@article{HeitmannFringsGeieretal.2021, author = {Heitmann, Johanna and Frings, Verena G. and Geier, Andreas and Goebeler, Matthias and Kerstan, Andreas}, title = {Non-alcoholic fatty liver disease and psoriasis - is there a shared proinflammatory network?}, series = {Journal der Deutschen Dermatologischen Gesellschaft}, volume = {19}, journal = {Journal der Deutschen Dermatologischen Gesellschaft}, number = {4}, doi = {10.1111/ddg.14425}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258424}, pages = {517-528}, year = {2021}, abstract = {Psoriasis is an immune-mediated systemic inflammatory disease that is not limited to the skin but may be associated with arthritis, cardiovascular diseases, metabolic syndrome including diabetes and obesity and, as identified more recently, non-alcoholic fatty liver disease (NAFLD) that occurs in approximately 50 \% of all patients with psoriasis. NAFLD is characterized by accumulation of fat in hepatocytes in the absence of excessive alcohol consumption. Over the last two decades, NAFLD has developed to the most common chronic liver disease with an estimated prevalence of 25 \% in the Western population. NAFLD ranges from non-inflammatory or bland hepatic steatosis to inflammation of hepatic tissue (non-alcoholic steatohepatitis, NASH) and consecutive liver fibrosis. It is controversial whether the underlying systemic inflammation of psoriasis is contributing to development of NAFLD or if comorbid diseases such as obesity enhance NAFLD development. Recent findings indicate that cytokine-mediated inflammation through TNFα, interleukin (IL)-6 and IL-17 might be the common link between psoriasis and NAFLD. Considering the shared inflammatory pathways, IL-17 pharmacological blockade, which is already well-established for psoriasis, may be a promising strategy to treat both psoriasis and NAFLD. Therefore, early detection of NAFLD and a better understanding of its pathophysiology in the context of the systemic inflammation in psoriasis is important with regard to individualized treatment approaches.}, language = {en} } @article{RaselliHearnWyssetal.2019, author = {Raselli, Tina and Hearn, Tom and Wyss, Annika and Atrott, Kirstin and Peter, Alain and Frey-Wagner, Isabelle and Spalinger, Marianne R. and Maggio, Ewerton M. and Sailer, Andreas W. and Schmitt, Johannes and Schreiner, Philipp and Moncsek, Anja and Mertens, Joachim and Scharl, Michael and Griffiths, William J. and Bueter, Marco and Geier, Andreas and Rogler, Gerhard and Wang, Yuqin and Misselwitz, Benjamin}, title = {Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis}, series = {Journal of Lipid Research}, volume = {60}, journal = {Journal of Lipid Research}, number = {7}, doi = {10.1194/jlr.M093229}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225004}, pages = {1270-1283}, year = {2019}, abstract = {Nonalcoholic steatohepatitis (NASH), a primary cause of liver disease, leads to complications such as fibrosis, cirrhosis, and carcinoma, but the pathophysiology of NASH is incompletely understood. Epstein-Barr virus-induced G protein-coupled receptor 2 (EBI2) and its oxysterol ligand 7 alpha,25-dihydroxycholesterol (7 alpha,25-diHC) are recently discovered immune regulators. Several lines of evidence suggest a role of oxysterols in NASH pathogenesis, but rigorous testing has not been performed. We measured oxysterol levels in the livers of NASH patients by LC-MS and tested the role of the EBI2-7 alpha,25-diHC system in a murine feeding model of NASH. Free oxysterol profiling in livers from NASH patients revealed a pronounced increase in 24- and 7-hydroxylated oxysterols in NASH compared with controls. Levels of 24- and 7-hydroxylated oxysterols correlated with histological NASH activity. Histological analysis of murine liver samples demonstrated ballooning and liver inflammation. No significant genotype-related differences were observed in Ebi2(-/-) mice and mice with defects in the 7 alpha,25-diHC synthesizing enzymes CH25H and CYP7B1 compared with wild-type littermate controls, arguing against an essential role of these genes in NASH pathogenesis. Elevated 24- and 7-hydroxylated oxysterol levels were confirmed in murine NASH liver samples. Our results suggest increased bile acid synthesis in NASH samples, as judged by the enhanced level of 7 alpha-hydroxycholest-4-en-3-one and impaired 24S-hydroxycholesterol metabolism as characteristic biochemical changes in livers affected by NASH.