Publications by authors named "Verena Keitel"

97 Publications

[Commercial soda lime ingestion during a dive].

Anaesthesist 2021 Feb 16. Epub 2021 Feb 16.

Zentrale Notaufnahme, Universitätsklinikum Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Deutschland.

Breathing lime is used in closed circuit and semi-closed circuit rebreathers (CCR/SCR) for technical diving. Similar to the use in anesthesia systems, the lime usually contains hydroxycarbamide, which can react to caustic soda under the influence of water. The ingestion of components of the soda lime can lead to burns of the esophageal mucosa with the formation of colliquation necrosis and the danger of esophageal perforation. Early endoscopy is essential in this case to assess the consequences of ingestion.
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http://dx.doi.org/10.1007/s00101-021-00920-zDOI Listing
February 2021

Diagnosis and management of secondary causes of steatohepatitis.

J Hepatol 2021 Feb 9. Epub 2021 Feb 9.

Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. Electronic address:

The term non-alcoholic liver disease (NAFLD) was originally coined to describe hepatic fat deposition as part of the metabolic syndrome. However, a variety of rare hereditary liver and metabolic diseases, intestinal diseases, endocrine disorders and drugs may cause hepatic steatosis reminiscent of NAFLD, aggravate obesity-/metabolic syndrome-associated lipid deposition, or coexist with NAFLD. In contrast to NAFLD, therapeutic interventions are available for many secondary causes of NAFLD. Accordingly, secondary causes of fatty liver disease should be considered during the diagnostic workup of patients with fatty liver disease, and treatment of the underlying disease should be started to halt disease progression. Common genetic variants in several genes involved in lipid handling and metabolism modulate the risk of progression from steatosis to fibrosis, cirrhosis and HCC development in NAFLD, alcohol-related liver disease and viral hepatitis. Hence, we speculate that genotyping of common risk variants for liver disease progression may be equally useful to gauge the likelihood of developing advanced liver disease in patients with secondary fatty liver disease.
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http://dx.doi.org/10.1016/j.jhep.2021.01.045DOI Listing
February 2021

Dubin-Johnson Syndrome as Differential Diagnosis for Neonatal Cholestasis.

J Pediatr Gastroenterol Nutr 2021 Jan 28. Epub 2021 Jan 28.

Hannover Medical School, Division for Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver, and Metabolic Diseases, Hannover, Germany Hannover Medical School, Division for Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver, and Metabolic Diseases, Department of Human Genetics, Hannover, Germany Hannover Medical School, Institute of Pathology, Hannover, Germany University Hospital, Heinrich Heine University Duesseldorf, Department of Gastroenterology, Hepatology and Infectious Diseases, Duesseldorf, Germany.

Objectives: Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder in which multidrug-resistance-associated protein 2 (MRP2) deficiency causes an excretion disorder of conjugated bilirubin from hepatocytes into bile canaliculi. Its clinical presentation as neonatal cholestasis (NC) is rare but represents an important differential diagnosis. We aimed to define DJS specific characteristics in NC, in particular in contrast to biliary atresia (BA) patients, and to highlight diagnostic tools that can help to avoid invasive diagnostic tests.

Methods: We performed a review of case records from 2006 to 2020 and compared 4 DJS patients to 26 patients with proven BA consecutively diagnosed from 2014 to 2017. DJS was diagnosed by urine coproporphyrin analysis (UCA) and by genetic analysis (GA) for disease-associated ABCC2 variants.

Results: Four male patients with NC were diagnosed with DJS by UCA and GA. DJS patients presenting as NC showed significantly lower values for aspartate aminotransferase (AST) (p < 0.001), for alanine aminotransferase (ALT) (p = 0.002) and for gamma-glutamyl transferase (GGT) (p < 0.001) compared to BA patients. However, other examinations could not clearly discriminate them (e.g. stool colour, serum bile acids, total serum bilirubin).

Conclusions: DJS is a rare differential diagnosis in NC with a suspicious phenotype (almost normal AST, ALT) but also shows overlapping features with BA. It should, therefore, be considered in every infant with NC and an atypical liver enzyme pattern to protect patients from unnecessary, invasive examinations. For this, UCA is a fast and reliable diagnostic tool. Confirmation based on GA is recommended. DJS patients have a good long-term prognosis.
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http://dx.doi.org/10.1097/MPG.0000000000003061DOI Listing
January 2021

Sensitivity of anti-SARS-CoV-2 serological assays in a high-prevalence setting.

Eur J Clin Microbiol Infect Dis 2021 Feb 3. Epub 2021 Feb 3.

Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany.

Evaluation and power of seroprevalence studies depend on the performed serological assays. The aim of this study was to assess four commercial serological tests from EUROIMMUN, DiaSorin, Abbott, and Roche as well as an in-house immunofluorescence and neutralization test for their capability to identify SARS-CoV-2 seropositive individuals in a high-prevalence setting. Therefore, 42 social and working contacts of a German super-spreader were tested. Consistent with a high-prevalence setting, 26 of 42 were SARS-CoV-2 seropositive by neutralization test (NT), and immunofluorescence test (IFT) confirmed 23 of these 26 positive test results (NT 61.9% and IFT 54.8% seroprevalence). Four commercial assays detected anti-SARS-CoV-2 antibodies in 33.3-40.5% individuals. Besides an overall discrepancy between the NT and the commercial assays regarding their sensitivity, this study revealed that commercial SARS-CoV-2 spike-based assays are better to predict the neutralization titer than nucleoprotein-based assays are.
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http://dx.doi.org/10.1007/s10096-021-04169-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856849PMC
February 2021

Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients.

Genome Med 2021 01 13;13(1). Epub 2021 Jan 13.

Systems Medicine, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

Background: The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases call for a better characterization and understanding of the changes in the immune system.

Methods: In order to dissect COVID-19-driven immune host responses, we performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis. Additionally, publicly available data was used to show the distinction from COVID-19 to other diseases. Reverse drug target prediction was used to identify known or novel drug candidates based on finding from data-driven findings.

