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ABSTRACT Background and Aims Methods Results Conclusions Trial Registration Individuals with primary sclerosing cholangitis (PSC) have expressed a need for more dietary information. The aim of this study was to evaluate the dietary intake of individuals with PSC and compare it with Nordic nutrition recommendations 2023 (NNR2023).A cross‐sectional assessment of dietary intake was performed using a food‐frequency questionnaire among 120 individuals with PSC from five regions across Sweden. Macro‐ and micronutrient intake was compared to NNR2023. Dietary quality was evaluated using an index developed by the National Food Agency in Sweden.The median age was 47 years (IQR 18), and median body mass index (BMI) was 25.2 kg/m2 (IQR 5.9). Eight percent had a BMI < 20, and 13% had a BMI > 30. The average fibre intake was 18 g (IQR 18). Median energy distribution included 36% from fat (15% saturated, 4.6% polyunsaturated), 17% from protein and 43% from carbohydrates, highlighting an imbalanced diet with low carbohydrate, fibre and polyunsaturated fat intake and high saturated fat consumption. More than half reported suboptimal intake of zinc, selenium and vitamins C, D and K and > 30% suboptimal intake of vitamins A, B6, E, niacin, folate, potassium, magnesium and iron. Forty percent had poor dietary quality. Longer PSC duration and previous colectomy were associated with a lower dietary quality.Many individuals with PSC do not reach the recommended levels of various micronutrients, especially fat‐soluble vitamins and report a poor dietary quality. The results highlight the need for a comprehensive approach to nutritional management in this population.ClinicalTrials.gov identifier: NCT04133792 [ABSTRACT FROM AUTHOR]

Abstract Cholestatic liver diseases (CLD) are characterized by impaired normal bile flow, culminating in excessive accumulation of toxic bile acids. The majority of patients with CLD ultimately progress to liver cirrhosis and hepatic failure, necessitating liver transplantation due to the lack of effective treatment. Recent investigations have underscored the pivotal role of the gut microbiota-bile acid axis in the progression of hepatic fibrosis via various pathways. The obstruction of bile drainage can induce gut microbiota dysbiosis and disrupt the intestinal mucosal barrier, leading to bacteria translocation. The microbial translocation activates the immune response and promotes liver fibrosis progression. The identification of therapeutic targets for modulating the gut microbiota-bile acid axis represents a promising strategy to ameliorate or perhaps reverse liver fibrosis in CLD. This review focuses on the mechanisms in the gut microbiota-bile acids axis in CLD and highlights potential therapeutic targets, aiming to lay a foundation for innovative treatment approaches.

The gut-liver axis disruption is a unified pathogenetic principle of cholestatic liver disease (CSLD). Increased gut permeability is the leading cause of gut-liver axis disruption. HO-1 is capable of protecting against gut-liver axis injury. However, it has rarely been reported whether autophagy is involved in HO-1 protecting gut-liver barrier integrity and the underlying mechanism. Mice underwent bile duct ligation (BDL) was established as CSLD model in vivo. Caco-2 cells with LPS treatment was established as in vitro cell model. Immunofluorescence, western blot and transepithelial electrical resistance (TER) assay were used to observe epithelial tight junction (TJ) and autophagy. Liver injury and fibrosis were evaluated as well through H&E staining, masson staining, sirius red staining and ELISA. Our study demonstrated that the epithelial TJ and TER were notably reduced both in BDL mice and in LPS treated intestinal epithelial cells. Increased HO-1 expression could significantly induce intestinal epithelial cell autophagy. Additionally, this increased autophagy level reversed the reduction effects of BDL or LPS on epithelial TJ and TER in vivo and in vitro, therefore decreased transaminase level in serum and relieved liver fibrosis in BDL mice. Besides, increased autophagy level in turn upregulated the expression of HO-1 by p62 degradation of Keap1 and subsequent activation of Nrf2 pathway. Collectively, these results indicate that HO-1 reduces gut permeability by enhancing autophagy level in CSLD, the increased autophagy establishes a HO-1-p62-Nrf2 positive feedback loop to further improve gut-liver axis disruption. Therefore, our study confirms the critical role of autophagy in HO-1 ameliorating gut-liver axis injury during CSLD, highlighting HO-1 as a promising therapeutic target. [ABSTRACT FROM AUTHOR]

Impaired formation of the biliary network can lead to congenital cholestatic liver diseases; however, the genes responsible for proper biliary system formation and maintenance have not been fully identified. Combining computational network structure analysis algorithms with a zebrafish forward genetic screen, we identified 24 new zebrafish mutants that display impaired intrahepatic biliary network formation. Complementation tests suggested these 24 mutations affect 24 different genes. We applied unsupervised clustering algorithms to unbiasedly classify the recovered mutants into three classes. Further computational analysis revealed that each of the recovered mutations in these three classes has a unique phenotype on node-subtype composition and distribution within the intrahepatic biliary network. In addition, we found most of the recovered mutations are viable. In those mutant fish, which are already good animal models to study chronic cholestatic liver diseases, the biliary network phenotypes persist into adulthood. Altogether, this study provides unique genetic and computational toolsets that advance our understanding of the molecular pathways leading to biliary system malformation and cholestatic liver diseases. [Display omitted] • 24 zebrafish mutants with intrahepatic biliary network defects were identified. • Unsupervised classification algorithms sorted the mutants into subgroups. • Computational analysis revealed the detailed network structures in the mutants. • This work provides computational and biological toolsets for biliary system biology. [ABSTRACT FROM AUTHOR]

Cholestatic liver diseases (CLD) are characterized by impaired normal bile flow, culminating in excessive accumulation of toxic bile acids. The majority of patients with CLD ultimately progress to liver cirrhosis and hepatic failure, necessitating liver transplantation due to the lack of effective treatment. Recent investigations have underscored the pivotal role of the gut microbiota-bile acid axis in the progression of hepatic fibrosis via various pathways. The obstruction of bile drainage can induce gut microbiota dysbiosis and disrupt the intestinal mucosal barrier, leading to bacteria translocation. The microbial translocation activates the immune response and promotes liver fibrosis progression. The identification of therapeutic targets for modulating the gut microbiota-bile acid axis represents a promising strategy to ameliorate or perhaps reverse liver fibrosis in CLD. This review focuses on the mechanisms in the gut microbiota-bile acids axis in CLD and highlights potential therapeutic targets, aiming to lay a foundation for innovative treatment approaches. [ABSTRACT FROM AUTHOR]

The erythropoietic protoporphyrias consist of three ultra‐rare genetic disorders of the erythroid heme biosynthesis, including erythropoietic protoporphyria (EPP1), X‐linked protoporphyria (XLEPP) and CLPX‐protoporphyria (EPP2), which all lead to the accumulation of protoporphyrin IX (PPIX) in erythrocytes. Affected patients usually present from early childhood with episodes of severe phototoxic pain in the skin exposed to visible light. The quantification of PPIX in erythrocytes with a metal‐free PPIX ≥3 times the upper limit of normal confirms the diagnosis. Protoporphyria‐related complications include liver failure, gallstones, mild anaemia and vitamin D deficiency with reduced bone mineral density. The management is focused on preventing phototoxic reactions and treating the complications. Vitamin D should be supplemented, and DEXA scans in adults should be considered. In EPP1, even in cases of biochemically determined iron deficiency, supplementation of iron may stimulate PPIX production, resulting in an increase in photosensitivity and the risk of cholestatic liver disease. However, for patients with XLEPP, iron supplementation can reduce PPIX levels, phototoxicity and liver damage. Because of its rarity, there is little data on the management of EPP‐related liver disease. As a first measure, any hepatotoxins should be eliminated. Depending on the severity of the liver disease, phlebotomies, exchange transfusions and ultimately liver transplantation with subsequent haematopoietic stem cell transplantation (HSCT) are therapeutic options, whereby multidisciplinary management including porphyria experts is mandatory. Afamelanotide, an alpha‐melanocyte‐stimulating hormone analogue, is currently the only approved specific treatment that increases pain‐free sunlight exposure and quality of life. [ABSTRACT FROM AUTHOR]

Primary Familial Intrahepatic Cholestasis type 3 is an exceedingly rare genetic cholestatic disorder characterized by the defective hepatocanaliculr bile acid transport leading to progressive liver disease. In this case report, we describe the course of treatment for a 12-year-old kid diagnosed with Wilson disease based on Leipzig score and copper investigations. The child did not improve with chelation therapy and was subsequently genetically classified as PFIC-3. This case highlighted the caveats in Wilson disease diagnostic scoring system. The diagnostic odyssey, therapeutic interventions, and outcome of this case underscore the intricate interplay between clinical suspicion, investigative strategies, and the pivotal role of genetic testing to elucidate rare liver disorders in children. [ABSTRACT FROM AUTHOR]

