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Background: Cholangitis is an uncommon and severe adverse reaction of nivolumab with unclear clinical features. The purpose of this study was to investigate the clinicopathological features, imaging, and treatment of nivolumab-induced cholangitis., Methods: Case reports, case series, and clinical studies of nivolumab-induced cholangitis were retrospectively analyzed by searching Chinese and English databases from January 1, 2017 to December 31, 2023., Results: Thirty-eight patients entered the study. The median number of cycles of cholangitis onset was seven cycles after administration (range 1, 28) and the median time was 11 days (range 78, 390). Abdominal pain (42.1%) and fever (18.4%) were the most important initial symptoms. Some patients (15.8%) showed elevated liver enzymes without any clinical symptoms. The median alkaline phosphatase level was 1721 IU/L (range 126, 9118), and the median γ-glutamyltranspeptidase level was 829 IU/L (range 104, 3442). Anti-nuclear antibodies, anti-mitochondrial antibodies, and IgG4 typically show negative results. Imaging shows extrahepatic bile duct and intrahepatic bile duct dilation, hypertrophy, and stenosis. Liver biopsy and biliary tract biopsy mainly found CD8 inflammatory cell infiltration. Systemic steroids (84.2%) and ursodeoxycholic acid (UDCA) (34.2%) were administered, and 24 patients (63.2%) had poor to moderate response to steroids. Thirty-one patients (81.6%) improved and seven patients (18.4%) did not improve., Conclusions: Clinicians must remain vigilant for patients experiencing cholestasis while on nivolumab and should assess for cholangitis and carry out appropriate imaging tests. Considering the excellent efficacy of UCDA in cholangitis, steroids combined with UDCA may be a viable treatment option in cases where steroids are ineffective for cholangitis.

Pembrolizumab induced hepatitis has received increasing attention, while pembrolizumab induced cholangitis is poorly understood. This study investigated the clinical features, treatment, and outcome of pembrolizumab induced cholangitis. Case reports, case series and clinical studies of pembrolizumab induced cholangitis were collected by retrieving English and Chinese database from inception until October 30, 2023. Fifty patients with cholecystitis entered our study with a median age of 68 years (range 48, 89). The median time to onset of cholecystitis was 1.1 months (range 0.3, 24), and the median number of cycles was 5 cycles (range 1, 27) after initial administration. Most of the patients had no clinical symptoms and only showed elevated biliary enzymes (24 cases, 48.0%), while some patients showed jaundice (12 cases, 24.0%), abdominal pain (10 cases, 20.0%) and fever (7 cases, 14.0%). The median alkaline phosphatase value was 1111 IU(range 130, 3515) and the median glutamyltransferase value was 649.5 IU(range 159, 3475). The imaging features of gallbladder were bile duct dilatation, stenosis and bile duct wall thickening and irregularity. Bile duct biopsy showed inflammatory infiltration, mainly CD8 + T cell infiltration. Immunosuppression treatment resulted in complete response in 4 cases (8.0%), partial response in 28 cases (56.0%), and poor response in 15 cases (30.0%). Cholangitis is a rare and serious adverse effect of pembrolizumab. Clinicians should be aware of the possibility of cholangitis when administering pembrolizumab. Steroids may not be effective in most patients with cholecystitis, and ursodeoxycholic acid may be an option., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Immune checkpoint inhibitors (ICIs) are remarkable anticancer therapies that have revolutionized the oncological prognosis of many cancers. 1 The considerable efficacy of ICIs is associated with the onset of more- or less-serious, immune-related adverse effects (irAEs) affecting several organs, which can concern up to 70% of patients, owing to a loss of self-tolerance during the restoration of antitumor immunity. 2 Checkpoint inhibitor-induced liver injury (CHILI), which may occur in up to 25% of patients, is treated with steroids as first-line treatment, and immunosuppressive drugs as second-line treatment. 3 Recently, ICI-induced cholangitis was described as an emerging irAE. Hence, Pi et al 4 reviewed all 53 published cases of ICI-induced cholangitis and compared the different types of bile duct involvement. We recently described CHILI according to the biological profile: cholestatic, hepatocellular, or mixed. 5 Cholestatic profiles were associated with macroscopic and/or microscopic bile duct damage, and time to resolution was significantly longer. More recently, Onoyama et al 6 and Parlati et al 7 described a poorer response to steroids in cases of biliary histologic damage or ICI-induced sclerosing cholangitis. The latest European Society for Medical Oncology guidelines include the management of cholangitis, which is succinct and still poorly documented. 3 The aim of this study therefore was to analyze the cases of ICI-induced cholangitis reported in the French pharmacovigilance system to describe their clinical characteristics, evolution, and outcome., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare that they have no conflict of interest.

Cholangitis has been reported as an immune-related adverse event, although it rarely occurs. Here we report a case of cholangitis due to atezolizumab in a 77-year-old woman who had been treated with atezolizumab and nab-paclitaxel for breast cancer and lung metastasis. On the seventh cycle, she presented with fever and epigastric pain, and computed tomography and endoscopic ultrasound showed slight wall thickening of the common bile duct, and transpapillary bile duct biopsy was performed. Pathologically, CD8 + T cells predominant infiltration was detected in the subepithelium of the bile duct, resulting in the diagnosis of atezolizumab-related cholangitis. The patient's symptoms were resolved immediately after discontinuing atezolizumab. Hepatobiliary enzymes returned to normal 21 days after onset, and bile duct wall thickening disappeared. Cholangitis should be included as the differential diagnosis of liver dysfunction in patients receiving immune checkpoint inhibitors., (© 2022. Japanese Society of Gastroenterology.)