}, language = {en} } @article{RauSchmittBergetal.2018, author = {Rau, Monika and Schmitt, Johannes and Berg, Thomas and Kremer, Andreas E. and Stieger, Bruno and Spanaus, Katharina and Bengsch, Bertram and Romero, Marta R. and Marin, Jose J. and Keitel, Verena and Klinker, Hartwig and Tony, Hans-Peter and M{\"u}llhaupt, Beat and Geier, Andreas}, title = {Serum IP-10 levels and increased DPPIV activity are linked to circulating CXCR3+ T cells in cholestatic HCV patients}, series = {PLoS ONE}, volume = {13}, journal = {PLoS ONE}, number = {12}, doi = {10.1371/journal.pone.0208225}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177674}, pages = {e0208225}, year = {2018}, abstract = {Background \& aims Serum interferon-gamma-inducible protein-10 (IP-10) is elevated in cholestatic liver diseases and predicts response to antiviral therapy in patients with chronic hepatitis C virus (HCV) infection. Dipeptidylpeptidase 4 (DPPIV) cleaves active IP-10 into an inactive form, which inhibits recruitment of CXCR3+ T cells to the liver. In this study the link between IP-10 levels, DPPIV activity in serum and CXCR3+ T cells is analysed in cholestatic and non-cholestatic liver patients. Methods In serum DPPIV activity (by enzymatic assay), IP-10 (by ELISA) and bile acids (BA) (by enzymatic assay) were analysed in 229 naive HCV genotype (GT) 1 patients and in 16 patients with cholestatic liver disease. In a prospective follow-up (FU) cohort of 27 HCV GT 1 patients peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ cells were measured by FACS. Results In 229 HCV patients serum IP-10 levels correlated positively to DPPIV serum activity. Higher IP-10 levels and DPPIV activity were detected in cholestatic and in cirrhotic HCV patients. Increased IP-10 serum levels were associated with therapeutic non-response to antiviral treatment with pegylated-interferon and ribavirin. In the HCV FU cohort elevated IP-10 serum levels and increased BA were associated with higher frequencies of peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ T cells. Positive correlation between serum IP-10 levels and DPPIV activity was likewise validated in patients with cholestatic liver diseases. Conclusions A strong correlation between elevated serum levels of IP-10 and DPPIV activity was seen in different cholestatic patient groups. Furthermore, in cholestatic HCV patients a functional link to increased numbers of peripheral CXCR3+ immune cells could be observed. The source of DPPIV release in cholestatic patients remains open.}, language = {en} } @article{CookGeierSchmidetal.2019, author = {Cook, Nigel and Geier, Andreas and Schmid, Andreas and Hirschfeld, Gideon and Kautz, Achim and Schattenberg, J{\"o}rn M. and Balp, Maria-Magdalena}, title = {The patient perspectives on future therapeutic options in NASH and patient needs}, series = {Frontiers in Medicine}, volume = {6}, journal = {Frontiers in Medicine}, doi = {10.3389/fmed.2019.00061}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223268}, year = {2019}, abstract = {Background: Non-alcoholic steatohepatitis (NASH) is a chronic liver disease with severe complications and without approved therapies. Currently, there is limited data on the overall burden of the disease for patients or on patient needs and preferences. This study investigates patient preferences in relation to potential future therapies for NASH. In addition, the factors that are relevant to patients and their importance in relation to future treatment options are explored. Method: Telephone in-depth interviews (TDIs) preceded an online 30-min quantitative survey. The online survey included (1) multiple choice questions (MCQs) on NASH diagnosis and disease background. (2) An exercise to determine patients' satisfaction levels with information provided at diagnosis, and to explore symptomatology in detail. (3) Exercises to evaluate potential new products and product attributes, including a "drag and drop" ranking exercise, and an adaptive choice-based conjoint exercise (ACBC). (4) The EQ-5D-5L questionnaire and the Visual Analog Scale (VAS), which measures patients' health status. (5) Collection of socio-demographic data, and (6) Questions to measure patient satisfaction with the survey. Results: There were 166 patients included in this study from Canada [n = 36], Germany [n = 50], the UK [n = 30], and USA [n = 50]. Fifty seven percent of patients [n = 94] had had a liver biopsy for confirmation of NASH. Patients were often unable to link their symptoms to NASH or other conditions. ACBC results showed that efficacy, defined as "impact on liver status" was the single most important attribute of a potential future NASH therapy. Other attributes considered to have secondary importance included impact on weight, symptom control and the presence of side effects. The EQ-5D utility score was 0.81 and VAS = 67.2. Conclusion: "Impact on liver status" is the primary outcome sought. Patients demonstrate a general lack of understanding of their disease and appeared to be unfamiliar with longer-term consequences of NASH. It is necessary to improve patient understanding of NASH and its progressive nature, and there is a need for improving confirmatory diagnosis and monitoring.