204 results on '"Alexander L. Gerbes"'
Search Results
2. p70 Ribosomal Protein S6 Kinase Is a Checkpoint of Human Hepatic Stellate Cell Activation and Liver Fibrosis in MiceSummary
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Florian P. Reiter, Liangtao Ye, Andrea Ofner, Tobias S. Schiergens, Andreas Ziesch, Lydia Brandl, Najib Ben Khaled, Simon Hohenester, Ralf Wimmer, Renate Artmann, Yulong He, Serene M.L. Lee, Doris Mayr, Changhua Zhang, Alexander L. Gerbes, Julia Mayerle, Gerald Denk, and Enrico N. De Toni
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Fibrosis ,Cirrhosis ,Chronic Liver Disease ,Transforming Growth Factor-β ,Platelet-Derived Growth Factor BB ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background & Aims: Progression of chronic liver disease (CLD) to liver cirrhosis and liver cancer is a major global cause of morbidity and mortality. Treatment options capable of inhibiting progression of liver fibrosis when etiological treatment of CLD is not available or fails have yet to be established. We investigated the role of serine/threonine kinase p70 ribosomal protein S6 kinase (p70S6K) as checkpoint of fibrogenesis in hepatic stellate cells (HSCs) and as target for the treatment of liver fibrosis. Approach & Results: Immunohistochemistry was used to assess p70S6K expression in liver resection specimen. Primary human or murine HSCs from wild-type or p70S6K–/– mice as well as LX-2 cells were used for in vitro experiments. Specific small interfering RNA or CEP-1347 were used to silence or inhibit p70S6K and assess its functional relevance in viability, contraction and migration assays, fluorescence-activated cell sorting, and Western blot. These results were validated in vivo by a chemical model of fibrogenesis using wild-type and p70S6K–/– mice. Expression of p70S6K was significantly increased in human cirrhotic vs noncirrhotic liver-tissue and progressively increased in vitro through activation of primary human HSCs. Conversely, p70S6K induced fibrogenic activation of HSCs in different models, including the small interfering RNA–based silencing of p70S6K in HSC lines, experiments with p70S6K–/– cells, and the pharmacological inhibition of p70S6K by CEP-1347. These findings were validated in vivo as p70S6K–/– mice developed significantly less fibrosis upon exposure to CCl4. Conclusions: We establish p70S6K as a checkpoint of fibrogenesis in vitro and in vivo and CEP-1347 as potential treatment option that can safely be used for long-term treatment.
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- 2022
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3. Drug‐Induced Liver Injury by Checkpoint Inhibitors: Benefit of a Causality Assessment Tool
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Sabine Weber, Andreas Benesic, Masatoshi Ishigami, and Alexander L. Gerbes
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Diseases of the digestive system. Gastroenterology ,RC799-869 - Published
- 2020
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4. Challenges and Future of Drug-Induced Liver Injury Research—Laboratory Tests
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Sabine Weber and Alexander L. Gerbes
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drug-induced liver injury ,hepatotoxicity ,biomarkers ,drug development ,adverse drug events ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Drug-induced liver injury (DILI) is a rare but potentially severe adverse drug event, which is also a major cause of study cessation and market withdrawal during drug development. Since no acknowledged diagnostic tests are available, DILI diagnosis poses a major challenge both in clinical practice as well as in pharmacovigilance. Differentiation from other liver diseases and the identification of the causative agent in the case of polymedication are the main issues that clinicians and drug developers face in this regard. Thus, efforts have been made to establish diagnostic testing methods and biomarkers in order to safely diagnose DILI and ensure a distinguishment from alternative liver pathologies. This review provides an overview of the diagnostic methods used in differential diagnosis, especially with regards to autoimmune hepatitis (AIH) and drug-induced autoimmune hepatitis (DI-AIH), in vitro causality methods using individual blood samples, biomarkers for diagnosis and severity prediction, as well as experimental predictive models utilized in pre-clinical settings during drug development regimes.
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- 2022
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5. Pretreatment with zinc protects Kupffer cells following administration of microbial products
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Jiang Zhang, Andreas Wieser, Hao Lin, Yuhui Fan, Hanwei Li, Tobias S. Schiergens, Julia Mayerle, Alexander L. Gerbes, and Christian J. Steib
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Primary non-parenchymal cell ,Spontaneous bacterial peritonitis ,Zinc ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Background: Systemic inflammation and severe fibrosis can reduce serum zinc levels, while zinc supplementation is reported to improve the prognosis of patients with chronic liver disease (CLD). Objectives: We aimed to investigate the clinical application of serum zinc in patients with CLD and the anti-infective mechanism of zinc supplementation. Methods: Based on the serum zinc level, 149 CLD patients were divided into 3 groups and their clinical parameters were compared. In in-vitro experiments, microbial isolates derived from patients were used to stimulate human liver non-parenchymal cells, and the zinc sulfate solution was added in certain experiments. The effect of zinc was compared by LDH and thromboxane A2 levels in the cell supernatant. Result: Compared with other groups, patients with low serum zinc levels had significantly higher C-reactive protein (CRP), total bilirubin, INR, creatinine, and MELD scores, while albumin and GOT levels were reduced. Only CRP and albumin were significantly correlated with serum zinc in both low and normal-zinc groups. Bacterial isolates significantly increased LDH levels in Kupffer cells (KCs) and stellate cells but had no effect on sinusoidal endothelial cells, whereas zinc pretreatment protected KCs but not stellate cells. Thromboxane A2 secreted by KCs can also be induced by bacterial stimulation, accompanied by increased gene expression of Myd88, MAPK and NF-kB, while zinc pretreatment can attenuate that. Conclusion: Serum zinc levels can be used to estimate infection and liver fibrosis in CLD patients. As a new antibacterial weapon, zinc supplementation acts on KCs through Myd88-MAPK related pathways.
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- 2020
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6. Data on chow, liver tissue and mitochondrial fatty acid compositions as well as mitochondrial proteome changes after feeding mice a western diet for 6â24 weeks
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Claudia Einer, Simon Hohenester, Ralf Wimmer, Lena Wottke, Renate Artmann, Sabine Schulz, Christian Gosmann, Alisha Simmons, Christin Leitzinger, Carola Eberhagen, Sabine Borchard, Sabine Schmitt, Stefanie M. Hauck, Christine von Toerne, Martin Jastroch, Ellen Walheim, Christian Rust, Alexander L. Gerbes, Bastian Popper, Doris Mayr, Max Schnurr, Angelika M. Vollmar, Gerald Denk, and Hans Zischka
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Computer applications to medicine. Medical informatics ,R858-859.7 ,Science (General) ,Q1-390 - Abstract
The data presented in this article describe the fatty acid composition of chow, liver tissue and isolated liver mitochondria from mice fed for 6â24 weeks with a high caloric western diet (WD) in comparison to control diet (normal diet, ND). The fatty acid composition was measured via gas chromatography flame ionization detection (GC-FID). Moreover, WD-induced mitochondrial protein changes are presented in this work and were analyzed by mass spectrometry (LCâMS/MS). For further interpretation and discussion of the presented data please refer to the research article entitled âMitochondrial adaptation in steatotic miceâ (Einer et al., 2017) [1].
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- 2017
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7. Albumin Might Attenuate Bacteria-Induced Damage on Kupffer Cells for Patients with Chronic Liver Disease
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Hao Lin, Yuhui Fan, Andreas Wieser, Jiang Zhang, Ivonne Regel, Hanno Nieß, Julia Mayerle, Alexander L. Gerbes, and Christian J. Steib
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hepatic non-parenchymal cells ,albumin ,chronic liver diseases ,bacteria ,Cytology ,QH573-671 - Abstract
Chronic liver diseases (CLDs) are complex diseases that cause long-term inflammation and infection, which in turn accelerate their development. The usage of albumin in patients with CLDs has been debated for years. Human serum albumin (HSA) plays a key role in immunomodulation during the process of CLDs. The correlation between albumin and C-reactive protein (CRP) in CLD patients was analyzed by linear regression with the Pearson statistic. The damage of THP-1 and primary cells was evaluated by measuring the lactate dehydrogenase (LDH) in the supernatant. Immunofluorescence staining was performed to determine underlying pathways in Kupffer cells (KCs). Albumin negatively correlated with infection in patients with CLDs. In vitro experiments with THP-1 cells and KCs showed that albumin reduced LDH release after stimulation with bacterial products, while no differences in hepatic stellate cells (HSCs) and sinusoidal endothelial cells (SECs) were detected. Moreover, immunofluorescence staining revealed an increase of p-ERK and p-NF-kB p65 density after albumin treatment of KCs stimulated by bacterial products. In conclusion, albumin could assist CLD patients in alleviating inflammation caused by bacterial products and might be beneficial to patients with CLDs by securing KCs from bacteria-induced damage, providing a compelling rationale for albumin therapy in patients with CLDs.
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- 2021
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8. Ischemic Postconditioning (IPostC) Protects Fibrotic and Cirrhotic Rat Livers after Warm Ischemia
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Julia Schewe, Marie-Christine Makeschin, Ingrid Liss, Doris Mayr, Jiang Zhang, Andrej Khandoga, Simon Rothenfußer, Max Schnurr, Alexander L. Gerbes, and Christian J. Steib
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Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background. Decreased organ function following liver resection is a major clinical issue. The practical method of ischemic postconditioning (IPostC) has been studied in heart diseases, but no data exist regarding fibrotic livers. Aims. We aimed to determine whether IPostC could protect healthy, fibrotic, and cirrhotic livers from ischemia reperfusion injury (IRI). Methods. Fibrosis was induced in male SD rats using bile duct ligation (BDL, 4 weeks), and cirrhosis was induced using thioacetamide (TAA, 18 weeks). Fibrosis and cirrhosis were histologically confirmed using HE and EvG staining. For healthy, fibrotic, and cirrhotic livers, isolated liver perfusion with 90 min of warm ischemia was performed in three groups (each with n=8): control, IPostC 8x20 sec, and IPostC 4x60 sec. additionally, healthy livers were investigated during a follow-up study. Lactate dehydrogenase (LDH) and thromboxane B2 (TXB2) in the perfusate, as well as bile flow (healthy/TAA) and portal perfusion pressure, were measured. Results. LDH and TXB2 were reduced, and bile flow was increased by IPostC, mainly in total and in the late phase of reperfusion. The follow-up study showed that the perfusate derived from a postconditioned group had much less damaging potential than perfusate derived from the nonpostconditioned group. Conclusion. IPostC following warm ischemia protects healthy, fibrotic, and cirrhotic livers against IRI. Reduced efflux of TXB2 is one possible mechanism for this effect of IPostC and increases sinusoidal microcirculation. These findings may help to improve organ function and recovery of patients after liver resection.
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- 2019
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9. IL-18 But Not IL-1 Signaling Is Pivotal for the Initiation of Liver Injury in Murine Non-Alcoholic Fatty Liver Disease
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Simon Hohenester, Veronika Kanitz, Tobias Schiergens, Claudia Einer, Jutta Nagel, Ralf Wimmer, Florian P. Reiter, Alexander L. Gerbes, Enrico N. De Toni, Christian Bauer, Lesca Holdt, Doris Mayr, Christian Rust, Max Schnurr, Hans Zischka, Andreas Geier, and Gerald Denk
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NAFLD ,Western diet ,NLRP3 ,inflammasome ,interleukin 1 ,interleukin 18 ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Non-alcoholic fatty liver disease (NAFLD) is rising in prevalence, and a better pathophysiologic understanding of the transition to its inflammatory phenotype (NASH) is key to the development of effective therapies. To evaluate the contribution of the NLRP3 inflammasome and its downstream effectors IL-1 and IL-18 in this process, we applied the true-to-life “American lifestyle-induced obesity syndrome” (ALiOS) diet mouse model. Development of obesity, fatty liver and liver damage was investigated in mice fed for 24 weeks according to the ALiOS protocol. Lipidomic changes in mouse livers were compared to human NAFLD samples. Receptor knockout mice for IL-1 and IL-18 were used to dissect the impact of downstream signals of inflammasome activity on the development of NAFLD. The ALiOS diet induced obesity and liver steatosis. The lipidomic changes closely mimicked changes in human NAFLD. A pro-inflammatory gene expression pattern in liver tissue and increased serum liver transaminases indicated early liver damage in the absence of histological evidence of NASH. Mechanistically, Il-18r−/−- but not Il-1r−/− mice were protected from early liver damage, possibly due to silencing of the pro-inflammatory gene expression pattern. Our study identified NLRP3 activation and IL-18R-dependent signaling as potential modulators of early liver damage in NAFLD, preceding development of histologic NASH.
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- 2020
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10. Proteomics Analysis of Monocyte-Derived Hepatocyte-Like Cells Identifies Integrin Beta 3 as a Specific Biomarker for Drug-Induced Liver Injury by Diclofenac
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Diana Dragoi, Andreas Benesic, Garwin Pichler, Nils A. Kulak, Harald S. Bartsch, and Alexander L. Gerbes
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DILI ,biomarker ,proteomics ,drug-development ,monocyte-derived hepatocyte-like cells ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Idiosyncratic drug-induced liver injury (iDILI) is a major cause of acute liver failure resulting in liver transplantation or death. Prediction and diagnosis of iDILI remain a great challenge, as current models provide unsatisfying results in terms of sensitivity, specificity, and prognostic value. The absence of appropriate tools for iDILI detection also impairs the development of reliable biomarkers. Here, we report on a new method for identification of drug-specific biomarkers. We combined the advantages of monocyte-derived hepatocyte-like (MH) cells, able to mimic individual characteristics, with those of a novel mass spectrometry-based proteomics technology to assess potential biomarkers for Diclofenac-induced DILI. We found over 2,700 proteins differentially regulated in MH cells derived from individual patients. Herefrom, we identified integrin beta 3 (ITGB3) to be specifically upregulated in Diclofenac-treated MH cells from Diclofenac-DILI patients compared to control groups. Finally, we validated ITGB3 by flow cytometry analysis of whole blood and histological staining of liver biopsies derived from patients diagnosed with Diclofenac-DILI. In summary, our results show that biomarker candidates can be identified by proteomics analysis of MH cells. Application of this method to a broader range of drugs in the future will exploit its full potential for the development of drug-specific biomarkers. Data are available via ProteomeXchange with identifier PXD008918.