Study Objective: Clinical trials have suggested that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may be associated with a higher risk of biliary-related diseases in patients with type 2 diabetes. Limited real-world studies have examined the comparative biliary safety of GLP-1RAs versus other antihyperglycemic drugs. We aimed to estimate the comparative risk of biliary-related diseases between GLP-1RAs and sodium glucose cotransporter 2 inhibitors (SGLT2is), which are indicated for patients with similar diabetes severity in Taiwan., Design: Retrospective cohort study., Data Source: Taiwan National Health Insurance Database during 2011 to 2018., Patients: Patients with type 2 diabetes who initiated GLP-1RAs or SGLT2is., Intervention: GLP-1RAs versus SGLT2is., Measurements and Main Results: We used an on-treatment approach to examine the effect of continuous use and an intention-to-treat approach to assess the effect of initiation of GLP-1RAs versus SGLT2is. We used Coxregression models to estimate the hazard ratios (HRs) and 95% confidenceintervals (CIs) for the composite hospitalized biliary-related diseases, including acute cholecystitis or cholecystectomy, choledocholithiasis, and acute cholangitis, after matching each GLP-1RA initiator to up to 10 SGLT2iinitiators using propensity scores (PSs). Among 78,253 PS-matched patients, GLP-1RA use was associated with a numerically higher risk of biliary-related diseases versus SGLT2i use in the on-treatment analysis, with an HR of 1.20 (95% CI, 0.93-1.56) for the composite outcome, an HR of 1.22 (95% CI, 0.92-1.62) for acute cholecystitis or cholecystectomy, an HR of 1.20 (95% CI, 0.69-2.07) for choledocholithiasis, and an HR of 1.14 (95% CI,0.82-2.42) for acute cholangitis. The HRs were more pronounced in theintention-to-treat analysis (1.27 [95% CI, 1.05-1.53] for the composite outcome, 1.29 [95% CI, 1.04-1.58] foracute cholecystitis or cholecystectomy, 1.74 [95% CI, 1.23-2.46] for choledocholithiasis, and 1.31 [95% CI, 0.89-1.94] for acute cholangitis). The increased risk of the composite outcome associated with GLP-1RAs was more evident in patients aged 〉60 years, women, and 120 days after treatment initiation. Liraglutide, but not dulaglutide, was associated with an elevated risk., Conclusions: GLP-1RAs might be associated with an elevated risk of biliary-related diseases compared to SGLT2is in Asian patients with type 2 diabetes., (© 2022 Pharmacotherapy Publications, Inc.)

A 60-year-old male with cStage IVB lung cancer was treated with pembrolizumab. However, after five courses of pembrolizumab, he developed pembrolizumab-related cholangitis. Imaging studies showed enlargement and diffuse wall thickening of the gallbladder and mild dilation of the bile ducts without any obvious obstruction. As the patient experienced severe abdominal pain, we suspected bile stasis and performed biliary drainage. However, his condition did not improve, and he developed multiple liver abscesses and died during immunosuppressive therapy. Our case suggests that in ir-cholangitis, the indication and method of endoscopic retrograde cholangiopancreatography should be carefully judged., (© 2022. Japanese Society of Gastroenterology.)

Immune checkpoint inhibitors (ICIs) cause various immune-related adverse events (irAEs). We encountered a patient in whom nivolumab was re-administered effectively and safely treat laryngeal cancer after nivolumab-induced cholangitis. A 60-year-old man with metastatic laryngeal squamous cell carcinoma received 3rd-line treatment with nivolumab. After the 8th cycle of chemotherapy, laboratory tests revealed grade 3 elevations of gamma-glutamyl transpeptidase and alkaline phosphatase. Computed tomography and endoscopic retrograde cholangiopancreatography showed diffuse hypertrophy, dilation of bile ducts, and intrahepatic bile ducts with irregular walls and mild stenosis. The histologic findings of a liver biopsy revealed portal inflammation and cholangitis, mainly composed of T cell infiltration. We diagnosed nivolumab-induced cholangitis and administered 30 mg of prednisolone (0.5 mg/kg) and ursodeoxycholic acid (600 mg) per day. Although we initiated 4th-line cytotoxic anticancer drug after the cholangitis improved, the laryngeal cancer progressed rapidly. Based on the improvement in hematologic parameters, radiologic imaging, and pathologic findings, we cautiously restarted nivolumab. During the 30 months after re-administration of nivolumab, the cholangitis did not recur and the disease was well-controlled., (© 2022. Japanese Society of Gastroenterology.)