Background and Aims The risk of intrahepatic cholestasis of pregnancy [ICP] is increased in thiopurine-exposed pregnancies. Thiopurine 'shunting', with a 6-methylmercaptopurine [MMP] to 6-thioguanine [TGN] ratio of >11, progresses over pregnancy, and may promote ICP development. We aimed to explore the association between thiopurine exposure and ICP, including the hypothesised impact of thiopurine shunting, and identify risk minimisation strategies. Methods This prospective multicentre cohort study compared thiopurine and biologic monotherapy-exposed pregnant participants. Disease activity and obstetric outcome data, thiopurine metabolites, bile acids, and transaminases were obtained before conception, in each trimester, at delivery, and postpartum. Thiopurine dose management was at the discretion of the treating physician. Results Included were 131 thiopurine and 147 biologic monotherapy-exposed pregnancies. MMP/TGN ratio increased from preconception to third trimester [ p  <0.01], with approximately 25% of participants shunting in pregnancy. Second trimester split dosing led to a decrease in the median MMP/TGN ratio from 18 (interquartile range [IQR] 6-57) to 3 [IQR 2-3.5] at delivery [ p  = 0.04]. The risk of ICP was increased in thiopurine-exposed pregnancies (6.7% [7/105] vs 0% [0/112], p  <0.001), with all ICP cases occurring in the setting of antenatal thiopurine shunting. Thiopurine dose increases (risk ratio [RR] 8.10, 95% confidence interval [CI] 1.88-34.85, p  = 0.005) and shunting in third trimester [6.20, 1.21-30.73, p  = 0.028] and at delivery [14.18, 1.62-123.9, p  = 0.016] were associated with an increased risk of ICP. Conclusions Thiopurine exposure is associated with an increased risk of ICP, particularly following dose increases antenatally and with shunting in late pregnancy. The latter may be effectively managed with split dosing, although further studies are warranted. [ABSTRACT FROM AUTHOR]

Cholestatic liver diseases in children often have an underlying genetic defect. Genetic testing by next-generation sequencing has become a crucial part of the diagnostic armamentarium in such clinical scenarios. Here, authors report an infant with recurrent cholestasis, pruritus, elevated gamma-glutamyl transpeptidase, patent biliary tract and biliary changes on histology who was detected to have a novel KIF12 mutation, which is crucial for intracellular transport of microtubules and cellular polarity in hepatocytes. The child developed progressive liver dysfunction and decompensation in the form of ascites and coagulopathy over a span of eight years. This case highlights the role of next-generation sequencing in identifying novel mutations, which can help in both diagnosis and prognostication. [ABSTRACT FROM AUTHOR]

Abstract Background ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. The correlation between genotype and clinical phenotype still unclear. This study retrospectively analyzed the clinical and pathological characteristics of 23 patients with ABCB4 gene-related cholestatic liver diseases. Next-generation sequencing was used to identify the genetic causes. Results The 23 included patients (15 children and 8 adults) were diagnosed as progressive familial intrahepatic cholestasis type 3 (PFIC3), drug-induced liver injury (DILI), cirrhosis cholestasis, cirrhosis, and mild liver fibrosis. Nineteen patients underwent liver pathological examination of the liver, exhibiting fibrosis, small bile duct hyperplasia, CK7(+), Cu(+), bile duct deletion, and cirrhosis. Thirty ABCB4 variants were identified, including 18 novel variants. Conclusion ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. Biallelic ABCB4 mutation carriers tended to severe PFIC3, which mostly occurs in children; while ABCB4 non-biallelic variants can lead to milder ICP, LACP, DILI or overlapping, mostly in adults. Thus, the ABCB4 genotype has a specific correlation with the phenotype, but there are exceptions. Non-biallelic null mutations can cause severe diseases. The mechanisms underlying this genetic phenotype require further investigation. Graphical Abstract

Summary: Background: Aetiological therapy improves liver function and may enable hepatic recompensation in decompensated cirrhosis. Aims: We explored the potential for recompensation in patients with decompensated primary biliary cholangitis (PBC) – considering a biochemical response to ursodeoxycholic acid (UDCA) according to Paris‐II criteria as a surrogate for successful aetiological treatment. Methods: Patients with PBC were retrospectively included at the time of first decompensation. Recompensation was defined as (i) resolution of ascites and hepatic encephalopathy (HE) despite discontinuation of diuretic/HE therapy, (ii) absence of variceal bleeding and (iii) sustained liver function improvement. Results: In total, 42 patients with PBC with decompensated cirrhosis (age: 63.5 [IQR: 51.9–69.2] years; 88.1% female; MELD‐Na: 13.5 [IQR: 11.0–15.0]) were included and followed for 41.9 (IQR: 11.0–70.9) months after decompensation. Seven patients (16.7%) achieved recompensation. Lower MELD‐Na (subdistribution hazard ratio [SHR]: 0.90; p = 0.047), bilirubin (SHR per mg/dL: 0.44; p = 0.005) and alkaline phosphatase (SHR per 10 U/L: 0.67; p = 0.001) at decompensation, as well as variceal bleeding as decompensating event (SHR: 4.37; p = 0.069), were linked to a higher probability of recompensation. Overall, 33 patients were treated with UDCA for ≥1 year and 12 (36%) achieved Paris‐II response criteria. Recompensation occurred in 5/12 (41.7%) and in 2/21 (9.5%) patients with vs. without UDCA response at 1 year, respectively. Recompensation was linked to a numerically improved transplant‐free survival (HR: 0.46; p = 0.335). Nonetheless, 4/7 recompensated patients presented with liver‐related complications after developing hepatic malignancy and/or portal vein thrombosis and 2 eventually died. Conclusions: Patients with PBC and decompensated cirrhosis may achieve hepatic recompensation under UDCA therapy. However, since liver‐related complications still occur after recompensation, patients should remain under close follow‐up. [ABSTRACT FROM AUTHOR]

Background: ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. The correlation between genotype and clinical phenotype still unclear. This study retrospectively analyzed the clinical and pathological characteristics of 23 patients with ABCB4 gene-related cholestatic liver diseases. Next-generation sequencing was used to identify the genetic causes. Results: The 23 included patients (15 children and 8 adults) were diagnosed as progressive familial intrahepatic cholestasis type 3 (PFIC3), drug-induced liver injury (DILI), cirrhosis cholestasis, cirrhosis, and mild liver fibrosis. Nineteen patients underwent liver pathological examination of the liver, exhibiting fibrosis, small bile duct hyperplasia, CK7(+), Cu(+), bile duct deletion, and cirrhosis. Thirty ABCB4 variants were identified, including 18 novel variants. Conclusion: ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. Biallelic ABCB4 mutation carriers tended to severe PFIC3, which mostly occurs in children; while ABCB4 non-biallelic variants can lead to milder ICP, LACP, DILI or overlapping, mostly in adults. Thus, the ABCB4 genotype has a specific correlation with the phenotype, but there are exceptions. Non-biallelic null mutations can cause severe diseases. The mechanisms underlying this genetic phenotype require further investigation. [ABSTRACT FROM AUTHOR]

Current therapy for hepatic injury induced by the accumulation of bile acids is limited. Leucine-rich repeat G protein-coupled receptor 4 (LGR4), also known as GPR48, is critical for cytoprotection and cell proliferation. Here, we reported a novel function for the LGR4 in cholestatic liver injury. In the bile duct ligation (BDL)-induced liver injury model, hepatic LGR4 expression was significantly downregulated. Deficiency of LGR4 in hepatocytes (Lgr4LKO) notably decreased BDL-induced liver injury measured by hepatic necrosis, fibrosis, and circulating liver enzymes and total bilirubin. Levels of total bile acids in plasma and liver were markedly reduced in these mice. However, deficiency of LGR4 in macrophages (Lyz2-Lgr4MKO) demonstrated no significant effect on liver injury induced by BDL. Deficiency of LGR4 in hepatocytes significantly attenuated S1PR2 and the phosphorylation of protein kinase B (AKT) induced by BDL. Recombinant Rspo1 and Rspo3 potentiated the taurocholic acid (TCA)-induced upregulation in S1PR2 and phosphorylation of AKT in hepatocytes. Inhibition of S1PR2-AKT signaling by specific AKT or S1PR2 inhibitors blocked the increase of bile acid secretion induced by Rspo1/3 in hepatocytes. Our studies indicate that the R-spondins (Rspos)- LGR4 signaling in hepatocytes aggravates the cholestatic liver injury by potentiating the production of bile acids in a S1PR2-AKTdependent manner. [ABSTRACT FROM AUTHOR]