Results: Here, we profiled whole blood transcriptomes of 39 COVID-19 patients and 10 control donors enabling a data-driven stratification based on molecular phenotype. Neutrophil activation-associated signatures were prominently enriched in severe patient groups, which was corroborated in whole blood transcriptomes from an independent second cohort of 30 as well as in granulocyte samples from a third cohort of 16 COVID-19 patients (44 samples). Comparison of COVID-19 blood transcriptomes with those of a collection of over 3100 samples derived from 12 different viral infections, inflammatory diseases, and independent control samples revealed highly specific transcriptome signatures for COVID-19. Further, stratified transcriptomes predicted patient subgroup-specific drug candidates targeting the dysregulated systemic immune response of the host.

Conclusions: Our study provides novel insights in the distinct molecular subgroups or phenotypes that are not simply explained by clinical parameters. We show that whole blood transcriptomes are extremely informative for COVID-19 since they capture granulocytes which are major drivers of disease severity.
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http://dx.doi.org/10.1186/s13073-020-00823-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805430PMC
January 2021

Bile-Based Cell-Free DNA Analysis Is a Reliable Diagnostic Tool in Pancreatobiliary Cancer.

Cancers (Basel) 2020 Dec 25;13(1). Epub 2020 Dec 25.

Institute of Pathology, Heinrich-Heine-University and University Hospital of Duesseldorf, 40225 Duesseldorf, Germany.

Currently available serum biomarkers for pancreatobiliary cancers lack sensitivity and specificity and ultimate diagnosis still requires invasive procedures for histological confirmation. The detection of tumor-specific genetic aberrations with utilization of cell free DNA (cfDNA) is a less invasive approach than traditional tissue biopsies; however, it has not been implemented into clinical routine. In this study, we investigated bile as a liquid biopsy source in pancreatobiliary cancers and compared its potential as cell-free DNA source to plasma. Blood (n = 37) and bile (n = 21) samples were collected from patients affected by pancreatic ductal adenocarcinoma (PDAC) and extrahepatic cholangiocarcinoma (CCA) or with non-malignant biliary obstructions (blood n = 16; bile n = 21). Panel-based next generation sequencing (NGS) and digital droplet PCR (ddPCR) were applied for tumor mutation profiling. NGS results from matched tumor tissues (n = 29) served as comparison. Sequencing of cfDNA from bile resulted in detection of 96.2% of the pathogenic tumor mutations found in matched tissue samples. On the other hand, only 31.6% of pathogenic tumor mutations found in tissue could be detected in plasma. In a direct comparison, only half of the mutations detected in bile cfDNA were concordantly detected in plasma from the same patients. Panel NGS and ddPCR displayed comparable sensitivity. In conclusion, bile is a suitable source of cfDNA for the diagnosis of pancreatobiliary cancer and performs more reliably than plasma. Although primary diagnosis still requires histologic confirmation, bile-derived cfDNA could offer an alternative if tissue sampling is not feasible and might allow less invasive disease monitoring.
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http://dx.doi.org/10.3390/cancers13010039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818177PMC
December 2020

IL-17A/F enable cholangiocytes to restrict T cell-driven experimental cholangitis by upregulating PD-L1 expression.

J Hepatol 2020 Nov 13. Epub 2020 Nov 13.

Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Background & Aims: IL-17A-producing T cells are present in autoimmune cholestatic liver diseases; however, little is known about the contribution of IL-17 to periductal immune responses. Herein, we investigated the role of IL-17 produced by antigen-specific CD8 T cells in a mouse model of cholangitis and in vitro in human cholangiocyte organoids.

Methods: K14-OVAp mice express a major histocompatibility complex I-restricted ovalbumin (OVA) peptide sequence (SIINFEKL) on cholangiocytes. Cholangitis was induced by the adoptive transfer of transgenic OVA-specific ovalbumin transgene (OT)-1 CD8 T cells that either had OT-1 or lacked IL-17A/F (OT-1). The response of mouse and human cholangiocytes/organoids to IL-17A was assessed in vitro.

Results: Transfer of OVA-specific OT-1 cells significantly aggravated periductal inflammation in K14-OVAp recipient mice compared with transfer of OT-1 T cells. OT-1 T cells were highly activated in the liver and displayed increased cytotoxicity and proliferation. IL-17A/F produced by transferred OT-1 CD8 T cells induced upregulation of the inhibitory molecule programmed cell death ligand 1 (PD-L1) on cholangiocytes, restricting cholangitis by limiting cytotoxicity and proliferation of transferred cells. In contrast, OT-1 T cells failed to induce PD-L1 on cholangiocytes, resulting in uncontrolled expansion of cytotoxic CD8 T cells and aggravated cholangitis. Blockade of PD-L1 after transfer of OT-1 T cells with anti-PD-L1 antibody also resulted in aggravated cholangitis. Using human cholangiocyte organoids, we were able to confirm that IL-17A induces PD-L1 expression in cholangiocytes.

Conclusions: We demonstrate that by upregulating PD-L1 on cholangiocytes, IL-17 has an important role in restricting cholangitis and protecting against CD8 T cell-mediated inflammatory bile duct injury. Caution should be exercised when targeting IL-17 for the treatment of cholangitis.

Lay Summary: IL-17 is assumed to be a driver of inflammation in several autoimmune diseases, such as psoriasis. IL-17 is also present in inflammatory diseases of the bile duct, but its role in these conditions is not clear, as the effects of IL-17 depend on the context of its expression. Herein, we investigated the role of IL-17 in an experimental autoimmune cholangitis mouse model, and we identified an important protective effect of IL-17 on cholangiocytes, enabling them to downregulate bile duct inflammation via checkpoint inhibitor PD-L1.
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http://dx.doi.org/10.1016/j.jhep.2020.10.035DOI Listing
November 2020

Soluble Urokinase Receptor (SuPAR) in COVID-19-Related AKI.

J Am Soc Nephrol 2020 11 22;31(11):2725-2735. Epub 2020 Sep 22.

Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan

Background: AKI commonly occurs in patients with coronavirus disease 2019 (COVID-19). Its pathogenesis is poorly understood. The urokinase receptor system is a key regulator of the intersection between inflammation, immunity, and coagulation, and soluble urokinase plasminogen activator receptor (suPAR) has been identified as an immunologic risk factor for AKI. Whether suPAR is associated with COVID-19-related AKI is unknown.

