Update on the diagnosis and management of neonatal intrahepatic cholestasis caused by citrin deficiency: Expert review on behalf of the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Citrin deficiency is an autosomal recessive metabolic liver disease caused by mutations in the SLC25A13 gene. The disease typically presents with cholestasis, elevated liver enzymes, hyperammonemia, hypercitrullinemia, and fatty liver in young infants, resulting in a phenotype known as "neonatal intrahepatic cholestasis caused by citrin deficiency" (NICCD). The diagnosis relies on clinical manifestation, biochemical evidence of hypercitrullinemia, and identifying mutations in the SLC25A13 gene. Several common mutations have been found in patients of East Asian background. The mainstay treatment is nutritional therapy in early infancy utilizing a lactose-free and medium-chain triglyceride formula. This approach leads to the majority of patients recovering liver function by 1 year of age. Some patients may remain asymptomatic or undiagnosed, but a small proportion of cases can progress to cirrhosis and liver failure, necessitating liver transplantation. Recently, advancements in newborn screening methods have improved the age of diagnosis. Early diagnosis and timely management improve patient outcomes. Further studies are needed to elucidate the long-term follow-up of NICCD patients into adolescence and adulthood.

Use of therapeutic plasma exchange to remove lipoprotein X in a patient with vanishing bile duct syndrome presenting with cholestasis, pseudohyponatremia, and hypercholesterolemia: A case report and review of literature.

INTRODUCTION: Lipoprotein X (Lp-X) is an abnormal lipoprotein found in multiple disease conditions, including liver dysfunction and cholestasis. High Lp-X concentrations can interfere with some laboratory testing that may result in spurious results. The detection of Lp-X can be challenging, and there is currently a lack of consensus regarding the management of Lp-X other than treating the underlying disease. CASE PRESENTATION: A 42-year-old female with Hodgkin's lymphoma treated with dexamethasone, high dose cytarabine and cisplatin and vanishing bile duct syndrome confirmed by liver biopsy presented with cholestasis, pseudohyponatremia (sodium, 113 mmol/L; reference range 136-146 mmL/L; serum osmolality, 303 mOsm/kg), and hypercholesterolemia (> 2800 mg/dL, reference range < 200 mg/dL). Lp-X was confirmed by lipoprotein electrophoresis (EP). Although she did not manifest any specific signs or symptoms, therapeutic plasma exchange (TPE) was initiated based on laboratory findings of extreme hypercholesterolemia, spuriously abnormal serum sodium, and HDL values, and the potential for short- and long-term sequelae such as hyperviscosity syndrome, xanthoma, and neuropathy. During the hospitalization, she was treated with four 1.0 plasma volume TPE over 6 days using 5% albumin for replacement fluid. After the first TPE, total cholesterol (TC) decreased to 383 mg/dL and sodium was measured at 131 mmol/L. The patient was transitioned into outpatient maintenance TPE to eliminate the potential of Lp-X reappearance while the underlying disease was treated. Serial follow-up laboratory testing with lipoprotein EP showed the disappearance of Lp-X after nine TPEs over a 10-week period. LITERATURE REVIEW: There are seven and four case reports of Lp-X treated with TPE and lipoprotein apheresis (LA), respectively. While all previous case reports showed a reduction in TC levels, none had monitored the disappearance of Lp-X after completing a course of therapeutic apheresis. CONCLUSION: Clinicians should have a heightened suspicion for the presence of abnormal Lp-X in patients with cholestasis, hypercholesterolemia, and pseudohyponatremia. Once Lp-X is confirmed by lipoprotein EP, TPE should be initiated to reduce TC level and remove abnormal Lp-X. Most LA techniques are not expected to be beneficial since Lp-X lacks apolipoprotein B. Therefore, we suggest that inpatient course of TPE be performed every other day until serum sodium, TC and HDL levels become normalized. Outpatient maintenance TPE may also be considered to keep Lp-X levels low while the underlying disease is treated. Serum sodium, TC, and HDL levels should be monitored while on maintenance TPE.

Association between two different lipid injectable emulsions and parenteral nutrition-associated cholestasis in very low birth weight infants: A retrospective cohort study.