Objective To observe the effect of modified Traditional Chinese Medicine external application in the treatment of pruritus in patients with chronic cholestatic liver disease, and to improve the quality of Tradition Chinese Medicine nursing of liver diseases. Methods Totally 112 patients with chronic cholestatic liver disease complicated with pruritus were randomly divided into the control group (n=55) and Traditional Chinese Medicine (TCM)group (n=57). According the occurrence time, frequency and influence of skin temperature on itch, the Traditional Chinese Medicine external application method was modified. Modified Traditional Chinese Medicine external application with calamine lotion and Qingre-Lishi-Zhiyang recipe was carried out in the control group and TCM group, respectively. The effect of nursing interventions was measured and compared between two groups. Results The rate of cured and remarkably improved outcome in the TCM group was 80. 70%(46/57) and 40%(22/55)in the control group, with a significant difference(P ＜0. 01). The levels of total bilirubin (TBIL) and Total bile acid (TBA)in the TCM group were lower than those in the control group after intervention (P＜0. 01). A lower pruritus symptom score and shorter duration of itching were found in the TCM group compared with those in the control group (P＜0. 01). Patients in the TCM group had a longer sleep time compared with that in the control group after nursing intervention (P＞0. 05). The lesion symptom score in the TCM group was lower than that in the control group (P＜0. 01). A better improvement of dry skin was observed in the TCM group compared with that in the control group after intervention (P＜0. 01). Conclusion The modified Traditional Chinese Medicine external application with Qingre-Lishi-Zhiyang recipe is effective in the treatment of pruritus in patients with chronic cholestatic liver disease. (目的 观察细化关键技术操作环节的中药涂药疗法干预胆汁淤积性肝病患者皮肤瘙痒症状的效果, 提升中医肝病专科护理质量。方法 选取2021年1月—2022年12月医院收治的慢性胆汁淤积性肝病并发皮肤瘙痒症患者112例为研究对象, 将患者随机分为对照组55例和中药组57例。结合患者皮肤瘙痒症状常出现的时间、频率及温度对其瘙痒程度影响的特点, 对涂药前清洁皮肤水温的设定和涂药时间进行细化研究。在此基础上, 采用中药涂药技术干预两组患者皮肤瘙痒症状, 分别给予对照组炉甘石洗剂和中药组清热利湿止痒方外涂进行干预。对比两组患者护理效果。结果 中药组护理干预愈显率80. 70%(46/57), 高于对照组的40%(22/55), 差异有统计学意义(P＜0. 01)。干预后, 中药组总胆红素(TBIL)和总胆汁酸(TBA)水平低于对照组, 差异有统计学意义(P＜0. 01); 与对照组比较, 中药组瘙痒程度积分降低, 瘙痒持续时间缩短, 差异有统计学意义(P＜0. 01); 中药组患者睡眠时间较对照组延长, 但差异无统计学差异(P＞0. 05); 中药组皮损状态积分低于对照组, 差异有统计学意义(P＜0. 05); 中药组皮肤干燥情况改善优于对照, 差异有统计学意义(P＜0. 01)。结论 临床护理慢性胆汁淤积性肝病患者皮肤瘙痒症状时, 采用细化后的中药涂药技术涂抹清热利湿止痒方效果良好, 有助于提高治疗效果, 改善患者生活质量。)

Bile acids are synthesized from cholesterol in the liver. Dysregulation of bile acid homeostasis, characterized by excessive accumulation in the liver, gallbladder and blood, can lead to hepatocellular damage and the development of cholestatic liver disease. Nuclear receptors play a crucial role in the control of bile acid metabolism by efficiently regulating bile acid synthesis and transport in the liver. Among these receptors, peroxisome proliferator‐activated receptor (PPAR), a ligand‐activated transcription factor belonging to the nuclear hormone receptor superfamily, controls the expression of genes involved in adipogenesis, lipid metabolism, inflammation and glucose homeostasis and has emerged as a potential therapeutic target for the treatment of the metabolic syndrome in the past two decades. Emerging evidence suggests that PPAR activation holds promise as a therapeutic target for cholestatic liver disease, as it affects both bile acid production and transport. This review provides a comprehensive overview of recent advances in elucidating the role of PPAR in the regulation of bile acid metabolism, highlighting the current position of PPAR agonists in the treatment of primary biliary cholangitis. By summarizing the specific regulatory effects of PPAR on bile acids, this review contributes to the exploration of novel therapeutic strategies for cholestatic liver diseases. [ABSTRACT FROM AUTHOR]

Background and Aims: Many patients with the chronic cholestatic liver disease primary biliary cholangitis (PBC) show fatigue and cognitive impairment that reduces their quality of life. Likewise, rats with bile duct ligation (BDL) are a model of cholestatic liver disease. Current PBC treatments do not improve symptomatic alterations such as fatigue or cognitive impairment and new, more effective treatments are therefore required. Golexanolone reduces the potentiation of GABAA receptors activation by neurosteroids. Golexanolone reduces peripheral inflammation and neuroinflammation and improves cognitive and motor function in rats with chronic hyperammonemia. The aims of the present study were to assess if golexanolone treatment improves fatigue and cognitive and motor function in cholestatic BDL rats and if this is associated with improvement of peripheral inflammation, neuroinflammation, and GABAergic neurotransmission in the cerebellum. Methods: Rats were subjected to bile duct ligation. One week after surgery, oral golexanolone was administered daily to BDL and sham-operated controls. Fatigue was analysed in the treadmill, motor coordination in the motorater, locomotor gait in the Catwalk, and short-term memory in the Y-maze. We also analysed peripheral inflammation, neuroinflammation, and GABAergic neurotransmission markers by immunohistochemistry and Western blot. Results: BDL induces fatigue, impairs memory and motor coordination, and alters locomotor gait in cholestatic rats. Golexanolone improves these alterations, and this was associated with improvement of peripheral inflammation, neuroinflammation, and GABAergic neurotransmission in the cerebellum. Conclusion: Golexanolone may have beneficial effects to treat fatigue, and motor and cognitive impairment in patients with the chronic cholestatic liver disease PBC. [ABSTRACT FROM AUTHOR]

There is a lack of biliary epithelial molecular markers for primary sclerosing cholangitis (PSC). We analyzed candidates from disease susceptibility genes identified in recent genome-wide association studies (GWAS). Expression levels of GWAS genes were analyzed in archival liver tissues of patients with PSC and controls. Immunohistochemical analysis was performed to evaluate expression levels in the biliary epithelia of PSC (N = 45) and controls (N = 12). Samples from patients with primary biliary cholangitis (PBC) were used as disease controls (N = 20). Hepatic expression levels of ATXN2, HHEX, PRDX5, MST1, and TNFRSF14 were significantly altered in the PSC group. We focused on the immune-related receptor, TNFRSF14. Immunohistochemistry revealed that high expression of TNFRSF14 in biliary epithelial cells was observed only in the PSC group. In addition, the expression of LIGHT , which encodes a TNFRSF14-activating ligand, was increased in PSC liver. Immunohistochemistry showed that high expression of LIGHT was more common in PSC biliary epithelia (53%) than in the PBC (15%) or control (0%) groups; moreover, it was positively associated with fibrotic progression, although it was not an independent prognostic factor. TNFRSF14 and LIGHT are promising candidate markers for PSC. [ABSTRACT FROM AUTHOR]