}, language = {en} } @article{BankogluTschoppSchmittetal.2016, author = {Bankoglu, Ezgi Eyluel and Tschopp, Oliver and Schmitt, Johannes and Burkard, Philipp and Jahn, Daniel and Geier, Andreas and Stopper, Helga}, title = {Role of PTEN in Oxidative Stress and DNA Damage in the Liver of Whole-Body Pten Haplodeficient Mice}, series = {PLoS One}, volume = {11}, journal = {PLoS One}, number = {11}, doi = {10.1371/journal.pone.0166956}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146970}, pages = {e0166956}, year = {2016}, abstract = {Type 2 diabetes (T2DM) and obesity are frequently associated with non-alcoholic fatty liver disease (NAFLD) and with an elevated cancer incidence. The molecular mechanisms of carcinogenesis in this context are only partially understood. High blood insulin levels are typical in early T2DM and excessive insulin can cause elevated reactive oxygen species (ROS) production and genomic instability. ROS are important for various cellular functions in signaling and host defense. However, elevated ROS formation is thought to be involved in cancer induction. In the molecular events from insulin receptor binding to genomic damage, some signaling steps have been identified, pointing at the PI3K/AKT pathway. For further elucidation Phosphatase and Tensin homolog (Pten), a tumour suppressor phosphatase that plays a role in insulin signaling by negative regulation of PI3K/AKT and its downstream targets, was investigated here. Dihydroethidium (DHE) staining was used to detect ROS formation in immortalized human hepatocytes. Comet assay and micronucleus test were performed to investigate genomic damage in vitro. In liver samples, DHE staining and western blot detection of HSP70 and HO-1 were performed to evaluate oxidative stress response. DNA double strand breaks (DSBs) were detected by immunohistostaining. Inhibition of PTEN with the pharmacologic inhibitor VO-OHpic resulted in increased ROS production and genomic damage in a liver cell line. Knockdown of Pten in a mouse model yielded increased oxidative stress levels, detected by ROS levels and expression of the two stress-proteins HSP70 and HO-1 and elevated genomic damage in the liver, which was significant in mice fed with a high fat diet. We conclude that PTEN is involved in oxidative stress and genomic damage induction in vitro and that this may also explain the in vivo observations. This further supports the hypothesis that the PI3K/AKT pathway is responsible for damaging effects of high levels of insulin.}, language = {en} } @article{BeckerRauSchmittetal.2015, author = {Becker, Philip P. and Rau, Monika and Schmitt, Johannes and Malsch, Carolin and Hammer, Christian and Bantel, Heike and M{\"u}llhaupt, Beat and Geier, Andreas}, title = {Performance of serum microRNAs -122, -192 and -21 as biomarkers in patients with non-alcoholic steatohepatitis}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {11}, doi = {10.1371/journal.pone.0142661}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145147}, pages = {e0142661}, year = {2015}, abstract = {Objectives Liver biopsies are the current gold standard in non-alcoholic steatohepatitis (NASH) diagnosis. Their invasive nature, however, still carries an increased risk for patients' health. The development of non-invasive diagnostic tools to differentiate between bland steatosis (NAFL) and NASH remains crucial. The aim of this study is the evaluation of investigated circulating microRNAs in combination with new targets in order to optimize the discrimination of NASH patients by non-invasive serum biomarkers. Methods Serum profiles of four microRNAs were evaluated in two cohorts consisting of 137 NAFLD patients and 61 healthy controls. In a binary logistic regression model microRNAs of relevance were detected. Correlation of microRNA appearance with known biomarkers like ALT and CK18-Asp396 was evaluated. A simplified scoring model was developed, combining the levels of microRNA in circulation and CK18-Asp396 fragments. Receiver operating characteristics were used to evaluate the potential of discriminating NASH. Results The new finding of our study is the