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- 2018
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11. High age and low sodium urine concentration are associated with poor survival in patients with hepatorenal syndrome
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Matthias Hinz, Alexander Wree, Christoph Jochum, Lars P. Bechmann, Fuat Saner, Alexander L. Gerbes, Guido Gerken, and A.l.i. Canbay, M.D.
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Terlipressin ,Urinary sodium ,Predictors of response and survival ,Overall mortality ,Specialties of internal medicine ,RC581-951 - Abstract
Background. Combination therapy with terlipressin and albumin substitution is considered a widely accepted treatment regimen for patients with hepatorenal syndrome (HRS). However, only half of the patients respond to treatment and to date albumin substitution and terlipressin therapy are among the most expensive medical treatments available for patients with liver diseases. Thus, we aimed to identify clinical and etiological parameters to predict treatment response and overall mortality in patients with HRS.Material and methods. We retrospectively evaluated 21 patients, 13 male/8 female, aged 43-72 years with HRS. Four patients were transplanted after following combination treatment. Terlipressin was administered by continuous intravenous perfusion (2–6 mg/d) and albumin drips (50 mg) were given daily. Treatment response was defined by a decrease in serum creatinine level to < 1.5 mg/dL or by a > 50% reduction of the baseline concentration.Results. 57% of the patients responded to treatment, which was associated with improved survival at day 60, compared to non-responders. However, the overall mortality was not different between the two groups. Median age of 63 years was a significant negative predictor for therapy response. High baseline urinary sodium levels were of prognostic value for survival. The Model of End stage Liver Disease score (MELD score) did not correlate with therapy response.Conclusion. In conclusion high age is a predictor of non-response. Low urinary sodium before treatment is associated with poor survival. Terli-pressin and albumin co-treatment is associated with increased two-months survival rate. This seemingly moderate extension in survival rate can, however, be decisive for obtaining liver transplantation.
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- 2013
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12. p70 Ribosomal Protein S6 Kinase Is a Checkpoint of Human Hepatic Stellate Cell Activation and Liver Fibrosis in Mice
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Najib Ben Khaled, Florian P. Reiter, Andreas Ziesch, Alexander L. Gerbes, Julia Mayerle, Gerald Denk, Liangtao Ye, Ralf Wimmer, Enrico N. De Toni, Renate Artmann, Tobias S. Schiergens, Doris Mayr, Simon Hohenester, Andrea Ofner, Serene M. L. Lee, Changhua Zhang, Yulong He, and Lydia Brandl
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Liver Cirrhosis ,Wt, wild-type ,Cirrhosis ,WST, water-soluble tetrazolium ,P70-S6 Kinase 1 ,RC799-869 ,Chronic liver disease ,PDGF, platelet-derived growth factor ,Chronic Liver Disease ,α-SMA, α-smooth muscle actin ,Mice ,Fibrosis ,TGF-β, transforming growth factor-β ,medicine ,Hepatic Stellate Cells ,Animals ,Humans ,p70S6K, p70 ribosomal protein S6 kinase ,Transforming Growth Factor-β ,Original Research ,Cell Proliferation ,Hepatology ,business.industry ,Platelet-Derived Growth Factor BB ,phHSC, primary human hepatic stellate cell ,Gastroenterology ,GFAP, glial fibrillary acidic protein ,Ribosomal Protein S6 Kinases, 70-kDa ,Diseases of the digestive system. Gastroenterology ,medicine.disease ,Hepatic stellate cell activation ,HSC, hepatic stellate cell ,pmHSC, murine hepatic stellate cell ,siRNA, small interfering RNA ,Ribosomal protein s6 ,CLD, chronic liver disease ,Hepatic stellate cell ,Cancer research ,Liver cancer ,business ,NASH, nonalcoholic steatohepatitis ,Signal Transduction - Abstract
Background & Aims Progression of chronic liver disease (CLD) to liver cirrhosis and liver cancer is a major global cause of morbidity and mortality. Treatment options capable of inhibiting progression of liver fibrosis when etiological treatment of CLD is not available or fails have yet to be established. We investigated the role of serine/threonine kinase p70 ribosomal protein S6 kinase (p70S6K) as checkpoint of fibrogenesis in hepatic stellate cells (HSCs) and as target for the treatment of liver fibrosis. Approach & Results Immunohistochemistry was used to assess p70S6K expression in liver resection specimen. Primary human or murine HSCs from wild-type or p70S6K–/– mice as well as LX-2 cells were used for in vitro experiments. Specific small interfering RNA or CEP-1347 were used to silence or inhibit p70S6K and assess its functional relevance in viability, contraction and migration assays, fluorescence-activated cell sorting, and Western blot. These results were validated in vivo by a chemical model of fibrogenesis using wild-type and p70S6K–/– mice. Expression of p70S6K was significantly increased in human cirrhotic vs noncirrhotic liver-tissue and progressively increased in vitro through activation of primary human HSCs. Conversely, p70S6K induced fibrogenic activation of HSCs in different models, including the small interfering RNA–based silencing of p70S6K in HSC lines, experiments with p70S6K–/– cells, and the pharmacological inhibition of p70S6K by CEP-1347. These findings were validated in vivo as p70S6K–/– mice developed significantly less fibrosis upon exposure to CCl4. Conclusions We establish p70S6K as a checkpoint of fibrogenesis in vitro and in vivo and CEP-1347 as potential treatment option that can safely be used for long-term treatment., Graphical abstract
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- 2021
13. Liver Injury Associated with Metamizole Exposure: Features of an Underestimated Adverse Event
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Andreas Benesic, Jens Neumann, Alexander L. Gerbes, and Sabine Weber
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Male ,medicine.medical_specialty ,Necrosis ,Antinuclear antibody positivity ,Dipyrone ,Toxicology ,Gastroenterology ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Original Research Article ,Prospective Studies ,Adverse effect ,Prospective cohort study ,Pharmacology ,Liver injury ,business.industry ,Jaundice ,Liver Failure, Acute ,Metamizole ,medicine.disease ,Cohort ,Female ,medicine.symptom ,Chemical and Drug Induced Liver Injury ,business ,medicine.drug - Abstract
Introduction and Objective The potential of metamizole to cause drug-induced liver injury (DILI) has received increasing attention. We investigated the distinguishing features of a case series comprising 32 patients with suspected metamizole-induced DILI. Methods For the current analysis, 32 of 238 patients with DILI included in our prospective study on drugs potentially causing DILI were included. Diagnosis of DILI was based on expert opinion and RUCAM (Roussel Uclaf Causality Assessment Method) score and supported by an in vitro test using monocyte-derived hepatocyte-like cells. Results Suspected metamizole-DILI was characterised by a female predominance, hepatocellular pattern of injury, high proportion of antinuclear antibody positivity, and predominance of eosinophilic cell infiltration and necrosis in the histopathological analysis. With 22%, a high proportion of these metamizole-associated liver injury cases developed acute liver failure, which was characterised by a longer latency of metamizole use and more pronounced liver biochemistry abnormalities at onset and peak levels. Furthermore, jaundice was a common finding in the metamizole-associated liver injury cases with 66% presenting with peak bilirubin levels of 3 mg/dL or higher, which was associated with a worse outcome and a higher frequency of acute liver failure. Conclusions Our analysis of a well-characterised DILI cohort further supports the potential of metamizole causing DILI and provides important features for the establishment of a signature pattern of liver injury observed in patients treated with metamizole. Clinical Trial Registration ClinicalTrials.gov: NCT 02353455. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01049-z.
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- 2021
14. Clinical features and evolution of bacterial infection-related acute-on-chronic liver failure
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Carlo Alessandria, Carmine Gambino, Javier Fernández, Hans Van Vlierberghe, Sophie Restellini, Marcos Girala, Luis Colombato, Tae Hee Lee, Nikolaos Pyrsopoulos, Eduardo Fassio, Sang Gyune Kim, Gisela Pinero, Paolo Caraceni, Shivaram Prasad Singh, Do Seon Song, Ji Won Park, Julio Vorobioff, Dong Joon Kim, C. Toledo, Aleksander Krag, Liane Rabinowich, Preetam Nath, Robert A. de Man, Elza Cotrim Soares, Xavier Verhelst, Tiago Sevá Pereira, Gustavo Romero, Macarena Simón-Talero, Sung Eun Kim, Michele Bartoletti, Alexander L. Gerbes, Sebastián Marciano, Tony Bruns, Hyoung Su Kim, Ki Tae Suk, Nicolas M. Intagliata, Annette Dam Fialla, Adrià Juanola, Manuela Merli, Rita de Cassia Ribeiro Barea, Laure Elkrief, Rakhi Maiwall, Laurentius A Lesmana, Pere Ginès, Vikas Gautam, E.L. Yoon, M. Marino, Paolo Angeli, Kalyan Ram Bhamidimarri, Victor Vargas, Virendra Singh, Juan Pablo Roblero, François Durand, Cosmas A. Rinaldi Lesmana, M. V. Maevskaya, Gustavo Navarro, Adrian Gadano, Florence Wong, Pramod Kumar, Tae Hun Kim, Daniela Campion, Salvatore Piano, Giacomo Zaccherini, Barbara Lattanz, Jae Seok Hwang, Sun Young Yim, Thomas D. Boyer, Jeong Han Kim, Carlos Brodersen, Wong F., Piano S., Singh V., Bartoletti M., Maiwall R., Alessandria C., Fernandez J., Soares E.C., Kim D.J., Kim S.E., Marino M., Vorobioff J., Barea R.D.C.R., Merli M., Elkrief L., Vargas V., Krag A., Singh S.P., Lesmana L.A., Toledo C., Marciano S., Verhelst X., Intagliata N., Rabinowich L., Colombato L., Kim S.G., Gerbes A., Durand F., Roblero J.P., Bruns T., Yoon E.L., Girala M., Pyrsopoulos N.T., Kim T.H., Yim S.Y., Juanola A., Gadano A., Angeli P., Bhamidimarri K., Boyer T.D., Brodersen C., Campion D., Caraceni P., de Man R.A., Fassio E., Fialla A.D., Gambino C., Gautam V., Gines P., Hwang J.S., Kim H.S., Kim J.H., Kumar P., Lattanz B., Lee T.H., Rinaldi Lesmana C.A., Maevskaya M., Nath P., Navarro G., Park J.-W., Pinero G., Restellini S., Romero G., Seva -Pereira T., Simon-Talero M., Song D.S., Suk K.T., Van Vlierberghe H., and Zaccherini G.