Purpose: Cholestatic liver diseases are groups of hepatobiliary diseases without curative drug-based therapy options. Regulation of bile acid (BA) metabolism, hepatoperiductal fibrosis, and inflammatory response indicated present novel methods for the treatment of cholestatic liver disease. Costunolide (COS) from herb Saussurea lappa exerts a pharmacological effect of regulation of BA metabolism, liver fbrosis and inflammatory response. The present study aimed to clarify the pharmacodynamic effects of COS against the murine model of cholestatic liver disease. Methods: We established a murine model of cholestatic liver disease through chronic feeding of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 28 days. Two independent in vivo experiments were designed to reveal the pharmacological effect of COS against cholestatic liver disease. In the first experiment, two dosages of COS (10 and 30 mg/kg) were intraperitoneally injected into model mice daily for 14 days. In the second experiment, high dosage of COS (30 mg/kg) was intraperitoneally injected into control and model mice daily for 28 days. Results: In the evaluation of the hepatoprotective effect of COS, COS showed dosage-dependent improvement of cholestatic liver disease, including ductular reaction, hepatoperiductal fibrosis, and inflammatory response. The mechanism of COS-mediated hepatoprotective effects mainly relies on the regulation of BA metabolism, and the inflammatory response. DDC diet feed induced hepatic BA metabolism, transport and circulation dysfunction. COS treatment not only regulated the BA metabolism and transport gene, but also reprogrammed hepatic primary and secondary BA concentrations. DDC induced hepatic infiltrated monocytes derived macrophages and lymphocytes were inhibited, while Kupffer cells were preserved by COS treatment. The liver elevating inflammatory cytokines of DDC diet feed were alleviated by COS. Moreover, high dosage of 30 mg/kg COS treatment for 28 days resulted in no significant serological changes and no obvious hepatic histopathological changes when compared with control mice. Conclusion: COS protected against DDC diet feeding-induced cholestatic liver disease since COS regulated BA metabolism, ductular reaction, hepatoperiductal fibrosis and inflammatory response. COS is suggested as a potential natural product for the treatment of cholestatic liver disease.

Aims The objective of this study is to examine the impact of inhibiting Sphingosine 1-phosphate receptor 2 (S1PR2) on liver inflammation, fibrogenesis, and changes of gut microbiome in the context of cholestasis-induced conditions. Methods The cholestatic liver injury model was developed by common bile duct ligation (CBDL). Sprague-Dawley rats were randomly allocated to three groups, sham operation, CBDL group and JTE-013 treated CBDL group. Biochemical and histological assessments were conducted to investigate the influence of S1PR2 on the modulation of fibrogenic factors and inflammatory infiltration. We conducted an analysis of the fecal microbiome by using 16S rRNA sequencing. Serum bile acid composition was evaluated through the utilization of liquid chromatography-mass spectrometry techniques. Results In the BDL rat model, the study findings revealed a significant increase in serum levels of conjugated bile acids, accompanied by an overexpression of S1PR2. Treatment with the specific inhibitor of S1PR2, known as JTE-013, resulted in a range of specific effects on the BDL rats. These effects included the improvement of liver function, reduction of liver inflammation, inhibition of hepatocyte apoptosis, and suppression of NETosis. These effects are likely mediated through the TCA/S1PR2/NOX2/NLRP3 pathway. Furthermore, the administration of JTE-013 resulted in an augmentation of the diversity of the bacterial community’s diversity, facilitating the proliferation of advantageous species while concurrently inhibiting the prevalence of detrimental bacteria. Conclusions The results of our study suggest that the administration of JTE-013 may have a beneficial effect in alleviating cholestatic liver disease and restoring the balance of intestinal flora.

Cholestatic liver disease is defined as the bile acids (BAs) accumulation in the liver caused by impaired synthesis, and secretion, together with excretion of BAs due to a variety of factors, which, if left untreated, can result in hepatic fibrosis, cholestatic cholangitis, cholestatic cirrhosis, eventually, end-stage liver disease. Currently, modulation of BA metabolism is still a prospective therapeutic strategy for treating the cholestatic diseases. Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor with far-reaching effects on the chronic liver disease. However, its role and mechanism in cholestatic liver damage is still unknown. Therefore, in this work, we explored the impact of AHR on the cholestatic liver injury using AHR overexpression mediated by adeno-associated viral (AAV) vectors. We found that AHR is differentially expressed in different stages of cholestatic liver disease, showing either down-regulation or an increase in protective effects. Overexpression of AHR increased body weight, decreased serum total bilirubin (TBil) and alkaline phosphatase (ALP), reduced porphyrin accumulation in liver tissue, and regulated the bile acid pool in the cholestatic mouse model induced by DDC diet. Overall, our data indicate that AHR attenuated cholestatic liver injury. AHR function indicates that it may have an action in the clinical management of cholestasis. • AHR attenuates initial weight loss by DDC intoxication. • AHR reduced the accumulation of porphyrin caused by the DDC diet. • AHR selectively reduces taurine-conjugated bile acid contents. [ABSTRACT FROM AUTHOR]

Background: Although several prognostic scores have been reported to correlate with the prognosis of primary biliary cholangitis (PBC) patients, there are limited tools to predict the prognosis of PBC with compensated cirrhosis. This study aimed to evaluate the prognostic performance of the albumin-bilirubin (ALBI) score in PBC patients with compensated cirrhosis. Methods: We conducted a retrospective longitudinal study of 219 patients with compensated PBC cirrhosis to evaluate the prognostic performance of the ALBI using Cox regression model, receiver operating characteristic (ROC) curve, and Kaplan-Meier method. Results: During follow-up, a total of 19 subjects (8.7%) met the primary endpoint of liver-related death or liver transplantation (LT). Patients who died/underwent LT have higher ALBI score (−1.06 vs. −2.06, p < 0.001) at baseline than those who survived. ALBI score (hazard ratio: 15.011, 95% confidence interval [CI]: 5.045–44.665, p < 0.001) was associated with an increase in liver-related mortality or LT. ALBI score had the best discriminative capacity to predict the 5-year liver-related mortality (area under the ROC curve: 0.871, 95% CI [0.820, 0.913]) compared with other prognostic scores. The ROC curve showed that the best cut-off value of ALBI score was −1.47, with 90.0% sensitivity and 76.6% specificity. Also, the probability of transplant-free survival decreased with increasing ALBI grade (log-rank p = 0.003). The 5-year transplant-free survival rates of patients in grade 1, grade 2, and grade 3 were 100.0%, 96.4%, and 89.4%, respectively. Conclusion: ALBI score is a simple and effective predictive factor estimating the clinical outcome of patients with compensated PBC cirrhosis and provides better prognostic performance compared with other prognostic scores. [ABSTRACT FROM AUTHOR]

Cholestatic liver disease is a common liver disease in infants and young children. Liver fibrosis is a key factor affecting the prognosis, and liver transplantation is the only treatment option for liver cirrhosis. This study aimed to explore the efficacy of Combi-elasto for diagnosing liver fibrosis in children affected by cholestatic liver disease. A total of 64 children with S1–S4-grade liver fibrosis were enrolled. The general data, routine ultrasound, Combi-elasto, aspartate aminotransferase-to-platelet ratio index (APRI) and Fibrosis-4 (FIB-4) score were compared among children with different grades of liver fibrosis, and the efficacy of the above indexes for evaluating the degree of liver fibrosis was reported. There were remarkable differences in liver size, liver echogenicity, Young's modulus (E), fibrosis index (FI), activity index (AI) and FIB-4 score among the groups (all p < 0.05). E and liver echogenicity were the independent impact factors of liver fibrosis. The areas under the curve of E, APRI, FIB-4 score and the combined model (E+ liver echogenicity) in the evaluation of liver fibrosis were 0.84, 0.61, 0.66 and 0.90, respectively. Ultimately, we concluded that CE is an effective method to evaluate liver fibrosis in children with cholestatic liver disease. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To probe into the efficacy of compound Danhuang formula in the treatment of cholestatic liver disease of liver-gallbladder dampness-heat pattern, and to further analyze its potential mechanism based on the synthesis, transport and metabolism, fibrosis, inflammation and oxidative stress of bile acid. METHODS: Totally 128 patients with cholestatic liver disease of liver-gallbladder dampness-heat pattern admitted into the hepatology department of the hospital from Mar. 2020 to Oct. 2022 were enrolled for study, the patients were divided into control group and observation group via random number table method, with 64 cases in each group. The control group was given Western expectant treatment, the observation group was given compound Danhuang formula based on the control group, both groups were treated for 4 weeks. The syndrome integrals, liver function and incidences of adverse drug reactions were compared between two groups, its effects on related parameters of the synthesis, transport and metabolism, fibrosis, inflammation and oxidative stress of bile acid were further analyzed. RESULTS: During research, 2 cases in the control group and 1 case in the observation group were loss to follow-up. After treatment, the syndrome integrals of lateral thorax pain, abdominal distension, fatigue and cutaneous pruritus of both groups were lower than those before treatment, and those of the observation group were lower than the control group; the alkaline phosphatase and glutamyl transpeptidase of both groups were lower than those before treatment, and those of the observation group were lower than the control group, with statistically significant differences ( P < 0. 05 ). The incidences of adverse drug reactions of control group and observation group were respectively 8. 06% ( 5 / 62) and 4. 76% (3 / 63), the difference had no statistical significance (P> 0. 05). After treatment, the total bile acid and fibroblast growth factor-19 of both groups were lower than those before treatment, and those of the observation group were lower than the control group; the Ⅲ-type procollagen, hyaluronic acid, laminin and Ⅳ-type collagen of both groups were lower than those before treatment, and those of the observation group were lower than the control group, with statistically significant differences (P<0. 05). After treatment, the interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) were lower and the superoxide dismutase (SOD) was higher in both groups than those before treatment, the IL-6 and TNF-α were lower and the SOD was higher in the observation group than those in the control group, with statistically significant differences ( P < 0. 05 ). CONCLUSIONS: Patients with cholestatic liver disease of livergallbladder dampness-heat pattern can obtain definite efficacy by receiving compound Danhuang formula based on Western expectant treatment, which can improve lover function, with few adverse drug reactions. The compound Danhuang formula can play a positive role in the synthesis, transport and metabolism, anti-fibrosis, anti-inflammatory reaction and oxidative stress of bile acid. [ABSTRACT FROM AUTHOR]