Methods: In a multinational observational study of adult patients hospitalized for COVID-19, we measured suPAR levels in plasma samples from 352 adult patients that had been collected within 48 hours of admission. We examined the association between suPAR levels and incident in-hospital AKI.

Results: Of the 352 patients (57.4% were male, 13.9% were black, and mean age was 61 years), 91 (25.9%) developed AKI during their hospitalization, of whom 25 (27.4%) required dialysis. The median suPAR level was 5.61 ng/ml. AKI incidence rose with increasing suPAR tertiles, from a 6.0% incidence in patients with suPAR <4.60 ng/ml (first tertile) to a 45.8% incidence of AKI in patients with suPAR levels >6.86 ng/ml (third tertile). None of the patients with suPAR <4.60 ng/ml required dialysis during their hospitalization. In multivariable analysis, the highest suPAR tertile was associated with a 9.15-fold increase in the odds of AKI (95% confidence interval [95% CI], 3.64 to 22.93) and a 22.86-fold increase in the odds of requiring dialysis (95% CI, 2.77 to 188.75). The association was independent of inflammatory markers and persisted across subgroups.

Conclusions: Admission suPAR levels in patients hospitalized for COVID-19 are predictive of in-hospital AKI and the need for dialysis. SuPAR may be a key component of the pathophysiology of AKI in COVID-19.
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http://dx.doi.org/10.1681/ASN.2020060829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608953PMC
November 2020

Dose-optimised chest computed tomography for diagnosis of Coronavirus Disease 2019 (COVID-19) - Evaluation of image quality and diagnostic impact.

J Radiol Prot 2020 09;40(3):877-891

Medical Faculty, Department of Diagnostic and Interventional Radiology, University Hospital Düsseldorf, Düsseldorf D-40225, Germany.

Objectives: The detection of Coronavirus Disease 2019 (COVID-19) by reverse transcription polymerase chain reaction (RT-PCR) has varying sensitivity. Computed tomography (CT) of the chest can verify infection in patients with clinical symptoms and a negative test result, accelerating treatment and actions to prevent further contagion. However, CT employs ionising radiation. The purpose of this study was to evaluate protocol settings, associated radiation exposure, image quality and diagnostic performance of a low-dose CT protocol in a university hospital setting.

Materials And Methods: Chest CT examinations were performed on a single scanner (Somatom Definition Edge, Siemens Healthineers, Germany) in 105 symptomatic patients (60 male, 45 female). Images were evaluated with regard to protocol parameters, image quality, radiation exposure and diagnostic accuracy. Serial RT-PCR served as the standard of reference. Based on this reference standard sensitivity, specificity, positive and negative predictive values of CT with 95% confidence interval were calculated.

Results: The mean effective dose was 1.3 ± 0.4 mSv (0.7-2.9 mSv) for the patient cohort (mean age 66.6 ± 16.7 years (19-94 years), mean body mass index (BMI) 26.6 ± 5.3 kg m (16-46 kg/m)). A sensitivity of 100 [95% CI: 82-100]%, a specificity of 78 [95% CI: 68-86]%, a positive predictive value of 50 [95% CI: 33-67]% and a negative predictive value of 100 [95% CI: 95-100]% were obtained. No COVID-19 diagnoses were missed by CT. Image noise did not strongly correlate with BMI or patient diameter and was rated as average.

Conclusions: We presented a robust imaging procedure with a chest CT protocol for confident diagnosis of COVID-19. Even for an overweight patient cohort, an associated radiation exposure of only 1.3 ± 0.4 mSv was achieved with sufficient diagnostic quality to exclude COVID-19.
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http://dx.doi.org/10.1088/1361-6498/aba16aDOI Listing
September 2020

Genetic structure of SARS-CoV-2 reflects clonal superspreading and multiple independent introduction events, North-Rhine Westphalia, Germany, February and March 2020.

Euro Surveill 2020 Jun;25(22)

Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

We whole-genome sequenced 55 SARS-CoV-2 isolates from Germany to investigate SARS-CoV-2 outbreaks in 2020 in the Heinsberg district and Düsseldorf. While the genetic structure of the Heinsberg outbreak indicates a clonal origin, reflecting superspreading dynamics from mid-February during the carnival season, distinct viral strains were circulating in Düsseldorf in March, reflecting the city's international links. Limited detection of Heinsberg strains in the Düsseldorf area despite geographical proximity may reflect efficient containment and contact-tracing efforts.
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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.22.2000746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336109PMC
June 2020

[Secondary causes of fatty liver disease - an update on pathogenesis, diagnosis and treatment strategies].

Dtsch Med Wochenschr 2020 02 4;145(3):140-145. Epub 2020 Feb 4.

Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Düsseldorf.

Secondary causes of fatty liver disease are important to recognize since specific therapy options are available for some of these causes. Common causes of secondary fatty liver disease comprise hepatitis C virus infection (HCV), endocrinological diseases, nutritional and intestinal diseases as well as genetic liver and metabolic diseases. Certain drugs may also predispose to the development of fatty liver disease. Primary fatty liver disease, also known as non-alcoholic fatty liver disease (NAFLD) is defined by the presence of steatosis hepatis without relevant alcohol consumption or other causes of secondary fatty liver disease. NAFLD occurs more frequently in patients with metabolic syndrome and thus can be seen as the hepatic manifestation of the metabolic syndrome.Therefore, presence of features of the metabolic syndrome should be assessed in all patients with fatty liver disease. Furthermore, alcohol consumption should be determined to rule out alcoholic liver disease (ASH). Further diagnostic work up for secondary causes of fatty liver disease should include screening for HCV infection, for hypothyroidism and for drugs associated with steatosis development. In a next step screening for Wilson's disease, hemochromatosis, celiac disease and lipid metabolism disorders should be performed. An extended endocrinological workup and a liver biopsy should be considered if the etiology of fatty liver disease remains unclear.Common genetic polymorphisms have been identified in several genes, such as PNPLA3, TM6SF2 and MBOAT7, which may promote the development and the progression of fatty liver disease irrespective of the underlying etiology (e. g. metabolic syndrome, ASH or HCV). The risk variants in these genes have additive effects on steatosis development and diseases progression towards fibrosis and cirrhosis. The diagnosis of secondary causes of fatty liver disease may allow for therapeutic intervention and prevent disease progression. Accordingly, secondary causes of fatty liver disease should be considered during the diagnostic workup of NAFLD patients.
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http://dx.doi.org/10.1055/a-0965-9648DOI Listing
February 2020

Dimerization energetics of the G-protein coupled bile acid receptor TGR5 from all-atom simulations.

