Biliary Inflammation Research Articles

Double Primary Cancer of the Pancreas and Gallbladder: Case Report

Synchronous tumors occurring in both the pancreas and gallbladder are uncommon. They are frequently linked to an atypical pancreatobiliary junction, which causes a continuous backflow of pancreatic enzymes, leading to ongoing biliary inflammation [1]. In this report, we discuss the case of a 51-year-old woman with concurrent pancreatic and gallbladder lesions, initially regarded as two separate primary cancers and managed with curative treatment.

Dissecting the genetic basis and mechanisms underlying the associations between multiple extrahepatic factors and autoimmune liver diseases

BackgroundAutoimmune liver diseases (AILDs) encompass autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The onset of these diseases is fundamentally influenced by genetic susceptibility. Although various extrahepatic factors are potentially linked to AILDs, the genetic underpinnings and mechanisms of these associations remain unclear. MethodsUtilizing large-scale genome-wide association study (GWAS) data, this study systematically investigated the relationships between extrahepatic autoimmune diseases (EHAIDs), immune cells, and various triggering factors with AILDs. Mendelian randomization (MR) was employed to assess the causal effects of these extrahepatic factors on AILDs, complemented by linkage disequilibrium score (LDSC) regression to uncover shared genetic architecture and causal effects underlying the associations between autoimmune diseases. We employed colocalization, enrichment analysis, and protein-protein interaction (PPI) network to identify the functions of shared loci. Additionally, we proposed that activated immune cells in the circulation may contribute to liver and biliary tract inflammation via migration, mediating the impact of extrahepatic factors on AILDs. This hypothesis was tested using two mediation analysis methods: two-step MR (TSMR) and multivariable MR (MVMR). ResultsCausal associations between multiple extrahepatic factors and AILDs were identified. Notably, CD27+ B cells were found to be a risk factor for PBC, while PSC progression was associated with CD28+ CD8+ T cells exhaustion and increased levels of CD28- CD8+ T cells. Mediation analyses revealed 64 pathways via TSMR and 15 pathways via MVMR, indicating that the effects of extrahepatic factors on AILDs may be mediated by circulating immune cells. The shared genetic architecture also contributed to these associations. Analysis of shared loci and gene functions identified ATXN2 as being shared between PBC and 9 EHAIDs, while SH2B3 and PSMG1 were shared with 6 and 5 EHAIDs, respectively, in PSC. ConclusionsOur research compared three distinct AILDs, enhancing the understanding of their etiology and providing new evidence on risk factors, diagnostic markers, and potential therapeutic targets.

Extracellular vesicles of Clonorchis sinensis promote the malignant phenotypes of cholangiocarcinoma via NF-κB/EMT axis.

Clonorchis sinensis infection is an important risk factor for cholangiocarcinoma (CCA). It has been reported that extracellular vesicles (EVs) are involved in the parasite-host interaction, and EVs of C. sinensis (CsEVs) can contribute to biliary injuries and inflammation. However, uncertainty surrounds the function of CsEVs in the progression of CCA. In this study, differential ultracentrifugation was used to separate CsEVs from the culture supernatant of C. sinensis adult worms, and they were then identified by transmission electron microscopy, nanoparticle tracking analysis and proteome assays. CCK8, EdU-488 and colony formation assays were used to explore the effect of CsEVs on the proliferation of CCA cells in vitro. Wound healing assays, transwell assays and in vivo lung metastasis model were conducted to evaluate the migration and invasion abilities. Moreover, the involvement of EMT process, as well as NF-κB and ERK signaling pathway was assessed. Results showed that CsEVs were successfully isolated and could be taken up by CCA cells, which promoted proliferation by accelerating cell cycle progression. In addition, CsEVs could facilitate cell metastasis by triggering the epithelial-mesenchymal transition (EMT). Mechanistically, activation of NF-κB signaling pathway was involved in the CsEVs-mediated EMT, which could be reversed partly by BAY 11-7082 (an inhibitor of NF-κB). In conclusion, these findings suggested that CsEVs could induce the aberrant proliferation and metastasis of CCA cells by stimulating the NF-κB/EMT axis, providing a novel theoretical explanation for liver fluke-associated CCA.