Alagille syndrome (ALGS) is a complex rare genetic disorder that involves multiple organ systems and is historically regarded as a disease of childhood. Since it is inherited in an autosomal dominant manner in 40% of patients, it carries many implications for genetic counselling of patients and screening of family members. In addition, the considerable variable expression and absence of a clear genotype–phenotype correlation, results in a diverse range of clinical manifestations, even in affected individuals within the same family. With recent therapeutic advancements in cholestasis treatment and the improved survival rates with liver transplantation (LT), many patients with ALGS survive into adulthood. Although LT is curative for liver disease secondary to ALGS, complications secondary to extrahepatic involvement remain problematic lifelong. This review is aimed at providing a comprehensive review of ALGS to adult clinicians who will take over the medical care of these patients following transition, with particular focus on certain aspects of the condition that require lifelong surveillance. We also provide a diagnostic framework for adult patients with suspected ALGS and highlight key aspects to consider when determining eligibility for LT in patients with this syndrome. [ABSTRACT FROM AUTHOR]

Ductular reaction (DR) is usually observed in biliary disorders or various liver disorders, including nonalcoholic fatty liver disease. Few studies have focused on interrupting the DR process in the cholestatic environment. Here, we investigated the impact of reversine on DR in rats that had undergone bile duct ligation (BDL). Cholestatic injury was induced in rats 2 weeks following BDL. DR was assessed with biliary markers by immunohistochemistry. Biliary epithelial cells (BECs) were isolated for the analysis of proliferation and biliary factor gene expression. The effects of reversine on DR and fibrosis were analyzed in vivo via intraperitoneal injection in rats for 2 weeks. Chemically‐induced BEC formation was used to investigate the biliary markers affected by reversine in vitro. DR with increased BEC expansion was identified in cholestatic liver injury, as indicated by CK7, CK19, and EpCAM expression around the portal vein in BDL rats. BDL‐induced DR cells showed the increased expression of genes regulating cell proliferation (Ki67, Foxm1, and Pcna) and biliary markers (Krt7, Krt19, Epcam, Sox9, Cftr, and Asbt). Reversine attenuated cholestatic fibrosis and DR in rats. Reversine affected chemically‐induced BEC formation, with the decreased expression of biliary Krt7, Cftr, and Ggt1 genes in vitro. BDL‐induced Notch activation was attenuated upon reversine treatment in vivo, in part via the Notch/Sox9 pathway. In conclusion, reversine attenuated cholestatic ductular reaction and fibrosis in rats and reduced the bile duct formation associated with Dlk1/Notch/Sox9 signaling. Reversine may be regarded as a potential drug for cholangiopathies for preventing a ductular reaction.

Background & aimsGut-homing lymphocytes that express the integrin α4β7 and CCR9 might contribute to development of primary sclerosing cholangitis (PSC). Vedolizumab, which blocks the integrin α4β7, is used to treat patients with inflammatory bowel diseases (IBD), but there are few data on its efficacy in patients with PSC. We investigated the effects of vedolizumab in a large international cohort of patients with PSC and IBD.MethodsWe collected data from European and North American centers participating in the International PSC Study Group from patients with PSC and IBD who received at least 3 doses of vedolizumab (n = 102; median vedolizumab treatment duration, 412 days). Demographic and clinical data were collected from baseline and during the follow-up period (until liver transplantation, death, or 56 days after the final vedolizumab infusion). We analyzed overall changes in biochemical features of liver and proportions of patients with reductions in serum levels of alkaline phosphatase (ALP) of 20% or more, from baseline through last follow-up evaluation. Other endpoints included response of IBD to treatment (improved, unchanged, or worsened, judged by the treating clinician, as well as endoscopic score) and liver-related outcomes.ResultsIn the entire cohort, the median serum level of ALP increased from 1.54-fold the upper limit of normal at baseline to 1.64-fold the upper limit of normal at the last follow-up examination (P = .018); serum levels of transaminases and bilirubin also increased by a small amount between baseline and the last follow-up examination. Serum levels of ALP decreased by 20% or more in 21 patients (20.6%); only the presence of cirrhosis (odds ratio, 4.48; P = .019) was independently associated with this outcome. Of patients with available endoscopic data, 56.8% had a response of IBD to treatment. Liver-related events occurred in 21 patients (20.6%), including bacterial cholangitis, cirrhosis decompensation, or transplantation.ConclusionsIn an analysis of patients with PSC and IBD in an international study group, we found no evidence for a biochemical response to vedolizumab, although serum level of ALP decreased by 20% or more in a subset of patients. Vedolizumab appears to be well tolerated and the overall response of IBD was the same as expected for patients without PSC.

Abstract Background Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with a largely unpredictable course. Due to limited treatment options, individuals may for many years suffer from distressing symptoms and the emotional burden of an uncertain future. The need to shift from cure to care of PSC has spurred an interest into patients’ health-related quality of life. Qualitative research in this context remains scarce. Hence, this study aimed to enrich the clinical understanding about the lived experience of PSC through a qualitative approach. Methods A total of 20 patients with PSC were recruited at a specialist centre for autoimmune liver disease in Germany and engaged in semi-structured telephone-based interviews between March and June 2022. Verbatim transcripts were interpreted using inductive thematic analysis. Results An overarching concept of ‘a wave-like experience’ was formulated to illustrate the dual and shifting nature of living with PSC. Reflecting upon this central idea, three major themes were generated to address important aspects of participants’ illness experiences: ‘Invisible presence’ focused on perceptions of suffering from a seemingly hidden illness that periodically reveals itself through specific trigger events. ‘Embracing the threat’ captured the psycho-emotional response shift to this chronic disease from a predominantly negative to a coping-oriented pattern with regular setbacks. ‘Between control and constraints’ uncovered restrictions that PSC enforces onto patients’ lives and their desire for controllability. Conclusions The present study provides an in-depth look at the fluctuating tensions arising from a life with PSC. Insights on perceived invisibility, disease-related triggers of emotional distress and the complexity behind self-management highlight opportunities for enhanced clinical support of this patient group.