BACKGROUND: Using soybean oil-based lipid emulsions (Intralipid), which contain higher amounts of ω-6 fatty acids and phytosterols in parenteral nutrition, is a risk factor for cholestasis (parenteral nutrition-associated cholestasis [PNAC]). An alternative form of a mixed lipid emulsion (SMOFlipid) has been developed to reduce the risk of PNAC, but significant benefits over Intralipid in very low birth weight (VLBW) infants have yet to be demonstrated. The aim of this study was to compare the differences in PNAC incidence in VLBW infants receiving SMOFlipid vs Intralipid. METHODS: The study was conducted in Sir Run Run Shaw Hospital of the Zhejiang University School of Medicine, Hangzhou, China, from January 2016 to March 2022. In total, 235 VLBW infants were administered SMOFlipid or Intralipid for ≥21 days and were included in the study. The primary outcome was the incidence of PNAC. Secondary outcomes included bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, late-onset sepsis, length of stay, weight 28 days after birth, severity of PNAC, and the time to reversal of PNAC. RESULTS: Forty-four VLBW infants (35.5%) in the SMOFlipid group vs 41 (36.9%) in the Intralipid group achieved PNAC (P = 0.817). The subgroup analysis showed that the peak direct bilirubin level was lower (median [interquartile range] 55.6 [36.4] vs 118.4 [77.2] µmol/L; P < 0.001), and the time to reversal of PNAC was shorter (44 [49] vs 96 [61]; P < 0.001) in the SMOFlipid group than in the Intralipid group. CONCLUSION: SMOFlipid may represent a better alternative for VLBW infants who require prolonged parenteral nutrition.

[Diagnosis and treatment of hereditary cholestasis].

With China's outstanding achievements in the prevention and treatment of hepatitis, hereditary cholestasis caused by genetic variants has gradually become an important cause of death or transplantation in children with liver disease. The continuous identification of new pathogenic genes expands the disease spectrum and clinician's understanding of disease. The disease characteristics and clinical manifestations of hereditary cholestasis caused by different gene variants vary, and the severity of diseases caused by the same gene variants and the response to treatment are also significantly different. Therefore, early genetic diagnosis is of great value for improving the clinical management of patients. In terms of treatment, in addition to traditional drugs and surgery, targeted therapy and gene therapy are also gradually moving towards clinical application. Advances in metabolomics, gene editing technology, and structural biology have made it possible to provide personalized and precise treatment of children with hereditary cholestasis in the future; however, this which will put forward higher requirements for on relevant practitioners.

Internal versus external biliary drainage in malignant biliary obstructions: is there a difference in the rate of infection?

BACKGROUND: Percutaneous biliary drainage is a frequently used method to provide biliary decompression in patients with biliary obstruction. PURPOSE: To investigate the between drainage type and infection risk in patients treated with internal-external and external biliary drainage catheterization for malignant biliary obstruction. MATERIAL AND METHODS: A total of 410 patients with malignant biliary obstruction who underwent internal-external or external biliary drainage catheterization between January 2012 and October 2016 were retrospectively evaluated. We investigated the correlation between percutaneous biliary drainage technique and infection frequency by evaluating patients with clinical findings, bile and blood cultures, complete blood counts, and blood biochemistry. RESULTS: There was no statistically significant difference between the selected patient groups (internal-external or external biliary drainage catheter placed) in terms of age, sex, primary diagnosis, receiving chemotherapy, catheter sizes, and outpatient-patient status. After catheterization, catheter-related infection was observed in 49 of 216 (22.7%) patients with internal-external and 18 of 127 (14.2%) patients with external biliary drainage catheters, according to the defined criteria. There was no difference in infection rate after the biliary drainage in the two groups (P > 0.05). There was also no difference concerning frequently proliferating microorganisms in bile cultures. CONCLUSION: Internal-external biliary drainage catheter placement does not bring an additional infection risk for uninfected cholestatic patients whose obstruction could be passed easily in the initial drainage.

Comparing the Safety and Efficacy of Intraluminal Brachytherapy vs Isolated Percutaneous Transhepatic Biliary Drainage with internalization for Unresectable Malignant Biliary Obstruction: A Prospective Observational Study.