A narrative review of genes associated with liver fibrosis in biliary atresia.

Biliary atresia (BA) is characterized by biliary inflammation and obstruction. In the later phase, liver fibrosis occurs. Although the etiology of BA is believed to be multi-factorial, genetic predisposition has been proposed to play a critical role in the pathogenesis. This review aimed to provide an updated summary of the genes that have been reported to be involved in BA-associated liver fibrosis. The review was conducted via evaluation of MalaCards (BA disease: MalaCards-research articles, drugs, genes, clinical trials) which is a universally applied website including various human disease database. The database of genes that are involved in liver fibrosis were studied. Thirty-one genes that are associated with BA according to the disease relevance score were reviewed after further evaluations. Eleven genes (GPT, NR1H4, TGF-B1, MMP7, CCN2, TIMP1, SPP1, ADD3, KRT7, ADD3-AS1, SOX9) that are specific and with a potential association with liver fibrosis were selected for detailed description. Increased expression of GPT, TGF-B1, MMP7, CCN2, TIMP1, SPP1, ADD3, KRT7 and ADD3-AS1 maybe associated with the development of liver fibrosis in BA patients, while the expression of NR1H4 and SOX9 are more likely to suppress liver fibrosis. Current scientific evidence using gene database has revealed a close association between genetic anomalies and the pathogenesis of liver fibrosis in BA. With a better understanding of these anomalies, therapy targeting these related genes may be a new therapeutic approach to alleviate liver fibrosis in BA.

The Impact of Biliary Injury on the Recurrence of Biliary Cancer and Benign Disease after Liver Transplantation: Risk Factors and Mechanisms.

Liver transplantation is known to generate significant inflammation in the entire organ based on the metabolic profile and the tissue's ability to recover from the ischemia-reperfusion injury (IRI). This cascade contributes to post-transplant complications, affecting both the synthetic liver function (immediate) and the scar development in the biliary tree. The new occurrence of biliary strictures, and the recurrence of malignant and benign liver diseases, such as cholangiocarcinoma (CCA) and primary sclerosing cholangitis (PSC), are direct consequences linked to this inflammation. The accumulation of toxic metabolites, such as succinate, causes undirected electron flows, triggering the releases of reactive oxygen species (ROS) from a severely dysfunctional mitochondrial complex 1. This initiates the inflammatory IRI cascade, with subsequent ischemic biliary stricturing, and the upregulation of pro-tumorigenic signaling. Such inflammation is both local and systemic, promoting an immunocompromised status that can lead to the recurrence of underlying liver disease, both malignant and benign in nature. The traditional treatment for CCA was resection, when possible, followed by cytotoxic chemotherapy. Liver transplant oncology is increasingly recognized as a potentially curative approach for patients with intrahepatic (iCCA) and perihilar (pCCA) cholangiocarcinoma. The link between IRI and disease recurrence is increasingly recognized in transplant oncology for hepatocellular carcinoma. However, smaller numbers have prevented similar analyses for CCA. The mechanistic link may be even more critical in this disease, as IRI causes the most profound damage to the intrahepatic bile ducts. This article reviews the underlying mechanisms associated with biliary inflammation and biliary pathology after liver transplantation. One main focus is on the link between transplant-related IRI-associated inflammation and the recurrence of cholangiocarcinoma and benign liver diseases of the biliary tree. Risk factors and protective strategies are highlighted.

Protective function of sclerosing cholangitis on IBD

ObjectiveThere is a strong clinical association between IBD and primary sclerosing cholangitis (PSC), a chronic disease of the liver characterised by biliary inflammation that leads to strictures and fibrosis. Approximately...

The new definition of dominant stricture in primary sclerosing cholangitis: Prevalence and clinical significance.