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Male ,0301 basic medicine ,Cirrhosis ,Organ Dysfunction Scores ,Antibiotic resistance ,medicine.medical_treatment ,Liver transplantation ,Severity of Illness Index ,0302 clinical medicine ,ACLF ,MDR ,Epidemiology ,Cross Infection ,Mortality rate ,Age Factors ,Bacterial Infections ,Middle Aged ,Prognosis ,Community-Acquired Infections ,Europe ,Hospitalization ,Female ,030211 gastroenterology & hepatology ,Alcohol-Related Disorders ,medicine.medical_specialty ,Sepsi ,India ,Risk Assessment ,Sepsis ,03 medical and health sciences ,Sex Factors ,Spontaneous bacterial peritonitis ,Internal medicine ,medicine ,Humans ,XDR ,Cirrhosi ,Hepatology ,business.industry ,Acute-On-Chronic Liver Failure ,medicine.disease ,Pneumonia ,030104 developmental biology ,antibiotic resistance ,liver transplantation ,sepsis ,business - Abstract
Background & Aims: Bacterial infections can trigger the development of organ failure(s) and acute-on-chronic liver failure (ACLF). Geographic variations in bacteriology and clinical practice could lead to worldwide differences in ACLF epidemiology, phenotypes and associated outcomes. Herein, we aimed to evaluate regional differences in bacterial infection-related ACLF in patients with cirrhosis admitted to hospital. Methods: This post hoc analysis included 1,175 patients with decompensated cirrhosis (with bacterial infection on admission or nosocomial infection) from 6 geographic regions worldwide. Clinical, laboratory and microbiological data were collected from the diagnosis of infection. Patients were followed-up for organ failure(s) and ACLF development according to the EASL-CLIF criteria from enrolment to discharge/death. Results: A total of 333 patients (28%) had ACLF at diagnosis of infection, while 230 patients developed ACLF after diagnosis of infection, resulting in an overall rate of bacterial infection related-ACLF of 48%, with rates differing amongst different geographic regions (38% in Southern Europe vs. 75% in the Indian subcontinent). Bacterial infection related-ACLF more frequently developed in younger patients (55 ± 13 vs. 58 ± 14 years), males (73% vs. 62%), patients with alcohol-related cirrhosis (59% vs. 45%) and those with a higher baseline MELD score (25 ± 11 vs. 16 ± 5) (all p
- Published
- 2021
15. Sympathetic nervous activation, mitochondrial dysfunction and outcome in acutely decompensated cirrhosis: the metabolomic prognostic models (CLIF-C MET)
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Emmanuel Weiss, Carlos de la Peña-Ramirez, Ferran Aguilar, Juan-Jose Lozano, Cristina Sánchez-Garrido, Patricia Sierra, Pedro Izquierdo-Bueno Martin, Juan Manuel Diaz, François Fenaille, Florence A Castelli, Thierry Gustot, Wim Laleman, Agustín Albillos, Carlo Alessandria, Marco Domenicali, Paolo Caraceni, Salvatore Piano, Faouzi Saliba, Stefan Zeuzem, Alexander L Gerbes, Julia A Wendon, Christian Jansen, Wenyi Gu, Maria Papp, Raj Mookerjee, Carmine Gabriele Gambino, Cesar Jiménez, Ilaria Giovo, Giacomo Zaccherini, Manuela Merli, Antonella Putignano, Frank Erhard Uschner, Thomas Berg, Tony Bruns, Christian Trautwein, Alexander Zipprich, Rafael Bañares, José Presa, Joan Genesca, Victor Vargas, Javier Fernández, Mauro Bernardi, Paolo Angeli, Rajiv Jalan, Joan Claria, Christophe Junot, Richard Moreau, Jonel Trebicka, and Vicente Arroyo
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cirrhosis ,liver failure ,Gastroenterology ,liver metabolism - Abstract
Background and aimsCurrent prognostic scores of patients with acutely decompensated cirrhosis (AD), particularly those with acute-on-chronic liver failure (ACLF), underestimate the risk of mortality. This is probably because systemic inflammation (SI), the major driver of AD/ACLF, is not reflected in the scores. SI induces metabolic changes, which impair delivery of the necessary energy for the immune reaction. This investigation aimed to identify metabolites associated with short-term (28-day) death and to design metabolomic prognostic models.MethodsTwo prospective multicentre large cohorts from Europe for investigating ACLF and development of ACLF, CANONIC (discovery, n=831) and PREDICT (validation, n=851), were explored by untargeted serum metabolomics to identify and validate metabolites which could allow improved prognostic modelling.ResultsThree prognostic metabolites strongly associated with death were selected to build the models. 4-Hydroxy-3-methoxyphenylglycol sulfate is a norepinephrine derivative, which may be derived from the brainstem response to SI. Additionally, galacturonic acid and hexanoylcarnitine are associated with mitochondrial dysfunction. Model 1 included only these three prognostic metabolites and age. Model 2 was built around 4-hydroxy-3-methoxyphenylglycol sulfate, hexanoylcarnitine, bilirubin, international normalised ratio (INR) and age. In the discovery cohort, both models were more accurate in predicting death within 7, 14 and 28 days after admission compared with MELDNa score (C-index: 0.9267, 0.9002 and 0.8424, and 0.9369, 0.9206 and 0.8529, with model 1 and model 2, respectively). Similar results were found in the validation cohort (C-index: 0.940, 0.834 and 0.791, and 0.947, 0.857 and 0.810, with model 1 and model 2, respectively). Also, in ACLF, model 1 and model 2 outperformed MELDNa 7, 14 and 28 days after admission for prediction of mortality.ConclusionsModels including metabolites (CLIF-C MET) reflecting SI, mitochondrial dysfunction and sympathetic system activation are better predictors of short-term mortality than scores based only on organ dysfunction (eg, MELDNa), especially in patients with ACLF.
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- 2023
16. Kupffer cell activation by different microbial lysates: Toll‐like receptor‐2 plays pivotal role on thromboxane A 2 production in mice and humans
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Jiang Zhang, Andreas Wieser, Christian J. Steib, Moyan Hu, Hanwei Li, Ina‐Kristin Behrens, Tobias S. Schiergens, Hao Lin, and Alexander L. Gerbes
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0301 basic medicine ,MAPK/ERK pathway ,Toll-like receptor ,Thromboxane ,Immunology ,Kupffer cell ,Pharmacology ,Biology ,03 medical and health sciences ,Thromboxane A2 ,chemistry.chemical_compound ,TLR2 ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,chemistry ,medicine ,Immunology and Allergy ,Phosphorylation ,Secretion ,030215 immunology - Abstract
Thromboxane (TX) A2 has been identified as an important intrahepatic vasoconstrictor upon Kupffer cell (KC) activation during infections such as spontaneous bacterial peritonitis (SBP). The study aimed to investigate the role of TLRs in the TXA2 increase in liver nonparenchymal cells and their related mechanisms. Here, we identified TLR-2 as a common pathway for different microbials: microbial lysates including Gram-positive bacteria, Gram-negative bacteria, and fungi all increased TXA2 secretion via activation of TLR-2 in human KCs, accompanied by increased expression and phosphorylation of Myd88-related pathway. Of all TLR agonists, only TLR-1, -2, and -4 agonists increased TXA2 in human KCs. These results were further confirmed by mouse liver nonparenchymal cells. Comparing the effects of TLR-1, -2, and -4 antagonists, only TLR-2 antagonist showed inhibitory effects with all tested microbial lysates. Pretreatment with TLR-2 antagonist in human KCs blocked the secretion of IL-10, CXCL-10, TNF-α, and IL-6 induced by Gram-positive and Gram-negative bacterial stimulation. IL-23 and IL-1β were only induced by Gram-negative bacteria. Thus, TLR-2 might be a potential marker and an attractive target for future treatment of patients with SBP. In addition, IL-23 and IL-1β might distinguish early between Gram-positive and Gram-negative SBP.
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- 2020
17. Metabolic implication of tigecycline as an efficacious second‐line treatment for sorafenib‐resistant hepatocellular carcinoma
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Helmut Pein, Alexander L. Gerbes, Johanna Pachmayr, Martin Müller, Martina Meßner, Simon Rothenfußer, Andreas Koeberle, Georg J. Arnold, Thomas Fröhlich, Angelika M. Vollmar, Alexandra K. Kiemer, Maximilian A. Ardelt, Sabine Schmitt, Carina Ortler, Lena Zobel, Petra Huber-Cantonati, Lars M. Koenig, and Hans Zischka
- Subjects
0301 basic medicine ,mitochondrial biogenesis ,Cell ,Apoptosis ,Mice, SCID ,Drug resistance ,Tigecycline ,Biochemistry ,antibiotics ,0302 clinical medicine ,Protein Synthesis Inhibitors ,Antibiotics ,Electron Acceptor Auxotrophy ,Mitochondrial Biogenesis ,Sorafenib Resistance ,Tumor Relapse ,tumor relapse ,Liver Neoplasms ,sorafenib resistance ,Sorafenib ,Mitochondria ,ddc ,medicine.anatomical_structure ,Hepatocellular carcinoma ,Female ,Biotechnology ,medicine.drug ,Carcinoma, Hepatocellular ,03 medical and health sciences ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,Adverse effect ,neoplasms ,Molecular Biology ,Cell Proliferation ,business.industry ,electron acceptor auxotrophy ,medicine.disease ,Xenograft Model Antitumor Assays ,digestive system diseases ,030104 developmental biology ,Mitochondrial biogenesis ,Drug Resistance, Neoplasm ,Cancer research ,Neoplasm Recurrence, Local ,business ,030217 neurology & neurosurgery ,Progressive disease - Abstract
Sorafenib represents the current standard of care for patients with advanced-stage hepatocellular carcinoma (HCC). However, acquired drug resistance occurs frequently during therapy and is accompanied by rapid tumor regrowth after sorafenib therapy termination. To identify the mechanism of this therapy-limiting growth resumption, we established robust sorafenib resistance HCC cell models that exhibited mitochondrial dysfunction and chemotherapeutic crossresistance. We found a rapid relapse of tumor cell proliferation after sorafenib withdrawal, which was caused by renewal of mitochondrial structures alongside a metabolic switch toward high electron transport system (ETS) activity. The translation-inhibiting antibiotic tigecycline impaired the biogenesis of mitochondrial DNA-encoded ETS subunits and limited the electron acceptor turnover required for glutamine oxidation. Thereby, tigecycline prevented the tumor relapse in vitro and in murine xenografts in vivo. These results offer a promising second-line therapeutic approach for advanced-stage HCC patients with progressive disease undergoing sorafenib therapy or treatment interruption due to severe adverse events.
- Published
- 2020
18. To Protect Fatty Livers from Ischemia Reperfusion Injury: Role of Ischemic Postconditioning
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Simon Rothenfußer, Andrej Khandoga, Marie-Christine Makeschin, Doris Mayr, Alexander L. Gerbes, Julia Schewe, Max Schnurr, Jiang Zhang, and Christian J. Steib
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Male ,medicine.medical_specialty ,Ischemia–reperfusion injury ,Physiology ,Ischemia ,CCL2 ,Diet, High-Fat ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,In vivo ,Internal medicine ,Lactate dehydrogenase ,medicine ,Animals ,Ischemic postconditioning ,Liver transplantation ,business.industry ,Fatty liver ,Gastroenterology ,medicine.disease ,Rats ,Fatty Liver ,Transplantation ,Endocrinology ,chemistry ,Reperfusion Injury ,030220 oncology & carcinogenesis ,Original Article ,030211 gastroenterology & hepatology ,business ,Reperfusion injury ,Perfusion - Abstract
Background The benefit of ischemic postconditioning (IPostC) might be the throttled inflow following cold ischemia. The current study investigated advantage and mechanisms of IPostC in healthy and fatty rat livers. Methods Male SD rats received a high-fat diet to induce fatty livers. Isolated liver perfusion was performed after 24 h ischemia at 4 °C as well as in vivo experiments after 90 min warm ischemia. The so-called follow-up perfusions served to investigate the hypothesis that medium from IPostC experiments is less harmful. Lactate dehydrogenase (LDH), transaminases, different cytokines, and gene expressions, respectively, were measured. Results Fatty livers showed histologically mild inflammation and moderate to severe fat storage. IPostC reduced LDH and TXB2 in healthy and fatty livers and increased bile flow. LDH, TNF-α, and IL-6 levels in serum decreased after warm ischemia + IPostC. The gene expressions of Tnf, IL-6, Ccl2, and Ripk3 were downregulated in vivo after IPostC. Conclusions IPostC showed protective effects after ischemia in situ and in vivo in healthy and fatty livers. Restricted cyclic inflow was an important mechanism and further suggested involvement of necroptosis. IPostC represents a promising and easy intervention to improve outcomes after transplantation. Electronic supplementary material The online version of this article (10.1007/s10620-020-06328-w) contains supplementary material, which is available to authorized users.
- Published
- 2020
19. Antifibrotic effects of hypocalcemic vitamin D analogs in murine and human hepatic stellate cells and in the CCl4 mouse model
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Enrico N. De Toni, Doris Mayr, Andreas Ziesch, Ivonne Regel, Renate Artmann, Simon Hohenester, Christian J. Steib, Michael Trauner, Liangtao Ye, Veronika Kanitz, Alexander L. Gerbes, Julia Mayerle, Gerald Denk, Florian Bösch, Florian P. Reiter, Ralf Wimmer, Graduate School, AGEM - Digestive immunity, and AGEM - Endocrinology, metabolism and nutrition
- Subjects
0301 basic medicine ,Paricalcitol ,biology ,Calcitriol ,Chemistry ,Alfacalcidol ,Cell Biology ,Transforming growth factor beta ,Pharmacology ,medicine.disease ,Pathology and Forensic Medicine ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Fibrosis ,In vivo ,030220 oncology & carcinogenesis ,biology.protein ,medicine ,Vitamin D and neurology ,Hepatic stellate cell ,Molecular Biology ,medicine.drug - Abstract
Liver cirrhosis is a life-threatening consequence of liver fibrosis. The aim of this study was to investigate the antifibrotic potential of clinically available vitamin D analogs compared to that of calcitriol in vitro and in vivo. Murine hepatic stellate cells, Kupffer cells, and human LX-2 cells were treated with vitamin D analogs, and the profibrotic behavior of these cells was studied. In vivo liver fibrosis was induced using CCl4 until measurable fibrosis was established. Animals were then treated with calcitriol and paricalcitol. Vitamin D and its analogs showed antifibrotic effects in vitro. Treatment with active vitamin D (calcitriol, CAL) and its analogs reduced the protein expression of α-smooth muscle actin (α-SMA) in mHSC. In human LX-2 cells alfacalcidol reduced transforming growth factor-β (TGF-β) induced platelet-derived growth factor receptor-β protein expression and contractility while paricalcitol (PCT), in its equipotent dose to CAL, reduced TGF-β induced α-SMA protein expression, and ACTA2 and TGF-β mRNA expression. No effects of a treatment with vitamin D and its analogs were observed in Kupffer cells. In vivo, PCT-treated mice had significantly lower calcium levels than CAL-treated mice. CAL and PCT reduced the hepatic infiltration of CD11b-positive cells and alanine transaminase levels, while PCT but not CAL significantly inhibited fibrosis progression, with a favorable side effect profile in the CCl4 model. We conclude that hypocalcemic vitamin D analogs should be considered in future studies investigating vitamin D for the treatment of liver fibrosis.