BACKGROUND AND OBJECTIVES: Intraluminal therapies, including brachytherapy, can locally destroy obstructing tumors and increase the duration of catheter/stent patency in patients with unresectable malignant biliary obstruction (MBO). In this prospective observational study, the safety and efficacy of percutaneous transhepatic biliary drainage (PTBD) followed by HDR intraluminal brachytherapy (ILBT) in the palliative treatment of malignant biliary obstruction was evaluated. PATIENTS AND METHODS: In total, 66 MBO patients (January 2021 to March 2022) who were unfit for alternate treatment modalities were enrolled in our study and underwent percutaneous transhepatic biliary drainage (PTBD) with internalization. Additionally, 11 patients underwent subsequent ILBT, which was administered over two sessions (800 cGy each session, one week apart) with iridium-192 prescribed at 1.5 cmfrom the central axis of the catheter via a percutaneous biliary catheter. The second session was followed up by endoluminal stenting in the same sitting. Patients with an Eastern Cooperative Oncology Group (ECOG) status <4 and a 50% decline in bilirubin/<5 mg/dL on day 10 after PTBD were selected for ILBT. The biliary stent/catheter patency period, survival duration, mean bilirubin level (mg/dL) decline, and incidence of complications were evaluated. RESULTS: Among the sixty-six patients included and classified into ILBT or PTBD-only groups, the median survival period for the ILBT group vs PTBD group was 172 (84.5-273.5) days vs 45 (30.75-83) days (p ≤ 0.0001) with an overall survival (OS) at 6 months of 62.34% vs 3.64% (p ≤ 0.0001). The stent/catheter patency period of the ILBT group in comparison to the PTBD group was 172 (83-273.5) days vs 30 (20-42.5) days (p ≤ 0.0001). No major treatment-related complications were observed in any of the patients. CONCLUSIONS: ILBT with stenting is a safe option for improving stent patency and survival duration with minimal complications with the condition that patients are carefully selected.

Impact of cholangitis on survival of patients with malignant biliary obstruction treated with percutaneous transhepatic biliary drainage.

PURPOSE: To evaluate the impact of cholangitis on survival of patients with gastrointestinal cancer and malignant biliary obstruction treated with percutaneous transhepatic biliary drainage (PTBD). METHODS: A retrospective registry study was performed at a tertiary center from 2000 to 2016 in Northern Finland. RESULTS: The study included 588 patients, 258 (43.9%) patients with pancreatic cancer, 222 (37.7%) with biliary tract cancer, and 108 (18.4%) with metastasis from gastrointestinal cancers. Patient mean age was 70 years, range 26 - 93 years. There were 288 [49.0%] women. The 30-day mortality rate was 30.8% for 156 patients with cholangitis before PTBD, 19.5% for 215 patients with cholangitis after PTBD and 25.8% for 217 patients without cholangitis (P = 0.039). The median survival was 1.8 months for patients with cholangitis before PTBD, 3.0 months for patients with cholangitis after PTBD, and 3.2 months for patients without cholangitis (P = 0.002). The hazard ratio (HR) for 1-year mortality for patients with cholangitis before PTBD was 1.3 (95% CI 1.06 - 1.67, P = 0.015) compared to patients with cholangitis after PTBD. After successful PTBD, 54 out of 291 patients received chemotherapy; the median survival was 5.2 months with cholangitis before PTBD, 9.4 months with cholangitis after PTBD and 15.3 months without cholangitis. CONCLUSION: In gastrointestinal cancers with malignant biliary obstruction, survival is poorer if cholangitis occurs before PTBD compared to cholangitis after PTBD. An oncologist's consultation is essential for assessing the possibility of chemotherapy in successfully treated PTBD patients, because of the notable survival benefit.

BM-MSCs overexpressing the Numb enhance the therapeutic effect on cholestatic liver fibrosis by inhibiting the ductular reaction.

BACKGROUND: Cholestatic liver fibrosis (CLF) is caused by inflammatory destruction of the intrahepatic bile duct and abnormal proliferation of the small bile duct after cholestasis. Activation of the Notch signaling pathway is required for hepatic stem cells to differentiate into cholangiocytes during the pathogenesis of CLF. Our previous research found that the expression of the Numb protein, a negative regulator of Notch signaling, was significantly reduced in the livers of patients with primary biliary cholangitis and CLF rats. However, the relationship between the Numb gene and CLF is largely unclear. In this study, we investigated the role of the Numb gene in the treatment of bile duct ligation (BDL)-induced CLF. METHODS: In vivo, bone marrow-derived mesenchymal stem cells (BM-MSCs) with Numb gene overexpression or knockdown obtained using lentivirus transfection were transplanted into the livers of rats with BDL-induced CLF. The effects of the Numb gene on stem cell differentiation and CLF were evaluated by performing histology, tests of liver function, and measurements of liver hydroxyproline, cytokine gene and protein levels. In vitro, the Numb gene was overexpressed or knocked down in the WB-F344 cell line by lentivirus transfection, Then, cells were subjected immunofluorescence staining and the detection of mRNA levels of related factors, which provided further evidence supporting the results from in vivo experiments. RESULTS: BM-MSCs overexpressing the Numb gene differentiated into hepatocytes, thereby inhibiting CLF progression. Conversely, BM-MSCs with Numb knockdown differentiated into biliary epithelial cells (BECs), thereby promoting the ductular reaction (DR) and the progression of CLF. In addition, we confirmed that knockdown of Numb in sodium butyrate-treated WB-F344 cells aggravated WB-F344 cell differentiation into BECs, while overexpression of Numb inhibited this process. CONCLUSIONS: The transplantation of BM-MSCs overexpressing Numb may be a useful new treatment strategy for CLF.