J Comput Chem 2020 04 27;41(9):874-884. Epub 2019 Dec 27.

Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany.

We describe the first extensive energetic evaluation of GPCR dimerization on the atomistic level by means of potential of mean force (PMF) computations and implicit solvent/implicit membrane end-point free energy calculations (MM-PBSA approach). Free energies of association computed from the PMFs show that the formation of both the 1/8 and 4/5 interface is energetically favorable for TGR5, the first GPCR known to be activated by hydrophobic bile acids and neurosteroids. Furthermore, formation of the 1/8 interface is favored over that of the 4/5 interface. Both results are in line with our previous FRET experiments in live cells. Differences in lipid-protein interactions are identified to contribute to the observed differences in free energies of association. A per-residue decomposition of the MM-PBSA effective binding energy reveals hot spot residues specific for both interfaces that form clusters. This knowledge may be used to guide the design of dimerization inhibitors or perform mutational studies to explore physiological consequences of distorted TGR5 association. Finally, we characterized the role of Y111, located in the conserved (D/E)RY motif, as a facilitator of TGR5 interactions. The types of computations performed here should be transferable to other transmembrane proteins that form dimers or higher oligomers as long as good structural models of the dimeric or oligomeric states are available. Such computations may help to overcome current restrictions due to an imperfect energetic representation of protein association at the coarse-grained level. © 2019 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcc.26135DOI Listing
April 2020

The G Protein-Coupled Bile Acid Receptor TGR5 (Gpbar1) Modulates Endothelin-1 Signaling in Liver.

Cells 2019 11 19;8(11). Epub 2019 Nov 19.

Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.

TGR5 (Gpbar1) is a G protein-coupled receptor responsive to bile acids (BAs), which is expressed in different non-parenchymal cells of the liver, including biliary epithelial cells, liver-resident macrophages, sinusoidal endothelial cells (LSECs), and activated hepatic stellate cells (HSCs). Mice with targeted deletion of TGR5 are more susceptible towards cholestatic liver injury induced by cholic acid-feeding and bile duct ligation, resulting in a reduced proliferative response and increased liver injury. Conjugated lithocholic acid (LCA) represents the most potent TGR5 BA ligand and LCA-feeding has been used as a model to rapidly induce severe cholestatic liver injury in mice. Thus, TGR5 knockout (KO) mice and wildtype (WT) littermates were fed a diet supplemented with 1% LCA for 84 h. Liver injury and gene expression changes induced by the LCA diet revealed an enrichment of pathways associated with inflammation, proliferation, and matrix remodeling. Knockout of TGR5 in mice caused upregulation of endothelin-1 (ET-1) expression in the livers. Analysis of TGR5-dependent ET-1 signaling in isolated LSECs and HSCs demonstrated that TGR5 activation reduces ET-1 expression and secretion from LSECs and triggers internalization of the ET-1 receptor in HSCs, dampening ET-1 responsiveness. Thus, we identified two independent mechanisms by which TGR5 inhibits ET-1 signaling and modulates portal pressure.
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http://dx.doi.org/10.3390/cells8111467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912679PMC
November 2019

Incidental F-FDG uptake in the colon: value of contrast-enhanced CT correlation with colonoscopic findings.

Eur J Nucl Med Mol Imaging 2020 04 7;47(4):778-786. Epub 2019 Nov 7.

Department of Diagnostic and Interventional Radiology, Medical Faculty, University Dusseldorf, Moorenstrasse 5, D-40225, Dusseldorf, Germany.

Objectives: To evaluate the impact of morphological information derived from contrast-enhanced CT in the characterization of incidental focal colonic uptake in F-FDG PET/CT examinations.

Methods: A total of 125 patients (female: n = 53, male: n = 72) that underwent colonoscopy secondary to contrast-enhanced, full-dose PET/CT without special bowel preparation were included in this retrospective study. PET/CT examinations were assessed for focal colonic tracer uptake in comparison with the background. Focal tracer uptake was correlated with morphological changes of the colonic wall in the contrast-enhanced CT images. Colonoscopy reports were evaluated for benign, inflammatory, polypoid, precancerous, and cancerous lesions verified by histopathology, serving as a reference standard. Sensitivity, specificity, PPV, NPV, and accuracy for detection of therapeutic relevant findings were calculated for (a) sole focal tracer uptake and (b) focal tracer uptake with correlating CT findings in contrast-enhanced CT.

Results: In 38.4% (48/125) of the patients, a focal F-FDG uptake was observed within 67 lesions. Malignant lesions were endoscopically and histopathologically diagnosed in eleven patients, and nine of these were detected by focal F-FDG uptake. A total of 34 lesions with impact on short- or long-term patient management (either being pre- or malignant) were detected. Sensitivity, Specificity, PPV, NPV, and accuracy for sole F-FDG uptake for this combined group were 54%, 69%, 29%, 85%, and 65%. Corresponding results for focal F-FDG uptake with correlating CT findings were 38%, 90%, 50%, 86%, and 80%. This resulted in a statistically significant difference for diagnostic accuracy (p = 0.0001) CONCLUSION: By analyzing additional morphological changes in contrast-enhanced CT imaging, the specificity of focal colonic F-FDG uptake for precancerous and cancerous lesions can be increased but leads to a considerate loss of sensitivity. Therefore, every focal colonic uptake should be followed up by colonoscopy.
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http://dx.doi.org/10.1007/s00259-019-04579-yDOI Listing
April 2020

iRhom2 inhibits bile duct obstruction-induced liver fibrosis.