A new definition of dominant stricture (NDS) has recently been defined for patients with primary sclerosing cholangitis (PSC). Prevalence and clinical features of this, compared to traditional dominant stricture (TDS), have not been reported. In this single-centre longitudinal prospective cohort study, all PSC patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) between October 2021 and 2022 were recruited. Symptoms of cholestasis, laboratory values (P-alkaline phosphatase, P-Bilirubin), Helsinki PSC-score, brush cytology findings and need for endoscopic therapy (i.e. dilation, stenting) were prospectively collected. Overall, 228 patients with PSC underwent 248 ERCPs. NDS was detected in 43 (17%; 36 patients) and TDS without NDS (TDS group) was detected in 62 (25%; 58 patients) ERCPs,respectively; in the remaining 143 ERCPs, neither TDS nor NDS was seen (no dominant stricture [NoDS] group). PSC duration (median 8 years) and patient's age did not differ between the three groups; males presented more often with NDS. Patients with NDS were more often symptomatic, had higher cholestatic liver enzymes, advanced bile duct disease and markers of biliary inflammation (p < .001). Patients with NDS needed dilation (81%) and stenting (21%) more often than the TDS group (60% and 5%, respectively). Dysplasia in brush cytology was more common in TDS (5%) and NDS (9%) than in NoDS (3%) groups (p = .04), but did not differ between TDS and NDS groups. Dominant stricture according to the new definition developed in 17% of PSC patients in our cohort and identifies patients with more advanced disease, biliary inflammation and need of endo-therapy.

CsHscB Derived from a Liver Fluke Clonorchis sinensis Ameliorates Cholestatic Hepatic Fibrosis in a Mouse Model of Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammatory fibrosis usually involving the whole biliary tree. However, there are very limited treatment options to treat this disease. Our previous study found a lipid-protein rCsHscB from a liver fluke - Clonorchis sinensis, which had full capacities of immune regulation. Therefore, we investigated the role of rCsHscB in a mouse model of sclerosing cholangitis induced by xenobiotic 3,5- diethoxycarbonyl-1,4-dihydrocollidine (DDC) to explore whether this protein had potential therapeutic value for PSC. Mice were fed 0.1% DDC for 4 weeks and treated with CsHscB (30 μg/mouse, intraperitoneal injection, once every 3 days); the control group was given an equal amount of PBS or CsHscB under normal diet conditions. All the mice were sacrificed at 4 weeks for the evaluation of biliary proliferation, fibrosis, and inflammation. rCsHscB treatment attenuated DDC-induced liver congestion and enlargement and significantly decreased the upregulation of serum AST and ALT levels. The administration of rCsHscB to DDC-fed mice significantly decreased cholangiocyte proliferation and pro-inflammatory cytokine production compared to mice fed with DDC alone. Also, rCsHscB treatment showed a decreased expression of α-SMA in the liver and other markers of liver fibrosis (Masson staining, Hydroxyproline content, and collagen deposit). More interestingly, DDC-fed mice treated with rCsHscB showed a significant up-regulation of PPAR-γ expression, which was similar to control mice, indicating the involvement of PPAR-γ signaling in the protective action of rCsHscB. Overall, our data show that rCsHscB attenuates the progression of cholestatic fibrosis induced by DDC and supports the potential for manipulating the parasite-derived molecule to treat certain immune-mediated disorders.