Primary sclerosing cholangitis (PSC) is characterised by the co-occurrence of inflammatory bowel diseases, particularly ulcerative colitis (UC). We investigated how the interaction of miR-125b with the sphingosine-1-phosphate (S1P)/ceramide axis may predispose patients with PSC, PSC/UC, and UC to carcinogenesis in the ascending and sigmoid colons. The overexpression of miR-125b was accompanied by the upregulation of S1P, ceramide synthases, ceramide kinases, and the downregulation of AT-rich interaction domain 2 in the ascending colon of PSC/UC, which contributed to the progression of high microsatellite instability (MSI-H) colorectal carcinoma. We also showed that the overexpression of sphingosine kinase 2 (SPHK2) and the genes involved in the glycolytic pathway in the sigmoid colon of UC led to the upregulation of Interleukin 17 (IL-17). In vitro stimulation of human intestinal epithelial cells (Caco-2, HT-29, and NCM460D) with lipopolysaccharide suppressed miR-125b and increased proinflammatory cytokines, whereas the induction of miR-125b activity by either a miR-125b mimetic or lithocholic acid resulted in the inhibition of miR-125b targets. In summary, miR-125b overexpression was associated with an imbalance in the S1P/ceramide axis that can lead to MSI-H cancer progression in PSC/UC. Furthermore, SPHK2 overexpression and a change in the cellular metabolic flux are important players in inflammation-associated colon cancer in UC. [ABSTRACT FROM AUTHOR]

Introduction: Hypoxic liver injury (HLI) is a frequent and life-threatening complication occurring in up to 10% of critically ill patients. Heart failure and age were previously identified as risk factors for occurrence of HLI. However, there is lack of data on incidence of HLI and its clinical implications on outcome in very old (≥90 years) patients. The aim of this study was to investigate occurrence, clinical characteristics, and outcome of HLI in critically ill patients ≥90 years. Methods: This is a retrospective analysis of all consecutive critically ill patients ≥90 years admitted to the intensive care unit (ICU) of a tertiary care university hospital in Hamburg, Germany. Clinical course and laboratory data were analyzed for all patients. HLI was defined according to established criteria as elevation of aminotransferase levels (>20-fold upper limit of normal). Predictors of HLI occurrence, clinical course, and outcome were assessed and compared to those of patients without HLI. Results: In total, 1,065 critically ill patients ≥90 years were included. During the ICU stay, 3% (n = 35) developed HLI. Main causes of HLI were cardiogenic shock (51%, n = 18), septic shock (23%, n = 8), and cardiac arrest (20%, n = 7). Presenting characteristics including age, gender, and BMI were comparable between patients with and without HLI. The admission cause was primary medical (HLI: 49% vs. No-HLI: 34%, p = 0.07), surgical – planned (9% vs. 38%, p < 0.001), and surgical – emergency (43% vs. 28%, p = 0.06). The median Charlson Comorbidity Index (CCI) and the median updated CCI were 2 (1–3) and 2 (1–2) points in patients with HLI and 1 (0–2) and 1 (0–2) in patients without HLI (p < 0.01 and p = 0.08). Patients with HLI presented with higher SAPS II (55 vs. 36 points p < 0.001) score on admission and required mechanical ventilation (66% vs. 34%, p < 0.001), vasopressor therapy (91% vs. 40%, p < 0.001), renal replacement therapy (20% vs. 2%, p < 0.001), and parenteral nutrition (29% vs. 7%, p < 0.001). The ICU mortality and hospital mortality in patients with HLI were 66% (n = 23) and 83% (n = 29) compared with 17% (n = 170) and 28% (n = 292) in patients without HLI, respectively (both p < 0.001). Regression analysis identified SAPS II (OR 1.05, 95% CI: [1.02–1.07]; p < 0.001) and vasopressor therapy (OR 9.21, 95% CI: [2.58–32.86]; p < 0.01) as factors significantly associated with new onset of HLI. Occurrence of HLI was independently associated with mortality (HR 2.23, 95% CI: [1.50–3.30]; p < 0.001). Conclusion: HLI is an uncommon but not rare condition in critically ill patients aged ≥90 years. Occurrence of HLI is associated with high mortality and is mainly caused by cardiogenic or septic shock. HLI may serve as early prognostic marker in critically ill patients aged ≥90 years. [ABSTRACT FROM AUTHOR]

Background: Pruritus is a symptom of several cholestatic liver diseases (CLDs) that can impair health-related quality of life (HRQoL). Despite evidence-based guideline therapy, managing cholestatic pruritus (CP) remains challenging, thus making the need for newer, more effective therapeutic agents more evident. Objective: Our study evaluated the efficacy of existing CP therapies. Design: Systematic review. Data sources: From inception until March 2023, we conducted a comprehensive search of MEDLINE, Cochrane, EMBASE, Scopus, ClinicalTrial.gov, and other sources, including pharmaceutical webpages and conference proceedings published in English that reported on CP interventions. Methods: Two reviewers independently conducted screening and full-text review of articles with extraction conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The methodological quality of studies included in our qualitative synthesis was assessed by using the Cochrane ROBINS-I and ROBINS-II tools for interventional studies and the National Heart, Lung, and Blood Institute Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. The primary outcome assessed in our systematic review was the severity of CP after therapy. Results: Of 3293 screened articles, 92 studies were eligible for inclusion in the qualitative synthesis. Some patients' HRQoL improved with evidence-based standard therapy. Others, particularly those with severe and refractory CP, often required conversion to or addition of experimental noninvasive (e.g., ondansetron) or extracorporeal liver support to alleviate CP. In addition, studies investigating a newer class drug, the ileal bile acid transporter inhibitor (IBATi), demonstrate its effectiveness in reducing serum bile acid and alleviating CP with sustained improvement noted in patients with the inherited childhood cholestatic disorders – progressive familial intrahepatic cholestasis and Alagille syndrome. Conclusion: Our findings consolidate data on the efficacy of guideline-based approaches and newer therapies for CP. While the initial findings are promising, additional clinical trials will be needed to determine the full extent of IBATi's efficacy and potential use in treating other common CLDs. These results provide a foundation for future research and highlight the need for continued investigation into the management and treatment of CLDs. [ABSTRACT FROM AUTHOR]

Primary sclerosing cholangitis (PSC) is characterized by inflammation of the whole bile duct system. Liver transplantation is only approved as a curative treatment when it comes to end-stage liver disease. The aim of our study was to assess morbidity, survival rates and PSC recurrence and the impact of donor characteristics in long-term follow-up. This was an IRB-approved retrospective study. A total of 82 patients were identified who were transplanted between January 2010 and December 2021 for PSC. Among these patients, 76 adult liver transplant PSC patients and their corresponding donors were analyzed. Three pediatric cases and three adult patients with a follow-up within <1 year were excluded from further analysis. Median (range) age was 47 years (18–70) with a median (range) lab-MELD of 16 (7–40). Median (range) ICU and hospital stays were 4.6 days (0–147) and 21 days (1–176), respectively. The majority of patients suffered from Crohn's disease or ulcerative colitis as a concomitant comorbidity (65.8%). The ten-year survival rate was 74.6%. A significantly lower lab-MELD score was identified in patients surviving for > 10 years (15 vs. 22, p = 0.004). Most patients (65%) passed in the first year following transplantation, with primary non-function (PNF), sepsis and arterial thrombosis being the most common causes of death. Donor characteristics did not affect patient survival. Patients with PSC show excellent 10-year survival rates. While the lab-MELD score significantly affected long term outcomes, donor characteristics did not affect survival rates. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests the complex interactions between gut microbiota and bile acids, which are crucial end products of cholesterol metabolism. Cholestatic liver disease is characterized by dysfunction of bile production, secretion, and excretion, as well as excessive accumulation of potentially toxic bile acids. Given the importance of bile acid homeostasis, the complex mechanism of the bile acid–microbial network in cholestatic liver disease requires a thorough understanding. It is urgent to summarize the recent research progress in this field. In this review, we highlight how gut microbiota regulates bile acid metabolism, how bile acid pool shapes the bacterial community, and how their interactions contribute to the pathogenesis of cholestatic liver disease. These advances might provide a novel perspective for the development of potential therapeutic strategies that target the bile acid pathway. [ABSTRACT FROM AUTHOR]

Ductular reaction (DR) is usually observed in biliary disorders or various liver disorders, including nonalcoholic fatty liver disease. Few studies have focused on interrupting the DR process in the cholestatic environment. Here, we investigated the impact of reversine on DR in rats that had undergone bile duct ligation (BDL). Cholestatic injury was induced in rats 2 weeks following BDL. DR was assessed with biliary markers by immunohistochemistry. Biliary epithelial cells (BECs) were isolated for the analysis of proliferation and biliary factor gene expression. The effects of reversine on DR and fibrosis were analyzed in vivo via intraperitoneal injection in rats for 2 weeks. Chemically‐induced BEC formation was used to investigate the biliary markers affected by reversine in vitro. DR with increased BEC expansion was identified in cholestatic liver injury, as indicated by CK7, CK19, and EpCAM expression around the portal vein in BDL rats. BDL‐induced DR cells showed the increased expression of genes regulating cell proliferation (Ki67, Foxm1, and Pcna) and biliary markers (Krt7, Krt19, Epcam, Sox9, Cftr, and Asbt). Reversine attenuated cholestatic fibrosis and DR in rats. Reversine affected chemically‐induced BEC formation, with the decreased expression of biliary Krt7, Cftr, and Ggt1 genes in vitro. BDL‐induced Notch activation was attenuated upon reversine treatment in vivo, in part via the Notch/Sox9 pathway. In conclusion, reversine attenuated cholestatic ductular reaction and fibrosis in rats and reduced the bile duct formation associated with Dlk1/Notch/Sox9 signaling. Reversine may be regarded as a potential drug for cholangiopathies for preventing a ductular reaction. [ABSTRACT FROM AUTHOR]