Sci Signal 2019 10 29;12(605). Epub 2019 Oct 29.

Department of Molecular Medicine II, Medical Faculty, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.

Chronic liver disease can induce prolonged activation of hepatic stellate cells, which may result in liver fibrosis. Inactive rhomboid protein 2 (iRhom2) is required for the maturation of A disintegrin and metalloprotease 17 (ADAM17, also called TACE), which is responsible for the cleavage of membrane-bound tumor necrosis factor-α (TNF-α) and its receptors (TNFRs). Here, using the murine bile duct ligation (BDL) model, we showed that the abundance of iRhom2 and activation of ADAM17 increased during liver fibrosis. Consistent with this, concentrations of ADAM17 substrates were increased in plasma samples from mice after BDL and in patients suffering from liver cirrhosis. We observed increased liver fibrosis, accelerated disease progression, and an increase in activated stellate cells after BDL in mice lacking iRhom2 ( ) compared to that in controls. In vitro primary mouse hepatic stellate cells exhibited iRhom2-dependent shedding of the ADAM17 substrates TNFR1 and TNFR2. In vivo TNFR shedding after BDL also depended on iRhom2. Treatment of mice with the TNF-α inhibitor etanercept reduced the presence of activated stellate cells and alleviated liver fibrosis after BDL. Together, these data suggest that iRhom2-mediated inhibition of TNFR signaling protects against liver fibrosis.
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http://dx.doi.org/10.1126/scisignal.aax1194DOI Listing
October 2019

Fragile X mental retardation protein protects against tumour necrosis factor-mediated cell death and liver injury.

Gut 2020 01 13;69(1):133-145. Epub 2019 Aug 13.

Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany

Objective: The Fragile X mental retardation (FMR) syndrome is a frequently inherited intellectual disability caused by decreased or absent expression of the FMR protein (FMRP). Lack of FMRP is associated with neuronal degradation and cognitive dysfunction but its role outside the central nervous system is insufficiently studied. Here, we identify a role of FMRP in liver disease.

Design: Mice lacking gene expression were used to study the role of FMRP during tumour necrosis factor (TNF)-induced liver damage in disease model systems. Liver damage and mechanistic studies were performed using real-time PCR, Western Blot, staining of tissue sections and clinical chemistry.

Results: mice exhibited increased liver damage during virus-mediated hepatitis following infection with the lymphocytic choriomeningitis virus. Exposure to TNF resulted in severe liver damage due to increased hepatocyte cell death. Consistently, we found increased caspase-8 and caspase-3 activation following TNF stimulation. Furthermore, we demonstrate FMRP to be critically important for regulating key molecules in TNF receptor 1 (TNFR1)-dependent apoptosis and necroptosis including CYLD, c-FLIP and JNK, which contribute to prolonged RIPK1 expression. Accordingly, the RIPK1 inhibitor Necrostatin-1s could reduce liver cell death and alleviate liver damage in mice following TNF exposure. Consistently, FMRP-deficient mice developed increased pathology during acute cholestasis following bile duct ligation, which coincided with increased hepatic expression of RIPK1, RIPK3 and phosphorylation of MLKL.

Conclusions: We show that FMRP plays a central role in the inhibition of TNF-mediated cell death during infection and liver disease.
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http://dx.doi.org/10.1136/gutjnl-2019-318215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943250PMC
January 2020

Bile Acid-Activated Receptors: GPBAR1 (TGR5) and Other G Protein-Coupled Receptors.

Handb Exp Pharmacol 2019 ;256:19-49

Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Düsseldorf, Germany.

The BA-responsive GPCRs S1PR2 and TGR5 are almost ubiquitously expressed in human and rodent tissues. In the liver, S1PR2 is expressed in all cell types, while TGR5 is predominately found in non-parenchymal cells. In contrast to S1PR2, which is mainly activated by conjugated bile acids (BAs), all BAs serve as ligands for TGR5 irrespective of their conjugation state and substitution pattern.Mice with targeted deletion of either S1PR2 or TGR5 are viable and develop no overt phenotype. In liver injury models, S1PR2 exerts pro-inflammatory and pro-fibrotic effects and thus aggravates liver damage, while TGR5 mediates anti-inflammatory, anti-cholestatic, and anti-fibrotic effects. Thus, inhibitors of S1PR2 signaling and agonists for TGR5 have been employed to attenuate liver injury in rodent models for cholestasis, nonalcoholic steatohepatitis, and fibrosis/cirrhosis.In biliary epithelial cells, both receptors activate a similar signaling cascade resulting in ERK1/2 phosphorylation and cell proliferation. Overexpression of both S1PR2 and TGR5 was found in human cholangiocarcinoma tissue as well as in CCA cell lines, where stimulation of both GPCRs resulted in transactivation of the epidermal growth factor receptor and triggered cell proliferation as well as increased cell migration and invasiveness.This chapter will focus on the function of S1PR2 and TGR5 in different liver cell types and summarizes current knowledge on the role of these receptors in liver disease models.
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http://dx.doi.org/10.1007/164_2019_230DOI Listing
September 2019

Targeting FXR in Cholestasis.

Handb Exp Pharmacol 2019 ;256:299-324

Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Düsseldorf, Germany.

