Ketamine-induced sclerosing cholangitis has been described with chronic intranasal and intravenous use. Our case follows chronic topical use for peripheral neuropathy. It is also uniquely associated with early inflammatory bowel disease, a known complication of primary sclerosing cholangitis.

BACKGROUND: The American Society for Gastrointestinal Endoscopy recommends prophylactic antibiotics before endoscopic retrograde cholangiopancreatography (ERCP) in primary sclerosing cholangitis (PSC). We assessed the impact of this approach on the incidence of post-ERCP outcomes using nationwide data.
METHODS: Using 2015-2021 Nationwide Inpatient Sample data and relevant ICD-10 codes, we analyzed adult hospitalizations for PSC who underwent ERCP, with and without antibiotic prophylaxis. Hierarchical multivariate logistic regression analysis was used to assess the association between prophylactic antibiotic use and post-ERCP complications including sepsis, acute cholangitis, and acute pancreatitis.
RESULTS: We analyzed 32,972 hospitalizations for PSC involving ERCP, with 12,891 admissions (39.1%) receiving antibiotics before ERCP (cases) and 20,081 (60.9%) serving as controls. Cases were older than controls (mean age: 64.2 ± 8.6 vs. 61.3 ± 6.1 years; P = 0.020). Compared with controls, hospitalizations with antibiotic prophylaxis had a higher male population (7,541 (58.5%) vs. 11,265 (56.1%); P < 0.001) and higher comorbidity burden (Charlson comorbidity index score of ≥2: 5,867 (45.5%) of cases vs. 8,996 (44.8%) of controls; P = 0.01). Incidence of post-ERCP septicemia was 19.1% (6,275) with 2,935 incidences (22.8%) among cases compared with 3,340 (16.6%) among controls. Antibiotic prophylaxis did not significantly improve the odds of septicemia (aOR: 0.85; 95% CI: 0.77 - 1.09; P = 0.179). Approximately 2,271 (6.9%) cases of acute cholangitis and 5,625 (17.1%) cases of acute post-ERCP pancreatitis were recorded. After adjustments for multiple variables, no significant difference was observed in the odds of cholangitis (aOR: 0.87; 95% CI: 0.98 - 1.45; P = 0.08). However, antibiotic prophylaxis was correlated with a statistically significant reduction in the odds ratio of acute post-ERCP pancreatitis (aOR: 0.61; 95% CI: 0.57 - 0.66; P < 0.001).
CONCLUSIONS: The use of antibiotic prophylaxis in hospitalizations with PSC was correlated with a significant reduction in the odds of post-ERCP pancreatitis. Antibiotic prophylaxis did not improve the odds of post-ERCP sepsis or cholangitis. Prophylactic use of antibiotics should be individualized, considering both their anti-infective benefits and potential impact on the biochemical markers of liver disease.

Background: Primary sclerosing cholangitis (PSC) is an immune-mediated disease that has an unfavorable prognosis and needs a liver transplant (LT). The aim of this paper was to show the usefulness of the Majoie classification on magnetic resonance cholangiopancreatography (MRCP) images in assessing the prognosis in adult patients with PSC. Methods: Our work presents a retrospective monocentric study performed on 64 adult patients with PSC of the large bile ducts. Two radiologists evaluated the MRCP of diagnosis and calculated MRCP scores using the Majoie classification. Liver-related outcome (LT or liver-related death) was marked as a primary endpoint. Results: Univariate analysis showed that patients with more severe lesions (sum score of intrahepatic and extrahepatic ducts > 3) had a lower age at diagnosis, of 37.2 years, complicated with liver cirrhosis (53.1% of patients) and recurrent cholangitis (28.1%) p < 0.05, without significant differences in mortality, association with IBD or LT. Concordance analysis between MRCP prognostic scores and progression to a PSC-related event showed a moderate relationship (c-statistic 0.662), and a good AUROC was observed for the UKPSC score (0.893) and the MRS (0.936). Conclusions: In the study, we observed a good correlation between the imaging scores based on the Majoie classification and the evolution of the patients. These scores were outperformed by the UKPSC, MRS, and PREsTo clinical models. Their utility was best in predicting recurrent cholangitis.

Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), result from an impairment of bile flow that leads to the hepatic retention of bile acids, causing liver injury. Until recently, the only approved treatments for PBC were ursodeoxycholic acid (UDCA) and obeticholic acid (OCA). While these therapies slow the progression of PBC in the early stage of the disease, approximately 40% of patients respond incompletely to UDCA, and advanced cases do not respond. UDCA does not improve survival in patients with PSC, and patients often have dose-limiting pruritus reactions to OCA. Left untreated, these diseases can progress to fibrosis and cirrhosis, resulting in liver failure and the need for transplantation. These shortcomings emphasize the urgent need for alternative treatment strategies. Recently, nuclear hormone receptors have been explored as pharmacological targets for adjunct therapy because they regulate enzymes involved in bile acid metabolism and detoxification. In particular, the peroxisome proliferator-activated receptor (PPAR) has emerged as a therapeutic target for patients with PBC or PSC who experience an incomplete response to UDCA. PPARα is predominantly expressed in the liver, and it plays an essential role in the regulation of cytochrome P450 (CYP) and uridine 5\'-diphospho-glucuronosyltransferase (UGT) enzymes, both of which are critical enzyme families involved in the regulation of bile acid metabolism and glucuronidation, respectively. Importantly, PPARα agonists, e.g., fenofibrate, have shown therapeutic benefits in reducing elevated markers of cholestasis in patients with PBC and PSC, and elafibranor, the first PPAR (dual α, β/δ) agonist, has been FDA-approved for the second-line treatment of PBC. Additionally, newer PPAR agonists that target various PPAR isoforms (β/δ, γ) are under development as an adjunct therapy for PBC or PSC, although their impact on glucuronidation pathways are less characterized. This review will focus on PPAR-mediated bile acid glucuronidation as a therapeutic pathway to improve outcomes for patients with PBC and PSC.