Background: Multidrug-resistant bacteria (MDRB) has rapidly spread worldwide and become a serious problem. Proton pump inhibitors (PPIs) are a class of commonly prescribed medications, but recent studies have suggested the increased risk of infection with MDRB in PPI users. We evaluated the association between PPI use and incidence of cholangitis with MDRB., Methods: Consecutive patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) between January 2010 and August 2019 were included in this retrospective study. The incidence of cholangitis with MDRB was compared between regular and non-regular PPI users., Results: A total of 1224 regular PPI users and 1528 non-regular PPI users were identified. There was no clinically significant difference in age and sex between the groups. Indication of ERCP was different between the groups. The number of ERCP sessions during the study periods was higher in regular PPI users. The incidence of cholangitis with MDRB was significantly higher in regular PPI users (3.0% vs 1.1%; P < .001). Multivariable-adjusted odds ratio for cholangitis with MDRB comparing regular PPI users to non-regular users was 2.19 (95% confidence interval 1.20-4.00; P = .01)., Conclusions: Regular PPI use was associated with a higher risk of cholangitis with MDRB., (© 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background Aims: Immune checkpoint inhibitors (ICIs) improve the survival of patients with advanced tumors. However, immune-related adverse events limit the use of ICIs. Although liver toxicity has been concerned gradually, little is known about bile duct injury associated with ICIs. Hence, this review aims to describe clinicopathological features, imaging, and management of immune-mediated cholangitis (IMC) induced by ICIs., Methods: We retrieved the literature from the PubMed database for case reports and series of IMC induced by ICIs. IMC was then classified as small-ducts type, large-ducts type and mixed type. Biochemical parameters, pathological characteristics, imaging features, treatment and response were evaluated and compared among three patterns., Results: Fifty-three cases of IMC were enrolled. The median values of alkaline phosphatase and alanine transaminase of IMC were 1328 and 156 IU/L. The ALP level of the large-ducts type was higher than that of the small-ducts type (P = 0.021). The main pathological characteristics of small-ducts cholangitis were portal inflammation, bile duct injury and ductular reaction. The imaging features of large-duct cholangitis were bile duct dilatation, stenosis and bile duct wall thickening and irregularity. Forty-eight (90%) cases received immunosuppression therapy. Biliary enzymes reduced in 79% of cases receiving immunosuppression therapy, but only 8.5% of cases returned to normal. It took a long time for biliary enzymes to recover., Conclusions: The clinicians should be aware of the possibility of IMC if the biliary enzymes increase significantly after the use of ICIs. The liver function can be improved partially by immunosuppressive therapy in the majority of IMC., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Aims: Earlier diagnosis and treatment of intrahepatic cholangiocarcinoma (iCCA) are necessary to improve therapy, yet limited information is available about initiation and evolution of iCCA precursor lesions. Therefore, there is a need to identify mechanisms driving formation of precancerous lesions and their progression toward invasive tumors using experimental models that faithfully recapitulate human tumorigenesis., Approach and Results: To this end, we generated a mouse model which combines cholangiocyte-specific expression of Kras G12D with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet-induced inflammation to mimic iCCA development in patients with cholangitis. Histological and transcriptomic analyses of the mouse precursor lesions and iCCA were performed and compared with human analyses. The function of genes overexpressed during tumorigenesis was investigated in human cell lines. We found that mice expressing Kras G12D in cholangiocytes and fed a DDC diet developed cholangitis, ductular proliferations, intraductal papillary neoplasms of bile ducts (IPNBs), and, eventually, iCCAs. The histology of mouse and human IPNBs was similar, and mouse iCCAs displayed histological characteristics of human mucin-producing, large-duct-type iCCA. Signaling pathways activated in human iCCA were also activated in mice. The identification of transition zones between IPNB and iCCA on tissue sections, combined with RNA-sequencing analyses of the lesions supported that iCCAs derive from IPNBs. We further provide evidence that tensin-4 (TNS4), which is stimulated by KRAS G12D and SRY-related HMG box transcription factor 17, promotes tumor progression., Conclusions: We developed a mouse model that faithfully recapitulates human iCCA tumorigenesis and identified a gene cascade which involves TNS4 and promotes tumor progression., (© 2021 by the American Association for the Study of Liver Diseases.)

Ketamine is a versatile analgesic that has become an increasingly popular recreational drug. Chronic ketamine use has been found to cause biliary duct damage and bladder dysfunction. Ketamine-induced cholangiopathy and ulcerative cystitis are uncommon diagnoses presenting with nonspecific symptoms, creating diagnostic challenges for emergency physicians. We report a case of a teenage patient with the rare simultaneous presentation of ketamine-induced cholangiopathy and ulcerative cystitis. Due to increased recreational and chronic ketamine use, cases of ketamine-induced cholangiopathy and ulcerative cystitis are likely to rise with the increased knowledge, awareness, and reporting of these entities by radiologists and emergency physicians., Competing Interests: Declaration of Competing Interest All authors have read and approved the manuscript. This manuscript or related manuscripts have not been previously published and are not under consideration elsewhere. We have no conflicts of interest to declare. This article has no funding source., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Immune checkpoint inhibitor-related liver injury usually appears as a hepatitis pattern, with a cholangitis pattern being a rare immune-related adverse event. We report a Japanese man in his fifties with immune checkpoint inhibitor-induced cholangitis and gastritis. The patient had been treated for approximately 7 months with carboplatin, pemetrexed sodium hydrate, and bevacizumab for an undifferentiated cancer of unknown primary, with metastases to the right pleura and nasolacrimal duct. The patient was then treated with immune checkpoint inhibitors, including 2 months of atezolizumab followed by 1 month of ramucirumab and docetaxel. Laboratory examinations showed elevated levels of biliary tract enzymes. He complained of generalized fatigue. Computed tomography revealed thickening of the gallbladder and external hepatic bile duct walls and the periportal collar sign. Endoscopic retrograde cholangiopancreatography was negative for bile duct obstruction but showed diffuse asymmetric irregular findings from the hilar region to the distal bile duct. Upper endoscopy showed diffuse irregular erosions and redness. Histopathological examination of specimens of bile duct and gastric mucosa revealed CD8-predominant inflammatory cell infiltrates. We diagnosed the findings as immunotherapy-induced cholangitis and gastritis. Because there are no published reports on immunotherapyinduced cholangitis combined with gastritis, we here report our patient as a rare case.