- Published
- 2019
20. Drug-Induced Liver Injury (DILI): A Major Challenge
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Alexander L. Gerbes
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Liver injury ,Drug ,business.industry ,media_common.quotation_subject ,General Medicine ,Pharmacology ,medicine.disease ,Liver ,Drug Discovery ,medicine ,Humans ,Chemical and Drug Induced Liver Injury ,business ,media_common - Published
- 2021
21. Biomarkers of idiosyncratic drug-induced liver injury (DILI) - a systematic review
- Author
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Francisco Javier Cubero, Alexander L. Gerbes, Guruprasad P. Aithal, Gerd A. Kullak-Ublick, Cristiana Freixo, Ismael Alvarez-Alvarez, Edmond Atallah, University of Zurich, and Aithal, Guruprasad P
- Subjects
Drug ,medicine.medical_specialty ,Drug-Related Side Effects and Adverse Reactions ,Adverse outcomes ,media_common.quotation_subject ,610 Medicine & health ,Toxicology ,Risk Factors ,medicine ,Humans ,Prospective Studies ,Intensive care medicine ,Methodological quality ,media_common ,Acute liver injury ,Liver injury ,Pharmacology ,business.industry ,3005 Toxicology ,General Medicine ,medicine.disease ,Transplantation ,3004 Pharmacology ,Liver ,10199 Clinic for Clinical Pharmacology and Toxicology ,Etiology ,Population study ,Chemical and Drug Induced Liver Injury ,business ,Biomarkers - Abstract
Introduction Idiosyncratic drug-induced liver injury (DILI) is an unpredictable event, and there are no specific biomarkers that can distinguish DILI from alternative explanations or predict its clinical outcomes. Areas covered This systematic review summarizes the available evidence for all biomarkers proposed to have a role in the diagnosis or prognosis of DILI. Following a comprehensive search, we included all types of studies in humans. We included DILI cases based on any threshold criteria but excluded intrinsic DILI, commonly caused by paracetamol overdose. We classified studies into diagnostic and prognostic categories and assessed their methodological quality. After reviewing the literature, 14 studies were eligible. Expert Opinion Diagnostic studies were heterogeneous with regard to the study population and outcomes measured. Prognostic models were developed by integrating novel biomarkers, risk scores, and traditional biomarkers, which increased their prognostic ability to predict death or transplantation by 6 months. This systematic review highlights the case of need for non-genetic biomarkers that distinguish DILI from acute liver injury related to alternative etiology. Biomarkers with the potential to identify serious adverse outcomes from acute DILI should be validated in independent prospective cohorts with a substantial number of cases.
- Published
- 2021
22. Marked Increase of Gamma-Glutamyltransferase as an Indicator of Drug-Induced Liver Injury in Patients without Conventional Diagnostic Criteria of Acute Liver Injury
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Sabine Weber, Alexander L. Gerbes, Gerald Denk, and Julian Allgeier
- Subjects
Acute liver injury ,Liver injury ,Drug ,medicine.medical_specialty ,biology ,business.industry ,media_common.quotation_subject ,Gastroenterology ,medicine.disease ,Internal medicine ,medicine ,biology.protein ,Surgery ,In patient ,Gamma-glutamyltransferase ,business ,media_common ,Research Article - Abstract
Introduction: Clinically significant drug-induced liver injury (DILI) is defined by elevations of alanine aminotransferase (ALT) ≥5 times the upper limit of normal (ULN), alkaline phosphatase (ALP) ≥2 × ULN, or ALT ≥3 × ULN and total bilirubin TBIL >2 × ULN. However, DILI might also occur in patients who do not reach those thresholds and still may benefit from discontinuation of medication. Methods: Fifteen patients recruited for our prospective study on potentially hepatotoxic drugs were included. DILI diagnosis was based on RUCAM (Roussel Uclaf Causality Assessment Method) score and expert opinion and was supported by an in vitro test using monocyte-derived hepatocyte-like (MH) cells. Results: Median RUCAM score was 6 (range 4–8), indicating that DILI was possible or probable in all cases. The predominant types of liver injury were mixed (60%) and cholestatic (40%). While no elevation above 2 × ULN of ALP and TBIL was observed, gamma-glutamyltransferase (GGT) above 2 × ULN was identified in 8 of the patients. Six of the 15 patients did not achieve full remission and showed persistent elevation of GGT, which was significantly associated with peak GGT elevation above 2 × ULN (p = 0.005). Conclusion: Here we present a case series of patients with liver enzyme elevation below the conventional thresholds who developed DILI with a predominant GGT elevation leading to drug withdrawal and/or chronic elevation of liver parameters, in particular of GGT. Thus, we propose that DILI should be considered in particular in cases with marked increase of GGT even if conventional DILI threshold levels are not reached, resulting in discontinuation of the causative drug and/or close monitoring of the patients.
- Published
- 2021
23. P041 Tandem mass tag-based quantitative proteomic profiling identifies novel putative serum biomarkers for the diagnosis of drug-induced liver injury in patients
- Author
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Raúl J. Andrade, Zhenyu Wang, Jane I. Grove, Shashi K. Ramaiah, Alexander L. Gerbes, Camilla Stephens, Andrew Fowell, Sabine Weber, Richard Virgen-Slane, Guido Stirnimann, Edmond Atallah, Einar Bjornsson, M. Isabel Lucena, James W. Dear, Hyder Hussaini, Vishal S. Vaidya, Ravi Kodihalli, Guruprasad P. Aithal, Robert A. Everley, Joel D. Federspiel, and Craig L. Hyde
- Subjects
Liver injury ,Drug ,Serum biomarkers ,Proteomic Profiling ,business.industry ,media_common.quotation_subject ,Cancer research ,Medicine ,In patient ,Tandem mass tag ,business ,medicine.disease ,media_common - Published
- 2021
24. Drug‐Induced Liver Injury by Checkpoint Inhibitors: Benefit of a Causality Assessment Tool
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Andreas Benesic, Sabine Weber, Alexander L. Gerbes, and Masatoshi Ishigami
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Drug ,Liver injury ,Hepatology ,business.industry ,Immune checkpoint inhibitors ,media_common.quotation_subject ,MEDLINE ,Bioinformatics ,medicine.disease ,Causality ,Correspondence ,Medicine ,lcsh:Diseases of the digestive system. Gastroenterology ,lcsh:RC799-869 ,business ,media_common - Published
- 2020
25. Severe liver failure during SARS-CoV-2 infection
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Julia Mayerle, Sabine Weber, Michael Irlbeck, and Alexander L. Gerbes
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0301 basic medicine ,Ramipril ,medicine.medical_specialty ,business.industry ,Gastroenterology ,Emergency department ,Azithromycin ,medicine.disease_cause ,medicine.disease ,Tazobactam ,03 medical and health sciences ,Liver disease ,030104 developmental biology ,0302 clinical medicine ,Hydrochlorothiazide ,Internal medicine ,medicine ,030211 gastroenterology & hepatology ,business ,medicine.drug ,Piperacillin ,Coronavirus - Abstract
We read with interest the recently described affections of the GI system in coronavirus disease (COVID-19).1 2 In addition to the effects on the gut, mild abnormalities in liver aminotransferase levels have been observed.3 4 We here report a previously non-described severe liver failure in a patient with COVID-19. A 65-year-old man was admitted to our emergency department with fever up to 40°C, dry cough and dyspnoea. The chest CT scan showed typical features of COVID-19, such as ground-glass opacities and peripheral consolidations. A throat swab confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Aminotransferase concentrations were slightly increased (alanine aminotransferase (ALT) 69 U/L and aspartate aminotransferase (AST) 92 U/L; upper limit of normal (ULN) ≤49 U/L). He had been receiving long-term treatment with hydrochlorothiazide and ramipril for arterial hypertension as sole medications and had no history of liver disease. The patient was admitted to the isolation ward and was given supplementary oxygen. He received piperacillin/tazobactam and azithromycin according to hospital standards, as well as paracetamol (1 g, up to two times per day). …
- Published
- 2020
26. Early ALT response to corticosteroid treatment distinguishes idiosyncratic drug‐induced liver injury from autoimmune hepatitis
- Author
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Andreas Benesic, Sabine Weber, Alexander L. Gerbes, and Isabelle Rotter
- Subjects
Adult ,Male ,Drug ,medicine.medical_specialty ,media_common.quotation_subject ,Corticosteroid treatment ,Autoimmune hepatitis ,Severity of Illness Index ,Gastroenterology ,Diagnosis, Differential ,Young Adult ,Adrenal Cortex Hormones ,immune system diseases ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Alanine aminotransferase ,Aged ,media_common ,Acute liver injury ,Liver injury ,Hepatology ,business.industry ,Alanine Transaminase ,Middle Aged ,medicine.disease ,digestive system diseases ,Current analysis ,Hepatitis, Autoimmune ,Toxicity ,Female ,Chemical and Drug Induced Liver Injury ,business - Abstract
Background Drug‐induced liver injury (DILI) and idiopathic autoimmune hepatitis (AIH) are competing diagnoses in patients with acute liver injury (ALI) and drug intake. In absence of unequivocal markers, scores like RUCAM and AIH are used to distinguish both entities. However, in some cases the diagnosis remains ambiguous. Our aim was to identify a simple parameter to discriminate DILI and AIH shortly after starting corticosteroid treatment. Methods For the current analysis, 44 patients with ALI who took at least one drug and who received corticosteroids were included and comprised 22 DILI and 22 AIH cases. Scores of AIH and RUCAM were calculated at initial presentation, the final diagnosis was made from analysing the course of disease. Changes in the serum alanine aminotransferase (ALT) concentrations after starting corticosteroid treatment were determined and compared between the DILI and AIH groups. Results Fifty‐nine per cent of patients (n = 26) were correctly classified at presentation by AIH score and RUCAM respectively. However, in one‐third (n = 13) of the 44 patients, results were inconclusive and five other patients were misclassified. The decrease in ALT levels 1 week after the initiation of steroid therapy was significantly more pronounced in patients with the final diagnosis of DILI than in AIH patients (accuracy 77%). This difference was also observed in the 18 initially misclassified or inconclusive cases (accuracy 83%). Conclusion Short‐term response of ALT to corticosteroid therapy helps to differentiate DILI and AIH. This finding may be helpful in treatment decision for patients with inconclusive diagnostic scores.
- Published
- 2019
27. Leitlinienreport zur aktualisierten S2k-Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) zu Komplikationen der Leberzirrhose
- Author
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Alexander L. Gerbes, Petra Lynen Jansen, Julia Jungnitsch, Pia van Leeuwen, and Joachim Labenz
- Subjects
Gynecology ,medicine.medical_specialty ,business.industry ,Gastroenterology ,Medicine ,business - Published
- 2019
28. Aktualisierte S2k-Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) 'Komplikationen der Leberzirrhose'
- Author
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Deutsche Gesellschaft für Interventionelle Radiologie und minimal-invasive Therapie, A Zipprich, Reiner Wiest, Felix Gundling, Christian J. Steib, Deutsche Gesellschaft für Allgemein und Viszeralchirurgie, Jonel Trebicka, Joachim Labenz, Deutsche Gesellschaft für Nephrologie, Petra Lynen-Jansen, Alexander L. Gerbes, Matthias Dollinger, Axel Holstege, Beate Appenrodt, Bdp, V Bundesverband deutscher Pathologen e., and Veit Gülberg
- Subjects
medicine.medical_specialty ,Evidence-based practice ,Cirrhosis ,business.industry ,MEDLINE ,Gastroenterology ,Guideline ,medicine.disease ,language.human_language ,German ,Patient support ,03 medical and health sciences ,0302 clinical medicine ,medicine ,language ,030211 gastroenterology & hepatology ,030212 general & internal medicine ,Intensive care medicine ,business ,Hepatic encephalopathy - Abstract
ZusammenfassungDie Leitlinie Komplikationen der Leberzirrhose der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) ersetzt die Leitlinie aus dem Jahr 2011. Sie basiert auf den Empfehlungen der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) für eine evidenzbasierte Konsensus-Leitlinie der Entwicklungsstufe S2k und wurde interdisziplinär unter Beteiligung aller relevanten Fachgesellschaften und der Patientenvertretung erstellt. Neben den in der Vorgängerversion behandelten Kapiteln Aszites, spontan bakterielle Peritonitis, hepatorenales Syndrom, hepatischer Hydrothorax und hepatopulmonales Syndrom wurden die Kapitel Diagnostik und Therapie der Hepatischen Enzephalopathie neu aufgenommen.
- Published
- 2019
29. The PI3K inhibitor copanlisib synergizes with sorafenib to induce cell death in hepatocellular carcinoma
- Author
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Enrico N. De Toni, Florian P. Reiter, Andreas Ziesch, Julia Mayerle, Alexander L. Gerbes, and Liangtao Ye
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Sorafenib ,Cancer Research ,Cell cycle checkpoint ,Immunology ,Cell ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Cyclin D1 ,medicine ,lcsh:QH573-671 ,Protein kinase B ,neoplasms ,PI3K/AKT/mTOR pathway ,Copanlisib ,business.industry ,lcsh:Cytology ,Cell Biology ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,female genital diseases and pregnancy complications ,digestive system diseases ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,business ,medicine.drug - Abstract
Sorafenib, a multikinase inhibitor targeting the Ras/Raf/MAPK (mitogen-activated protein kinase) and vascular endothelial growth factor signaling pathways is an established treatment option for patients with advanced-stage hepatocellular carcinoma (HCC); however, despite its clinical benefit, chemoresistance and disease progression eventually occur almost invariably during treatment. Activation of the PI3K/AKT (phosphatidylinositol-3-kinase/serine/threonine kinase) pathway plays a role in the pathogenesis of HCC and may contribute to determine resistance to sorafenib. We thus evaluated in vitro the effects of the combination of sorafenib and copanlisib, a PI3K inhibitor recently approved for clinical use. The effects of copanlisib alone and in combination with sorafenib were assessed in several HCC cell lines by proliferation and colony formation assays, fluorescence-activated cell sorting analyses, and western blot. In addition, sorafenib-resistant cell clones were used. Copanlisib strongly reduced cell viability and colony formation in different native and sorafenib-resistant HCC cell lines by affecting cyclin D1/CDK4/6 signaling and causing cell cycle arrest. Elevation of phosphorylated (p)-AKT was observed upon incubation with sorafenib and was consistently found in six different unstimulated sorafenib-resistant cell clones. Copanlisib counteracted sorafenib-induced phosphorylation of p-AKT and synergistically potentiated its antineoplastic effect. In summary, copanlisib shows potent anticancer activity as a single agent and acts synergistically in combination with sorafenib in human HCC. Combination of sorafenib with copanlisib represents a rational potential therapeutic option for advanced HCC.