The farnesoid X receptor (FXR, NR1H4) is a bile acid (BA)-activated transcription factor, which is essential for BA homeostasis. FXR and its hepatic and intestinal target genes, small heterodimer partner (SHP, NR0B2) and fibroblast growth factor 15/19 (Fgf15 in mice, FGF19 in humans), transcriptionally regulate BA synthesis, detoxification, secretion, and absorption in the enterohepatic circulation. Furthermore, FXR modulates a large variety of physiological processes, such as lipid and glucose homeostasis as well as the inflammatory response. Targeted deletion of FXR renders mice highly susceptible to cholic acid feeding resulting in cholestatic liver injury, weight loss, and increased mortality. Combined deletion of FXR and SHP spontaneously triggers early-onset intrahepatic cholestasis in mice resembling human progressive familial intrahepatic cholestasis (PFIC). Reduced expression levels and activity of FXR have been reported in human cholestatic conditions, such as PFIC type 1 and intrahepatic cholestasis of pregnancy. Recently, two pairs of siblings with homozygous FXR truncation or deletion variants were identified. All four children suffered from severe, early-onset PFIC and liver failure leading to death or need for liver transplantation before the age of 2. These findings underscore the central role of FXR as regulator of systemic and hepatic BA levels. Therefore, targeting FXR has been exploited in different animal models of both intrahepatic and obstructive cholestasis, and the first FXR agonist obeticholic acid (OCA) has been approved for the treatment of primary biliary cholangitis (PBC). Further FXR agonists as well as a FGF19 analogue are currently tested in clinical trials for different cholestatic liver diseases. This chapter will summarize the current knowledge on the role of FXR in cholestasis both in rodent models and in human diseases.
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http://dx.doi.org/10.1007/164_2019_231DOI Listing
September 2019

A rare cause of a cholestatic jaundice in a North African teenager.

Liver Int 2019 11 24;39(11):2036-2041. Epub 2019 Jul 24.

Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland.

We report an unusual case of intermittent episodes of cholestasis in a young patient. The cholestatic attacks were preceded in each case by an infection and subsequent antibiotic therapies. After ruling out many possible causes of cholestatic hepatitis, the differential diagnoses were a benign recurrent intrahepatic cholestasis or a drug-induced liver injury. We discuss here the diagnostic approach and interpretation of the genetic analysis.
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http://dx.doi.org/10.1111/liv.14122DOI Listing
November 2019

Reply.

Hepatology 2019 09;70(3):1074-1075

Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

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http://dx.doi.org/10.1002/hep.30600DOI Listing
September 2019

Alloimmunity and Cholestasis After Liver Transplantation in Children With Progressive Familial Intrahepatic Cholestasis.

J Pediatr Gastroenterol Nutr 2019 Feb;68(2):169-174

University Children's Hospital, Pediatric Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg.

Objectives: Bile salt export pump (BSEP) deficiency is an important reason for chronic cholestasis leading to liver transplantation (LT) in early childhood. The underlying pathology is a dysfunction of BSEP due to various mutations in the ABCB11 gene. Cases of clinical recurrence after LT due to alloantibodies directed against BSEP (antibody-induced BSEP deficiency [AIBD]) have been reported. Most of these patients could be controlled by intensified immunosuppression.

Methods: We here report on 3 children with BSEP-deficiency and end-stage liver disease, which developed AIBD after LT refractory to extensive immunosuppressive and immunomodulatory treatments; retransplantation was necessary in all 3 patients. In 1 patient, a stem cell transplantation was performed successfully.

Results: AIBD seems to be induced by triggering factors such as initial impaired graft function or infections after LT.

Conclusions: The underlying mutation may play a role in this process. Intensifying immunosuppression may be able to control AIBD, but some cases seem to be refractory to treatment and require retransplantation. Stem cell transplantation may provide a new therapeutic option for cases refractory to conservative treatment.
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http://dx.doi.org/10.1097/MPG.0000000000002200DOI Listing
February 2019

Serum IP-10 levels and increased DPPIV activity are linked to circulating CXCR3+ T cells in cholestatic HCV patients.

PLoS One 2018 3;13(12):e0208225. Epub 2018 Dec 3.

Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany.

Background & Aims: Serum interferon-gamma-inducible protein-10 (IP-10) is elevated in cholestatic liver diseases and predicts response to antiviral therapy in patients with chronic hepatitis C virus (HCV) infection. Dipeptidylpeptidase 4 (DPPIV) cleaves active IP-10 into an inactive form, which inhibits recruitment of CXCR3+ T cells to the liver. In this study the link between IP-10 levels, DPPIV activity in serum and CXCR3+ T cells is analysed in cholestatic and non-cholestatic liver patients.

Methods: In serum DPPIV activity (by enzymatic assay), IP-10 (by ELISA) and bile acids (BA) (by enzymatic assay) were analysed in 229 naive HCV genotype (GT) 1 patients and in 16 patients with cholestatic liver disease. In a prospective follow-up (FU) cohort of 27 HCV GT 1 patients peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ cells were measured by FACS.

Results: In 229 HCV patients serum IP-10 levels correlated positively to DPPIV serum activity. Higher IP-10 levels and DPPIV activity were detected in cholestatic and in cirrhotic HCV patients. Increased IP-10 serum levels were associated with therapeutic non-response to antiviral treatment with pegylated-interferon and ribavirin. In the HCV FU cohort elevated IP-10 serum levels and increased BA were associated with higher frequencies of peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ T cells. Positive correlation between serum IP-10 levels and DPPIV activity was likewise validated in patients with cholestatic liver diseases.

Conclusions: A strong correlation between elevated serum levels of IP-10 and DPPIV activity was seen in different cholestatic patient groups. Furthermore, in cholestatic HCV patients a functional link to increased numbers of peripheral CXCR3+ immune cells could be observed. The source of DPPIV release in cholestatic patients remains open.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208225PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277069PMC
May 2019

Nuclear Translocation of RELB Is Increased in Diseased Human Liver and Promotes Ductular Reaction and Biliary Fibrosis in Mice.

Gastroenterology 2019 03 13;156(4):1190-1205.e14. Epub 2018 Nov 13.

Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany. Electronic address:

Background & Aims: Cholangiocyte proliferation and ductular reaction contribute to the onset and progression of liver diseases. Little is known about the role of the transcription factor nuclear factor-κB (NF-κB) in this process. We investigated the activities of the RELB proto-oncogene NF-κB subunit in human cholangiocytes and in mouse models of liver disease characterized by a ductular reaction.