different profile of circulating miR-21 in NASH patients (p<0.0001). Also, it validates recently published results of miR-122 and miR-192 to be differentially regulated in NAFL and NASH. Combined microRNA expression profiles with CK18-Asp396 fragment level scoring model had a higher potential of NASH prediction compared to other risk biomarkers (AUROC = 0.83, 95\% CI = 0.754-0.908; p<0.001). Evaluation of score model for NAFL (Score = 0) and NASH (Score = 4) had shown high rates of sensitivity (91\%) and specificity (83\%). Conclusions Our study defines candidates for a combined model of miRNAs and CK18-Asp396 levels relevant as a promising expansion for diagnosis and in turn treatment of NASH.}, language = {en} } @article{WeissRauGeier2014, author = {Weiss, Johannes and Rau, Monika and Geier, Andreas}, title = {Non-Alcoholic Fatty Liver Disease Epidemiology, Clinical Course, Investigation, and Treatment}, series = {Deautsches {\"A}rzteblatt International}, volume = {111}, journal = {Deautsches {\"A}rzteblatt International}, number = {26}, doi = {10.3238/arztebl.2014.0447}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119557}, pages = {447-52}, year = {2014}, abstract = {Background: The global obesity epidemic has increased the prevalence of fatty liver disease. At present, 14\% to 27\% of the general population in the industrialized world has non-alcoholic fatty liver disease (NAFLD). Methods: We review pertinent publications retrieved by a selective search of the PubMed database for the years 1995 to 2013. Results: The term "non-alcoholic fatty liver disease" covers cases of a wide spectrum of severity, ranging from bland fatty liver without any inflammation and with little or no tendency to progress all the way to non-alcoholic steatohepatitis (NASH) with inflammatory reactions and hepatocyte damage, with or without fibrosis. Some 5\% to 20\% of patients with NAFLD develop NASH, which undergoes a further transition to higher-grade fibrosis in 10\% to 20\% of cases. In fewer than 5\% of cases, fibrosis progresses to cirrhosis. These approximate figures lead to an estimate of 0.05\% to 0.3\% for the prevalence of cirrhosis in the general population. About 2\% of all cirrhosis patients per year develop hepatocellular carcinoma. The diagnosis of fatty liver disease can be suspected initially on the basis of abnormally high aspartate aminotransferase (ASAT) and/or alanine aminotransferase (ALAT) levels and abnormal ultrasonographic findings. The positive predictive value of an ultrasonographic study for mild steatosis is 67\% at most. The NAFLD fibrosis score, which is computed on the basis of multiple parameters (age, body-mass index, diabetes status, ASAT, ALAT, platelet count, and albumin level), has a positive predictive value of 82\% to 90\% and a negative predictive value of 88\% to 93\%. Liver biopsy is the gold standard for diagnosis but should be performed sparingly in view of its rare but sometimes life-threatening complications, such as hemorrhage. The treatment of NAFLD and NASH consists mainly of changes in lifestyle and nutrition. Conclusion: NAFLD can, in principle, be reversed. This is only possible with weight reduction by at least 3\% to 5\%.}, language = {en} } @article{RauBaurGeier2012, author = {Rau, Monika and Baur, Katharina and Geier, Andreas}, title = {Host Genetic Variants in the Pathogenesis of Hepatitis C.}, series = {Viruses}, volume = {4}, journal = {Viruses}, number = {12}, doi = {10.3390/v4123281}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123611}, pages = {3281-302}, year = {2012}, abstract = {Direct-acting antiviral drugs (DAAs) are currently replacing antiviral therapy for Hepatitis C infection. Treatment related side effects are even worse and the emergence of resistant viruses must be avoided because of the direct-antiviral action. Altogether it remains a challenge to take treatment decisions in a clinical setting with cost restrictions. Genetic host factors are hereby essential to implement an individualized treatment concept. In recent years results on different genetic variants have been published with a strong association with therapy response, fibrosis and treatment-related side effects. Polymorphisms of the IL28B gene were identified as accurate predictors for therapy response and spontaneous clearance of HCV infection and are already used for diagnostic decisions. For RBV-induced side effects, such as hemolytic anemia, associations to genetic variants of inosine triphosphatase (ITPA) were described and different SLC28 transporters for RBV-uptake have been successfully analyzed. Fibrosis progression has been associated with variants of Vitamin D receptor (VDR) and ABCB11 (bile salt export pump). Cirrhotic patients especially have a high treatment risk and low therapy response, so that personalized antiviral treatment is mandatory. This review focuses on different host genetic variants in the pathogenesis of Hepatitis C at the beginning of a new area of treatment.