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Background Potential indications for surgery frequently arise in patients awaiting liver transplantation. There is a risk of hepatic decompensation and death triggered by surgical trauma, but this has not been studied in detail in this unique population. We aimed to quantify the impact of surgical interventions in patients awaiting liver transplantation on hepatic function and identify risk factors for decompensation. Methods All surgeries between 2000 and 2018 in patients awaiting liver transplantation in a highvolume German liver transplant center were analyzed retrospectively. Change in liver function measured as indicated by MELD score was assessed and complication rates recorded. The primary endpoint was a composite of an increase in MELD score by > 5 points or death. A logistic regression model was used for multivariate analysis to identify risk factors. Results In total, 177 surgical procedures in 148 patients were analyzed. The primary endpoint was reached in 42 cases (23.7%). The overall in-hospital complication rate (including death) was 44.1%. Multivariate analysis identified elevated leukocyte count, perioperative blood transfusion, preoperative presence of ascites, and preoperative circulatory support as independent risk factors for a decline in liver function or death. Conclusion Surgery in patients awaiting liver transplantation carries a relevant risk of hepatic decompensation and death that needs to be considered when deciding whether to perform elective surgery prior to or defer until after liver transplantation.

Population screening; Liver fibrosis; Early diagnosis Cribratge de població; Fibrosi hepàtica; Diagnòstic precoç Cribado de población; Fibrosis hepática; Diagnóstico precoz Cirrhosis, highly prevalent worldwide, develops after years of hepatic inflammation triggering progressive fibrosis. Currently, the main etiologies of cirrhosis are non-alcoholic fatty liver disease and alcohol-related liver disease, although chronic hepatitis B and C infections are still major etiological factors in some areas of the world. Recent studies have shown that liver fibrosis can be assessed with relatively high accuracy noninvasively by serological tests, transient elastography, and radiological methods. These modalities may be utilized for screening for liver fibrosis in at-risk populations. Thus far, a limited number of population-based studies using noninvasive tests in different areas of the world indicate that a significant percentage of subjects without known liver disease (around 5% in general populations and a higher rate −18% to 27%-in populations with risk factors for liver disease) have significant undetected liver fibrosis or established cirrhosis. Larger international studies are required to show the harms and benefits before concluding that screening for liver fibrosis should be applied to populations at risk for chronic liver diseases. Screening for liver fibrosis has the potential for changing the current approach from diagnosing chronic liver diseases late when patients have already developed complications of cirrhosis to diagnosing liver fibrosis in asymptomatic subjects providing the opportunity of preventing disease progression. LiverScreen Consortium and the European Commission under the H20/20 program (847989); AGAUR (2017SGR-01281); Centro de Investigacion Biomedica en Enfermedades Hepaticas y Digestivas; Fundación de Investigación Sanitaria, cofunded by Instituto Carlos III–Subdirección General de Evaluación and the European Regional Development Fund (PI18/01330, PI18/00662, and PI18/00862); and Gilead’s Investigator–sponsored research program (IN-ES-989-5309)

Standard treatment of hepatitis delta virus (HDV) infection remains pegylated-interferon alfa (peg-IFN?) in most centers, which is not only associated with rather low efficacy but several adverse events. Hepatitis B core-related antigen (HBcrAg) is linked to intrahepatic covalently closed circular DNA levels and has previously been suggested as response predictor in IFN-based treatment of hepatitis B virus (HBV) mono-infection. This study aimed to investigate the value of HBcrAg in the management of patients with HBV/HDV co-infection undergoing peg-IFN? treatment. The Hep-Net-International-Delta-Hepatitis-Intervention Trial-2 study included 120 patients co-infected with HBV/HDV. Patients were treated for 96 weeks with peg-IFN? and either tenofovir or placebo. Ninety-nine patients with HDV-RNA results 24 weeks after end of treatment (FU24) were included in this analysis, of whom 32 patients (32.3%) had undetectable HDV RNA at FU24. HBcrAg was measured at baseline, week 12, 24, 48, 96, and FU24. HBcrAg levels showed no significant correlation with HDV RNA but were significantly linked to treatment outcome. HBcrAg levels < 4.5 log IU/mL at baseline, week 24, and week 48 had high negative predictive value (NPV) for achieving undetectable HDV RNA at FU24 (81.8%, 87.1% and 95.0%, respectively). Similarly, HBcrAg levels at week 96 were significantly higher in patients with viral relapse until FU24 (3.0 vs. 3.63 log IU/mL; P = 0.0089). Baseline, week 24, and week 48 HBcrAg levels were also associated with the likelihood of achieving HBsAg level < 100 IU/mL at FU24 (HBcrAg < 3.0 log IU/mL: NPV 91.7%, 90.4% and 92.3%, respectively). Test statistics improved when combining HBcrAg with additional viral and clinical parameters. Conclusion: HBcrAg is linked to treatment response to peg-IFN? in patients with HBV/HDV co-infection and could be a promising marker to determine treatment futility., Fujirebio Europe; Gilead Sciences; F. Hoffmann?La Roche; HepNet Study House