3D-printed versatile biliary stents with nanoengineered surface for anti-hyperplasia and antibiofilm formation

Biliary strictures are characterized by the narrowing of the bile duct lumen, usually caused by surgical biliary injury, cancer, inflammation, and scarring from gallstones. Endoscopic stent placement is a well-established method for the management of biliary strictures. However, maintaining optimal mechanical properties of stents and designing surfaces that can prevent stent-induced tissue hyperplasia and biofilm formation are challenges in the fabrication of biodegradable biliary stents (BBSs) for customized treatment. This study proposes a novel approach to fabricating functionalized polymer BBSs with nanoengineered surfaces using 3D printing. The 3D printed stents, fabricated from bioactive silica poly(ε-carprolactone) (PCL) via a sol–gel method, exhibited tunable mechanical properties suitable for supporting the bile duct while ensuring biocompatibility. Furthermore, a nanoengineered surface layer was successfully created on a sirolimus (SRL)-coated functionalized PCL (fPCL) stent using Zn ion sputtering-based plasma immersion ion implantation (S-PIII) treatment to enhance the performance of the stent. The nanoengineered surface of the SRL-coated fPCL stent effectively reduced bacterial responses and remarkably inhibited fibroblast proliferation and initial burst release of SRL in vitro systems. The physicochemical properties and biological behaviors, including in vitro biocompatibility and in vivo therapeutic efficacy in the rabbit bile duct, of the Zn-SRL@fPCL stent demonstrated its potential as a versatile platform for clinical applications in bile duct tissue engineering.

Triamcinolone acetonide alleviates benign biliary stricture by ameliorating biliary fibrosis and inflammation

Triamcinolone acetonide alleviates benign biliary stricture by ameliorating biliary fibrosis and inflammation

Antagonistic effects of the cytotoxic molecules granzyme B and TRAIL in the immunopathogenesis of sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by biliary inflammation and fibrosis. We showed an elevated interferon γ response in patients with primary sclerosing cholangitis and in multidrug resistance protein 2-deficient ( Mdr2-/- ) mice developing sclerosing cholangitis. Interferon γ induced expression of the cytotoxic molecules granzyme B (GzmB) and TRAIL in hepatic lymphocytes and mediated liver fibrosis in sclerosing cholangitis. In patient samples and Mdr2-/- mice, we identified lymphocyte clusters with a cytotoxic gene expression profile using single-cell RNA-seq and cellular indexing of transcriptomes and epitopes by sequencing analyses combined with multi-parameter flow cytometry. CD8 + T cells and NK cells showed increased expression of GzmB and TRAIL in sclerosing cholangitis. Depletion of CD8 + T cells ameliorated disease severity in Mdr2-/- mice. By using Mdr2-/- × Gzmb-/- and Mdr2-/- × Tnfsf10-/- mice, we investigated the significance of GzmB and TRAIL for disease progression in sclerosing cholangitis. Interestingly, the lack of GzmB resulted in reduced cholangiocyte apoptosis, liver injury, and fibrosis. In contrast, sclerosing cholangitis was aggravated in the absence of TRAIL. This correlated with elevated GzmB and interferon γ expression by CD8 + T cells and NK cells enhanced T-cell survival, and increased apoptosis and expansion of cholangiocytes. GzmB induces apoptosis and fibrosis in sclerosing cholangitis, whereas TRAIL regulates inflammatory and cytotoxic immune responses, subsequently leading to reduced liver injury and fibrosis.

A297 EXAMINING THE IMPACT OF INFLAMMATORY BOWEL DISEASE IN PRIMARY SCLEROSING CHOLANGITIS PATIENTS POST LIVER TRANSPLANTATION