Inflammatory diseases of the bile ducts like primary sclerosing colangitis (PSC) are characterized by a robust cellular response targeting the biliary epithelium leading to chronic inflammation and fibrosis. Driving fibro-inflammatory diseases, NOD-like receptors such as NLRP3 have been identified as a central component to immune-mediated pathology. However, to date the role of NLRP3 in biliary diseases has been poorly explored. Here, we addressed the role of NLRP3 in the OVAbil mouse model of antigen-mediated cholangitis. As obesity continues to spread worldwide, we also evaluated the NLRP3 response in experimental cholangitis after high-fat diet exposure. We compared the extent of histopathological liver damage between OVAbil and OVAbilxNLRP3-/- mice after either a standard chow or a high-fat diet. Infiltrating immune cells were characterized by flow cytometry and levels of cytokines, chemokines and liver enzymes in blood samples were analyzed at the end of the experiment. We observed a more severe histopathological phenotype of cholangitis in absence of NLRP3, characterized by loss of bile ducts and larger inflammatory foci and higher levels of IL- 6 and CXCL10 as compared with NLRP3 sufficient mice. This phenotype was further exaggerated in the context of obesity, where cholangitis induced in NLRP3-deficient obese mice resulted in further exacerbated histopathology and increased levels of IL-13 and TNFα, suggesting a diet-specific profile. The absence of NLRP3 caused a supressed IL-17 response. In summary, our data suggest that activation of NLRP3 attenuates this antigen-mediated OVAbil model of cholangitis., (© 2020 The Author(s).)

Background: Current animal models of chronic pancreatitis (CP) often provide only limited pathophysiological insights since they incompletely reflect the human disease. CP induced by injection of dibutyltin dichloride (DBTC-pancreatitis) shares with human CP the important feature of extended fibrosis and would be an even more attractive model if it could be transferred from rats to mice, as recently suggested in the context of combined ethanol and DBTC application. This study aimed to evaluate the effects of DBTC in pancreas and liver of C57BL/6 mice, a strain commonly used to engineer genetic mouse models., Methods: C57BL/6 mice and Lewis rats were exposed to variable doses of DBTC. After an investigation period of up to 4 weeks, laboratory findings and histopathological changes of pancreas and liver were evaluated., Results: Chronic DBTC-pancreatitis in rats was characterized by acinar cell damage, ductal changes, fibrosis, and inflammatory cell infiltrates. Mice treated with DBTC at 6-8 mg/kg body weight, the standard doses in rats, showed transient increases of lipase activities but no morphological signs of chronic DBTC-pancreatitis 4 weeks after injection of the drug. Increased doses of 10-12 mg/kg DBTC were intolerable due to their high toxicity. In contrast, mice and rats presented with a similar histopathology of the liver that can be characterized as a chronic-proliferative DBTC-cholangitis with predominating damage and proliferation of the small bile ducts as well as secondary portal inflammatory cell infiltrates and a beginning portal fibrosis., Conclusions: The DBTC-model cannot be transferred from rats to C57BL/6 mice with respect to chronic DBTC-pancreatitis, but might be of interest to study DBTC-cholangitis in both species., Competing Interests: Competing interest No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article., (Copyright © 2019. Published by Elsevier B.V.)

Background: A significant role in pathogenesis of cholangitis is attributed to excessive reactive oxygen species production and oxidative stress. Therefore, antioxidants could be promising therapeutics., Aims: The effects of powerful free radical scavenger C 60 fullerene on hepatic and pancreatic manifestations of acute and chronic cholangitis in rats were aimed to be discovered., Methods: Acute (AC, 3 days) and chronic (CC, 28 days) cholangitis models were simulated by single (AC) and 4 weekly (CC) α-naphthylisothiocyanate per os administrations. Pristine C 60 fullerene aqueous colloid solution (C 60 FAS, 0.15 mg/ml, size of aggregates 1.2-100 nm) was administered either per os or intraperitoneally at a dose of 0.5 mg/kg C 60 fullerene daily (AC) and every other day (CC). Prednisolone was used as a reference. Liver and pancreas autopsies were analyzed, and blood serum biochemical markers were measured. Pan-cytokeratin expression in HepG2 cells was assessed after 48-h incubation with C 60 FAS., Results: On AC, C 60 FAS normalized elevated bilirubin, alkaline phosphatase, and triglycerides, diminished fibrotic alterations in liver, and improved pancreas state when applied by both ways. Additionally, C 60 FAS per os significantly reduced the signs of inflammation in liver and pancreas. On CC, C 60 FAS also mitigated liver fibrosis and inflammation, improved pancreas state, and normalized alkaline phosphatase and triglycerides. The remedy effect of C 60 FAS was more expressed compared to that of prednisolone on both models. Furthermore, C 60 FAS inhibited pan-cytokeratin expression in HepG2 cells in a dose-dependent manner., Conclusion: Pristine C 60 fullerene inhibits liver inflammation and fibrogenesis and partially improved liver and pancreas state under acute and chronic cholangitis.