Effect of Percutaneous Biliary Drainage on Enzyme Activity of Serum Matrix Metalloproteinase-9 in Patients with Malignant Hilar Obstructive Hyperbilirubinemia.

Background and Objectives. Cholestasis activates complex mechanisms of liver injury and as a result has an increased production of matrix metalloproteinases (MMP). Depending on the stage of liver disease, different matrix metalloproteinases expressions have been detected and could serve as indirect biomarkers as well as therapeutic targets. MMP-9 proteolytic activity has a proven role in both liver regeneration and neoplastic cell invasion in various malignancies. The purpose of this prospective cohort study was to evaluate the effect of external biliary drainage on enzyme activity of MMP-9 in the serum of patients with malignant hilar biliary obstruction. Materials and Methods. Between November 2020 and April 2021, 45 patients with malignant hilar biliary obstruction underwent percutaneous biliary drainage following determination of serum MMP-9 enzyme activity (before treatment and 4 weeks after the treatment) by gelatin zymography. Results. MMP-9 values decreased statistically significantly 4 weeks after percutaneous biliary drainage (p = 0.028) as well as the value of total bilirubin (p < 0.001), values of direct bilirubin (p < 0.001), aspartate aminotransferase (AST) (p < 0.001), alanine transaminase (ALT) (p < 0.001), and gamma-glutamyl transferase (GGT) (p < 0.001). Conclusions. In patients with malignant hilar biliary obstruction treated by external percutaneous biliary drainage for cholestasis resolution, a significant reduction in MMP-9 serum values was noted 4 weeks after the treatment.

Effect of ursodeoxycholic acid after self-expandable metal stent placement in malignant distal biliary obstruction: a propensity score-matched cohort analysis.

BACKGROUND AND AIMS: Sludge occlusion is a primary reason for recurrent biliary obstruction (RBO) after self-expandable metallic stent (SEMS) placement. However, the efficacy of ursodeoxycholic acid (UDCA) for SEMS occlusion remains unexplored to date. This study aimed to evaluate the efficacy of UDCA after SEMS placement for malignant distal biliary obstruction (MDBO). METHODS: Three hundred fifty-four patients were included, of which 60 received UDCA. Additionally, we conducted a propensity score-matched cohort analysis on 110 patients with SEMS placement for MDBO to reduce selection bias. Patients were categorized into 2 groups of 55 each, based on whether they received UDCA. In the UDCA group, the treatment was administered for more than a month. The primary endpoint was the time to RBO (TRBO) after SEMS placement. The secondary endpoint was to evaluate SEMS occlusion rate and early adverse events (AEs). RESULTS: The cumulative SEMS occlusion rate was 41.8% and 18.2% in the groups with and without UDCA, respectively (P = .0119). Median TRBO was significantly longer in the control group than in the UDCA group (528 vs 154 days, P = .0381). In the multivariate analysis, UDCA administration was identified as the independent risk factor for reducing TRBO (hazard ratio, 2.28; 95% confidence interval, 1.06-4.88; P = .0348). The overall early AE rate showed insignificant differences between groups. CONCLUSIONS: Administering UDCA after SEMS placement was not efficacious for prolonging the TRBO in MDBO. Moreover, administering UDCA beyond a month might increase the risk of stent sludge occlusion. (Clinical trial registration number: UMIN000046862.).

Incidence and development of cholestasis in surgical neonates receiving an intravenous mixed-oil lipid emulsion.