Serum alkaline phosphatase (ALP) and the enhanced liver fibrosis (ELF) score are used as endpoints in trials of patients with primary sclerosing cholangitis (PSC). We aimed to quantify inter- and intra-individual variation in levels of ALP and the ELF score over time, and evaluated their association with fibrosis progression.We analyzed data from 234 patients with large-duct PSC enrolled in a 2-year, phase 2b placebo-controlled trial of simtuzumab. Participants were assessed by laboratory tests every 4 weeks, and liver biopsies collected at time of screening, week 48, and week 96.Serum levels of ALP and ELF scores did not differ significantly between simtuzumab and placebo groups, so the data were pooled. Median per-patient variations in ALP between clinic visits were approximately 12% over 12 weeks, 20% over 48 weeks, and 20% over 96 weeks. Reductions, unrelated to study intervention, of more than 40% in ALP were observed in 10.9% of patients with baseline activity greater than 2-fold the upper limit of normal (ULN) and 12.5% of patients with more than 3-fold the ULN at 1 year. At 2 years, reductions of more than 40% in ALP were observed in 15.8% of patients with baseline activity greater than 2-fold the ULN and 17.9% of patients with more than 3-fold the ULN. Among the 209 patients with Ishak fibrosis stage 0-4 at baseline, serum ALP activity did not associate with development of cirrhosis or with a 2-point increase in fibrosis stage at 2 years. In contrast, the median per-patient variation in ELF scores between clinic visits was approximately 3% over 12 weeks, 4% over 48 weeks, and 4% over 96 weeks. Elevated ELF scores at baseline and at weeks 12, 24 and 48, each associated with development of cirrhosis at 2 years (odds ratio2.75; P.01 for all timepoints). ELF scores at baseline and weeks 12, 24 and 48, also associated with a 2-point increase in fibrosis stage at 2 years (odds ratios all greater than 2; P.01 for all timepoints).In an analysis of data from patients with large-duct PSC enrolled in a prospective trial, we found large interindividual and intraindividual variations in serum ALP activity. Serum ALP activity did not associate with disease progression over a 2-year period. Variations in ELF score were smaller, and scores determined at multiple timepoints associated with fibrosis progression and development of cirrhosis.

Background & Aims HCV-infected patients with cirrhosis achieve high sustained virological response (SVR) rates with direct-acting antivirals (DAAs) even after hepatic decompensation. We aimed to assess the clinical outcome following DAAs among patients with compensated and decompensated cirrhosis in relation to SVR and changes in model for end-stage liver disease (MELD) score. Methods Consecutive DAA-treated chronic HCV-infected patients with cirrhosis from 4 hepatology clinics were included. The primary endpoint in survival analyses was clinical disease progression, defined as liver failure, hepatocellular carcinoma, liver transplantation or death. Results In total, 868 patients were included with a median age of 59 (IQR 54–65) years; 719 (83%) with Child-Pugh A cirrhosis and 149 (17%) with Child-Pugh B/C cirrhosis. SVR was attained by 647 (90%) Child-Pugh A patients and 120 (81%) Child-Pugh B/C patients. During a median follow-up of 28 (IQR 20–36) months, 102 (14%) Child-Pugh A patients and 96 (64%) Child-Pugh B/C patients experienced clinical disease progression. SVR was independently associated with an improved event-free survival in patients with Child-Pugh A cirrhosis (adjusted hazard ratio [HR] 0.47; 95% CI 0.27–0.82, p = 0.007), but not in patients with Child-Pugh B/C cirrhosis (adjusted HR 1.23; 95% CI 0.67–2.26; p = 0.51). Twelve weeks post-DAAs, 28 (19%) patients with Child-Pugh B/C cirrhosis had ≥2-point MELD decline, but their 2-year event-free survival did not differ from those with a stable MELD (47.9%; 95% CI 28.7–67.1 vs. 48.9%; 95% CI 38.1–59.7, respectively, p = 0.99). Conclusions Among patients with chronic HCV infection, DAA-induced SVR was associated with a reduced risk of clinical disease progression in patients with Child-Pugh A cirrhosis but not in patients with Child-Pugh B/C cirrhosis. In Child-Pugh B/C cirrhosis, a ≥2-point MELD decline did not translate into improved clinical outcome. Lay summary Chronic HCV infection can be cured with antiviral therapy. In this study, we evaluated the long-term effects of antiviral therapy on liver-related complications in patients with cirrhosis. Our results suggest that patients with compensated cirrhosis who were cured of their HCV infection have a lower rate of complications. In contrast, the rate of complications was not related to virological cure among those with decompensated cirrhosis. While these patients seem to remain in need of liver transplantation, antiviral therapy may lower their priority on the liver transplantation waiting list.

Background & Aims There are limited data on patients with chronic HCV infection in whom combination voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment fails. Thus, we aimed to assess treatment failure and rescue treatment options in these patients. Methods Samples from 40 patients with HCV genotypes (GT) 1-4 in whom VOX/VEL/SOF retreatment failed were collected within the European Resistance Study Group. Population-based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients. Results Most VOX/VEL/SOF failure patients were infected with HCV GT3a (n = 18, 45%) or GT1a (n = 11, 28%) and had cirrhosis (n = 28, 70%). Previous treatments included an NS3-inhibitor (30%), an NS5A-inhibitor (100%) and SOF (85%). Baseline RAS data from a subgroup of patients before VOX/VEL/SOF retreatment (78%) showed few NS3 RASs apart from Q80K in GT1a (40%), typical NS5A RAS patterns in most patients (74%) and no S282T in NS5B. Sequencing after VOX/VEL/SOF failure was available in 98% of patients and showed only minor changes for NS3 and NS5A RASs. In 22 patients, rescue treatment was initiated with glecaprevir, pibrentasvir alone (n = 2) or with SOF±ribavirin (n = 15), VOX/VEL/SOF±ribavirin (n = 4) or VEL/SOF and ribavirin (n = 1) for 12 to 24 weeks. Sustained virologic response was achieved in 17/21 (81%) patients with a final treatment outcome. Of these, 2 GT3a-infected patients had virologic failure after rescue treatment with VEL/SOF or glecaprevir/pibrentasvir+SOF+ribavirin, and 2 patients with cirrhosis died during treatment or before reaching SVR12. Conclusions VOX/VEL/SOF failure was mainly observed in HCV GT3- and GT1a-infected patients with cirrhosis and was not associated with specific RAS patterns within NS3, NS5A or NS5B target regions. Rescue treatment with multiple targeted therapies was effective in most patients. Lay summary The advent of direct-acting antivirals has enabled the effective cure of chronic hepatitis C in most patients. However, treatment failure occurs in some patients, who are often retreated with a combination regimen called VOX/VEL/SOF, which is associated with very high rates of cure. However, VOX/VEL/SOF retreatment also fails in some patients. Herein, we analysed samples from patients in whom VOX/VEL/SOF retreatment failed and we assessed the efficacy of different rescue therapies, showing that rescue treatment is effective in most patients (81%).