Increasing numbers of patients are now offered immunotherapy as part of their cancer treatment. These treatments, while often very effective, have a wide range of adverse effects that are distinct from those of traditional chemotherapy regimens. Thyroid disease, dermatological disease, colitis and pneumonitis are some of the most commonly reported immune side effects. We present a case of life-threatening de novo autoimmune haemolytic anaemia (AIHA) complicated by immune cholangitis induced by pembrolizumab. An 81-year-old woman with metastatic melanoma completed a two-year course of pembrolizumab in August 2018 and six weeks later presented to hospital with jaundice. Admission haemoglobin (Hb) was 91 g/L, rapidly decreasing to 31 g/L, at which point she required admission to the intensive care unit. AIHA is a rare but potentially life-threatening complication of checkpoint inhibitors and should be considered in patients presenting with anaemia during or after immunotherapy treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Proton pump inhibitor (PPI) use may alter the gut microbiome and increase the risk of cholangitis. However, the association of PPI use with the risk of incident cholangitis has not been evaluated., Aim: To evaluate whether PPI use was associated with a higher risk of cholangitis., Methods: This cohort study included a nationwide representative sample of the Korean general population followed up for 10 years (1 January 2003 to 31 December 2013). PPI use was identified from treatment claims and considered as a time-varying variable. Incident cholangitis was identified from hospitalisation and out-patient visit claims., Results: During 4 212 003 person-years of follow-up, 58,863 participants had at least one PPI prescription and 1 834 participants developed cholangitis. The age-, sex-, residential area- and income-adjusted hazard ratio (HR) for incident cholangitis comparing PPI use with non-use was 6.06 (95% CI, 4.64-7.91). The association was essentially unchanged in fully adjusted models (HR 5.75; 95% CI, 4.39-7.54). The risk was highest during PPI treatment and decreased gradually after PPI discontinuation (P trend  <.001)., Conclusions: In this large cohort, PPI use was associated with an increased risk of cholangitis. Physicians prescribing PPIs should consider cholangitis as a potential complication of PPI use., (© 2019 John Wiley & Sons Ltd.)

The patient was a 76-year-old man who was treated with nivolumab due to recurrent gastric cancer. A blood examination revealed grade 3 alkaline phosphatase (ALP) elevation. A histopathological examination revealed marked portal infiltration, including eosinophils and CD4+ and CD8+ T lymphocytes, suggesting nivolumab-related cholangitis accompanied by the features of both an immune-related adverse event (irAE) and drug-induced liver injury (DILI) with allergic reaction. The patient's ALP level immediately decreased after the administration of prednisolone. Although nivolumab-related cholangitis, a rare irAE, has been reported to be refractory to steroid therapy, patients with features of irAE and allergic DILI might immediately respond to prednisolone.

Background & Aims: Primary biliary cholangitis (PBC) is an autoimmune-associated chronic liver disease triggered by environmental factors, such as exposure to xenobiotics, which leads to a loss of tolerance to the lipoic acid-conjugated regions of the mitochondrial pyruvate dehydrogenase complex, typically to the E2 component. We aimed to identify xenobiotics that might be involved in the environmental triggering of PBC., Methods: Urban landfill and control soil samples from a region with high PBC incidence were screened for xenobiotic activities using analytical, cell-based xenobiotic receptor activation assays and toxicity screens., Results: A variety of potential xenobiotic classes were ubiquitously present, as identified by their interaction with xenobiotic receptors - aryl hydrocarbon receptor, androgen receptor and peroxisome proliferator activated receptor alpha - in cell-based screens. In contrast, xenoestrogens were present at higher levels in soil extracts from around an urban landfill. Furthermore, two landfill sampling sites contained a chemical(s) that inhibited mitochondrial oxidative phosphorylation and induced the apoptosis of a hepatic progenitor cell. The mitochondrial effect was also demonstrated in human liver cholangiocytes from three separate donors. The chemical was identified as the ionic liquid [3-methyl-1-octyl-1H-imidazol-3-ium] + (M8OI) and the toxic effects were recapitulated using authentic pure chemical. A carboxylate-containing human hepatocyte metabolite of M8OI, bearing structural similarity to lipoic acid, was also enzymatically incorporated into the E2 component of the pyruvate dehydrogenase complex via the exogenous lipoylation pathway in vitro., Conclusions: These results identify, for the first time, a xenobiotic in the environment that may be related to and/or be a component of an environmental trigger for PBC. Therefore, further study in experimental animal models is warranted, to determine the risk of exposure to these ionic liquids., Lay Summary: Primary biliary cholangitis is a liver disease in which most patients have antibodies to mitochondrial proteins containing lipoic acid binding site(s). This paper identified a man-made chemical present in soils around a waste site. It was then shown that this chemical was metabolized into a product with structural similarity to lipoic acid, which was capable of replacing lipoic acid in mitochondrial proteins., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Competing Interests: None