Abstract Background Primary sclerosing cholangitis (PSC) is an immune-mediated disease that is characterized by biliary inflammation and fibrosis. It is associated with inflammatory bowel disease (IBD) in 80% of cases. To date, the impact of IBD in liver transplantation (LT) recipients is not completely understood. Aims To assess the impact of IBD in individuals with PSC who underwent liver transplantation (LT) in terms of graft survival, infections, and mortality. Methods This was a retrospective cohort study that included individuals with PSC who received a LT between 1999–2021. Statistical analysis included Kaplan-Meier survival curves, a binary logistic regression to estimate infection risk, and a competing-risk analysis to estimate post-LT mortality (with re-transplantation being a competing risk). Results 122 LT recipients were included. Mean age at LT was 44.9±12.6 years old. The median MELD-Na at LT was 22 [17–28]. Twenty-nine (23.8%) LT recipients died during follow-up (median 1,248 [413–3,857] days) and 5 (4.1%) required re-transplantation (median 1,460 [923–2,563] days). Estimated graft survival was 93.2% (95%CI: 86.9%–96.6%) at 1 year and 81.3% (95%CI: 72.5%–87.6%) at 5 years. An adjusted competing-risk model demonstrated that increasing age (sHR 1.05, 95%CI: 1.01–1.10; p=0.018), baseline MELD-Na (sHR 1.07, 95%CI: 1.02–1.12; p=0.005), and ERCP requirements before LT (sHR 6.33; 95%CI: 1.63–24.65; p=0.008) were associated with higher post-LT mortality, while IBD was not associated with post-LT mortality (sHR 1.02, 95%CI: 0.38–2.70; p=0.962). The incidence of infections after LT was 50.8% at 30 days. IBD was not associated with development of infections at 30 days (OR 1.01, 95%CI: 0.98–1.04; p=0.615) post-LT. Conclusions Based on this retrospective review, an older age, higher MELD-Na at LT and prior ERCP requirements were independently associated with a higher mortality post-LT in PSC patients. However, a background history of IBD was not associated with higher mortality or with infections post-LT. Table 1: Baseline Demographics Funding Agencies None

Primary sclerosing cholangitis and inflammatory bowel disease: a complicated yet unique relationship.

Primary sclerosing cholangitis (PSC) is a rare liver disorder characterized by biliary ducts inflammation, fibrosis and consequently chronic cholestasis, which progressively lead to liver cirrhosis. The main feature of PSC is the frequent association with inflammatory bowel disease (IBD), with an estimated prevalence of around 70% of the cases. This strong relationship seems due to the presence of shared pathogenetic mechanisms, which seem to involve the intestinal barrier function, the human gut microbiota and the immune innated and adaptative response to antigens derived from the bowel. Of relevance, PSC-IBD have specific clinical and pathological features that differ from PSC and IBD as separate entities, explaining the diversity in outcomes among these categories, and therefore the distinct clinical management that is required. The aim of this review is to present recent data regarding the epidemiology, pathobiology and clinical features of PSC-IBD.

Therapeutic potential of berberine in attenuating cholestatic liver injury: insights from a PSC mouse model

Background and aimsPrimary sclerosing cholangitis (PSC) is a chronic liver disease characterized by progressive biliary inflammation and bile duct injury. Berberine (BBR) is a bioactive isoquinoline alkaloid found in various herbs and has multiple beneficial effects on metabolic and inflammatory diseases, including liver diseases. This study aimed to examine the therapeutic effect of BBR on cholestatic liver injury in a PSC mouse model (Mdr2−/− mice) and elucidate the underlying mechanisms.MethodsMdr2−/−mice (12–14 weeks old, both sexes) received either BBR (50 mg/kg) or control solution daily for eight weeks via oral gavage. Histological and serum biochemical analyses were used to assess fibrotic liver injury severity. Total RNAseq and pathway analyses were used to identify the potential signaling pathways modulated by BBR in the liver. The expression levels of key genes involved in regulating hepatic fibrosis, bile duct proliferation, inflammation, and bile acid metabolism were validated by qRT-PCR or Western blot analysis. The bile acid composition and levels in the serum, liver, small intestine, and feces and tissue distribution of BBR were measured by LC–MS/MS. Intestinal inflammation and injury were assessed by gene expression profiling and histological analysis. The impact on the gut microbiome was assessed using 16S rRNA gene sequencing.ResultsBBR treatment significantly ameliorated cholestatic liver injury, evidenced by decreased serum levels of AST, ALT, and ALP, and reduced bile duct proliferation and hepatic fibrosis, as shown by H&E, Picro-Sirius Red, and CK19 IHC staining. RNAseq and qRT-PCR analyses indicated a substantial inhibition of fibrotic and inflammatory gene expression. BBR also mitigated ER stress by downregulating Chop, Atf4 and Xbp-1 expression. In addition, BBR modulated bile acid metabolism by altering key gene expressions in the liver and small intestine, resulting in restored bile acid homeostasis characterized by reduced total bile acids in serum, liver, and small intestine and increased fecal excretion. Furthermore, BBR significantly improved intestinal barrier function and reduced bacterial translocation by modulating the gut microbiota.ConclusionBBR effectively attenuates cholestatic liver injury, suggesting its potential as a therapeutic agent for PSC and other cholestatic liver diseases.