Background and Aims: Autoimmune liver diseases (AILDs) are associated with impaired health‐related quality of life (HrQoL). The aim of this project was to identify potentially modifiable factors related to HrQoL in a large transnational cohort of patients with AILDs. Methods: A cross‐sectional online survey was conducted on patients with autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) or primary sclerosing cholangitis from 15 European countries. HrQoL was measured with EQ‐5D‐5L and EQ visual analogue scale (EQ‐VAS) and analysed in relation to demographic, psychosocial, disease‐ and treatment‐related factors. A Patient Health Questionnaire‐2 score >3 indicated relevant depression. Multivariable linear regression analyses were used to identify potentially modifiable factors associated with HrQoL and confidence in treatment whilst adjusting for known confounders. Results: A group of 1178 European patients (79% female, mean age 48 ± 14 years) participated in the study. HrQoL was impaired in all three diseases (mean EQ‐5D‐5L = 0.75, mean EQ VAS = 68.9), most markedly in PBC (mean EQ‐5D‐5L = 0.73, mean EQ‐VAS = 66.2). Relevant depression, which was detected in 17% of patients, was prominently associated with impaired HrQoL. In the regression analysis, treatment confidence was identified as an important modifiable factor positively contributing to HrQoL. This influence was observable even after adjusting for other covariates including depression. Management in a transplant centre, treatment with azathioprine in AIH, and with ursodeoxycholic acid in PBC, was associated with increased treatment confidence. Finally, improved patient‐physician relationships contributed to treatment confidence. Conclusion: Treatment confidence is a relevant modifiable determinant of HrQoL and should be further investigated to improve the standards of care for patients with AILDs. [ABSTRACT FROM AUTHOR]

Background: Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with a largely unpredictable course. Due to limited treatment options, individuals may for many years suffer from distressing symptoms and the emotional burden of an uncertain future. The need to shift from cure to care of PSC has spurred an interest into patients' health-related quality of life. Qualitative research in this context remains scarce. Hence, this study aimed to enrich the clinical understanding about the lived experience of PSC through a qualitative approach. Methods: A total of 20 patients with PSC were recruited at a specialist centre for autoimmune liver disease in Germany and engaged in semi-structured telephone-based interviews between March and June 2022. Verbatim transcripts were interpreted using inductive thematic analysis. Results: An overarching concept of 'a wave-like experience' was formulated to illustrate the dual and shifting nature of living with PSC. Reflecting upon this central idea, three major themes were generated to address important aspects of participants' illness experiences: 'Invisible presence' focused on perceptions of suffering from a seemingly hidden illness that periodically reveals itself through specific trigger events. 'Embracing the threat' captured the psycho-emotional response shift to this chronic disease from a predominantly negative to a coping-oriented pattern with regular setbacks. 'Between control and constraints' uncovered restrictions that PSC enforces onto patients' lives and their desire for controllability. Conclusions: The present study provides an in-depth look at the fluctuating tensions arising from a life with PSC. Insights on perceived invisibility, disease-related triggers of emotional distress and the complexity behind self-management highlight opportunities for enhanced clinical support of this patient group. [ABSTRACT FROM AUTHOR]

Primary biliary cholangitis (PBC) is an autoimmune liver disease that may progress into liver cirrhosis. Ursodeoxycholic acid (UDCA) is known to prevent or delay the disease progression, but little is known about work incapacity in PBC patients. We aimed to compare clinical outcomes (transplantation-free survival; cirrhosis development) and sick leave in patients with PBC with and without UDCA therapy. The medical records of 526 patients with PBC diagnosed from 2004 to 2016 were reviewed retrospectively. Sick leave data retrieved from the Swedish Social Insurance Agency were analysed for a sub-cohort of patients and matched controls. Cox regression was used for analysis of clinical outcomes. Logistic and conditional logistic regressions were used for sick leave analysis. A total of 10.6% of patients died and 3.4% received liver transplantation over a median follow-up time of 5.7 years. UDCA-untreated patients (HR 3.62 (95%CI 2.02–6.49)) and UDCA non-responders (HR 3.78 (95% CI 1.87–7.66)) had higher mortality or transplantation rates than UDCA responders. Patients with PBC had higher odds of sick leave (OR 2.50; 95% CI 1.69–3.70) than matched controls. Untreated patients were more likely to be on sick leave (OR 3.22; 95% CI 1.12–9.25) two years after diagnosis than UDCA responders. Both untreated patients and UDCA non-responders had lower liver transplantation-free survival rates than UDCA responders. Patients with PBC were more likely to be on sick leave compared to matched controls from the general population. [ABSTRACT FROM AUTHOR]

Dicliptera chinensis (L.) Juss., is an herb known for its anti-inflammatory and anti-oxidant properties. In the previous studies, the chemical composition of the polysaccharide from Dicliptera chinensis (L.) Juss. (DCP) has been characterized as consisting of DCP 1 and DCP 2 , of which DCP 2 has hepatoprotective effects. The study examined the hepatoprotective potential of DCP 2 against alpha-naphthyl isothiocyanate (ANIT)-induced cholestatic liver disease (CLD). In this study, RNA sequencing identified key research pathways involving bile acid metabolism, oxidative stress, and inflammation. Furthermore, qRT-PCR and Western blot analyses were conducted to further characterize these pathways. Additionally, the study included in vitro experiments with HepG2 cells to further investigate the effects of DCP 2 on bile acid metabolism. In summary, the protective effect of DCP 2 on the liver was reflected in alleviating the inflammatory response and oxidative stress, regulating the metabolism of bile acids, and mitigating liver damage caused by bile acids. This study further elucidated the hepatoprotective effects of DCP 2 by examining its ability to counteract ANIT-induced CLD, suggesting that DCP 2 is a promising biomacromolecule for hepatoprotection. [Display omitted] • DCP 2 alleviated CLD by improving bile acid metabolism mainly through the FXR signaling pathway. • DCP 2 reduced inflammation and oxidative stress through the NF-κB and Nrf2 signaling pathways. • DCP consisted of DCP 1 and DCP 2 , of which DCP 2 was a bioactive macromolecule with hepatoprotective properties. [ABSTRACT FROM AUTHOR]

Cholestatic liver disease is a common liver disease in infants and young children. Liver fibrosis is a key factor affecting the prognosis, and liver transplantation is the only treatment option for liver cirrhosis. This study aimed to explore the efficacy of Combi-elasto for diagnosing liver fibrosis in children affected by cholestatic liver disease. A total of 64 children with S1–S4-grade liver fibrosis were enrolled. The general data, routine ultrasound, Combi-elasto, aspartate aminotransferase-to-platelet ratio index (APRI) and Fibrosis-4 (FIB-4) score were compared among children with different grades of liver fibrosis, and the efficacy of the above indexes for evaluating the degree of liver fibrosis was reported. There were remarkable differences in liver size, liver echogenicity, Young’s modulus (E), fibrosis index (FI), activity index (AI) and FIB-4 score among the groups (all p < 0.05). E and liver echogenicity were the independent impact factors of liver fibrosis. The areas under the curve of E, APRI, FIB-4 score and the combined model (E+ liver echogenicity) in the evaluation of liver fibrosis were 0.84, 0.61, 0.66 and 0.90, respectively. Ultimately, we concluded that CE is an effective method to evaluate liver fibrosis in children with cholestatic liver disease.