Background RNA detection in plasma/stool is the gold-standard for diagnosis of hepatitis E virus (HEV) infection. The impact of viral extraction methods on HEV RNA detection is poorly investigated. Methods We determined the limit of detection of the RealStar HEV RT-PCR V2.0 Kit (altona Diagnostics, RS) utilizing 3 RNA extraction methods (COBAS® AmpliPrep Total Nucleic Acid Isolation Kit, TNAi Roche; MagNA Pure 96 DNA, Viral NA SV Kit, MgP; QIAamp Viral RNA mini Kit Qiagen; VRK) in plasma and stool. The most sensitive method was evaluated in a total of 307 longitudinal samples of patients with HEV infection (acute = 18/chronic = 36) and compared to results with the former diagnostic standard of our centre (TNAi/FastTrack Diagnostic; FTD). Results The plasma-LOD was 49, 94 and 329 IU/mL for extraction with MgP, VRK and TNAi respectively. In stool, the LOD was 21 IU/mL, 528 IU/mL and indefinable for extraction with TNAi, VRK and MgP respectively. Utilizing longitudinal patient plasma samples, MgP/RS revealed 56 HEV RNA-positive samples in 158 negative samples as determined by TNAi/FTD. In stool, from 37 HEV negative samples (TNAi/FTD), 15 were positive with TNAi/RS. At end of treatment, 8 out of 27 chronically infected patients were RNA positive with MgP/RS, while classified negative with TNAi/FTD. A relapse occurred in 3 of these patients. Conclusion Different methods for RNA extraction and quantification have a significant, compartment-specific impact on the sensitivity of HEV detection. Knowledge about the favourable combinations of extraction and quantification has important implications for diagnosis and patients receiving antiviral therapy.

ZusammenfassungAbdominelle Schmerzen sind oft Konsultationsanlass in Arztpraxen und Notaufnahmen. Die häufigsten Differenzialdiagnosen lassen sich mit gut verfügbarer, kosteneffektiver und risikoarmer Diagnostik (Laboruntersuchungen, Sonographie, Gastroskopie) bestätigen. Zum Ausschluss seltener Ursachen, wie kleiner solider oder hämatologischer Malignome, Stoffwechselstörungen oder Polyneuropathien unterschiedlichster Genese, kann eine erweiterte Diagnostik erforderlich sein. Im Folgenden stellen wir den Fall eines Patienten mit massivsten epigastrischen Beschwerden infolge einer Neuroborreliose vor und rekapitulieren die diagnostischen Schritte zur Abklärung des abdominellen Schmerzes.

Hepatology 75(1), 13-27 (2022). doi:10.1002/hep.32134, Published by Wolters Kluwer Health, [Alphen aan den Rijn]

Background Treatment with direct-acting antivirals (DAAs) in patients with chronic hepatitis C infection leads to partial restoration of soluble inflammatory mediators (SIMs). In contrast, we hypothesized that early DAA treatment of acute hepatitis C virus (HCV) with DAAs may normalize most SIMs. Methods In this study, we made use of a unique cohort of acute symptomatic hepatitis C patients who cleared HCV with a 6-week course of ledipasvir/sofosbuvir. Plasma samples were used for proximity extension assay measuring 92 proteins. Results Profound SIM alterations were observed in acute HCV patients, with marked upregulation of interleukin (IL)-6 and CXCL-10, whereas certain mediators were downregulated (eg, monocyte chemoattractant protein-4, IL-7). During treatment and follow-up, the majority of SIMs decreased but not all normalized (eg, CDCP1, IL-18). Of note, SIMs that were downregulated before DAA treatment remained suppressed, whereas others that were initially unchanged declined to lower values during treatment and follow-up (eg, CD244). Conclusions Acute hepatitis C was associated with marked changes in the soluble inflammatory milieu compared with both chronic hepatitis patients and healthy controls. Whereas early DAA treatment partly normalized this altered signature, long-lasting imprints of HCV remained.

Background and aims: Autoimmune hepatitis (AIH) has been well characterised and codified through the development of diagnostic criteria. These criteria have been adapted and simplified and are widely used in clinical practice. However, there is a need to update and precisely define the criteria for both treatment response and treatment. Methods: a systematic review was performed and a modified Delphi consensus process was used to identify and redefine the response criteria in autoimmune hepatitis. Results: the consensus process initiated by the International Autoimmune Hepatitis Group proposes that the term 'complete biochemical response' defined as 'normalization of serum transaminases and IgG below the upper limit of normal' be adopted to include a time point at 6 months after initiation of treatment. An insufficient response by 6 months was a failure to meet the above definition. Non-response was defined as ', YAEL Foundation

To develop and evaluate a deep learning algorithm for fully automated detection of primary sclerosing cholangitis (PSC)-compatible cholangiographic changes on three-dimensional magnetic resonance cholangiopancreatography (3D-MRCP) images. The datasets of 428 patients (n = 205 with confirmed diagnosis of PSC; n = 223 non-PSC patients) referred for MRI including MRCP were included in this retrospective IRB-approved study. Datasets were randomly assigned to a training (n = 386) and a validation group (n = 42). For each case, 20 uniformly distributed axial MRCP rotations and a subsequent maximum intensity projection (MIP) were calculated, resulting in a training database of 7720 images and a validation database of 840 images. Then, a pre-trained Inception ResNet was implemented which was conclusively fine-tuned (learning rate 10−3). Applying an ensemble strategy (by binning of the 20 axial projections), the mean absolute error (MAE) of the developed deep learning algorithm for detection of PSC-compatible cholangiographic changes was lowered from 21 to 7.1%. Sensitivity, specificity, positive predictive (PPV), and negative predictive value (NPV) for detection of these changes were 95.0%, 90.9%, 90.5%, and 95.2% respectively. The results of this study demonstrate the feasibility of transfer learning in combination with extensive image augmentation to detect PSC-compatible cholangiographic changes on 3D-MRCP images with a high sensitivity and a low MAE. Further validation with more and multicentric data is now desirable, as it is known that neural networks tend to overfit the characteristics of the dataset. • The described machine learning algorithm is able to detect PSC-compatible cholangiographic changes on 3D-MRCP images with high accuracy. • The generation of 2D projections from 3D datasets enabled the implementation of an ensemble strategy to boost inference performance.