}, language = {en} } @article{LeichtWeinigMayeretal.2018, author = {Leicht, Hans Benno and Weinig, Elke and Mayer, Beate and Viebahn, Johannes and Geier, Andreas and Rau, Monika}, title = {Ceftriaxone-induced hemolytic anemia with severe renal failure: a case report and review of literature}, series = {BMC Pharmacology and Toxicology}, volume = {19}, journal = {BMC Pharmacology and Toxicology}, number = {67}, doi = {10.1186/s40360-018-0257-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176637}, year = {2018}, abstract = {Background: Drug induced immune hemolytic anemia (DIIHA) is a rare complication and often underdiagnosed. DIIHA is frequently associated with a bad outcome, including organ failure and even death. For the last decades, ceftriaxone has been one of the most common drugs causing DIIHA, and ceftriaxone-induced immune hemolytic anemia (IHA) has especially been reported to cause severe complications and fatal outcomes. Case Presentation: A 76-year-old male patient was treated with ceftriaxone for cholangitis. Short time after antibiotic exposure the patient was referred to intensive care unit due to cardiopulmonary instability. Hemolysis was observed on laboratory testing and the patient developed severe renal failure with a need for hemodialysis for 2 weeks. Medical history revealed that the patient had been previously exposed to ceftriaxone less than 3 weeks before with subsequent hemolytic reaction. Further causes for hemolytic anemia were excluded and drug-induced immune hemolytic (DIIHA) anemia to ceftriaxone could be confirmed. Conclusions: The case demonstrates the severity of ceftriaxone-induced immune hemolytic anemia, a rare, but immediately life-threatening condition of a frequently used antibiotic in clinical practice. Early and correct diagnosis of DIIHA is crucial, as immediate withdrawal of the causative drug is essential for the patient prognosis. Thus, awareness for this complication must be raised among treating physicians.}, language = {en} } @article{RauBuggischMaussetal.2022, author = {Rau, Monika and Buggisch, Peter and Mauss, Stefan and Boeker, Klaus H. W. and Klinker, Hartwig and M{\"u}ller, Tobias and Stoehr, Albrecht and Schattenberg, J{\"o}rn M. and Geier, Andreas}, title = {Prognostic impact of steatosis in the clinical course of chronic HCV infection-Results from the German Hepatitis C-Registry}, series = {PLoS ONE}, volume = {17}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0264741}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300549}, year = {2022}, abstract = {Background Liver steatosis is often observed in chronic HCV infection and associated to genotype or comorbidities. NAFLD is an important risk factor for end-stage liver disease. We aimed to analyse the course of NAFLD as a concomitant disease in a cohort of HCV patients. Methods The German Hepatitis C-Registry is a national multicenter real-world cohort. In the current analysis, 8789 HCV patients were included and separated based on the presence of steatosis on ultrasound and/or histology. Fibrosis progression was assessed by transient elastography (TE), ultrasound or non-invasive surrogate scores. Results At the time of study inclusion 12.3\% (n = 962) of HCV patients presented with steatosis (+S) (higher rate in GT-3). Diabetes mellitus was more frequent in GT-1 patients. HCV patients without steatosis (-S) had a slightly higher rate of fibrosis progression (FP) over time (30.3\%) in contrast to HCV patients +S (26\%). This effect was mainly observed in GT-3 patients (34.4\% vs. 20.6\%). A larger decrease of ALT, AST and GGT from baseline to FU-1 (4-24 weeks after EOT) was found in HCV patients (without FP) +S compared to -S. HCV patients -S and with FP presented more often metabolic comorbidities with a significantly higher BMI (+0.58kg/m\(^{2}\)) compared to patients -S without FP. This was particularly pronounced in patients with abnormal ALT. Conclusion Clinically diagnosed steatosis in HCV patients does not seem to contribute to significant FP in this unique cohort. The low prevalence of steatosis could reflect a lower awareness of fatty liver in HCV patients, as patients -S and with FP presented more metabolic risk factors.}, language = {en} }