Associations of fatty acids with the risk of biliary tract calculus and inflammation: a Mendelian randomization study

BackgroundThe presence of gallstones in both the gallbladder and bile ducts is referred to as cholelithiasis. The prevalence of cholecystolithiasis and bile duct stones differs. Observational and Mendelian randomization (MR) studies have elucidated the significant contributing role of numerous fatty acids (FAs) in the development of cholelithiasis. Despite numerous studies about cholelithiasis, evidence on the relationship between serum FA levels and cholecystolithiasis, as well as bile duct stones with or without inflammation, remains insufficient.MethodsA two-sample MR study was designed to clarify the impact of serum FA levels on various bile duct inflammatory diseases. The summary statistics of single nucleotide polymorphisms (SNPs) associated with fatty acids were obtained from the UK Biobank (UKB) and included data from 114,999 participants. The researchers obtained GWAS summary statistics for cholecystolithiasis and bile duct stones in 463,010 and 361,194 European participants, including cases with and without inflammation. No sample overlap between the exposure and outcome was verified through the “mr-lap” package. The SNPs were screened to identify instrumental variables (IVs). Cochran’s Q test was applied for heterogeneity assessment. Inverse variance weighting (IVW) (fixed effects or random effects), MR-Egger regression and weighted median methods were used for MR. Multivariable MR was applied to determine the direct effect of each exposure on the outcome. A false discovery rate (FDR) was applied to adjust for multiple testing correction based on the Benjamini-Hochberg method. Finally, the FinnGen Consortium was used to validate some results.ResultsThe overall concentration of polyunsaturated fatty acids (PUFAs) in the serum was negatively associated with the risk of calculus of the gallbladder with acute cholecystitis (IVW, OR = 0.996, P = 0.038, CI 0.992–0.999; weighted median, OR = 0.995, P = 0.025, CI 0.991–0.999). The percentage of PUFAs to total monounsaturated fatty acids(MUFAs) (IVW, OR = 0.998, P = 0.045, CI 0.997–0.999) and the percentage of PUFAs to total FAs (IVW, OR = 0.997, P = 0.025, CI 0.995–0.999) had a protective role against cholecystitis. The percentage of PUFAs to total FAs had a protective role against calculus of the gallbladder without cholecystitis (IVW, OR = 0.995, P = 0.026, CI 0.990–0.999; MR Egger, OR = 0.99, P = 0.03, CI 0.982–0.998; weighted median, OR = 0.991, P = 5.41e-06, CI 0.988–0.995). Conversely, the percentage of MUFAs to total FAs increased the risk for cholecystitis (IVW, OR = 1.001, P = 0.034, CI 1.0001–1.002). However, there were no causal effects of the above exposures on the outcomes through multivariable MR and multiple testing correction. Finally, the causal effects of the above exposures on cholecystitis were validated in the FinnGen Consortium, which suggested that the percentage of PUFAs to total FAs (IVW, OR = 0.744, P = 0.021, CI 0.579–0.957) had a protective role against cholecystitis.ConclusionThese Mendelian randomization findings suggested that more attention should be focused on people who have low serum PUFA levels, which may have a potential role in the occurrence of calculus of the gallbladder or cholecystitis rather than calculus of the bile duct without cholangitis or cholecystitis.

