TY - JOUR A1 - Becker, Philip P. A1 - Rau, Monika A1 - Schmitt, Johannes A1 - Malsch, Carolin A1 - Hammer, Christian A1 - Bantel, Heike A1 - Müllhaupt, Beat A1 - Geier, Andreas T1 - Performance of serum microRNAs -122, -192 and -21 as biomarkers in patients with non-alcoholic steatohepatitis JF - PLoS ONE N2 - 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. KW - fatty liver disease KW - independent marker KW - expression KW - injury KW - NAFLD KW - circulating micrornas KW - caspase activation KW - fibrosis KW - miR-122 KW - apoptosis Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145147 VL - 10 IS - 11 ER - TY - JOUR A1 - Weiss, Johannes A1 - Rau, Monika A1 - Geier, Andreas T1 - Non-Alcoholic Fatty Liver Disease Epidemiology, Clinical Course, Investigation, and Treatment JF - Deautsches Ärzteblatt International N2 - 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%. KW - fatty liver disease Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119557 VL - 111 IS - 26 ER - TY - JOUR A1 - Rau, Monika A1 - Baur, Katharina A1 - Geier, Andreas T1 - Host Genetic Variants in the Pathogenesis of Hepatitis C. JF - Viruses N2 - 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. KW - host genetics KW - Hepatitis C infection KW - IL28B KW - SVR KW - fibrosis progression Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123611 VL - 4 IS - 12 ER - TY - JOUR A1 - Leicht, Hans Benno A1 - Weinig, Elke A1 - Mayer, Beate A1 - Viebahn, Johannes A1 - Geier, Andreas A1 - Rau, Monika T1 - Ceftriaxone-induced hemolytic anemia with severe renal failure: a case report and review of literature JF - BMC Pharmacology and Toxicology N2 - 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. KW - ceftriaxone KW - drug-induced immune hemolytic anemia KW - hemolysis Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176637 VL - 19 IS - 67 ER - TY - JOUR A1 - Rau, Monika A1 - Buggisch, Peter A1 - Mauss, Stefan A1 - Boeker, Klaus H. W. A1 - Klinker, Hartwig A1 - Müller, Tobias A1 - Stoehr, Albrecht A1 - Schattenberg, Jörn M. A1 - Geier, Andreas T1 - Prognostic impact of steatosis in the clinical course of chronic HCV infection-Results from the German Hepatitis C-Registry JF - PLoS ONE N2 - 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. KW - steatosis KW - HCV infection KW - liver Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300549 VL - 17 IS - 6 ER - TY - JOUR A1 - John, Katharina A1 - Franck, Martin A1 - Al Aoua, Sherin A1 - Rau, Monika A1 - Huber, Yvonne A1 - Schattenberg, Joern M. A1 - Geier, Andreas A1 - Bahr, Matthias J. A1 - Wedemeyer, Heiner A1 - Schulze-Osthoff, Klaus A1 - Bantel, Heike T1 - Non-invasive detection of fibrotic NASH in NAFLD patients with low or intermediate FIB-4 JF - Journal of Clinical Medicine N2 - Background: Non-alcoholic steatohepatitis (NASH) and fibrosis are the main prognostic factors in non-alcoholic fatty liver disease (NAFLD). The FIB-4 score has been suggested as an initial test for the exclusion of progressed fibrosis. However, increasing evidence suggests that also NASH patients with earlier fibrosis stages are at risk of disease progression, emphasizing the need for improved non-invasive risk stratification. Methods: We evaluated whether the apoptosis biomarker M30 can identify patients with fibrotic NASH despite low or intermediate FIB-4 values. Serum M30 levels were assessed by ELISA, and FIB-4 was calculated in an exploration (n = 103) and validation (n = 100) cohort of patients with histologically confirmed NAFLD. Results: The majority of patients with