BACKGROUND: Intestinal failure-associated liver disease (IFALD), initially manifesting as cholestasis, is a complication in neonates receiving parenteral nutrition (PN). Soybean oil lipid emulsion (SOLE), though implicated in IFALD, was the only US Food and Drug Administration (FDA)-approved initial intravenous lipid emulsion (ILE) for infants and children in the United States. A mixed-oil lipid emulsion (MOLE) gained popularity in patients at risk for IFALD and was recently FDA approved as an initial ILE in children. Given the presence of soybean oil in MOLE, we hypothesized that MOLE would not be effective at preventing cholestasis in surgical neonates. METHODS: Neonates with gastrointestinal surgical conditions necessitating PN for ≥14 days and receiving MOLE (SMOFlipid) from July 2016 to July 2019 were analyzed retrospectively. Unpaired and pair-matched historical surgical neonates treated with SOLE (Intralipid) served as controls. The primary outcome measure was development of cholestasis (direct bilirubin ≥2 mg/dl). RESULTS: Overall, 63% (10 of 16) of MOLE patients and 22% (30 of 136) of SOLE patients developed cholestasis after ≥14 days of therapy (P = 0.005). The latency to developing cholestasis was significantly shorter in MOLE patients compared with SOLE patients. CONCLUSION: In surgical neonates, MOLE may not prevent cholestasis and should not be considered hepatoprotective. Regardless of ILE source, all surgical neonates should be closely monitored for development of IFALD. To date, there is still no ILE able to prevent IFALD.

[Gastrointestinal endoscopy in the diagnosis and treatment of biliary liver disease].

Biliary liver disease refers to intrahepatic and extrahepatic bile duct system lesions or bile duct epithelial cells damage, resulting in abnormal liver function, inflammation and fibrosis, which mainly manifests as chronic cholestatic liver disease. The common causes include primary biliary cholangitis, primary sclerosing cholangitis, progressive familial intrahepatic cholangitis, bile duct complications after liver transplantation, and vanishing bile duct syndrome caused by drugs or serious infections, and the most prominent symptoms affecting the patients quality life is pruritus and jaundice. Endoscopic retrograde duodenoscopic cholangiopancreatography and cholangiopancreatoscopy (SpyGlass) and other endoscopic examinations can significantly improve the accuracy of early differential diagnosis,cytology and biopsy of primary sclerosing cholangitis, immunoglobulin G4-related cholangitis and cholangiocarcinoma. Endoscopic nasobiliary drainage, balloon dilatation and intrabiliary stent implantation can significantly improve pruritus symptoms, liver biochemical indicators and prognosis. Therefore, gastrointestinal endoscopy has important value and application prospects in the diagnosis and treatment of biliary liver diseases.

Percutaneous Cholangioscopy for the Diagnosis and Management of Biliary Pathology in Pediatric Patients: A Single-Center Experience.

Transhepatic percutaneous cholangioscopy (PC) can be used for the diagnosis and treatment of biliary pathology. It allows for direct visualization of the biliary system to identify pathologic changes, perform biopsies, and treat biliary obstruction. The effectiveness and safety of PC in adults have been established. However, the data on the use of PC in pediatric patients are limited. In this case series, the outcomes in 4 pediatric patients (3 girls; mean age, 4 [range, 1-8] years) who underwent 6 PC procedures were examined. Three out of the 6 (50%) PC procedures were performed for diagnostic visualization of the biliary tree and/or small intestine, whereas the remaining 3 (50%) were performed for the treatment of biliary obstruction causing chronic cholestasis. The technical and procedural success rate was 100%, and no complications were encountered during or 30 days after the procedure. This study supports the feasibility and safety of PC in pediatric patients for the management of biliary pathology.

Comparative efficacy and safety of local palliative therapeutics for unresectable malignant biliary obstruction: a Bayesian network meta-analysis.

BACKGROUND: Both radiofrequency ablation (RFA), photodynamic therapy (PDT), and biliary stent alone are common local palliative therapies for unresectable malignant biliary obstruction (MBO), but the best modality is uncertain. RESEARCH DESIGN AND METHODS: Embase, Cochrane Library, PubMed, and Web of Science were systematically searched up to 30 January 2022, for eligible studies that compared either two or all modalities in unresectable MBO. RESULTS: Thirty-three studies with 2974 patients were included in this study. The PDT+Stent and RFA+Stent groups had better overall survival and longer mean survival time than Stent alone (all P < 0.05). Moreover, patients with RFA+Stent demonstrated better mean duration of stent patency (MD: 2.0, 95%CI,1.1 to 2.8, P < 0.05) than Stent alone. The three modalities had similar postoperative mild bleeding, cholangitis, and pancreatitis (all P ≥ 0.05). According to network ranking, PDT+Stent was most likely to provide better survival, RFA+Stent was most likely to maintain stent patency. CONCLUSIONS: RFA or PDT plus biliary stent is effective and safe local palliative therapy for unresectable MBO, but the current studies cannot absolutely determine which modality is the best. We should offer patients the most appropriate treatment according to the advantage of each therapy and the patient's performance status.