Background: Although very rare, pantoprazole can result in acute hepatitis. It has yet to be reported, however, that it can also cause chronic autoimmune hepatitis., Aim, Method and Results: We report the case of a patient in whom pantoprazole administration for 2 months was followed by acute liver injury with severe jaundice and features of autoimmunity. A liver biopsy revealed acute hepatocellular lesions associated with cholestasis, acute cholangitis and polymorphous inflammatory infiltration suggestive of drug-induced liver injury. The jaundice disappeared following discontinuation of the pantoprazole. There was, however, chronic autoimmune liver injury, with the occurrence of extensive liver fibrosis within a few months. This led to the administration of immunosuppressive agents, which led to progressive and complete recovery associated with the disappearance of autoantibodies., Conclusion: This observation further supports the notion that pantoprazole can induce acute hepatocellular hepatitis, and it strongly suggests that it may trigger acute cholangitis and autoimmune liver injury. This case also helps document that some drugs can induce chronic autoimmune hepatitis that can resolve with immunosuppressive treatment., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Anti-programmed cell death-1 (PD-1) monoclonal antibodies, such as nivolumab, used for the treatment of several tumors, can trigger effector T-cells against tumor- and self-antigens, leading to the occurrence of different immune-related adverse events. Among them, liver injuries are rare and usually transient. To date, only four cases of immune-related cholangitis in non-small cell lung cancer (NSCLC) patients have been described during nivolumab treatment. Here, we describe laboratory tests, imaging and liver biopsy features that confirm this diagnosis as opposed to other forms of autoimmune liver disease; nevertheless, we also provide evidence of the presence of different clinical-pathological patterns of immune-related cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the destruction of interlobular biliary ductules, which progressively leads to cholestasis, hepatic fibrosis, cirrhosis, and eventually liver failure. Several mouse models have been used to clarify the pathogenesis of PBC and are generally considered reflective of an autoimmune cholangitis. Most models focus on issues of molecular mimicry between the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the major mitochondrial autoantigen of PBC and xenobiotic cross reactive chemicals. None have focused on the classic models of breaking tolerance, namely immunization with self-tissue. Here, we report a novel mouse model of autoimmune cholangitis via immunization with syngeneic bile duct protein (BDP). Our results demonstrate that syngeneic bile duct antigens efficiently break immune tolerance of recipient mice, capturing several key features of PBC, including liver-specific inflammation focused on portal tract areas, increased number and activation state of CD4 and CD8 T cells in the liver and spleen. Furthermore, the germinal center (GC) responses in the spleen were more enhanced in our mouse model. Finally, these mice were 100% positive for anti-mitochondrial antibodies (AMAs). In conclusion, we developed a novel mouse model of PBC that may help to elucidate the detailed mechanism of this complex disease.

Background Nivolumab demonstrates promising efficacy for the treatment of non-small cell lung cancer and other malignancies. The clinical benefit of nivolumab, however, may be hampered by specific immune-related adverse events (irAEs), and little is known regarding nivolumab-related cholangitis. Methods A computerized search of our clinical database identified 3 metastatic non-small cell lung cancer patients with nivolumab-related cholangitis. All patients were treated with intravenous nivolumab monotherapy (3.0 mg/kg) every 2 weeks until disease progression or irAEs occurred. Clinical data regarding the duration of nivolumab treatment, symptoms, laboratory abnormalities, pathological findings of liver parenchyma biopsy specimens, and management of nivolumab-related cholangitis were analyzed. Results Our analysis revealed that nivolumab-related cholangitis was characterized by (1) localized extrahepatic bile duct dilation without obstruction; (2) diffuse hypertrophy of the extrahepatic bile duct wall; (3) a dominant increase in the biliary tract enzymes alkaline phosphatase and gamma-glutamyl transpeptidase relative to the hepatic enzymes aspartate and alanine aminotransferase; (4) normal or reduced levels of the serum immunological markers antinuclear antibody, antimitochondrial antibody, smooth muscle antibody, and immunoglobulin G4; (5) the pathological finding of biliary tract cluster of differentiation 8-positive T cell infiltration from liver biopsy; and (6) a moderate to poor response to steroid therapy. Conclusions Nivolumab-related cholangitis is associated with distinct imaging and clinicopathological features that distinguish it from acute cholangitis of common etiologies and other immune-related cholangitis. Further studies are warranted to establish the optimal management of patients with this irAE.

The identification of environmental factors that lead to loss of tolerance has been coined the holy grail of autoimmunity. Our work has focused on the reactivity of antimitochondrial autoantibodies (AMA) to chemical xenobiotics and has hypothesized that a modified peptide within PDC-E2, the major mitochondrial autoantigen, will have been immunologically recognized at the time of loss of tolerance. Herein, we successfully applied intein technology to construct a PDC-E2 protein fragment containing amino acid residues 177-314 of PDC-E2 by joining a recombinant peptide spanning residues 177-252 (PDC-228) with a 62-residue synthetic peptide from 253 to 314 (PP), which encompasses PDC-E2 inner lipoyl domain (ILD). We named this intein-constructed fragment PPL. Importantly, PPL, as well as lipoic acid conjugated PPL (LA-PPL) and xenobiotic 2-octynoic acid conjugated PPL (2OA-PPL), are recognized by AMA. Of great importance, AMA has specificity for the 2OA-modified PDC-E2 ILD peptide backbone distinct from antibodies that react with native lipoylated PDC-E2 peptide. Interestingly, this unique AMA subfraction is of the immunoglobulin M isotype and more dominant in early-stage primary biliary cholangitis (PBC), suggesting that exposure to 2OA-PPL-like compounds occurs early in the generation of AMA. To understand the structural basis of this differential recognition, we analyzed PPL, LA-PPL, and 2OA-PPL using electron paramagnetic resonance spectroscopy, with confirmations by enzyme-linked immunosorbent assay, immunoblotting, and affinity antibody analysis. We demonstrate that the conformation of PDC-E2 ILD is altered when conjugated with 2OA, compared to conjugation with lipoic acid., Conclusion: A molecular understanding of the conformation of xenobiotic-modified PDC-E2 is critical for understanding xenobiotic modification and loss of tolerance in PBC with widespread implications for a role of environmental chemicals in the induction of autoimmunity. (Hepatology 2017;65:1670-1682)., (© 2017 by the American Association for the Study of Liver Diseases.)