Zusammenfassung Einleitung Die ökonomischen Einflüsse einer spontan bakteriellen Peritonitis (SBP), nosokomialer Infektionen (nosInf) und eines akut auf chronischen Leberversagens (ACLF) sind bislang wenig untersucht. Wir analysierten die Einflüsse dieser Komplikationen auf die Behandlungserlöse von hospitalisierten Patienten mit dekompensierter Leberzirrhose. Methodik 371 hospitalisierte, konsekutive Patienten mit Leberzirrhose und aszitischer Dekompensation, die zwischen 2012 und 2016 eine Parazentese erhielten, wurden retrospektiv eingeschlossen. DRG (Diagnosebezogene Fallgruppen), ZE/NUB (Zusatzentgelte/Neue Untersuchungs- und Behandlungsmethoden), Medikamentenkosten, Krankenhausverweildauer, therapeutische und klinische Leistungen (u. a. Dialyse, hochaufwendige Pflege) wurden für die Auswertung berücksichtigt. Ausschlusskriterien waren u. a. ein malignes Grundleiden, eine Organtransplantation sowie fehlende Abrechnungsdaten. Ergebnisse Die Gesamterlöse (DRG + ZE/NUB) waren im Fall einer nosInf deutlich höher (10.653 € vs. 5.611 €; p Schlussfolgerung Bei dekompensierter Leberzirrhose führt das Auftreten einer SBP, nosokomialer Infektionen und/oder eines ACLF zu einer signifikanten Erhöhung des Behandlungsaufwands, der Erlöse und der Krankenhausverweildauer. Die dazu im Widerspruch stehenden numerisch niedrigeren Erlöse/Tag bei wesentlich höherer Zahl erbrachter Leistungen weisen möglicherweise darauf hin, dass diese Komplikationen im deutschen DRG-System zurzeit nicht ausreichend berücksichtigt werden.

Hepatitis delta virus (HDV) infection causes the most severe form of viral hepatitis. PEG-interferon alpha-2a (PEG-IFN alpha-2a) is the only effective treatment but its long-term clinical impact is unclear. the aim of this study was to investigate the long-term outcome after 48 weeks of pegylated interferon alpha-2a therapy. We performed a retrospective follow-up study of the Hep-Net-International-Delta-Hepatitis-Intervention-Study 1 (HIDIT-I trial). Patients had received 48 weeks of treatment with either PEG-IFN alpha-2a plus adefovir dipivoxil (ADV) (Group I), PEG-IFN alpha-2a alone (Group II) or adefovir dipivoxil alone (Group III). Liver-related complications were defined as liver-related death, liver transplantation, liver cancer and hepatic decompensation defined as development of Child-Pugh scores B or C or an increase in Model for End-stage Liver Disease (MELD) scores of five or more points in relation to baseline values. Patients were considered for further analysis when they were retreated with PEG-IFN alpha-2a. Follow-up data (at least 1 visit beyond post-treatment week 24) were available for 60 patients [Group I, (n = 19), Group II (n = 20), Group III (n = 21)]. Mean time of follow-up was 8.9 (1.6 - 13.4) years. 19 patients were retreated with IFN-based therapy: 42% (n = 8) in PEG-IFN alpha-2a arms and 58% (n = 11) in the adefovir only arm. Clinical complications on long-term follow-up occurred in 17 patients and were associated with nonresponse to therapy and baseline cirrhosis. the annual event-free survival rate in patients with cirrhosis vs noncirrhotic patients at year 5 and 10 was 70% vs 91% and 35% vs 76%. Long-term follow-up of a large randomized clinical trial suggests that off-treatment HDV RNA response to PEG-IFN alpha-2a treatment leads to improved clinical long-term outcome., German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig; German Liver Foundation; EASL registry grant, This study was funded by the German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig with a grand to the HepNet Study-House, the German Liver Foundation and an EASL registry grant.

BACKGROUND Hepatocellular carcinoma (HCC) is one of the most lethal cancers. After many years of stagnation, there are now several systemic treatments available for patients with HCC. AIM To analyse the feasibility and efficacy of sequential systemic treatments in patients with HCC in clinical practice. METHODS In this multicentre study, patients who were treated with novel systemic therapies for HCC between 2014 and 2019 at two referral centres, Hannover Medical School, Germany, and Medical University of Vienna, Austria, were included. RESULTS Overall, 85 patients were included of which 76 patients (89.4%) received more than one and a maximum of five systemic treatment lines. The most common therapy sequence was sorafenib (n = 72; 84.7%) followed by regorafenib (n = 37; 48.7%), whereas 11 patients were initially treated with lenvatinib (12.9%). Other second-line treatments included pembrolizumab, nivolumab, cabozantinib and ramucirumab. Hepatic function deteriorated during sequential systemic treatment in 48.6% of the patients as defined by an increase in at least one Child-Pugh point. Median overall survival (mOS) from the start of first systemic treatment was 35 months for patients with sequential systemic treatment compared to 9 months for patients with one systemic treatment line (P

Background Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) is an emerging disease with grim prognosis. Objective Our aim was the analysis of prognostic factors, long-term outcome and risk of tumour development in SSC-CIP compared with primary sclerosing cholangitis (PSC) patients. Methods Retrospective analysis between 2008 and 2018. Results One hundred and eleven patients with SSC-CIP and 408 PSC patients were identified. Median orthotopic liver transplantation (OLT)-free survival was 16 months for SSC-CIP and 147 months for PSC (p