- Published
- 2019
30. Age independent survival benefit for patients with hepatocellular carcinoma (HCC) without metastases at diagnosis: a population-based study
- Author
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Helmut Friess, Jens Ricke, Wolfgang Schepp, Fabian Geisler, Jutta Engel, Ursula Ehmer, Julia Mayerle, Martin Fuchs, Anne Schlesinger-Raab, Alexander L. Gerbes, Enrico N. De Toni, P Paprottka, and Jens Werner
- Subjects
Male ,Gadolinium DTPA ,Oncology ,medicine.medical_specialty ,Prognostic variable ,Carcinoma, Hepatocellular ,real-life-data ,Kaplan-Meier Estimate ,Disease ,survival ,Germany ,Internal medicine ,medicine ,Data Systems ,Humans ,Early Detection of Cancer ,Aged ,Neoplasm Staging ,Proportional Hazards Models ,Cause of death ,Aged, 80 and over ,Hepatology ,Relative survival ,business.industry ,Incidence ,Incidence (epidemiology) ,Liver Neoplasms ,Gastroenterology ,hepatocellular carcinoma ,Middle Aged ,Prognosis ,medicine.disease ,ddc ,Cancer registry ,Survival Rate ,Survival benefit ,Liver ,Hepatocellular carcinoma ,Female ,business ,tumor stage - Abstract
ObjectiveHepatocellular carcinoma (HCC) is a major cause of death worldwide and its incidence is expected to increase globally. Aim of this study was to assess whether the implementation of screening policies and the improvement of treatment options translated into a real-world survival benefit in HCC patients.Design4078 patients diagnosed with HCC between 1998 and 2016 from the Munich Cancer Registry were analysed. Tumour characteristics and outcome were analysed by time period and according to age and presence of metastases at diagnosis. Overall survival (OS) was analysed using Kaplan-Meier method and relative survival (RS) was computed for cancer-specific survival. Cox proportional hazard models were conducted to control for prognostic variables.ResultsWhile incidence of HCC remained substantially stable, tumours were diagnosed at increasingly earlier stages, although the median age at diagnosis increased. The 3 years RS in HCC improved from 19.8% in 1998–2002, 22.4% in 2003–2007, 30.6% in 2008–2012 up to 31.0% in 2013–2016. Median OS increased from 6 months in 1998–2002 to 12 months in 2008–2016. However, analysis according to the metastatic status showed that survival improved only in patients without metastases at diagnosis whereas the prognosis of patients with metastatic disease remained unchanged.ConclusionThese real-world data show that, in contrast to the current assumptions, the incidence of HCC did not increase in a representative German region. Earlier diagnosis, likely related to the implementation of screening programmes, translated into an increasing employment of effective therapeutic options and a clear survival benefit in patients without metastases at diagnosis, irrespective of age.
- Published
- 2019
31. Inhibition of Cyclin‐Dependent Kinase 5: A Strategy to Improve Sorafenib Response in Hepatocellular Carcinoma Therapy
- Author
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Veronika Kanitz, Thorsten Lehr, Laura Posselt, Alexander L. Gerbes, Martin Müller, Simon Rothenfußer, Thomas Fröhlich, Lars M. König, Carina Atzberger, Emanuele Martini, Jan-Georg Wojtyniak, Georg J. Arnold, Stefan Zahler, Doris Mayr, Johanna Pachmayr, Melanie Ulrich, Dario Parazzoli, Petra Cantonati, Angelika M. Vollmar, Giorgio Scita, Maximilian A. Ardelt, and Martina Meßner
- Subjects
0301 basic medicine ,Sorafenib ,Carcinoma, Hepatocellular ,Cellular homeostasis ,Small hairpin RNA ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Growth factor receptor ,Liver Biology/Pathobiology ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Dinaciclib ,Protein Kinase Inhibitors ,neoplasms ,Gene knockdown ,Hepatology ,business.industry ,Cyclin-dependent kinase 5 ,Liver Neoplasms ,Cyclin-Dependent Kinase 5 ,Original Articles ,medicine.disease ,digestive system diseases ,Treatment Outcome ,030104 developmental biology ,nervous system ,chemistry ,Hepatocellular carcinoma ,Cancer research ,Original Article ,Female ,030211 gastroenterology & hepatology ,business ,medicine.drug - Abstract
Therapeutic options for patients with advanced-stage hepatocellular carcinoma (HCC) are very limited. The only approved first-line treatment is the multi-tyrosine kinase inhibitor sorafenib, which shows low response rates and severe side effects. In particular, the compensatory activation of growth factor receptors leads to chemoresistance and limits the clinical impact of sorafenib. However, combination approaches to improve sorafenib have failed. Here we investigate the inhibition of cyclin-dependent kinase 5 (Cdk5) as a promising combination strategy to improve sorafenib response in HCC. Combination of sorafenib with Cdk5 inhibition (genetic knockdown by short hairpin RNA or CRISPR/Cas9 and pharmacologic inhibition) synergistically impaired HCC progression in vitro and in vivo by inhibiting both tumor cell proliferation and migration. Importantly, these effects were mediated by a mechanism for Cdk5: A liquid chromatography-tandem mass spectrometry-based proteomic approach revealed that Cdk5 inhibition interferes with intracellular trafficking, a process crucial for cellular homeostasis and growth factor receptor signaling. Cdk5 inhibition resulted in an accumulation of enlarged vesicles and respective cargos in the perinuclear region, considerably impairing the extent and quality of growth factor receptor signaling. Thereby, Cdk5 inhibition offers a comprehensive approach to globally disturb growth factor receptor signaling that is superior to specific inhibition of individual growth factor receptors. Conclusion: Cdk5 inhibition represents an effective approach to improve sorafenib response and to prevent sorafenib treatment escape in HCC. Notably, Cdk5 is an addressable target frequently overexpressed in HCC, and with Dinaciclib, a clinically tested Cdk5 inhibitor is readily available. Thus, our study provides evidence for clinically evaluating the combination of sorafenib and Dinaciclib to improve the therapeutic situation for patients with advanced-stage HCC.
- Published
- 2018
32. Liver function test abnormalities at hospital admission are associated with severe course of SARS-CoV-2 infection: a prospective cohort study
- Author
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Alexander L. Gerbes, Johannes C. Hellmuth, Julia Mayerle, Sabine Weber, Clemens Scherer, and Maximilian Muenchhoff
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Severity of Illness Index ,law.invention ,03 medical and health sciences ,Liver disease ,0302 clinical medicine ,Liver Function Tests ,law ,Risk Factors ,Internal medicine ,Severity of illness ,medicine ,Humans ,Aspartate Aminotransferases ,Prospective Studies ,Risk factor ,Prospective cohort study ,Aged ,Mechanical ventilation ,Aged, 80 and over ,medicine.diagnostic_test ,biology ,business.industry ,SARS-CoV-2 ,Liver Diseases ,Gastroenterology ,COVID-19 ,Alanine Transaminase ,gamma-Glutamyltransferase ,Middle Aged ,medicine.disease ,Intensive care unit ,Hospitalization ,030104 developmental biology ,Alanine transaminase ,biology.protein ,030211 gastroenterology & hepatology ,Female ,Liver function tests ,business ,Biomarkers - Abstract
ObjectiveLiver injury has frequently been reported in COVID-19 patients. The clinical relevance of liver injury related to SARS-CoV-2 infection remains unclear with a need for prospective studies on the impact of liver function test (LFT) abnormalities at baseline.DesignData of 217 patients without pre-existing liver disease prospectively included in the COVID-19 registry of the LMU university hospital were analysed in order to assess the association of abnormal LFT at admission and course of the disease. Severe course was defined as admission to the intensive care unit (ICU) or as COVID-19-related death.ResultsAbnormal LFT at baseline was present in 58% of patients, with a predominant elevation of aspartate aminotransferase (AST) (42%), gamma-glutamyltransferase (GGT) (37%) and alanine aminotransferase (ALT) (27%), hypoalbuminaemia was observed in 33%. Elevation of ALT and GGT, as well as hypoalbuminaemia, was associated with higher proportions of patients requiring ICU treatment and mechanical ventilation. After adjusting for age, gender and comorbidities, hypoalbuminaemia combined with abnormal AST or GGT at hospital admission was a highly significant independent risk factor for ICU admission (OR 46.22 and 38.8, respectively) and for a composite endpoint of ICU admission and/or COVID-19-related death (OR 42.0 and 26.9, respectively).ConclusionAbnormal LFTs at hospital admission, in particular GGT and albumin, are associated with a severe course of SARS-CoV-2 infection.
- Published
- 2021
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33. PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis
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William Bernal, Agustín Albillos, Alex Amoros, Wim Laleman, Michael Manns, Javier Martínez, Maximilian J. Brol, Pere Ginès, Alessandra Pohlmann, Joerg Tobiasch Moritz, Francois Smits, Elisabet Garcia-Lopez, Joan Clària, Jennifer Lehmann, Jonel Trebicka, Christoph Welsch, Vicente Arroyo, Richard Moreau, Tony Bruns, Monica Mesquita, Christian Jansen, Peter Jarcuska, Harald Rupprechter, Martin Janicko, Thierry Gustot, Macarena Simón-Talero, Giacomo Zaccherini, Cristina Ripoll, Luise Aamann, Oliviero Riggio, Martina Rizzo, Karen Vagner Danielsen, Javier Romaní Fernández, Jelte J Schaapman, Frank Erhard Uschner, Juan Acevedo, Miguel Á. Rodríguez, David Semela, Carlo Alessandria, Carmine Gambino, Lise Lotte Gluud, Paolo Caraceni, Emanuela Ciraci, István Altorjay, Cristina Solé, Salvatore Piano, Minneke J. Coenraad, Pierre Nahon, Haluk Tarik Kani, Faouzi Saliba, Agnese Antognoli, Andrea De Gottardi, Osman Ozdogan, Henning Grønbæk, Christian J. Steib, Anna Curto, Hans Van Vlierberghe, Manuel Romero-Gómez, T.M. Welzel, Roland Amathieu, Sylvie Tresson, Carla Pitarch, Frederik Nevens, Alexander Zipprich, Christian Trautwein, Ilaria Giovo, Victor Vargas, Laure Elkrief, Giorgio Maria Saracco, Johannes Chang, Mattias Mandorfer, Paul Horn, Thomas Berg, Nesrine Amari, Sara Mareso, Heinz Zoller, Osagie Akpata, Mária Papp, Adam Herber, Thomas Reiberger, Flemming Bendtsen, Elsa Solà, Ferran Aguilar, Jose Presa Ramos, Miriam Maschmeier, Tamas Tornai, Manuela Merli, Rajiv Jalan, Martina Gagliardi, Cornelius Engelmann, Rafael Bañares, Daniela Campion, Antonella Putignano, Natalie Van den Ende, Claire Francoz, Marco Pavesi, Paola Ponzo, Rita Garcia, Sven Francque, Vish Patel, Esau Moreno, Alessandra Brocca, Rudolf E. Stauber, Zsuzsanna Vitális, Rajeshwar P. Mookerjee, Ahmed Elsharkawy, Eleonora Bertoli, Michael Praktiknjo, Stephen D. Ryder, Cristina Sanchez, Boglarka Balogh, Debbie L. Shawcross, Manuel Tufoni, Paolo Angeli, Florian Rainer, Pavel Strnad, István Tornai, Edilmar Alvarado-Tapias, Alexander L. Gerbes, Didier Samuel, Maurizio Baldassarre, Cesar Jimenez, Stefan Zeuzem, Pietro Gatti, Germán Soriano, Robert Schierwagen, Ana Clemente, Mauro Bernardi, Daniel Markwardt, Trebicka, Jonel, Fernandez, Javier, Papp, Maria, Caraceni, Paolo, Laleman, Wim, Gambino, Carmine, Giovo, Ilaria, Uschner, Frank Erhard, Jansen, Christian, Jimenez, Cesar, Mookerjee, Rajeshwar, Gustot, Thierry, Albillos, Agustin, Bañares, Rafael, Jarcuska, Peter, Steib, Christian, Reiberger, Thoma, Acevedo, Juan, Gatti, Pietro, Shawcross, Debbie L, Zeuzem, Stefan, Zipprich, Alexander, Piano, Salvatore, Berg, Thoma, Bruns, Tony, Danielsen, Karen Vagner, Coenraad, Minneke, Merli, Manuela, Stauber, Rudolf, Zoller, Heinz, Ramos, José Presa, Solé, Cristina, Soriano, Germán, de Gottardi, Andrea, Gronbaek, Henning, Saliba, Faouzi, Trautwein, Christian, Kani, Haluk Tarik, Francque, Sven, Ryder, Stephen, Nahon, Pierre, Romero-Gomez, Manuel, Van Vlierberghe, Han, Francoz, Claire, Manns, Michael, Garcia-Lopez, Elisabet, Tufoni, Manuel, Amoros, Alex, Pavesi, Marco, Sanchez, Cristina, Praktiknjo, Michael, Curto, Anna, Pitarch, Carla, Putignano, Antonella, Moreno, Esau, Bernal, William, Aguilar, Ferran, Clària, Joan, Ponzo, Paola, Vitalis, Zsuzsanna, Zaccherini, Giacomo, Balogh, Boglarka, Gerbes, Alexander, Vargas, Victor, Alessandria, Carlo, Bernardi, Mauro, Ginès, Pere, Moreau, Richard, Angeli, Paolo, Jalan, Rajiv, Arroyo, Vicente, Banares, Rafael, Reiberger, Thomas, Shawcross, Debbie L., Berg, Thomas, Ramos, Jose Presa, Sole, Cristina, Soriano, German, Van Vlierberghe, Hans, Claria, Joan, Gines, Pere, Maschmeier, Miriam, Semela, David, Elkrief, Laure, Elsharkawy, Ahmed, Tornai, Tamas, Tornai, Istvan, Altorjay, Istvan, Antognoli, Agnese, Baldassarre, Maurizio, Gagliardi, Martina, Bertoli, Eleonora, Mareso, Sara, Brocca, Alessandra, Campion, Daniela, Saracco, Giorgio Maria, Rizzo, Martina, Lehmann, Jennifer, Pohlmann, Alessandra, Brol, Maximilian J., Chang, Johannes, Schierwagen, Robert, Sola, Elsa, Amari, Nesrine, Rodriguez, Miguel, Nevens, Frederik, Clemente, Ana, Janicko, Martin, Markwardt, Daniel, Mandorfer, Mattias, Welsch, Christoph, Welzel, Tanja M., Ciraci, Emanuela, Patel, Vish, Ripoll, Cristina, Herber, Adam, Horn, Paul, Bendtsen, Flemming, Gluud, Lise Lotte, Schaapman, Jelte, Riggio, Oliviero, Rainer, Florian, Moritz, Joerg Tobiasch, Mesquita, Monica, Alvarado-Tapias, Edilmar, Akpata, Osagie, Aamann, Luise, Samuel, Didier, Tresson, Sylvie, Strnad, Pavel, Amathieu, Roland, Simon-Talero, Macarena, Smits, Francois, van den Ende, Natalie, Martinez, Javier, Garcia, Rita, Rupprechter, Harald, Engelmann, Cornelius, and Ozdogan, Osman Cavit