Subtotal vs total cholecystectomy for difficult gallbladders: A systematic review and meta-analysis

IntroductionWith severely inflamed gallbladders, laparoscopic cholecystectomy can be difficult and may require procedures like subtotal cholecystectomy (SC). Few studies exist comparing SC and total cholecystectomy (TC) in the setting of severe biliary inflammation. This meta-analysis aims to compare SC and TC for difficult gallbladders. MethodsMedline-OVID, Embase-OVID, and Cinahl were searched including only studies comparing SC to TC for difficult gallbladders. Primary outcome was CBD injury. Secondary outcomes included bile leak, duodenal injury, retained stone, bleeding, intraabdominal collection, wound infection, reoperation, and mortality. ResultsTen studies were included. Compared to TC, SC significantly lowered the risk for CBD injury (0 ​% vs. 1.6 ​%, RR 0.30, 95%CI 0.10–0.87) but increased risk of bile leaks (RR 3.5, 95%CI 1.79–6.84), postoperative ERCP (RR 2.86, 95%CI 1.53–5.35), intraabdominal collections (RR 2.55, 95%CI 1.32–4.93), and reoperation (RR 2.92, 95%CI 1.14–7.47). ConclusionSC is a reasonable alternative to difficult gallbladders that may decrease the risk of CBD injuries. Knowing both approaches is crucial to manage the difficult gallbladder while minimizing harm. Further studies are needed to understand the value of SC for difficult cholecystectomy.

Microbial exposure during early life regulates development of bile duct inflammation

Objectives The early life microbiome has been linked to inflammatory diseases in adulthood and a role for the microbiome in bile duct inflammation is supported by both human and murine studies. We utilized the NOD.c3c4 mouse model that develops a spontaneous immune-driven biliary disease with a known contribution of the microbiome to evaluate the temporal effects of the early life microbiome. Materials and methods Germ-free (GF) NOD.c3c4 mice were conventionalized into a specific pathogen free environment at birth (conventionally raised, CONV-R) or at weaning (germ-free raised, GF-R) and compared with age and gender-matched GF and conventional (CONV) NOD.c3c4 mice. At 9 weeks of age, liver pathology was assessed by conventional histology and flow cytometry immunophenotyping. Results Neonatal exposure to microbes (CONV-R) increased biliary inflammation to similar levels as regular conventional NOD.c3c4 mice, while delayed exposure to microbes (GF-R) restrained the biliary inflammation. Neutrophil infiltration was increased in all conventionalized mice compared to GF. An immunophenotype in the liver similar to CONV was restored in both CONV-R and GF-R compared to GF mice displaying a proportional increase of B cells and reduction of T cells in the liver. Conclusions Microbial exposure during early life has a temporal impact on biliary tract inflammation in the NOD.c3c4 mouse model suggesting that age-sensitive interaction with commensal microbes have long-lasting effects on biliary immunity that can be of importance for human cholangiopathies.

Current Therapeutics in Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is an orphan, cholestatic liver disease that is characterized by inflammatory biliary strictures with variable progression to end-stage liver disease. Its pathophysiology is poorly understood. Chronic biliary inflammation is likely driven by immune dysregulation, gut dysbiosis, and environmental exposures resulting in gut-liver crosstalk and bile acid metabolism disturbances. There is no proven medical therapy that alters disease progression in PSC, with the commonly prescribed ursodeoxycholic acid being shown to improve liver biochemistry at low-moderate doses (15-23 mg/kg/day) but not alter transplant-free survival or liver-related outcomes. Liver transplantation is the only option for patients who develop end-stage liver disease or refractory complications of PSC. Immunosuppressive and antifibrotic agents have not proven to be effective, but there is promise for manipulation of the gut microbiome with fecal microbiota transplantation and antibiotics. Bile acid manipulation via alternate synthetic bile acids such as norursodeoxycholic acid, or interaction at a transcriptional level via nuclear receptor agonists and fibrates have shown potential in phase II trials in PSC with several leading to larger phase III trials. In view of the enhanced malignancy risk, statins, and aspirin show potential for reducing the risk of colorectal cancer and cholangiocarcinoma in PSC patients. For patients who develop clinically relevant strictures with cholestatic symptoms and worsening liver function, balloon dilatation is safer compared with biliary stent insertion with equivalent clinical efficacy.