Aim: To establish a severe acute cholangitis (SAC) model in mice., Methods: Cholecystic catheterization was performed under the condition of bile duct ligation (BDL). Trans-cholecystic injection of lipopolysaccharide (LPS) was defined as the SAC animal model. Sham operation group, intraperitoneal injection of LPS without BDL group, intraperitoneal injection of LPS with BDL group and trans-cholecystic injection of normal saline with BDL group were defined as control groups. The survival rates and tissue injuries in liver, lungs and kidney were evaluated., Results: Mice in the SAC group showed a time-dependent mortality and much more severe tissue injuries in liver, lungs and kidney, compared with other groups. However, relieving biliary obstruction could effectively reduce mortality and attenuate liver injury in the SAC mouse model., Conclusion: Trans-cholecystic injection of LPS under the condition of biliary obstruction could establish a repeatable and reversible mouse model of SAC., Competing Interests: Conflict-of-interest statement: The authors declare that there are no other conflicts of interest.

Background: Gallbladder toxicity was reported in most motesanib studies with varying frequency and at variable times after initiation of treatment., Method and Results: A 44-year-old man was admitted due to severe epigastric pain. The patient was diagnosed with non-small cell lung cancer 9 months ago and received 6 cycles of chemotherapy with motesanib, paclitaxel, and carboplatin. Ultrasonography showed a large amount of sludge within gallbladder. Computed tomography scan demonstrated diffuse dilatation of biliary tree with distended gallbladder without evidence of stone and mild pancreatic swelling. Endoscopic retrograde cholangiopancreatography showed yellowish viscous mucoid plug impacting ampullary orifice and dilated bile duct with amorphous filling defect at distal half of common duct. Endoscopic sphincterotomy was performed to prevent biliary obstruction and recurrent pancreatitis after removal of mucoid material., Conclusion: To the best of our knowledge, this is the first report of obstructive cholangitis and acute pancreatitis associated with sludge formation during motesanib therapy. Endoscopic sphincterotomy appears to be useful to treat and prevent biliary obstruction caused by motesanib-induced biliary sludge.

Aim: To provoke persistent/chronic multiorgan inflammatory response and to contribute to stones formation followed by fibrosis in hepatobiliary and pancreatic tissues., Methods: Tumor necrosis factor receptors 1 and 2 (TNFR1/R2) deficient mice reared in-house were given dibutyltin dichloride (DBTC) twice within 10 d by oral gavage delivery. Sham control animals received vehicle treatment and naïve animals remained untreated throughout the study. Animals were monitored daily for symptoms of pain and discomfort. The abdominal and hindpaw hypersensitivity were assessed with von Frey microfilaments. Exploratory behaviors were recorded at the baseline, after initiation of treatment, and before study termination. Histopathological changes were examined postmortem in tissues. Collagen accumulation and fibrosis were confirmed with Sirius Red staining., Results: Animals lost weight after oral administration of DBTC and developed persistent inflammatory abdominal and hindpaw hypersensitivity compared to sham-treated controls (P < 0.0001). These pain related secondary mechanical hypersensitivity responses increased more than 2-fold in DBTC-treated animals. The drastically diminished rearing and grooming rates persisted after DBTC administration throughout the study. Gross as well as micropathology at one month confirmed that animals treated with DBTC developed chronic hepatobiliary injuries evidenced with activation of stellate cells, multifocal necrosis, fatty degeneration of hepatocytes, periportal infiltration of inflammatory cells, and prominent biliary ductal dilation. The severity of hepatitis was scored 3.7 ± 0.2 (severe) in DBTC-treated animals vs score 0 (normal) in sham-treated animals. Fibrotic thickening was extensive around portal ducts, in hepatic parenchyma as well as in lobular pancreatic structures and confirmed with Sirius Red histopathology. In addition, pancreatic microarchitecture was presented with distortion of islets, and parenchyma, infiltration of inflammatory cells, degeneration, vacuolization, and necrosis of acinar cells and distention of pancreatic ducts. Extent of pancreatic damage and pancreatitis were scored 3.6 ± 0.4 (severe) for DBTC-treated in contrast to score 0 (normal) in sham-treated animals. The gall bladder became expanded with ductal distention, and occasional bile stones were detected along with microscopic hepatic lesions. DBTC-treated animals developed splenic hypertrophy with increased weight and length (P < 0.01) along with thymic atrophy (P < 0.001). Finally, colitic lesions and colitis were prominent in DBTC-treated animals and scored 3.4 ± 0.3 (moderately severe) vs 0 (normal) for the sham-treated animals., Conclusion: This is the first report of chronic inflammatory multiorgan hepatobiliary pancreatitis, along with fibrosis and calculi formation induced reliably utilizing oral DBTC administration in TNFR1/R2 deficient mice.

When confronting a biliary stricture, both benign and malignant etiologies must be carefully considered as a variety of benign biliary strictures can masquerade as hilar cholangiocarcinoma (CCA). Therefore, patients could undergo a major surgery despite the possibility of a benign biliary disease. Approximately 15% to 24% of patients undergoing surgical resection for suspected biliary malignancy will have benign pathology. Eosinophilic cholangitis (EC) is a rare benign disorder of the biliary tract, which can cause obstructive jaundice and can pose a difficult diagnostic task. We present a rare case of a young woman who was referred to our hospital with obstructive painless jaundice due to a biliary stricture at the confluence of the hepatic bile ducts, with a provisional diagnosis of cholangiocarcinoma. Though, during her work up she was found to have EC, an extremely rare benign cause of biliary stricture, which is characterized by a dense eosinophilic infiltration of the biliary tree causing stricturing, fibrosis, and obstruction and which is reversible with short-term high-dose steroids. Despite its rarity, EC should be taken into consideration when imaging modalities demonstrate a biliary stricture, especially if preoperative diagnosis of malignancy cannot be made, in the setting of peripheral eosinophilia and the absence of cardinal symptoms of malignancy.