Background Endoscopic placement of intestinal decompression tubes is a feasible technique for treatment of acute intestinal dilation. Given the heterogeneity of the underlying diseases leading to intestinal obstruction data on the significance of endoscopic procedures for treatment of these conditions are sparse. Methods In the study period from 2008 to 2019 all patients receiving a decompression tube were identified by retrospective chart review and analyzed. Results A total of 59 decompression tubes were placed in 50 patients. Technical success was achieved in 98% (58/59 tubes). As major complication one small bowel perforation occurred (1/59; 1.7%). Causes for impaired intestinal transit comprised tumor stenoses 22% (11/50), infections 18% (9/50), post-operative paralysis 14% (7/50), neurological diseases 8% (4/50), trauma 2% (1/50) and others 36% (18/50). Most patients (74%; 37/50) were critically ill and treated on intensive care unit. Treatment response after tube insertion was documented in 76% of patients (38/50) whereas 24% (12/50) did not fulfill response criteria. Patients with treatment response showed a significantly better outcome compared to non-responders. Responders had a median survival of 113 days (95% CI 41–186) compared to 15 days (95% CI 6–24) in non-responders (p = 0.002). Analysis of laboratory parameters after stratification in responders and non-responders to endoscopic therapy showed that non-responders had significantly higher levels of CRP and lower platelet count at baseline (CRP 262 mg/L (IQR 101–307) vs. 94 mg/L (IQR 26–153): p = 0.027; platelets 69 thsd/μL (IQR 33–161) vs. 199 thsd/μL (IQR 138–289): p = 0.009). Conclusions Endoscopic decompression is a safe procedure for acute management of impaired intestinal transit even in critically ill patients. Response to therapy is associated with improved outcome and markers of inflammation and organ function such as CRP, platelet count and serum lactate have to be taken into account for therapy monitoring and evaluation of prognosis.

Background Nosocomial infections are a particular threat for patients with liver cirrhosis. It is not uncommon that individuals develop even several consecutive infections during a single hospital stay. We aimed to investigate the impact and characteristics of multiple, consecutive nosocomial infections. Methods A total of 514 consecutive patients with liver cirrhosis and ascites were included and followed up for 28 days for nosocomial infection, death or liver transplantation (LTx). Laboratory values were assessed at the time of hospitalization as well as at the onset of each new infectious episode. Results 58% (n = 298) of the patients developed at least one nosocomial infection and in 23% (n = 119) even multiple infections were documented during a single hospital stay. Consecutive infections usually occurred shortly after the previous episode. Spontaneous bacterial peritonitis (SBP) was the most common infection. However, the proportion of SBP declined from 43% at the first to only 31% at the third nosocomial infection (p = 0.096). In contrast, the likelihood for other, less common types of infection such as blood stream infections increased. Third nosocomial infections were also more likely to be linked to the detection of fungal pathogens (21% vs. 52%; p = 0.001). Each additional infectious episode had a dramatic detrimental impact on LTx-free survival that was independent from the stage of liver disease (adjusted-HR: 6.76, p = 0.002 for first nosocomial infection; adjusted-HR: 14.69, p

Background Detection of cholangiocarcinoma (CCA) remains a diagnostic challenge. We established diagnostic peptide biomarkers in bile and urine based on capillary electrophoresis coupled to mass spectrometry (CE-MS) to detect both local and systemic changes during CCA progression. In a prospective cohort study we recently demonstrated that combined bile and urine proteome analysis could further improve diagnostic accuracy of CCA diagnosis in patients with unknown biliary strictures. As a continuation of these investigations, the aim of the present study was to investigate the pathophysiological mechanisms behind the molecular determinants reflected by bile and urine peptide biomarkers. Methods Protease mapping and gene ontology cluster analysis were performed for the previously defined CE-MS based biomarkers in bile and urine. For that purpose, bile and urine peptide profiles (from samples both collected at the date of endoscopy) were investigated from a representative cohort of patients with benign (n = 76) or CCA-associated (n = 52) biliary strictures (verified during clinical follow-up). This was supplemented with a literature search for the association of the individual biomarkers included in the proteomic patterns with CCA or cancer progression. Results For most of the peptide markers, association to CCA has been described in literature. Protease mapping revealed ADAMTS4 activity in cleavage of both bile and urine CCA peptide biomarkers. Furthermore, increased chymase activity in bile points to mast cell activation at the tumor site. Gene ontology cluster analysis indicates cellular response to chemical stimuli and stress response as local and extracellular matrix reorganization by tissue destruction and repair as systemic events. The analysis further supports that the mapped proteases are drivers of local and systemic events. Conclusions The study supports connection of the CCA-associated peptide biomarkers to the molecular pathophysiology and indicates an involvement in epithelial-to-mesenchymal transition, generation of cancer-associated fibroblasts and activation of residual immune cells. Proteases, extracellular matrix components, inflammatory cytokines, proangiogenic, growth and vasoactive factors released from the tumor microenvironment are drivers of systemic early events during CCA progression.

BACKGROUND & AIMS: Hepatitis B virus (HBV) contains three viral surface proteins, large, middle and small hepatitis B surface protein (LHBs, MHBs, SHBs). Proportions of LHBs and MHBs are lower in patients with inactive versus active chronic infection. Interferon alfa may convert HBeAg-positive chronic hepatitis B (CHB) to an inactive carrier state, but prediction of sustained response is unsatisfactory. The aim of this study was to test the hypothesis that quantification of MHBs and LHBs may allow for a better prognosis of therapeutic response than total hepatitis B surface antigen (HBsAg) concentration. METHODS: HBs proteins were measured before and during peginterferon alfa-2a therapy in serum from 127 Asian patients with HBeAg-positive CHB. Sustained response was defined as hepatitis B e antigen (HBeAg) seroconversion 24 weeks post-treatment. RESULTS: Mean total HBs levels were significantly lower in responders versus nonresponders at all time points (P0.70). CONCLUSIONS: HBs proteins levels differ by HBV genotype. However, quantification of HBs proteins has no advantage over the already established HBsAg assays to predict response to peginterferon alfa-2a therapy in HBeAg-positive patients.