Perceived Feasibility of Endoscopic Ultrasound-Guided Gastroenteric Anastomosis: An Italian Survey.

Background and Objectives: Endoscopic ultrasound-guided gastroenteric anastomosis (EUS-GEA) using lumen-apposing metal stents (LAMS) is emerging as a minimally invasive alternative to surgery across several indications. The aim of this survey is to investigate the perceived feasibility of this technique nationwide, within a working group skilled in interventional endosonography. Materials and Methods: Endoscopists were asked to answer to 49 items on a web-based questionnaire about expertise, peri- and intra-procedural aspects in the three main settings of EUS-GEA performance, budget/refund, and future perspectives. Statistical analysis was performed through SPSS® (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.). Results: Sixty endosonographers belonging to forty Italian centers were I-EUS app users and were all invited to participate. In total, 29 participants from 24 Italian centers completed the survey. All the participants were endosonographers with a broad range of experience both in the field of EUS (only 10.3% with more than 20 years of experience) and duodenal stenting (only 6.9% placed more than 10 stents in 2020), whereas 86.2% also performed ERCP. A total of 27.6% of participants performed EUS-GEA (3.4% more than 20 during their career); on the other hand, 79.3% of participants routinely performed drainage of peri-pancreatic fluid collections, 62.1% performed biliary drainage, and 62.1% performed gallbladder drainage with LAMS. A total of 89.7% of participants thought that EUS-GEA could be useful in their daily clinical practice, with 100% concluding that this procedure will need to be performed in referral centers in the near future; however, in 55.2% of cases, organizational obstacles may occur and affect the diffusion of the procedure. With regard to indications: 44.8% of participants performed the procedure with palliative intent for malignant indication (96.6% pancreatic adenocarcinoma), and 13.6% also for benign indication. A total of 20.7% of participants experienced adverse events (none severe or fatal, 66.6% moderate). A total of 62.1% of participants considered the procedure technically challenging, although 82.8% considered the risk of adverse events acceptable when considering the benefit. Conclusions: To our knowledge, this is the first survey assessing the perceived feasibility of EUS-guided anastomoses after its advent. There are currently wide variations in practice nationwide, which demonstrate a need to define technical, qualitative, and peri-procedural requirements to carry out this procedure. Therefore, a standardization of these requirements is needed in order to overcome the technical, economical, and organizational obstacles relative to its diffusion.

Human menstrual blood-derived stem cell transplantation suppresses liver injury in DDC-induced chronic cholestasis.

BACKGROUND: Cholestatic liver injury can lead to serious symptoms and prognoses in the clinic. Currently, an effective medical treatment is not available for cholestatic liver injury. Human menstrual blood-derived stem cells (MenSCs) are considered as an emerging treatment in various diseases. This study aimed to explore the treatment effect of MenSCs in cholestatic liver injury. METHODS: The treatment effect of MenSCs on chronic cholestatic liver injury was verified in 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC)-induced C57/BL6 mice. Pathological, fibrosis area in the liver tissue and serum liver enzymes were tested. Proteomics and western blot were used to explore the related targets and molecular mechanisms. Adeno-associated virus (AAV) 9-infected mice were applied for verification. RESULTS: MenSCs markedly improved the survival rate of the DDC-treated mice (60% vs. 100%), and decreased the mouse serum aspartate aminotransferase (AST) (169.4 vs. 108.0 U/L, p < 0.001), alanine aminotransferase (ALT) (279.0 vs. 228.9 U/L, p < 0.01), alkaline phosphatase (ALP) (45.6 vs. 10.6 U/L, p < 0.0001), direct bilirubin (DBIL) (108.3 vs. 14.0 µmol/L, p < 0.0001) and total bilirubin (TBIL) (179.2 vs. 43.3 µmol/L, p < 0.0001) levels as well as intrahepatic cholestasis, bile duct dilation and fibrotic areas (16.12 vs. 6.57%, p < 0.05). The results further indicated that MenSCs repaired the DDC-induced liver tight junction (TJ) pathway and bile transporter (OATP2, BSEP and NTCP1) injury, thereby inhibiting COL1A1, α-SMA and TGF-ß1 activation by upregulating liver ß-catenin expression. CONCLUSIONS: MenSC transplantation could be an effective treatment method for cholestatic liver injury in mice. MenSCs may exhibit therapeutic effects by regulating ß-catenin expression.