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0301 basic medicine ,Liver Cirrhosis ,Male ,Cirrhosis ,Organ Dysfunction Scores ,acute complication ,Chronic liver disease ,Acute complications ,Non-elective admission ,Outcome ,Risk factors ,0302 clinical medicine ,Preventive Health Services ,Medicine and Health Sciences ,Gastro-entérologie ,risk factors ,610 Medicine & health ,Medical History Taking ,factors ,Toxic encephalopathy ,Bacterial Infections ,Middle Aged ,Prognosis ,Europe ,Cohort ,Disease Progression ,outcome ,030211 gastroenterology & hepatology ,Female ,medicine.symptom ,Needs Assessment ,Risk ,medicine.medical_specialty ,Alcoholic hepatitis ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Decompensation ,Medical history ,Inflammation ,Hepatology ,business.industry ,Hepatitis, Alcoholic ,Organ dysfunction ,Acute-On-Chronic Liver Failure ,chronic liver disease ,medicine.disease ,Precipitating Factors ,030104 developmental biology ,Human medicine ,business ,non-elective admission - Abstract
Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF phenotype (AD-ACLF) defined by organ failure(s). Precipitants may induce AD. This multicenter, prospective, observational PREDICT study (NCT03056612) analyzes and characterizes the precipitants leading to both of these AD phenotypes., info:eu-repo/semantics/published
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- 2021
34. Anschriften der Herausgeber und Autoren
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Reinhard Brunkhorst, Jürgen Schölmerich, Hans-Dieter Allescher, Thomas Berger, Peter Berlit, Franziska Bertram, Cornelius Bollheimer, Herbert Bruckmayer, Peter Brunotte, Roland Büttner, Klaus-Peter Czudaj, Dominic Dellweg, Matthias Dollinger, Dorothee Dorlars, Matthias Ebert, Matthias Eder, Esther Endlicher, Markus Fahlbusch, Peter Fickert, Gabriele Fluhr, Tobias Freundt, Baptist Gallwitz, Mirja Geelvink, Alexander L. Gerbes, Jens Gerth, Beate Gleissner, Thomas Glück, Stefan K. Gölder, Laura Gottschalk, Oliver Gross, Dietrich Gulba, Marianne Haag-Weber, Viola Hach-Wunderle, Michael Hamm, Thomas R.W. Herrmann, Walter Hermann, Felix J.F. Herth, Mirja Hickstein, Silke Hörnschemeyer-Decker, Axel Holstege, Oliver Kastrup, Ahmed A. Khattab, Jutta Keller, Philipp Klemm, Gunnar Klein, Stefan Köppen, Michael Kreuter, Markus A. Kuczyk, Frank Lammert, Ulf Landmesser, Thea Laurentius, Markus Lerch, Guntram Lock, J.-Matthias Löhr, Hans Peter Lorenzen, Gert Mayer, Stephanie Mayer, Julia Mayerle, Martina Mayr, Axel S. Merseburger, Gerhard A. Müller, Ulf Müller-Ladner, Karsten Müssig, Ralph Naumann, Michael Nebel, Jost Niedermeyer, Florian Obermeier, Peter Otto, Jens Panse, Klaus G. Parhofer, Susanne Petri, Michael Pfeifer, Antje Prasse, Ulrike Raap, Walter Reinisch, Gert Richardt, Katrin Richter-Bastian, Felix Rockmann, Bernd Salzberger, Tilman Sauerbruch, Philippe Schafhausen, Carsten Schmidt, Bernd Schönhofer, Friedrich Schorr, Christoph Schrader, Michael Schumann, Andreas Schwartz, Jochen Seufert, Britta Siegmund, Peter Simon, Peter Staib, Andreas Stallmach, Erwin Stark, Bernhard Steinhoff, Johannes Strunk, Ingo H. Tarner, Christian Teschendorf, Theodoros Thomas, Herbert Tilg, Ralph Tölg, Michael Trauner, Jenny Unterkofler, Peter Wagener, Manuel Wallbach, Thomas Weiss, Fritz von Weizsäcker, Martin Welker, Hans-Jürgen Welkoborsky, Tobias Welte, Burkhard Wiechens, Uwe Wiegand, Reiner Wiest, Jürgen Wilke, Ulrike Woenckhaus, Gunter Wolf, and Christian Wrede
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- 2021
35. Risk of recurrent hepatic encephalopathy in patients with liver cirrhosis : A German registry study
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H Mix, Maria von Karpowitz, Benjamin Seeliger, T.M. Welzel, Alexander L. Gerbes, Peter Buggisch, Daniel Markwardt, Heiner Wedemeyer, Heinz Hartmann, Kurt Grüngreiff, Maria M. Gabriel, Julia Kälsch, Karin Weissenborn, Gerald Kircheis, and Svenja Hardtke
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Liver Cirrhosis ,medicine.medical_specialty ,Cirrhosis ,Psychometrics ,Medizin ,03 medical and health sciences ,0302 clinical medicine ,Quality of life ,Internal medicine ,Statistical significance ,medicine ,Clinical endpoint ,Humans ,Prospective Studies ,Registries ,Risk factor ,Hepatic encephalopathy ,Hepatology ,business.industry ,Gastroenterology ,medicine.disease ,030220 oncology & carcinogenesis ,Hepatic Encephalopathy ,Cohort ,Quality of Life ,030211 gastroenterology & hepatology ,Observational study ,business - Abstract
BACKGROUND AND AIMS Patients with hepatic encephalopathy (HE) show low quality of life, recurrent hospitalizations and an increased mortality. We aimed to assess the natural course of patients after a recent episode of overt HE and to identify risk factors for HE recurrence in Germany. METHODS Fifteen sites took part in a prospective, observational study including patients with liver cirrhosis who had been hospitalized for HE within 3 months before recruitment. Clinical data, psychometric hepatic encephalopathy score (PHES) and critical flicker frequency were assessed quarterly for 1 year. Primary endpoint was HE recurrence requiring hospitalization, all-cause-mortality was treated as a competing risk factor. RESULTS From January 2014 to March 2016, a total of 115 patients were recruited. Overall 14 premature deaths were documented. For 78 subjects follow-up data were available in accordance with the protocol. After a median of 118 days, more than half of the per-protocol cohort was readmitted to hospital due to HE (N = 34) or died (N = 11). The risk for hospitalization was significantly increased in patients who had been recruited by liver transplant centers (P = 0.003), had had frequent HE relapses prior to recruitment (P =
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- 2021
36. Acute liver injury in a patient with adult-onset Still’s disease—the challenge of differential diagnosis
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Sabine Weber and Alexander L. Gerbes
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Adult-onset Still's disease ,medicine.medical_specialty ,omcrep/800 ,Case Report ,Disease ,030204 cardiovascular system & hematology ,Microbiology ,omcrep/2000 ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,In patient ,030212 general & internal medicine ,Acute liver injury ,business.industry ,food and beverages ,medicine.disease ,Rash ,omcrep/1100 ,Infectious Diseases ,Macrophage activation syndrome ,Parasitology ,medicine.symptom ,Differential diagnosis ,business ,AcademicSubjects/MED00010 - Abstract
In addition to the cardinal symptoms of fever, rash and arthralgia, liver involvement in patients with adult-onset Still’s disease (AOSD) has been described. However, acute liver injury in AOSD patients can have various other causes: it can be a result of an AOSD-induced macrophage activation syndrome or be associated to the drugs given for the underlying diseases and symptoms. Differential diagnosis can therefore be challenging. We here present a case of a 32-year-old male with acute liver injury following the initial diagnosis of AOSD to discuss the possible underlying reasons.
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- 2020
37. Correspondence (letters to the editor): Liver Involvement
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Alexander L. Gerbes and Sabine Weber
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Respiratory Distress Syndrome ,Liver ,SARS-CoV-2 ,COVID-19 ,Humans ,General Medicine ,Letters to the Editor ,Neoplasm Staging - Published
- 2020
38. Correction to 'Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF' [J Hepatol 2020 (72) 688-701]
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Paolo Caraceni, Christophe Junot, Tania M. Welzel, Christian J. Steib, Thaïs Hautbergue, Christophe Moreno, Sara Montagnese, Ferran Aguilar, Joan Clària, R.P. Mookerjee, Henning Grønbæk, Christian Jansen, Jonel Trebicka, Pere Ginès, Benoit Colsch, Noémie Butin, Mauro Bernardi, Thierry Gustot, François Durand, Daniela Campion, Rudolf E. Stauber, Daniel Benten, Faouzi Saliba, Joan Genescà, Marco Pavesi, Maurizio Baldassarre, Rajiv Jalan, François Fenaille, Carlo Alessandria, Javier Fernández, Juan José Lozano, Elsa Solà, Victor Vargas, Sophie Cholet, Richard Moreau, Vicente Arroyo, Minneke J. Coenraad, William Bernal, Frederik Nevens, Giacomo Zaccherini, Salvatore Piano, Agustín Albillos, Germán Soriano, Florence Castelli, Alexander L. Gerbes, Paolo Angeli, M.A. Rodríguez-Gandía, and R. Bañares
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Metabolomics ,Hepatology ,business.industry ,Medicine ,Inflammation ,medicine.symptom ,Bioinformatics ,business ,Potential mechanism - Published
- 2020
39. Pretreatment with zinc protects Kupffer cells following administration of microbial products
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Hanwei Li, Christian J. Steib, Hao Lin, Jiang Zhang, Julia Mayerle, Tobias S. Schiergens, Andreas Wieser, Yuhui Fan, and Alexander L. Gerbes
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0301 basic medicine ,Adult ,Liver Cirrhosis ,Male ,medicine.medical_specialty ,Bilirubin ,Kupffer Cells ,chemistry.chemical_element ,Zinc ,RM1-950 ,Chronic liver disease ,Systemic inflammation ,03 medical and health sciences ,chemistry.chemical_compound ,Thromboxane A2 ,0302 clinical medicine ,Internal medicine ,medicine ,Hepatic Stellate Cells ,Spontaneous bacterial peritonitis ,Humans ,Aged ,Pharmacology ,Creatinine ,Liver Diseases ,Albumin ,Primary non-parenchymal cell ,General Medicine ,Middle Aged ,medicine.disease ,Zinc Sulfate ,030104 developmental biology ,Endocrinology ,chemistry ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Chronic Disease ,Hepatic stellate cell ,Female ,Therapeutics. Pharmacology ,medicine.symptom - Abstract
Background Systemic inflammation and severe fibrosis can reduce serum zinc levels, while zinc supplementation is reported to improve the prognosis of patients with chronic liver disease (CLD). Objectives We aimed to investigate the clinical application of serum zinc in patients with CLD and the anti-infective mechanism of zinc supplementation. Methods Based on the serum zinc level, 149 CLD patients were divided into 3 groups and their clinical parameters were compared. In in-vitro experiments, microbial isolates derived from patients were used to stimulate human liver non-parenchymal cells, and the zinc sulfate solution was added in certain experiments. The effect of zinc was compared by LDH and thromboxane A2 levels in the cell supernatant. Result Compared with other groups, patients with low serum zinc levels had significantly higher C-reactive protein (CRP), total bilirubin, INR, creatinine, and MELD scores, while albumin and GOT levels were reduced. Only CRP and albumin were significantly correlated with serum zinc in both low and normal-zinc groups. Bacterial isolates significantly increased LDH levels in Kupffer cells (KCs) and stellate cells but had no effect on sinusoidal endothelial cells, whereas zinc pretreatment protected KCs but not stellate cells. Thromboxane A2 secreted by KCs can also be induced by bacterial stimulation, accompanied by increased gene expression of Myd88, MAPK and NF-kB, while zinc pretreatment can attenuate that. Conclusion Serum zinc levels can be used to estimate infection and liver fibrosis in CLD patients. As a new antibacterial weapon, zinc supplementation acts on KCs through Myd88-MAPK related pathways.