The priming of T cells in the liver is widely accepted. Nonetheless, it is controversial whether immune activation in autoimmune hepatitis (AIH) occurs in the liver or in the spleen. To address this issue, we splenectomized mice and induced experimental murine AIH (emAIH) with an adenovirus (Ad)-expressing formiminotransferase cyclodeaminase (FTCD). Post-splenectomy, the experimental mice developed emAIH to a higher extent than the control mice. In addition, splenectomized mice harboured more intrahepatic B cells and a disproportionately small number of regulatory T cells (Tregs) within a reduced T cell population at the site of inflammation. These results imply that the spleen is not the site of AIH induction. In contrast, the spleen seems to have a protective function since the pathological score was more severe in splenectomized animals. These findings have important implications for the aetiology of AIH.

Background & Aims Treatment options remain limited for patients with autoimmune hepatitis (AIH), while there are still concerns over the consequences of long-term corticosteroid use. A few studies have suggested a role for B cell-driven autoimmune liver injury in AIH. This multicentre, international retrospective cohort study from the International Autoimmune Hepatitis Group aims to evaluate the clinical efficacy and safety of rituximab in difficult-to-manage AIH. Methods Clinical data from 22 patients who received rituximab between 2007 and 2017 were collected from centres in the United Kingdom, Germany and Canada. Clinical response was assessed using changes in biochemical and immunological parameters up to 24 months post-rituximab infusion. In addition, we compared the doses of prednisolone used 3 months before and 12 months after treatment, and assessed freedom from AIH flares over the post-treatment period. Results Twenty-two patients with type-1 AIH were included, with a median age of 40 years at diagnosis (range 19–79); 15/22 (68%) were female and 18/22 (82%) were Caucasian. The median period from diagnosis to the end of follow-up in these patients was 11 years (range 3–28). Values of alanine aminotransferase, aspartate aminotransferase and albumin improved significantly following rituximab therapy, and were sustained for up to 2 years (all p ≪0.001). Prednisolone doses were significantly reduced by 12 months post-treatment (p = 0.003), with 13/21 (62%) patients having a dose reduction. Over a median post-treatment follow-up period of 6 years (range 1–10), 5 patients developed AIH flares at a median of 22 months post-treatment, giving an estimated 71% freedom from AIH flare at 2 years. Four of these patients received a second course of treatment, of whom 2 had subsequent further flares. No serious adverse events attributable to rituximab were recorded. Conclusion In patients with difficult-to-manage AIH, rituximab appears to be clinically effective and well tolerated. Rituximab was associated with sustained improvements in serum liver tests, an absence of clinical disease flares, and a reduction in prednisolone dose. Controlled trials are warranted to further evaluate B cell-targeting therapies in patients with AIH. Lay summary Autoimmune hepatitis is an autoimmune condition of the liver, usually treated with medications that suppress the immune system, such as steroids. However, some patients do not respond to this treatment. We analysed the safety and efficacy of rituximab in patients who were not responding to first- or second-line therapies. Rituximab was safe and improved liver blood tests in 70% of patients over a 2-year follow-up period, while enabling steroid doses to be reduced in two-thirds of patients, which is a very positive clinical outcome., Graphical abstract Unlabelled Image, Highlights • Study of rituximab therapy in 22 patients with autoimmune hepatitis over a follow-up period of 24 months. • No serious adverse events were noted during follow-up in patients treated with rituximab. • Rituximab therapy improved liver enzymes significantly during the 2 years of follow-up. • Prednisolone dose reductions were seen in 62% of patients at 12-month follow-up. • A total of 71% of patients were free of AIH flares during the 24 months of follow-up.

BACKGROUND Direct-acting antiviral agents (DAAs) have revolutionized treatment of chronic hepatitis C in patients with normal glomerular filtration rate (GFR). However, patients with impaired kidney function have been excluded from several clinical trials. We, therefore, investigated the use, effectiveness, and tolerability of DAAs in patients with GFR less than 30 ml/min in the real-world setting. PATIENTS AND METHODS An analysis was done within the German Hepatitis C-Registry on 5733 patients including 46 individuals with a baseline GFR less than 30 ml/min treated with sofosbuvir-based (61%) or paritaprevir/ritonavir-based (39%) regimens. RESULTS Sustained virological response 12 rates did not differ significantly between patients with baseline GFR less than 30 versus more than 30 ml/min (91 vs. 96%). Nine individuals with a baseline GFR more than 30 ml/min presented with a GFR less than 30 ml/min at the end of treatment. GFR improvement from less than 30 ml/min to more than 30 ml/min was observed in 9/46 cases. Adverse events did not differ in patients with GFR less than 30 versus more than 30 ml/min. However, serious adverse events were significantly more frequent in individuals with GFR less than 30 ml/min and associated with ribavirin. CONCLUSION Different DAA therapies can be safely used with high sustained virological response rates in patients with GFR less than 30 ml/min. Ribavirin has to be avoided because of poor tolerability.

Hepatocellular carcinoma (HCC) is known to be associated with protein alterations and extracellular fibrous deposition. We investigated the urinary proteomic profiles of HCC patients in this prospective cross sectional multicentre study. 195 patients were recruited from the UK (Coventry) and Germany (Hannover) between 1 January 2013 and 30 June 2019. Out of these, 57 were HCC patients with a background of liver cirrhosis (LC) and 138 were non-HCC controls, 72 patients with LC, 57 with non-cirrhotic liver disease and 9 with normal liver function. Analysis of the urine samples was performed by capillary electrophoresis (CE) coupled to mass spectrometry (MS). Peptide sequences were obtained and 31 specific peptide markers for HCC were identified and further integrated into a multivariate classification model. The peptide model demonstrated 79.5% sensitivity and 85.1% specificity (95% CI: 0.81–0.93, p &lt, 0.0001) for HCC and 4.1-fold increased risk of death (95% CI: 1.7–9.8, p = 0.0005). Proteases potentially involved in HCC progression were mapped to the N- and C-terminal sequence motifs of the CE-MS peptide markers. In silico protease prediction revealed that kallikrein-6 (KLK6) elicits increased activity, whilst Meprin A subunit α (MEP1A) has reduced activity in HCC compared to the controls. Tissue expression of KLK6 and MEP1A was subsequently verified by immunohistochemistry.