Primary sclerosing cholangitis (PSC) is a challenging cholestatic liver disease marked by progressive bile duct inflammation and fibrosis that has no FDA-approved therapy. Although obeticholic acid (OCA) has been sanctioned for PSC, its clinical utility in PSC is constrained by its potential hepatotoxicity. Here, we introduce a novel therapeutic construct consisting of OCA encapsulated within a reactive oxygen species (ROS)-responsive, biodegradable polymer, further cloaked with human placenta-derived mesenchymal stem cell (hP-MSC) membrane (MPPFTU@OCA). Using PSC patient-derived organoid models, we assessed its cellular uptake and cytotoxicity. Moreover, using a PSC mouse model induced by 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC), we demonstrated that intravenous administration of MPPFTU@OCA not only improved cholestasis via the FXR-SHP pathway but also reduced macrophage infiltration and the accumulation of intracellular ROS, and alleviated mitochondria-induced apoptosis. Finally, we verified the ability of MPPFTU@OCA to inhibit mitochondrial ROS thereby alleviating apoptosis by measuring the mitochondrial adenosine triphosphate (ATP) concentration, ROS levels, and membrane potential (ΔΨm) using H2O2-stimulated PSC-derived organoids. These results illuminate the synergistic benefits of integrating an ROS-responsive biomimetic platform with OCA, offering a promising therapeutic avenue for PSC.

OBJECTIVE: Cholangiocarcinoma (CCA) is a dreaded complication of primary sclerosing cholangitis (PSC), difficult to diagnose and associated with high mortality. Lack of animal models of CCA recapitulating the hepatic microenvironment of sclerosing cholangitis hinders development of novel treatments. Here we sought to develop such PSC-associated CCA model in mice.
METHODS: Ten-week-old Mdr2-/- mice with congenital PSC-like disease, and healthy wild-type littermates were subjected to either modified retrograde biliary instillation or hydrodynamic tail vein injection of sleeping beauty transposon-transposase plasmid system with activated AKT (myr-AKT) and Yap (YapS127A) protooncogenes (SB AKT/YAP1). The role of TGFβ was interrogated via ALK5 inhibitor (SB-525334) administration. Tumor phenotype, burden and desmoplastic reaction were analyzed histologically and via RNA-seq.
RESULTS: While SB AKT/YAP1 plasmids via retrograde biliary injection caused tumors in Mdr2-/-, only 26.67% (4/15) of these tumors were CCA. Alternatively, hydrodynamic tail vein injection of SB AKT/YAP1 resulted in robust tumorigenesis in all fibrotic Mdr2-/- mice with high CCA burden compared to healthy mice. Tumors phenotypically resembled human CCA, expressed multiple CCA (but not hepatocellular carcinoma) markers, and exhibited a profound desmoplastic reaction. RNA-seq analysis revealed profound transcriptional changes in CCA evolving in PSC-like context, with specific alterations in multiple immune pathways. Pharmacological TGFβ inhibition led to enhanced immune cell tumor infiltration, reduced tumor burden and suppressed desmoplastic collagen accumulation compared to placebo CONCLUSION: We established a new high-fidelity cholangiocarcinoma model in mice, termed SB CCA.Mdr2-/-, which recapitulates the increased susceptibility to CCA in the setting of biliary injury and fibrosis observed in PSC. Through transcriptomics and pharmacological studies, we show dysregulation of multiple immune pathways and TGFβ signaling as potential drivers of CCA in PSC-like microenvironment.
UNASSIGNED: There is a lack of animal models for primary sclerosing cholangitis (PSC) related cholangiocarcinoma (PSC-CCA). We have developed and characterized a new mouse model of PSC-CCA, termed SB CCA.Mdr2-/-, which features reliable tumor induction in PSC-like background of biliary injury and fibrosis. Global gene expression alterations were identified and standardized tools, including automated whole slide image analysis methodology for tumor burden and feature analysis, were established to enable systematic research into PSC-CCA biology and formal pre-clinical drug testing.