Non-neoplastic Liver Lesions after Biliary Stenting: Gadoxetic Acid-enhanced MRI Findings and Clinical association.

Non-neoplastic liver lesions show low signal intensity in the hepatobiliary phase (HBP) of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) after biliary stenting and require differentiation from liver metastases. The study aimed to evaluate the imaging findings and clinical association of non-neoplastic liver lesions showing hypointensity in the HBP of EOB-MRI after biliary stenting, and assess their differentiation from liver metastases. This study included 30 patients who underwent EOB-MRI after biliary stenting for pancreaticobiliary malignancies. Among these, 7 patients had pathologically diagnosed non-neoplastic liver lesions, which appeared hypointense in the HBP, and were categorized into the non-neoplastic group. The remaining 23 patients without non-neoplastic liver lesions were included in the control group. Additionally, 29 patients with liver metastasis were included in the liver metastasis group. Clinical associations and imaging features were compared between the groups. A history of cholangitis and two or more biliary interventional procedures were significantly more frequently observed in the non-neoplastic group (p=0.002 and p=0.01, respectively) than in the control groups. Regarding the imaging findings, the liver-to-lesion signal intensity ratio in the HBP in the liver metastasis group was significantly higher than that in the non-neoplastic group (2.13 vs. 1.53, p=0.002). Additionally, liver metastases were visualized significantly more clearly on diffusion-weighted images (p=0.033) and HBP images (p<0.001) in comparison to non-neoplastic lesions. Non-neoplastic liver lesions due to biliary inflammation may be observed in the HBP of EOB-MRI in patients after biliary stenting. These lesions may be associated with a history of cholangitis and repeated biliary intervention procedure, and need to be differentiated from liver metastases.

The Use of Inflammatory Markers for Treatment Response Monitoring in Acute Cholangitis: A Retrospective Cohort Study

IntroductionIn acute cholangitis (AC), monitoring treatment response to antimicrobial therapy allows for making timely decisions on early biliary decompression. The aims of this study were to compare the discriminating powers of traditional blood inflammatory markers and propose new inflammatory markers that have a better ability to distinguish between patients with and without biliary tract infection. MethodsThis was a retrospective cohort study. Patients who underwent endoscopic retrograde cholangio-pancreaticography for AC and those without biliary tract inflammation were randomly selected in the 4:3 ratio of their hospital admissions from our hospital endoscopic retrograde cholangio-pancreaticography database. The exclusion criterion was the absence of C-reactive protein (CRP) measurements. ResultsThe discriminating powers of the neutrophil count, lymphocytes, albumin, neutrophil-to-lymphocyte ratio, and CRP were superior to that of white blood cell (P1 < 0.005; P2 = 0.004; P3 < 0.0005; P4 < 0.0005; P5 < 0.0005). In monitoring treatment response in AC, lymphocyte count, albumin, neutrophil-to-lymphocyte ratio, and CRP were better than neutrophil count (P6 = 0.037, P7 < 0.005, P8, 9 < 0.0005). The area under the receiver operating characteristic curve (AUC) of CRP was higher than the AUC for lymphocytes, 96% (95% confidence interval [CI]: 94-98%) versus 81% (95% CI: 76-86%) (P < 0.0005), and larger than the AUC for albumin, 88% (95% CI: 84-92%) (P < 0.0005), indicating a greater discriminating power of CRP. However, the discriminating power of CRP-to-lymphocyte ratio (CLR) was more than that for CRP (P = 0.006) but equal to CRP-to-(lymphocytes∗albumin) ratio (CLAR) (P = 0.249). The AUCs of CLR and CLAR were both 98% (95% CI: 96-99%). ConclusionsCLR and CLAR have superior discriminating powers than traditional inflammatory markers used for monitoring treatment response in AC.