Nonalcoholic steatohepatitis (NASH) is induced by steatosis and metabolic inflammation. While involvement of the innate immune response has been shown, the role of the adaptive immune response in NASH remains controversial. Likewise, the role of regulatory T cells (Treg) in NASH remains unclear although initial clinical trials aim to target these regulatory responses. High-fat high-carbohydrate (HF-HC) diet feeding of NASH-resistant BALB/c mice as well as the corresponding recombination activating 1 (Rag)-deficient strain was used to induce NASH and to study the role of the adaptive immune response. HF-HC diet feeding induced strong activation of intrahepatic T cells in BALB/c mice, suggesting an antigen-driven effect. In contrast, the effects of the absence of the adaptive immune response was notable. NASH in BALB/c Rag1−/− mice was substantially worsened and accompanied by a sharp increase of M1-like macrophage numbers. Furthermore, we found an increase in intrahepatic Treg numbers in NASH, but either adoptive Treg transfer or anti-cluster of differentiation (CD)3 therapy unexpectedly increased steatosis and the alanine aminotransferase level without otherwise affecting NASH. Conclusion: Although intrahepatic T cells were activated and marginally clonally expanded in NASH, these effects were counterbalanced by increased Treg numbers. The ablation of adaptive immunity in murine NASH led to marked aggravation of NASH, suggesting that Tregs are not regulators of metabolic inflammation but rather enhance it. OA Förderung 2022

BACKGROUND & AIMS Four major autoimmune diseases target the liver. They develop because of bile duct destruction, leading to chronic cholestasis or result from hepatocyte damage like autoimmune hepatitis (AIH). Interestingly, some patients simultaneously show features of both cholangitis and AIH. Our goal was to mimic such concurrent characteristics in a mouse model that would help deciphering mechanisms possibly involved in an inflammatory crosstalk between cholestatic disease and hepatitis. METHODS Mdr2-/- mice, which spontaneously develop sclerosing cholangitis because of accumulation of toxic bile salts, were infected with adenovirus (Ad) encoding human Cytochrome P4502D6 (hCYP2D6), the major target autoantigen in type-2 AIH, to trigger hepatocyte injury. Wild type FVB mice were controls. RESULTS Resulting Ad-Mdr2-/- mice presented with cholangitis, fibrosis and cellular infiltrations that were higher than in Mdr2-/- or Ad-FVB mice. Increased levels of anti-neutrophil cytoplasmic antibodies but similar anti-hCYP2D6 antibody titres were detected in Ad-Mdr2-/- compared to Mdr2-/- and Ad-FVB mice respectively. IFNγ-expressing hCYP2D6-specific CD4 T cells declined, whereas hCYP2D6-specific CD8 T cells increased in Ad-Mdr2-/- compared to Ad-FVB mice. The overall T cell balance in Ad-Mdr2-/- mice was a combination of a type 17 T cell response typically found in Mdr2-/- mice with a type 1 dominated T cell response characteristic for Ad-FVB mice. Simultaneously, the type 2 T cell compartment was markedly reduced. CONCLUSIONS Experimental hepatitis induction in a mouse with sclerosing cholangitis results in a disorder which represents not simply the sum of the individual characteristics but depicts a more complex entity which urges on further analysis.

Background: Endoscopic biliary drainage is the standard of care for patients with cholangiocarcinoma (CCA)-induced, obstructive jaundice. Self-expanding metal stents are supposed to be supe...

Background: To analyze demography, clinical signs, and survival of intensive care patients diagnosed with nonocclusive mesenteric ischemia (NOMI) and to evaluate the effect of a local intra-arterial prostaglandin therapy. Methods: Retrospective observational study screening 455 intensive care patients with acute arterial mesenteric perfusion disorder in a tertiary care hospital within the past 8 years. Lastly, 32 patients with NOMI were enrolled, of which 11 received local intra-arterial prostaglandin therapy. The diagnosis of NOMI was based on the clinical presentation and established biphasic computed tomography criteria. Clinical and biochemical data were obtained 24 hours before, at the time, and 24 hours after diagnosis. Results: Patients were 60.5 (49.3-73) years old and had multiple comorbidities. Most of them were diagnosed with septic shock requiring high doses of norepinephrine (NE: 0.382 [0.249-0.627] μg/kg/min). The Sequential Organ Failure Assessment (SOFA) score was 18 (16-20). A decrease in oxygenation (Pao 2/Fio 2), pH, and bicarbonate and an increase in international normalized ratio, lactate, bilirubin, leucocyte count, and NE dose were early indicators of NOMI. Median SOFA score significantly increased in the last 24 hours before diagnosis of NOMI (16 vs 18, P < .0001). Overall, 28-day mortality was 75% (81% nonintervention vs 64% intervention cohort; P = .579). Median SOFA scores 24 hours after intervention increased by +5% in the nonintervention group and decreased by 5.5% in the intervention group ( P = .0059). Conclusions: Our data suggest that NOMI is a detrimental disease associated with progressive organ failure and a high mortality. Local intra-arterial prostaglandin application might hold promise as a rescue treatment strategy. These data encourage future randomized controlled trials are desirable.