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- 2020
40. Albumin in decompensated cirrhosis: new concepts and perspectives
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Joan Clària, Thierry Thevenot, Alexander L. Gerbes, Paolo Caraceni, Jonel Trebicka, Pere Ginès, Rajiv Jalan, Javier Fernández, Vicente Arroyo, Paolo Angeli, Mauro Bernardi, Richard Moreau, Alastair O'Brien, Bernardi M., Angeli P., Claria J., Moreau R., Gines P., Jalan R., Caraceni P., Fernandez J., Gerbes A.L., O'Brien A.J., Trebicka J., Thevenot T., and Arroyo V.
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Oncotic pressure ,Cirrhosis ,Cirrosi hepàtica ,Endothelium ,liver cirrhosis ,Serum albumin ,Pharmacology ,Proinflammatory cytokine ,Immune system ,Albumins ,Recent Advances in Clinical Practice ,Ascites ,Albúmines ,medicine ,Animals ,Humans ,Serum Albumin ,biology ,business.industry ,liver cirrhosi ,Animal ,Gastroenterology ,Albumin ,Acute-On-Chronic Liver Failure ,medicine.disease ,Metabolisme ,medicine.anatomical_structure ,Metabolism ,Hepatic cirrhosis ,biology.protein ,medicine.symptom ,business ,Human - Abstract
The pathophysiological background of decompensated cirrhosis is characterised by a systemic proinflammatory and pro-oxidant milieu that plays a major role in the development of multiorgan dysfunction. Such abnormality is mainly due to the systemic spread of bacteria and/or bacterial products from the gut and danger-associated molecular patterns from the diseased liver triggering the release of proinflammatory mediators by activating immune cells. The exacerbation of these processes underlies the development of acute-on-chronic liver failure. A further mechanism promoting multiorgan dysfunction and failure likely consists with a mitochondrial oxidative phosphorylation dysfunction responsible for systemic cellular energy crisis. The systemic proinflammatory and pro-oxidant state of patients with decompensated cirrhosis is also responsible for structural and functional changes in the albumin molecule, which spoil its pleiotropic non-oncotic properties such as antioxidant, scavenging, immune-modulating and endothelium protective functions. The knowledge of these abnormalities provides novel targets for mechanistic treatments. In this respect, the oncotic and non-oncotic properties of albumin make it a potential multitarget agent. This would expand the well-established indications to the use of albumin in decompensated cirrhosis, which mainly aim at improving effective volaemia or preventing its deterioration. Evidence has been recently provided that long-term albumin administration to patients with cirrhosis and ascites improves survival, prevents complications, eases the management of ascites and reduces hospitalisations. However, variant results indicate that further investigations are needed, aiming at confirming the beneficial effects of albumin, clarifying its optimal dosage and administration schedule and identify patients who would benefit most from long-term albumin administration.
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- 2020
41. The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology
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Sylvie Tresson, Sara Mareso, Daniela Campion, Agustín Albillos, Alex Amoros, Hans Van Vlierberghe, Manuel Romero-Gómez, Andrea De Gottardi, Thomas Reiberger, Vicente Arroyo, Boglarka Balogh, Miriam Maschmeier, Marco Pavesi, Javier Martínez, Harald Rupprechter, Sara Montagnese, Alessandra Pohlmann, Minneke J. Coenraad, Pierre Nahon, Agnese Antognoli, Jose Presa Ramos, Christoph Welsch, Alexander L. Gerbes, Pietro Gatti, Richard Moreau, Wim Laleman, Mauro Bernardi, Karen Vagner Danielsen, Laure Elkrief, Christian Jansen, Alexander Zipprich, Lise Lotte Gluud, Paul Horn, Ilaria Giovo, Roland Amathieu, Martina Rizzo, Elisabet Garcia, Joan Clària, Oliviero Riggio, Cristina Sanchez, Rita Garcia, Florian Rainer, Sven Francque, Manuela Merli, Giorgio Maria Saracco, Javier J.M. Fernández, Mária Papp, Martina Gagliardi, Antonella Putignano, Claire Francoz, Debbie L. Shawcross, Manuel Tufoni, Ferran Aguilar, Paola Ponzo, Heinz Zoller, Elsa Solà, Faouzi Saliba, Pavel Strnad, Stefan Zeuzem, Miguel Á. Rodríguez, David Semela, Peter Lykke Eriksen, Anna Curto, Rajiv Jalan, Emanuela Ciraci, Alessandra Brocca, István Altorjay, István Tornai, Edilmar Alvarado-Tapias, Jennifer Lehmann, Rajeshwar P. Mookerjee, Paolo Angeli, Rudolf E. Stauber, Ahmed Elsharkawy, Cristina Solé, Didier Samuel, Daniel Markwardt, Maurizio Baldassarre, Cornelius Engelmann, Cesar Jimenez, Pere Ginès, Frederik Nevens, Osagie Akpata, Germán Soriano, Robert Schierwagen, Eleonora Bertoli, Adam Herber, Jörg Tobiasch Moritz, Michael Praktiknjo, Natalie Van den Ende, William Bernal, Nesrine Amari, Stephen D. Ryder, Ana Clemente, Martin Janicko, Victor Vargas, Mattias Mandorfer, Flemming Bendtsen, Peter Jarcuska, Juan Acevedo, Vish Patel, Esau Moreno, Zsuzsanna Vitális, Tamas Tornai, Rafael Bañares, Christian J. Steib, Christian Trautwein, Thomas Berg, Michael Manns, Paolo Caraceni, Jelte J Schaapman, Carlo Alessandria, Carmine Gambino, Salvatore Piano, Carla Pitarch, Thierry Gustot, Osman Ozdogan, Francois Smits, Henning Grønbæk, Giacomo Zaccherini, Cristina Ripoll, Tony Bruns, Jonel Trebicka, Macarena Simón-Talero, Frank Erhard Uschner, Monica Mesquita, PREDICT STUDY Group, EASL-CLIF Consortium, Trebicka, Jonel, Fernandez, Javier, Papp, Maria, Caraceni, Paolo, Laleman, Wim, Gambino, Carmine, Giovo, Ilaria, Uschner, Frank Erhard, Jimenez, Cesar, Mookerjee, Rajeshwar, Gustot, Thierry, Albillos, Agustin, Banares, Rafael, Janicko, Martin, Steib, Christian, Reiberger, Thomas, Acevedo, Juan, Gatti, Pietro, Bernal, William, Zeuzem, Stefan, Zipprich, Alexander, Piano, Salvatore, Berg, Thomas, Bruns, Tony, Bendtsen, Flemming, Coenraad, Minneke, Merli, Manuela, Stauber, Rudolf, Zoller, Heinz, Ramos, Jose Presa, Sole, Cristina, Soriano, German, de Gottardi, Andrea, Gronbaek, Henning, Saliba, Faouzi, Trautwein, Christian, Ozdogan, Osman Cavit, Francque, Sven, Ryder, Stephen, Nahon, Pierre, Romero-Gomez, Manuel, Van Vlierberghe, Hans, Francoz, Claire, Manns, Michael, Garcia, Elisabet, Tufoni, Manuel, Amoros, Alex, Pavesi, Marco, Sanchez, Cristina, Curto, Anna, Pitarch, Carla, Putignano, Antonella, Moreno, Esau, Shawcross, Debbie, Aguilar, Ferran, Claria, Joan, Ponzo, Paola, Jansen, Christian, Vitalis, Zsuzsanna, Zaccherini, Giacomo, Balogh, Boglarka, Vargas, Victor, Montagnese, Sara, Alessandria, Carlo, Bernardi, Mauro, Gines, Pere, Jalan, Rajiv, Moreau, Richard, Angeli, Paolo, Arroyo, Vicente, Trebicka J., Fernandez J., Papp M., Caraceni P., Laleman W., Gambino C., Giovo I., Uschner F.E., Jimenez C., Mookerjee R., Gustot T., Albillos A., Banares R., Janicko M., Steib C., Reiberger T., Acevedo J., Gatti P., Bernal W., Zeuzem S., Zipprich A., Piano S., Berg T., Bruns T., Bendtsen F., Coenraad M., Merli M., Stauber R., Zoller H., Ramos J.P., Sole C., Soriano G., de Gottardi A., Gronbaek H., Saliba F., Trautwein C., Ozdogan O.C., Francque S., Ryder S., Nahon P., Romero-Gomez M., Van Vlierberghe H., Francoz C., Manns M., Garcia E., Tufoni M., Amoros A., Pavesi M., Sanchez C., Curto A., Pitarch C., Putignano A., Moreno E., Shawcross D., Aguilar F., Claria J., Ponzo P., Jansen C., Vitalis Z., Zaccherini G., Balogh B., Vargas V., Montagnese S., Alessandria C., Bernardi M., Gines P., Jalan R., Moreau R., Angeli P., Arroyo V., Maschmeier M., Semela D., Elkrief L., Elsharkawy A., Tornai T., Tornai I., Altorjay I., Antognoli A., Baldassarre M., Gagliardi M., Bertoli E., Mareso S., Brocca A., Campion D., Saracco G.M., Rizzo M., Lehmann J., Pohlmann A., Praktiknjo M., Schierwagen R., Sola E., Amari N., Rodriguez M., Nevens F., Clemente A., Jarcuska P., Gerbes A., Mandorfer M., Welsch C., Ciraci E., Patel V., Ripoll C., Herber A., Horn P., Danielsen K.V., Gluud L.L., Schaapman J., Riggio O., Rainer F., Moritz J.T., Mesquita M., Alvarado-Tapias E., Akpata O., Lykke Eriksen P., Samuel D., Tresson S., Strnad P., Amathieu R., Simon-Talero M., Smits F., van den Ende N., Martinez J., Garcia R., Markwardt D., Rupprechter H., and Engelmann C.
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Liver Cirrhosis ,Male ,CHRONIC LIVER-FAILURE ,Cirrhosis ,medicine.medical_treatment ,Trasplantament hepàtic ,Liver transplantation ,Chronic liver disease ,Severity of Illness Index ,Acute complications ,Non-elective admission ,Outcome ,Risk factors ,acute complications ,Ascites ,Medicine and Health Sciences ,Prospective Studies ,610 Medicine & health ,Hepatic encephalopathy ,Mortality rate ,Sciences bio-médicales et agricoles ,Middle Aged ,Prognosis ,Europe ,Survival Rate ,Hepatic cirrhosis ,Portal hypertension ,Female ,medicine.symptom ,medicine.medical_specialty ,Cirrosi hepàtica ,Gastrointestinal hemorrhage ,INFLAMMATION ,Internal medicine ,Hypertension, Portal ,SCORE ,medicine ,Humans ,Decompensation ,Hepatology ,business.industry ,MORTALITY ,Acute-On-Chronic Liver Failure ,Acute complication ,Hemorràgia gastrointestinal ,medicine.disease ,Human medicine ,Hepatic transplantation ,business ,Follow-Up Studies - Abstract
Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF., info:eu-repo/semantics/published
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- 2020
42. Prognostic Significance and Functional Relevance of Olfactomedin 4 in Early-Stage Hepatocellular Carcinoma
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Julia Mayerle, Timo Itzel, Andreas Ziesch, Helga Paula Török, Andreas Teufel, Thomas Kirchner, Liangtao Ye, Florian P. Reiter, Enrico N. De Toni, Markus Guba, Lydia Kriegl, Alexander L. Gerbes, and S Munker
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Tissue microarray ,Cell growth ,business.industry ,Gastroenterology ,Motility ,medicine.disease ,Article ,03 medical and health sciences ,0302 clinical medicine ,Liver ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Carcinoma ,medicine ,Cancer research ,Immunohistochemistry ,030211 gastroenterology & hepatology ,Stage (cooking) ,business ,Survival rate - Abstract
Objectives Hepatocellular carcinoma (HCC) is a leading cancer-related cause of death. Unfortunately, recurrence is common even after curative treatment of early-stage patients, and no adjuvant treatment has yet been established. Aberrant expression of OLFM4 in human cancers has been reported; yet, its specific function during tumor development remains poorly understood, and its role in HCC is unknown. The purpose of this study is to examine the prognostic significance of OLFM4 and its functional relevance in determining recurrence in patients with early-stage HCC. Methods Immunohistochemical staining to assess expression, cellular distribution, and prognostic significance of OLFM4 was performed in a tissue microarray comprising 157 HCC tissues and matched nontumor tissues. In addition, expression of OLFM4-coding mRNA was assessed in a separate patients' cohort. The findings were validated by in vitro functional studies using siRNA directed against OLFM4 to assess its effect on cell motility and proliferation. Results The fraction of HCC samples exhibiting positive OLFM4 staining was higher in comparison with that observed in hepatocytes from matched nontumor tissue (61% vs 39%). However, cytoplasmic-only staining for OLFM4 was associated with vascular invasion (P = 0.048), MMP-7 expression (P = 0.002), and poorer survival (P = 0.008). A multivariate analysis confirmed the independent significance of OLFM4 in determining patients' outcome (5-year survival [58.3% vs 17.3%; HR: 2.135 {95% confidence interval: 1.135-4.015}; P = 0.019]). Correspondingly, inhibition of OLFM4 by siRNA modulated the expression of MMP-7 and E-cadherin, causing inhibition of cell proliferation, motility, and migration. Discussion To the best of our knowledge, we provide the first report on the prognostic significance of OLFM4 in HCC and identify its mechanistic role as crucial mediator of MMP family protein and E-Cadherin in determining cell invasion and metastasis formation.