UNASSIGNED: No intervention definitively extends transplant-free survival in primary sclerosing cholangitis (PSC). Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), may enhance PSC prognosis, but their efficacy is debated.
UNASSIGNED: We analyzed HMGCR single-nucleotide polymorphisms from published genome-wide association studies using Mendelian randomization to assess the causal relationship between HMGCR and PSC risk. Effects of HMGCR were compared with proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, common lipid-lowering drugs, using coronary heart disease risk as a positive control. The inverse-variance weighted (IVW) method was the primary analysis, complemented by the weighted median method. Heterogeneity analysis, examination of horizontal pleiotropy, and leave-one-out sensitivity analysis were conducted for result robustness.
UNASSIGNED: Genetically predicted HMGCR exhibited a pronounced detrimental effect on PSC in both the IVW method (odds ratio [OR] [95%] = 2.43 [1.23-4.78], P = 0.010) and the weighted median method (OR [95%] = 2.36 [1.02-5.45], P = 0.044). However, PCSK9 did not reach statistical significance. Moreover, all analyses passed through heterogeneity analysis, horizontal pleiotropy analysis, and leave-one-out sensitivity analysis.
UNASSIGNED: This study has confirmed a causal relationship between HMGCR and PSC risk, suggesting statins targeting HMGCR could enhance PSC patient outcomes.

Total astragalus saponins (TAS) are the main active components of astragali radix, and have potent anti-hepatic fibrosis effect. However, the therapeutic efficacy of TAS and their potential mechanisms in the treatment of primary sclerosing cholangitis (PSC) remain unclear. In this study, two mouse models of PSC, including 3,5-Diethoxycarbonyl-1,4-Dihydro-2,4,6-Collidine (DDC)-induced PSC and Mdr2-/- spontaneous PSC, and the Tgr5-/- mice were used to investigate the therapeutic effect and mechanisms of TAS. Treatment with TAS, particularly with a dose of 56 mg/kg, significantly ameliorated the PSC-related liver injury, cholestasis, collagen deposition, ductular reaction (DR), and fibrosis in the DDC-induced and Mdr2-/-spontaneous PSC mice. Furthermore, treatment with TAS significantly mitigated the PSC-related inflammatory responses in vivo and HIBEpiC cells by inhibiting the expression of TNF-α, IL-6, and IL-1β. Mechanistically, treatment with TAS rescued the PSC-decreased hepatic TGR5 expression to attenuate the NF-κB p65 phosphorylation. Notably, the therapeutic efficacy of TAS on PSC in DDC-induced mice was abrogated in Tgr5-/- mice, suggesting the anti-PSC effect of TAS may depend on enhancing TGR5 expression. In conclusion, TAS ameliorated DR, inflammation and liver fibrosis in both models of PSC mice by rescuing TGR5 expression. Our findings may aid in the design of new therapeutic strategies for the treatment of PSC.

暂无摘要。

UNASSIGNED: Blood metabolite abnormalities have revealed an association with cholestatic liver diseases (CLDs), while the underlying metabolic mechanisms have remained sluggish yet. Accordingly, the present evaluation aims to investigate the causal relationship between blood metabolites and the risk of two major CLDs, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).
UNASSIGNED: Univariable and multivariable Mendelian randomization (MR) approaches were employed to uncover potential causal associations between blood metabolites and 2 CLDs, including PBS and PSC, through extracting instrumental variables (IVs) for metabolites from genome-wide association studies (GWAS) conducted on European individuals. The GWAS summary data of PBC or PSC were sourced from two distinct datasets. The initial analysis employed inverse variance weighted (IVW) and an array of sensitivity analyses, followed by replication and meta-analysis utilizing FinnGen consortium data. Finally, a multivariable MR analysis was carried out to ascertain the independent effects of each metabolite. Furthermore, the web-based tool MetaboAnalyst 5.0 was used to perform metabolic pathway examination.
UNASSIGNED: A genetic causality between 15 metabolites and CLDs was recognized after preliminary analysis and false discovery rate (FDR) correction. Subsequently, 9 metabolites consistently represented an association through replication and meta-analysis. Additionally, the independent causal effects of 7 metabolites were corroborated by multivariable MR analysis. Specifically, the metabolites isovalerylcarnitine (odds ratio [OR] = 3.146, 95% confidence intervals [CI]: 1.471-6.726, p = 0.003), valine (OR = 192.44, 95%CI: 4.949-7483.27, p = 0.005), and mannose (OR = 0.184, 95%CI: 0.068-0.499, p < 0.001) were found to have a causal relationship with the occurrence of PBC. Furthermore, erythrose (OR = 5.504, 95%CI: 1.801-16.821, p = 0.003), 1-stearoylglycerophosphocholine (OR = 6.753, 95%CI: 2.621-17.399, p = 7.64 × 10-5), X-11847 (OR = 0.478, 95%CI: 0.352-0.650, p = 2.28 × 10-6), and X-12405 (OR = 3.765, 95%CI: 1.771-8.005, p = 5.71 × 10-4) were independently associated with the occurrence of PSC. Furthermore, the analysis of metabolic pathways identified seven significant pathways in two CLDs.
UNASSIGNED: The findings of the present study have unveiled robust causal relationships between 7 metabolites and 2 CLDs, thereby providing novel insights into the metabolic mechanisms and therapeutic strategies for these disorders.