low FIB-4 (cut-off value < 1.3) in the exploration cohort revealed increased M30 levels (>200 U/L) and more than 80% of them had NASH, mostly with fibrosis. NASH was also detected in all patients with intermediate FIB-4 (1.3 to 2.67) and elevated M30, from which ~80% showed fibrosis. Importantly, in the absence of elevated M30, most patients with FIB-4 < 1.3 and NASH showed also no fibrosis. Similar results were obtained in the validation cohort. Conclusions: The combination of FIB-4 with M30 enables a more reliable identification of patients at risk for progressed NAFLD and might, therefore, improve patient stratification. KW - apoptosis KW - biomarker KW - fibrosis KW - FIB-4 KW - NAFLD KW - NASH KW - keratin-18 KW - M30 Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281824 SN - 2077-0383 VL - 11 IS - 15 ER - TY - JOUR A1 - Rau, Monika A1 - Schmitt, Johannes A1 - Berg, Thomas A1 - Kremer, Andreas E. A1 - Stieger, Bruno A1 - Spanaus, Katharina A1 - Bengsch, Bertram A1 - Romero, Marta R. A1 - Marin, Jose J. A1 - Keitel, Verena A1 - Klinker, Hartwig A1 - Tony, Hans-Peter A1 - Müllhaupt, Beat A1 - Geier, Andreas T1 - Serum IP-10 levels and increased DPPIV activity are linked to circulating CXCR3+ T cells in cholestatic HCV patients JF - PLoS ONE N2 - 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. KW - hepatitis C virus KW - T cells KW - liver diseases KW - chemokines KW - cytotoxic T cells KW - immune cells KW - cirrhosis KW - bile Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177674 VL - 13 IS - 12 ER - TY - JOUR A1 - Trujillo‐Viera, Jonathan A1 - El‐Merahbi, Rabih A1 - Schmidt, Vanessa A1 - Karwen, Till A1 - Loza‐Valdes, Angel A1 - Strohmeyer, Akim A1 - Reuter, Saskia A1 - Noh, Minhee A1 - Wit, Magdalena A1 - Hawro, Izabela A1 - Mocek, Sabine A1 - Fey, Christina A1 - Mayer, Alexander E. A1 - Löffler, Mona C. A1 - Wilhelmi, Ilka A1 - Metzger, Marco A1 - Ishikawa, Eri A1 - Yamasaki, Sho A1 - Rau, Monika A1 - Geier, Andreas A1 - Hankir, Mohammed A1 - Seyfried, Florian A1 - Klingenspor, Martin A1 - Sumara, Grzegorz T1 - Protein Kinase D2 drives chylomicron‐mediated lipid transport in the intestine and promotes obesity JF - EMBO Molecular Medicine N2 - Lipids are the most energy‐dense components of the diet, and their overconsumption promotes obesity and diabetes. Dietary fat content has been linked to the lipid processing activity by the intestine and its overall capacity to absorb triglycerides (TG). However, the signaling cascades driving intestinal lipid absorption in response to elevated dietary fat are largely unknown. Here, we describe an unexpected role of the protein kinase D2 (PKD2) in lipid homeostasis. We demonstrate that PKD2 activity promotes chylomicron‐mediated TG transfer in enterocytes. PKD2 increases chylomicron size to enhance the TG secretion on the basolateral side of the mouse and human enterocytes, which is associated with decreased abundance of APOA4. PKD2 activation in intestine also correlates positively with circulating TG in obese human patients. Importantly, deletion, inactivation, or inhibition of PKD2 ameliorates high‐fat diet‐induced obesity and diabetes and improves gut microbiota profile in mice. Taken together, our findings suggest that PKD2 represents a key signaling node promoting dietary fat absorption and may serve as an attractive target for the treatment of obesity. KW - chylomicron KW - fat absorption KW - intestine KW - obesity KW - protein kinase D2/PKD2/PRKD2 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239018 VL - 13 IS - 5 ER -