Cholangiopathy is a chronic immune-mediated disease of the liver, which is characterized by cholangitis, ductular reaction and biliary-type hepatic fibrosis. There is no proven medical therapy that changes the course of the disease. In previous studies, melittin was known for attenuation of hepatic injury, inflammation and hepatic fibrosis. This study investigated whether melittin provides inhibition on cholangitis and biliary fibrosis in vivo. Feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to mice is a well-established animal model to study cholangitis and biliary fibrosis. To investigate the effects of melittin on cholangiopathy, mice were fed with a 0.1% DDC-containing diet with or without melittin treatment for four weeks. Liver morphology, serum markers of liver injury, cholestasis markers for inflammation of liver, the degree of ductular reaction and the degree of liver fibrosis were compared between with or without melittin treatment DDC-fed mice. DDC feeding led to increased serum markers of hepatic injury, ductular reaction, induction of pro-inflammatory cytokines and biliary fibrosis. Interestingly, melittin treatment attenuated hepatic function markers, ductular reaction, the reactive phenotype of cholangiocytes and cholangitis and biliary fibrosis. Our data suggest that melittin treatment can be protective against chronic cholestatic disease in DDC-fed mice. Further studies on the anti-inflammatory capacity of melittin are warranted for targeted therapy in cholangiopathy.

In 35 patients who underwent balloon-occluded transarterial chemoembolization (B-TACE) for hepatocellular carcinoma (HCC) since January 2013, 5 patients (14%) had postoperative cholangitis, 1 of whom required drainage of a liver abscess. Four of these patients(80%)were treated with cisplatin (CDDP)-epirubicin (EPI)-Lipiodol (Lp) emulsion, and 1 was treated with EPI-Lp emulsion.The balloon was located and inflated at the lobar level (C: conventional)in 3 patients (60%) and at the subsegmental or more distal level (SS: superselective) in 2 patients (40%). Chemical vascular damage was considered to cause the cholangitis.We conclude that it is necessary to determine the optimal drug for B-TACE to reduce vascular damage. Miriplatin may be useful because of its lower vascular damage compared with CDDP-Lp and EPI-Lp.

Although primary biliary cirrhosis (PBC) is considered a model autoimmune disease, it has not responded therapeutically to traditional immunosuppressive agents. In addition, PBC may recur following liver transplantation, despite the absence of major histocompatibility complex (MHC) matching, in sharp contrast to the well-known paradigm of MHC restriction. We have suggested previously that invariant natural killer T (iNK T) cells are critical to the initiation of PBC. In this study we have taken advantage of our ability to induce autoimmune cholangitis with 2-octynoic acid, a common component of cosmetics, conjugated to bovine serum albumin (2-OA-BSA), and studied the natural history of pathology in mice genetically deleted for CD4 or CD8 following immunization with 2-OA-BSA in the presence or absence of α-galactosylceramide (α-GalCer). In particular, we address whether autoimmune cholangitis can be induced in the absence of traditional CD4 and CD8 responses. We report herein that CD4 and CD8 knock-out mice immunized with 2-OA-BSA/PBS or 2-OA-BSA/α-GalCer develop anti-mitochondrial antibodies (AMAs), portal infiltrates and fibrosis. Indeed, our data suggest that the innate immunity is critical for immunopathology and that the pathology is exacerbated in the presence of α-GalCer. In conclusion, these data provide not only an explanation for the recurrence of PBC following liver transplantation in the absence of MHC compatibility, but also suggest that effective therapies for PBC must include blocking of both innate and adaptive pathways., (© 2014 British Society for Immunology.)

Introduction: The aim of this study was to develop a model of fibrous cholangitis in the offspring of gravid domestic pigs through the administration of 1,4-phenylene diisothiocyanate (DITC)., Material and Methods: Six young domestic pigs and two gravid pigs with their offspring (21 pigs) were used as experimental models and six wild-type animals were used as controls. All pigs were divided into five main groups and five subgroups, according to their developmental stage and time of exposure to DITC. The following histopathological characteristics were quantitatively evaluated on a scale of 0-5: ductal proliferation, periportal fibrosis, inflammatory infiltration, periductal fibrosis and edema, intraluminal fibrosis, duct wall thickening, epithelial apoptosis, and arterial hyperplasia/hypertrophy., Results: Statistically significant differences were observed for most of the histopathological markers between the group of pigs' offspring that received DITC at early gestation and their control group. Moreover, the group of animals that were exposed to the agent at early gestation exhibited significant differences for all histopathological characteristics compared to the animals that were exposed at late gestation. On the other hand, no statistically significant differences were observed between the group of animals that received the agent at late gestation and their healthy controls., Conclusions: Administration of DITC to domestic pigs in early pregnancy may induce histopathological patterns of fibrous cholangitis to their offspring imitating biliary atresia. This model may provide insight to the pathogenesis of the obstructive cholangitis in pigs.