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- 2020
43. Benefit in liver transplantation: a survey among medical staff, patients, medical students and non-medical university staff and students
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Lorenz Frey, Martin K. Angele, Markus Guba, Bruno Meiser, Daniela Eser, Christine Englschalk, Alexander L. Gerbes, Ralf J. Jox, Manfred Stangl, Jens Werner, and Derek Dubay
- Subjects
Male ,Students, Medical ,Health (social science) ,medicine.medical_treatment ,Benefit ,030230 surgery ,Liver transplantation ,Principle-Based Ethics ,0302 clinical medicine ,Utility ,Willingness to donate ,Surveys and Questionnaires ,Health care ,Medical Staff ,Medicine ,Critical variable ,Aged, 80 and over ,lcsh:R723-726 ,Health Policy ,Beneficence ,Stakeholder ,Middle Aged ,Female ,030211 gastroenterology & hepatology ,Research Article ,Prospect of success ,Quality of life ,Adult ,medicine.medical_specialty ,Legal aspects ,Tissue and Organ Procurement ,Universities ,Waiting Lists ,Allocation ,Young Adult ,03 medical and health sciences ,Quality of life (healthcare) ,Stakeholder Participation ,Humans ,Aged ,Ethics ,business.industry ,Patient Selection ,Urgency ,Transplantation ,Issues, ethics and legal aspects ,Attitude ,Philosophy of medicine ,Family medicine ,business ,lcsh:Medical philosophy. Medical ethics - Abstract
Background The allocation of any scarce health care resource, especially a lifesaving resource, can create profound ethical and legal challenges. Liver transplant allocation currently is based upon urgency, a sickest-first approach, and does not utilize capacity to benefit. While urgency can be described reasonably well with the MELD system, benefit encompasses multiple dimensions of patients’ well-being. Currently, the balance between both principles is ill-defined. Methods This survey with 502 participants examines how urgency and benefit are weighted by different stakeholders (medical staff, patients on the liver transplant list or already transplanted, medical students and non-medical university staff and students). Results Liver transplant patients favored the sickest-first allocation, although all other groups tended to favor benefit. Criteria of a successful transplantation were a minimum survival of at least 1 year and recovery of functional status to being ambulatory and capable of all self-care (ECOG 2). An individual delisting decision was accepted when the 1-year survival probability would fall below 50%. Benefit was found to be a critical variable that may also trigger the willingness to donate organs. Conclusions The strong interest of stakeholder for successful liver transplants is inadequately translated into current allocation rules.
- Published
- 2018
44. Transarterial chemoembolization for hepatocellular carcinoma
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M. Göller, Jörg Trojan, Andreas Herbst, Peter Göhring, Philip op den Winkel, Enrico N. De Toni, Petra Stieber, Mark op den Winkel, Markus Rentsch, Philipp M. Paprottka, Laura A. Schmidt, B. Göke, Frank T. Kolligs, Alexander L. Gerbes, Christian J. Steib, and Dorothea Nagel
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Time Factors ,Clinical Decision-Making ,Kaplan-Meier Estimate ,Risk Assessment ,Decision Support Techniques ,03 medical and health sciences ,0302 clinical medicine ,Predictive Value of Tests ,Risk Factors ,Internal medicine ,Biomarkers, Tumor ,medicine ,Carcinoma ,Humans ,International Normalized Ratio ,Chemoembolization, Therapeutic ,Aged ,Neoplasm Staging ,Proportional Hazards Models ,Retrospective Studies ,Aged, 80 and over ,Hepatology ,Proportional hazards model ,business.industry ,Patient Selection ,Liver Neoplasms ,Gastroenterology ,Reproducibility of Results ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Treatment Outcome ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Predictive value of tests ,Multivariate Analysis ,Cohort ,Female ,030211 gastroenterology & hepatology ,Liver function ,Liver cancer ,business ,Algorithms - Abstract
BACKGROUND Allocation of patients with hepatocellular carcinoma (HCC) to the adequate therapy is determined by both tumor burden and liver function. The Barcelona Clinic Liver Cancer (BCLC) staging system and therapeutic algorithm recommends transarterial chemoembolization (TACE) based on the best evidence available to patients with intermediate-stage HCC (BCLC-B). However, many centers also treat subgroups of patients outside these recommendations and with more advanced disease by TACE. The purpose of this study was to identify prognostic factors in a TACE cohort, including BCLC-B patients, as well as patients treated outside of BCLC-B, to test the prognostic capabilities of published staging systems and to optimize prognostication for TACE patients. PATIENTS AND METHODS A cohort of 186 first-line TACE patients was analyzed. Independent prognostic factors were identified and used to construct the Munich-TACE score (M-TACE). M-TACE was tested against established staging systems (including BCLC and two recently published TACE-specific scores) and a ranking using concordance index and Akaike Information Criterion was performed. Finally, an external validation in an independent TACE cohort (n=71) was conducted. RESULTS Bilirubin, Quick/international normalized ratio, C-reactive protein, creatinine, α-feto protein, and tumor extension were identified as independent prognostic factors and used to construct M-TACE. M-TACE identifies three distinct subgroups (P
- Published
- 2018
45. Data on chow, liver tissue and mitochondrial fatty acid compositions as well as mitochondrial proteome changes after feeding mice a western diet for 6–24 weeks
- Author
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Christian Gosmann, Ralf Wimmer, Sabine Schmitt, Renate Artmann, Max Schnurr, Sabine Borchard, Martin Jastroch, Bastian Popper, Alisha Simmons, Claudia Einer, Doris Mayr, Christine von Toerne, Alexander L. Gerbes, Stefanie M. Hauck, Simon Hohenester, Hans Zischka, Angelika M. Vollmar, Gerald Denk, Ellen Walheim, Carola Eberhagen, Lena Wottke, Sabine Schulz, Christian Rust, and Christin Leitzinger
- Subjects
0301 basic medicine ,Isolated liver ,medicine.medical_specialty ,Multidisciplinary ,Normal diet ,Mitochondrion ,Biology ,lcsh:Computer applications to medicine. Medical informatics ,Mitochondrial proteome ,Mitochondrial fatty acid ,03 medical and health sciences ,030104 developmental biology ,Endocrinology ,Cell biology ,Biochemistry ,Liver tissue ,Internal medicine ,Western diet ,medicine ,lcsh:R858-859.7 ,lcsh:Science (General) ,Mitochondrial protein ,lcsh:Q1-390 - Abstract
The data presented in this article describe the fatty acid composition of chow, liver tissue and isolated liver mitochondria from mice fed for 6–24 weeks with a high caloric western diet (WD) in comparison to control diet (normal diet, ND). The fatty acid composition was measured via gas chromatography flame ionization detection (GC-FID). Moreover, WD-induced mitochondrial protein changes are presented in this work and were analyzed by mass spectrometry (LC–MS/MS). For further interpretation and discussion of the presented data please refer to the research article entitled “Mitochondrial adaptation in steatotic mice” (Einer et al., 2017) [1] .
- Published
- 2017
46. Gut roundtable meeting paper: selected recent advances in hepatocellular carcinoma
- Author
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Matías A. Avila, Markus Peck-Radosavljevic, Valérie Paradis, Fabien Zoulim, Jean-Charles Nault, Riad Salem, Jean-François Dufour, Jordi Bruix, Tim F. Greten, Peter R. Galle, Herbert Tilg, and Alexander L. Gerbes
- Subjects
Oncology ,medicine.medical_specialty ,Pathology ,Phase iii trials ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Fatty liver ,Personalized treatment ,Gastroenterology ,Immunotherapy ,medicine.disease ,03 medical and health sciences ,Key point ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Liver biopsy ,Internal medicine ,medicine ,030211 gastroenterology & hepatology ,610 Medicine & health ,business ,Predictive biomarker - Abstract
Hepatocellular carcinoma (HCC) ranks number three among the most frequent causes of death from solid tumors worldwide. With obesity and fatty liver diseases as risk factors on the rise, HCC represents an ever increasing challenge. While there is still no curative treatment for most patients numerous novel drugs have been proposed, but most ultimately failed in phase III trials. This manuscript targets therapeutic advances and most burning issues. Expert key point summaries and urgent research agenda are provided regarding risk factors, including microbiota, need for prognostic and predictive biomarkers and the equivocal role of liver biopsy. Therapeutic topics highlighted are locoregional techniques, combination therapies and the potential of immunotherapy. Finally the manuscript provides a critical evaluation of novel targets and strategies for personalized treatment of HCC.
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- 2017
47. Albumin Might Attenuate Bacteria-Induced Damage on Kupffer Cells for Patients with Chronic Liver Disease
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Hanno Nieß, Christian J. Steib, Andreas Wieser, Hao Lin, Alexander L. Gerbes, Jiang Zhang, Yuhui Fan, Julia Mayerle, and Ivonne Regel
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Male ,QH301-705.5 ,Kupffer Cells ,THP-1 Cells ,Stimulation ,Inflammation ,chronic liver diseases ,Pharmacology ,Chronic liver disease ,Article ,Cell Line ,chemistry.chemical_compound ,Albumins ,Lactate dehydrogenase ,Hepatic Stellate Cells ,Humans ,Medicine ,Biology (General) ,albumin ,Bacteria ,business.industry ,Liver Diseases ,Albumin ,Endothelial Cells ,General Medicine ,Middle Aged ,Human serum albumin ,medicine.disease ,In vitro ,Liver ,chemistry ,Hepatic stellate cell ,Female ,medicine.symptom ,business ,hepatic non-parenchymal cells ,medicine.drug - Abstract
Chronic liver diseases (CLDs) are complex diseases that cause long-term inflammation and infection, which in turn accelerate their development. The usage of albumin in patients with CLDs has been debated for years. Human serum albumin (HSA) plays a key role in immunomodulation during the process of CLDs. The correlation between albumin and C-reactive protein (CRP) in CLD patients was analyzed by linear regression with the Pearson statistic. The damage of THP-1 and primary cells was evaluated by measuring the lactate dehydrogenase (LDH) in the supernatant. Immunofluorescence staining was performed to determine underlying pathways in Kupffer cells (KCs). Albumin negatively correlated with infection in patients with CLDs. In vitro experiments with THP-1 cells and KCs showed that albumin reduced LDH release after stimulation with bacterial products, while no differences in hepatic stellate cells (HSCs) and sinusoidal endothelial cells (SECs) were detected. Moreover, immunofluorescence staining revealed an increase of p-ERK and p-NF-kB p65 density after albumin treatment of KCs stimulated by bacterial products. In conclusion, albumin could assist CLD patients in alleviating inflammation caused by bacterial products and might be beneficial to patients with CLDs by securing KCs from bacteria-induced damage, providing a compelling rationale for albumin therapy in patients with CLDs.
- Published
- 2021
48. Lectures
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M. König, Michael Thomas, Alexander L. Gerbes, Daniela Eser-Valeri, Markus Guba, J. Werner, M. B. Schönberg, Martin K. Angele, Julian Nikolaus Bucher, and Alexander Crispin
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German ,Transplantation ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,General surgery ,language ,Medicine ,In patient ,Liver transplantation ,business ,Single Center ,language.human_language - Published
- 2017
49. Aquaporin-2 excretion in hospitalized patients with cirrhosis: Relation to development of renal insufficiency and mortality
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Troels M. Busk, Aleksander Krag, Erling B. Pedersen, Flemming Bendtsen, Alexander L. Gerbes, Minneke J. Coenraad, Sören Möller, S. Frankova, and Markus Peck-Radosavljevic
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Cirrhosis ,Urinary system ,Urology ,Renal function ,Nephron ,urologic and male genital diseases ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Creatinine ,Univariate analysis ,Water transport ,Hepatology ,urogenital system ,business.industry ,Gastroenterology ,medicine.disease ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Urine osmolality ,030211 gastroenterology & hepatology ,business - Abstract
Background and Aim Urinary aquaporin-2 (AQP2) is a parameter of water transport in the principal cells in the distal part of the nephron and involved in water retention in cirrhosis and may be a marker of renal function. The aim of the study was to evaluate AQP2 as a predictor of renal insufficiency and death in patients with cirrhosis. Methods Urine samples from 199 patients (90 patients without organ failure (Group 1), 58 patients with organ failure excluding renal failure (Group 2) and 51 patients with organ failure including renal failure (Group 3)) from the CANONIC study were analyzed for urine AQP2 and urine osmolality. Results There was no difference in AQP2 between the three groups. Urine osmolality was significantly lower in patients in Group 3 versus Group 1 and Group 2 (p = 0.0004). We found no relation between AQP2 and glomerular filtration rate or creatinine, however AQP2 was a significant predictor of the development of renal insufficiency (p = 0.0485). In a univariate analysis AQP2 was a significant predictor of 14 and 28-day survival, but this was not confirmed in multivariate analysis. Conclusions AQP2 was not associated with disease severity or markers of renal function, but was a predictor for the development of renal insufficiency and death. Therefore, its future use as marker of renal insufficiency could be promising, but further research is needed before it can be considered a clinical useful tool.
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- 2017
50. Further evidence for the hepatotoxic potential of metamizole
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Andreas Benesic, Alexander L. Gerbes, and Sabine Weber
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Pharmacology ,business.industry ,medicine ,MEDLINE ,Pharmacology (medical) ,Metamizole ,business ,Bioinformatics ,medicine.drug - Published
- 2020
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