Primary biliary cholangitis (PBC), which is formally known as primary biliary cirrhosis, is a progressive chronic cholestatic liver disease. Previous epidemiologic studies have demonstrated female predominance. Furthermore, the pathophysiology of PBC is multifactorial, and involves loss of immune tolerance to biliary epithelial cells, with interdependent biliary injury, cholestasis, and progressive liver fibrosis. Moreover, its progression to liver fibrosis highly varies among individuals, but most cases are indolent and slowly progressive. Over the past decade, research has provided great insight into personalized care for patients with PBC. Individualized care and early utilization of second- and third-line therapies have improved the outcomes, and decreased the progression of this disease. The present mini-review focused in providing an overview of PBC, including its pathophysiology, clinical presentation, treatment, treatment goals, recommended follow-up, and future research. [ABSTRACT FROM AUTHOR]

Background and Aim: Secondary sclerosing cholangitis (SSC) is a progressive disease with high mortality and characterized by chronic inflammation and biliary obstruction. Therapeutic options are limited. The aim of this retrospective study was to evaluate the effects of endoscopic treatment in patients with SSC, the outcome, and association with potential risk factors. Methods: Data from all patients with SSC from 1996 to April 2021 were included. Results: Eighty patients with SSC were included. Seventy‐five patients (93.8%) underwent diagnostic endoscopic retrograde cholangiography; 46 patients (57.5%) could be treated endoscopically. Endoscopic treatment comprised removal of biliary casts (n = 36/75), dilatation of bile ducts (n = 17/75), and intermittent stenting (n = 11/75). Twenty patients underwent orthotopic liver transplantation (25%); 27 patients died (33.8%). Transplantation‐free survival was affected neither by endoscopic treatment nor by presence of biliary strictures, but bacteria positive bile culture was associated with better and increased levels of serum alkaline phosphatase and bilirubin levels with poor outcome. Conclusions: Secondary sclerosing cholangitis is a progressive disease with poor long‐term prognosis. Endoscopic treatment options seem to be limited regarding transplantation‐free survival but might improve quality of life and prevent local complications such as cholangitis. The observed limited effect of endoscopic treatment might be attributed to the rapid progression of this disease. [ABSTRACT FROM AUTHOR]

Liver diseases pose a significant threat to human health. Although effective therapeutic agents exist for some liver diseases, there remains a critical need for advancements in research to address the gaps in treatment options and improve patient outcomes. This article reviews the assessment of Elafibranor's effects on liver fibrosis and intestinal barrier function in a mouse model of alcoholic liver disease (ALD), as reported by Koizumi et al in the World Journal of Gastroenterology . We summarize the impact and mechanisms of Elafibranor on ALD, metabolic-associated fatty liver disease, and cholestatic liver disease based on current research. We also explore its potential as a dual agonist of PPARα/δ, which is undergoing Phase III clinical trials for metabolic-associated steatohepatitis. Our goal is to stimulate further investigation into Elafibranor's use for preventing and treating these liver diseases and to provide insights for its clinical application., Competing Interests: Conflict-of-interest statement: All the authors have nothing to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background & Aims: Liver transplantation (LT) for primary sclerosing cholangitis (PSC) is complicated by recurrence of PSC (rPSC) in up to 25% of recipients. Recurrence has been shown to be detrimental for both graft and patient survival. For both PSC and rPSC, a medical cure is not available. To predict and ideally to prevent rPSC, it is imperative to find risk factors for rPSC that can be potentially modified. Therefore, we aimed to identify such factors for rPSC in a large international multicentre study including 6 centres in PSC-prevalent countries. Methods: In this international multicentre, retrospective cohort study, 531 patients who underwent transplantation for PSC were included. In 25% of cases (n = 131), rPSC was diagnosed after a median follow-up of 6.72 (3.29–10.11) years post-LT. Results: In the multivariable competing risk model with time-dependent covariates, we found that factors representing an increased inflammatory state increase the risk for rPSC. Recurrent cholangitis before LT as indication for LT (hazard ratio [HR] 3.6, 95% CI 2.5–5.2), increased activity of inflammatory bowel disease after LT (HR 1.7, 95% CI 1.08–2.75), and multiple acute cellular rejections (HR: non-linear) were significantly and independently associated with an increased risk of rPSC. In contrast to the findings of previous studies, pretransplant colectomy was not found to be independently protective against the development of rPSC. Conclusions: An increased inflammatory state before and after LT may play a causal and modifiable role in the development of rPSC. Pretransplant colectomy did not reduce the risk of rPSC per se. Recurrent cholangitis as indication for LT was associated with an increased risk of rPSC. Impact and implications: Recurrence of PSC (rPSC) negatively affects survival after liver transplant (LT). Modifiable risk factors could guide clinical management and prevention of rPSC. We demonstrate that an increased inflammatory state both before and after LT increases the incidence of rPSC. As these are modifiable factors, they could serve as targets for future studies and therapies. We also added further evidence to the ongoing debate regarding preventive colectomy for rPSC by reporting that in our multicenter study, we could not find an independent association between colectomy and risk of rPSC.

Background & Aims: Farnesoid X receptor (FXR) agonists and fibroblast growth factor 19 (FGF19) analogues suppress bile acid synthesis and are being investigated for their potential therapeutic efficacy in cholestatic liver diseases. We investigated whether bile acid synthesis associated with outcomes in 2 independent populations of people with primary sclerosing cholangitis (PSC) not receiving such therapy. Methods: Concentrations of individual bile acids and 7α-hydroxy-4-cholesten-3-one (C4) were measured in blood samples from 330 patients with PSC attending tertiary care hospitals in the discovery and validation cohorts and from 100 healthy donors. We used a predefined multivariable Cox proportional hazards model to evaluate the prognostic value of C4 to predict liver transplantation-free survival and evaluated its performance in the validation cohort. Results: The bile acid synthesis marker C4 was negatively associated with total bile acids. Patients with fully suppressed bile acid synthesis had strongly elevated total bile acids and short liver transplantation-free survival. In multivariable models, a 50% reduction in C4 corresponded to increased hazards for liver transplantation or death in both the discovery (adjusted hazard ratio [HR] = 1.24, 95% CI 1.06–1.43) and validation (adjusted HR = 1.23, 95% CI 1.03–1.47) cohorts. Adding C4 to established risk scores added value to predict future events, and predicted survival probabilities were well calibrated externally. There was no discernible impact of ursodeoxycholic acid treatment on bile acid synthesis. Conclusions: Bile acid accumulation-associated suppression of bile acid synthesis was apparent in patients with advanced PSC and associated with reduced transplantation-free survival. In a subset of the patients, bile acid synthesis was likely suppressed beyond a tipping point at which any further pharmacological suppression may be futile. Implications for patient stratification and inclusion criteria for clinical trials in PSC warrant further investigation. Lay summary: We show, by measuring the level of the metabolite C4 in the blood from patients with primary sclerosing cholangitis (PSC), that low production of bile acids in the liver predicts a more rapid progression to severe disease. Many people with PSC appear to have fully suppressed bile acid production, and both established and new drugs that aim to reduce bile acid production may therefore be futile for them. We propose C4 as a test to find those likely to respond to these treatments.

Cholestatic liver disease (CLD) is a chronic liver disease characterized by ductular reaction, inflammation and fibrosis. As there are no effective chemical or biological drugs now, majority of CLD patients eventually require liver transplantation. Astragali radix (AR) is commonly used in the clinical treatment of cholestatic liver disease and its related liver fibrosis in traditional Chinese medicine, however its specific active constituents are not clear. Total astragalus saponins (ASTs) were considered to be the main active components of AR. The aim of this study is to investigate the improvement effects of the total astragalus saponins (ASTs) and its main constituents in cholestatic liver disease. The ASTs from AR was prepared by macroporous resin, the content of saponins was measured at 60.19 ± 1.68%. The ameliorative effects of ASTs (14, 28, 56 mg/kg) were evaluated by 3, 5-Diethoxycarbonyl-1, 4-dihydrocollidine (DDC)-induced CLD mouse model. The contents of hydroxyproline (Hyp), the mRNA and protein expression of cytokeratin 19 (CK19) and α-smooth muscle actin (α-SMA) in liver tissue were dose-dependently improved after treatment for ASTs. 45 astragalus saponins were identified in ASTs by UHPLC-Q-Exactive Orbitrap HRMS, including astragaloside I, astragaloside II, astragaloside III, astragaloside IV, isoastragaloside I, isoastragaloside II, cycloastragenol, etc. And, it was found that ductular reaction in sodium butyrate-induced WB-F344 cell model were obviously inhibited by these main constituents. Finally, the improvement effects of astragaloside I, astragaloside II, astragaloside IV and cycloastragenol (50 mg/kg) were evaluated in DDC-induced CLD mice model. The results showed that astragaloside I and cycloastragenol significantly improved mRNA and protein expression of CK19 and α-SMA in liver tissue. It suggested that astragaloside I and cycloastragenol could alleviate ductular reaction and liver fibrosis. In summary, this study revealed that ASTs could significantly inhibit ductular reaction and liver fibrosis, and astragaloside I and cycloastragenol were the key substances of ASTs for treating cholestatic liver disease.