Methods: We obtained liver tissue samples from patients with primary sclerosing cholangitis, primary biliary cholangitis, hepatitis B or C virus infection, autoimmune hepatitis, alcoholic liver disease, or without these diseases (controls) from a tissue bank in Germany. Tissues were analyzed by immunohistochemistry for levels of RELB and lymphotoxin β (LTB). We studied mice with liver parenchymal cell (LPC)-specific disruption of the cylindromatosis (CYLD) lysine 63 deubiquitinase gene (Cyld), with or without disruption of Relb (Cyld mice and Cyld/Relb mice) and compared them with C57BL/6 mice (controls). Mice were fed 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or standard chow diets to induce biliary injury or were given injections of CCl to induce non-cholestatic liver fibrosis. Liver tissues were analyzed by histology, immunohistochemistry, immunoblots, in situ hybridization, and quantitative real-time polymerase chain reaction. Cholangiocytes were isolated from normal human liver, incubated with LTB receptor agonist, and transfected with small interfering RNAs to knock down RELB.

Results: In liver tissues from patients with primary sclerosing cholangitis, primary biliary cholangitis, chronic infection with hepatitis B or C virus, autoimmune hepatitis, or alcoholic liver disease, we detected increased nuclear translocation of RELB and increased levels of LTB in cholangiocytes that formed reactive bile ducts compared with control liver tissues. Human cholangiocytes, but not those with RELB knockdown, proliferated with exposure to LTB. The phenotype of Cyld mice, which included ductular reaction, oval cell activation, and biliary fibrosis, was completely lost from Cyld/Relb mice. Compared with livers from control mice, livers from Cyld mice (but not Cyld/Relb mice) had increased levels of mRNAs encoding cytokines (LTB; CD40; and tumor necrosis factor superfamily [TNFSF] members TNFSF11 [RANKL], TNFSF13B [BAFF], and TNFSF14 [LIGHT]) produced by reactive cholangiocytes. However, these strains of mice developed similar levels of liver fibrosis in response to CCl exposure. Cyld mice and Cyld/Relb mice had improved liver function on the DDC diet compared with control mice fed the DDC diet.

Conclusion: Reactive bile ducts in patients with chronic liver diseases have increased levels of LTB and nuclear translocation of RELB. RELB is required for the ductular reaction and development of biliary fibrosis in Cyld mice. Deletion of RELB and CYLD from LPCs protects mice from DDC-induced cholestatic liver fibrosis.
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http://dx.doi.org/10.1053/j.gastro.2018.11.018DOI Listing
March 2019

The Epidermal Growth Factor Receptor Ligand Amphiregulin Protects From Cholestatic Liver Injury and Regulates Bile Acids Synthesis.

Hepatology 2019 04 4;69(4):1632-1647. Epub 2019 Mar 4.

Hepatology Program, University of Navarra, Cima, Pamplona, Spain.

Intrahepatic accumulation of bile acids (BAs) causes hepatocellular injury. Upon liver damage, a potent protective response is mounted to restore the organ's function. Epidermal growth factor receptor (EGFR) signaling is essential for regeneration after most types of liver damage, including cholestatic injury. However, EGFR can be activated by a family of growth factors induced during liver injury and regeneration. We evaluated the role of the EGFR ligand, amphiregulin (AREG), during cholestatic liver injury and regulation of AREG expression by BAs. First, we demonstrated increased AREG levels in livers from patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). In two murine models of cholestatic liver injury, bile duct ligation (BDL) and alpha-naphthyl-isothiocyanate (ANIT) gavage, hepatic AREG expression was markedly up-regulated. Importantly, Areg mice showed aggravated liver injury after BDL and ANIT administration compared to Areg mice. Recombinant AREG protected from ANIT and BDL-induced liver injury and reduced BA-triggered apoptosis in liver cells. Oral BA administration induced ileal and hepatic Areg expression, and, interestingly, cholestyramine feeding reduced postprandial Areg up-regulation in both tissues. Most interestingly, Areg mice displayed high hepatic cholesterol 7 α-hydroxylase (CYP7A1) expression, reduced serum cholesterol, and high BA levels. Postprandial repression of Cyp7a1 was impaired in Areg mice, and recombinant AREG down-regulated Cyp7a1 mRNA in hepatocytes. On the other hand, BAs promoted AREG gene expression and protein shedding in hepatocytes. This effect was mediated through the farnesoid X receptor (FXR), as demonstrated in Fxr mice, and involved EGFR transactivation. Finally, we show that hepatic EGFR expression is indirectly induced by BA-FXR through activation of suppressor of cytokine signaling-3 (SOC3). Conclusion: AREG-EGFR signaling protects from cholestatic injury and participates in the physiological regulation of BA synthesis.
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http://dx.doi.org/10.1002/hep.30348DOI Listing
April 2019

Role of TGR5 (GPBAR1) in Liver Disease.

Semin Liver Dis 2018 Nov 24;38(4):333-339. Epub 2018 Oct 24.

Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Düsseldorf, Germany.

TGR5 (GPBAR1) is a G protein-coupled receptor activated by primary and secondary bile acids, which is expressed in different nonparenchymal cells of the liver, such as sinusoidal endothelial cells, Kupffer cells, cholangiocytes as well as activated hepatic stellate cells. In liver, TGR5 modulates microcirculation, inflammation, regeneration, biliary secretion and proliferation as well as gallbladder filling. Absence of TGR5 renders mice more susceptible toward infectious, inflammatory, metabolic as well as cholestatic liver injuries. It is unknown whether TGR5 plays a role in the pathogenesis of human nonalcoholic steatohepatitis and cholestatic liver diseases such as primary sclerosing cholangitis and primary biliary cholangitis. However, overexpression of TGR5 has been detected in human intra- and extrahepatic cholangiocarcinoma as well as in cystic cholangiocytes, where the receptor promotes cell proliferation, anti-apoptosis as well as cyst growth. While TGR5 agonists may improve various aspects of metabolic, inflammatory, and cholestatic liver diseases, TGR5 inhibitors may attenuate disease progression in polycystic liver disease and cholangiocarcinoma.
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http://dx.doi.org/10.1055/s-0038-1669940DOI Listing
November 2018

Bile Acid G Protein-Coupled Membrane Receptor TGR5 Modulates Aquaporin 2-Mediated Water Homeostasis.

J Am Soc Nephrol 2018 11 10;29(11):2658-2670. Epub 2018 Oct 10.

Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China;

Background: The bile acid-activated receptors, including the membrane G protein-coupled receptor TGR5 and nuclear farnesoid X receptor (FXR), have roles in kidney diseases. In this study, we investigated the role of TGR5 in renal water handling and the underlying molecular mechanisms.

