT-free survival rate than those with a score of ≥ 1.265. A score of ≥ 1.265 was associated with lower LT-free survival rate independent of the presence of histological cirrhosis or GLOBE score 1 year after ursodeoxycholic acid treatment. Assessment of the pretreatment GLOBE score in PBC patients may be useful as a noninvasive prognostic tool.

Pharmaceutical and Nutraceutical Therapies for Liver Disease.

Bezafibrate for Primary Biliary Cholangitis: a Number Needed to Treat Analysis.

Small intestinal bacterial overgrowth (SIBO) refers to an abnormal increase in the number of bacteria in the small intestine and is observed in various diseases. SIBO can also develop after long-term use of proton pump inhibitors (drug-induced SIBO), bariatric surgery, gastrectomy, and other surgeries (postoperative SIBO). The aim of this narrative review is to summarize all of the published information on the treatment of SIBO in as much detail as possible and present it separately for each specific disease and intervention associated with SIBO. The most extensively studied drug for the treatment of SIBO is rifaximin. It eliminates SIBO in 63% of cases; however, most studies lack a control group. Small RCTs assessing the effects of this antibiotic on SIBO have reported conflicting results, and a meta-analysis showed no effect. A large RCT is required to verify the results of uncontrolled studies. Neomycin and norfloxacin showed efficacy in the treatment of SIBO in single RCTs, with elimination rates of 20 and 100%, respectively. Ciprofloxacin, rifamycin, metronidazole, and other antibiotics, as well as ursodeoxycholic acid, showed positive effects for the treatment of SIBO, but only in uncontrolled studies or in comparison with rifaximin or other drugs. The reported elimination rates were 54%, 67%, 79%, and 75%, respectively. Eradication therapy for Helicobacter pylori infection eliminated SIBO at a rate of approximately 70%. Probiotics have been tested for treatment of SIBO in various diseases. VSL#3 and Saccharomyces boulardii CNCM I-745 were effective in RCTs, with elimination rates of 58% and 80%, respectively. In conclusion, when selecting SIBO treatment regimens, those that have demonstrated the greatest efficacy for a specific concomitant disease should be preferred, despite the generally low level of evidence supporting these approaches in most cases.

Ursocholic acid ameliorates hepatic steatosis via direct AMPK activation in preclinical models of MASLD.

Ursodeoxycholic acid (UDCA) downregulates angiotensin-converting enzyme 2, the cellular entry receptor for SARS-CoV-2, and may reduce acute COVID-19 severity. However, it remains unknown whether UDCA prevents long COVID outcomes in patients with steatotic liver disease (SLD)-a population vulnerable to adverse outcomes. We investigated the association between pre-infection UDCA use and risk of long COVID outcomes in patients with SLD. We conducted a nationwide retrospective cohort study using the Korean COVID-19 registry linked to National Health Insurance Service claims data (2019-2022). Patients with SLD (fatty liver index ≥30) who experienced COVID-19 were included. Exposure was defined as at least one UDCA prescription within the 90 days preceding infection. Outcomes of interest were 20 incident long COVID conditions across eight organ systems assessed ≥84 days post-infection. After propensity score (PS) fine stratification, hazard ratios (HR) with 95% confidence intervals (CI) were estimated using Cox regression. Among 469,108 patients with SLD and COVID-19, 23,560 (5.0%) were UDCA users. After PS fine stratification weighting, UDCA use was not associated with reduced risk for most long COVID outcomes. A protective association was observed for atrial fibrillation (HR 0.51, 95% CI 0.30-0.88), whereas increased risks were found for type 2 diabetes mellitus (HR 1.24, 95% CI 1.09-1.42) and epilepsy (HR 1.69, 95% CI 1.09-2.61). Pre-infection UDCA use was not associated with reduced risk for most long COVID outcomes in patients with SLD. The observed associations warrant cautious interpretation given potential residual confounding and surveillance bias.

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder specific to pregnancy. The condition is characterised by raised serum bile acids and aminotransferases and typically presents with pruritus as its defining symptom. Ursodeoxycholic acid remains the first line therapeutic option. Clinical management — including decisions regarding the timing of delivery — is guided principally by serum bile acid concentrations, with the aim of reducing perinatal complications. This review offers a clear and integrated overview of current diagnostic criteria, management strategies, and the evidence underpinning contemporary therapeutic recommendations.