Methods: We used tubule suspensions of inner medullary collecting duct (IMCD) cells from rat kidneys to investigate the effect of TGR5 signaling on aquaporin-2 (AQP2) expression, and examined the effects of TGR5 in mice with lithium-induced nephrogenic diabetes insipidus (NDI) and knockout () mice.

Results: Activation of TGR5 by lithocholic acid (LCA), an endogenous TGR5 ligand, or INT-777, a synthetic TGR5-specific agonist, induced AQP2 expression and intracellular trafficking in rat IMCD cells a cAMP-protein kinase A signaling pathway. In mice with NDI, dietary supplementation with LCA markedly decreased urine output and increased urine osmolality, which was associated with significantly upregulated AQP2 expression in the kidney inner medulla. Supplementation with endogenous FXR agonist had no effect. In primary IMCD suspensions from lithium-treated rats, treatment with INT-767 (FXR and TGR5 dual agonist) or INT-777, but not INT-747 (FXR agonist), increased AQP2 expression. mice exhibited an attenuated ability to concentrate urine in response to dehydration, which was associated with decreased AQP2 expression in the kidney inner medulla. In lithium-treated mice, LCA treatment failed to prevent reduction of AQP2 expression.

Conclusions: TGR5 stimulation increases renal AQP2 expression and improves impaired urinary concentration in lithium-induced NDI. TGR5 is thus involved in regulating water metabolism in the kidney.
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http://dx.doi.org/10.1681/ASN.2018030271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218869PMC
November 2018

Cholestasis induced liver pathology results in dysfunctional immune responses after arenavirus infection.

Sci Rep 2018 08 15;8(1):12179. Epub 2018 Aug 15.

Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstrasse. 1, 40225, Düsseldorf, Germany.

Immune responses are critical for defense against pathogens. However, prolonged viral infection can result in defective T cell immunity, leading to chronic viral infection. We studied immune activation in response to arenavirus infection during cholestasis using bile duct ligation (BDL). We monitored T cell responses, virus load and liver pathology markers after infection with lymphocytic choriomeningitis virus (LCMV). BDL mice failed to induce protective anti-viral immunity against LCMV and consequently exhibited chronic viral infection. BDL mice exhibited reduced anti-viral T cell immunity as well as reduced type 1 interferon production early after LCMV infection. Consistently, the presence of serum from BDL mice reduced the responsiveness of dendritic cell (DC) and T cell cultures when compared to Sham controls. Following fractionation and mass spectrometry analyses of sera, we identified several serum factors to be upregulated following BDL including bilirubin, bile acids, 78 kDa Glucose regulated protein (GRP78) and liver enzymes. Bilirubin and GRP78 were capable of inhibiting DC and T cell activation. In this work, we demonstrate that liver damage mediated by cholestasis results in defective immune induction following arenavirus infection.
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http://dx.doi.org/10.1038/s41598-018-30627-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093869PMC
August 2018

Bile Microinfarcts in Cholestasis Are Initiated by Rupture of the Apical Hepatocyte Membrane and Cause Shunting of Bile to Sinusoidal Blood.

Hepatology 2019 02 19;69(2):666-683. Epub 2018 Nov 19.

Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.

Bile duct ligation (BDL) is an experimental procedure that mimics obstructive cholestatic disease. One of the early consequences of BDL in rodents is the appearance of so-called bile infarcts that correspond to Charcot-Gombault necrosis in human cholestasis. The mechanisms causing bile infarcts and their pathophysiological relevance are unclear. Therefore, intravital two photon-based imaging of BDL mice was performed with fluorescent bile salts (BS) and non-BS organic anion analogues. Key findings were followed up by matrix-assisted laser desorption ionization imaging, clinical chemistry, immunostaining, and gene expression analyses. In the acute phase, 1-3 days after BDL, BS concentrations in bile increased and single-cell bile microinfarcts occurred in dispersed hepatocytes throughout the liver caused by the rupture of the apical hepatocyte membrane. This rupture occurred after loss of mitochondrial membrane potential, followed by entry of bile, cell death, and a "domino effect" of further death events of neighboring hepatocytes. Bile infarcts provided a trans-epithelial shunt between bile canaliculi and sinusoids by which bile constituents leaked into blood. In the chronic phase, ≥21 days after BDL, uptake of BS tracers at the sinusoidal hepatocyte membrane was reduced. This contributes to elevated concentrations of BS in blood and decreased concentrations in the biliary tract. Conclusion: Bile microinfarcts occur in the acute phase after BDL in a limited number of dispersed hepatocytes followed by larger infarcts involving neighboring hepatocytes, and they allow leakage of bile from the BS-overloaded biliary tract into blood, thereby protecting the liver from BS toxicity; in the chronic phase after BDL, reduced sinusoidal BS uptake is a dominant protective factor, and the kidney contributes to the elimination of BS until cholemic nephropathy sets in.
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http://dx.doi.org/10.1002/hep.30213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587841PMC
February 2019

Allogeneic haematopoietic stem cell transplantation eliminates alloreactive inhibitory antibodies after liver transplantation for bile salt export pump deficiency.

J Hepatol 2018 Oct 21;69(4):961-965. Epub 2018 Jun 21.

University Children's Hospital, Pediatric Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Progressive familial intrahepatic cholestasis 2 is an autosomal-recessive disorder caused by mutations in the ABCB11 gene, which encodes the bile salt export pump (BSEP). Recurrence of BSEP deficiency after liver transplantation is caused by the development of anti-BSEP antibodies. Antibody-induced BSEP deficiency is typically treated by increasing immunosuppressive therapy. We report, in a child, the first case of allogeneic haematopoietic stem cell transplantation for antibody-induced BSEP deficiency that was refractory to intensive pharmacological immunosuppression and immunoadsorption. After haematopoietic stem cell transplantation, anti-BSEP antibodies were cleared from the patient's serum and later from the canalicular space of the liver graft.
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http://dx.doi.org/10.1016/j.jhep.2018.06.003DOI Listing
October 2018