BACKGROUND Hepatocellular carcinoma (HCC) is one of the most lethal cancers. Nutrition- and life style-associated risk factors are increasingly prevalent. Metformin, the mainstay of type 2 diabetes mellitus (T2DM)-treatment, reduces the risk of hepatocarcinogenesis. However, its influence on the prognosis of patients with HCC has not been investigated on a large scale, yet. METHODS Five thousand and ninety-three patients treated for HCC between 2000 and 2016 at three referral centres were included in this retrospective multicentre study. The aim of this study was to assess whether treatment with metformin for T2DM is associated with a prolonged overall survival (OS) in patients diagnosed with HCC. RESULTS Among 5093 patients with HCC, 1917 patients (37.6%) were diagnosed with T2DM, of which 338 (17.6%) received treatment with metformin. Compared to diabetic patients not treated with metformin, patients on metformin had a significantly better hepatic function (Child-Pugh-Score A: 69.2% vs 47.4%, P

Zusammenfassung Einleitung In Deutschland sind mehr als 250 000 Patienten an einer chronischen Hepatitis C (CHC) erkrankt. Seit 2014 sind zahlreiche potente direkt antivirale Substanzen gegen HCV zugelassen worden. Ziel des Deutschen Hepatitis-C-Registers (DHC-R) ist es, die Epidemiologie und Versorgung von Patienten mit CHC abzubilden und die Effektivität und Sicherheit der neuen Behandlungsmöglichkeiten im Praxisalltag zu untersuchen. Methoden Das DHC-R ist eine prospektive, multizentrische, nicht interventionelle Registerstudie. Bundesweit sind 327 Zentren für die Dokumentation freigeschaltet. Alle in Deutschland zugelassenen Medikamente wurden im DHC-R dokumentiert. Für die aktuelle Auswertung wurden 4 Phasen unterschieden: 2/2014 bis 12/2014, 1/2015 bis 12/2015, 1/2016 bis 7/2017 und 8/2017 bis 7/2018. Ergebnisse Zwischen Februar 2014 und Juli 2018 wurden 12 170 Patienten in das Register eingeschlossen (61,3 % Männer), eine antivirale Therapie erhielten 11 268. Das Behandlungsalter sank von 52,3 (Phase 1) auf 49,3 Jahre (Phase 4), der Anteil der Behandelten mit einer Drogenanamnese nahm zu (von 26,9 auf 43,1 %). 2014 wurden viele Patienten mit Leberzirrhose (35,1 %) behandelt, deren Anteil im Verlauf deutlich abnahm (Phase 4: 16,5 %). Die HCV-Genotypenverteilung änderte sich im Zeitverlauf deutlich, zuletzt stieg der Anteil des HCV-Genotyps 3 (30 % in Phase 4). Die Ausheilungsrate (PP-Analyse) steigerte sich von 92,8 % im Jahre 2014 auf zuletzt 97,4 % bei sehr guter Verträglichkeit. Zusammenfassung Das DHC-R beschreibt die Versorgungssituation der Patienten mit CHC in Deutschland, zeigt epidemiologische Tendenzen auf und belegt die ausgezeichneten Behandlungsmöglichkeiten.

Autoimmune hepatitis (AIH) is an orphan disease characterized by an autoimmune attack against hepatocytes. The exact sequence of events that leads to a breach of tolerance is incompletely understood. Current hypotheses suggest that environmental agents such as toxins or infectious agents like viruses cause a tissue damage that initiates autoimmunity in genetically susceptible individuals. The growing knowledge of the multi-facetted immune dysregulation, which involves Th1/Th17 polarization and the suspected inability of regulatory T cells to revert autoimmunity in the otherwise tolerogenic milieu of the liver, offers multiple new therapeutic approaches and targets. Standard of care (SOC) is treatment with corticosteroids with or without azathioprine, which is sufficient to induce remission in the majority of patients. However, it rarely cures AIH or restores intrahepatic immune tolerance. Hence, life-long therapy is required in the majority of patients. In addition, several studies suggest a weakening of immune regulation mediated by intrahepatic T cells under current therapies. Furthermore, second line therapies for non-responders, intolerant or otherwise difficult to treat patients are urgently needed as this is relevant for at least one fifth of all patients with inefficacy or intolerance to SOC. Current second line therapies are mainly based on single center retrospective experiences and none of them have been approved by regulatory authorities for AIH, yet. This article highlights new therapeutic approaches based on our growing knowledge on the pathophysiology of AIH. It focuses on cell-based therapies that strengthen or restore immune tolerance. An additional focus lies on new therapeutic agents showing promising results in non-hepatic autoimmune diseases that have a potential for treating AIH. The dynamics in the whole field of innovative therapies for non-hepatic autoimmune diseases will hopefully improve the therapeutic armamentarium for AIH patients in the future.

Treatment decisions are based on extent of fibrosis in patients with chronic hepatitis C (HCV) infection. Noninvasive diagnostic tools may help to avoid liver biopsy. We investigated the diagnostic accuracy of noncommercial serum scores in comparison with transient elastography (TE). Data analysis was undertaken based on 2458 patients enrolled in the German Hepatitis C Registry, in a prospective, observational study. Aspartate aminotransferase-to-platelet ratio index (APRI), FORNS index and FIB-4 score were calculated and the diagnostic accuracy was compared to TE. As estimated by TE, 955 (38.9%) patients had absence of significant fibrosis (SF), 736 (29.9%) patients had SF, and 767 (31.2%) patients were shown to have cirrhosis. Patients with absence of SF had a sustained virological response (SVR) rate of 97.9%, whereas SVR was attained in 96.2% and 92.2% in those with SF and cirrhosis, respectively (P 0.0001). The area under the receiver operator characteristic curve (AUROC), sensitivity and specificity in discriminating of SF were 0.789, 0.596 and 0.939 by APRI; 0.838, 0.852 and 0.748 by FORNS index; and 0.828, 0.658 and 0.946 by FIB-4 score. AUROCs for the prediction of cirrhosis, sensitivity and specificity were 0.881, 0.851 and 0.854 by APRI; 0.846, 0.948 and 0.628 by FORNS index; and 0.907, 0.907 and 0.848 by FIB-4 score. In conclusion, in the present multicentre real-world cohort, SF and cirrhosis were predicted with high accuracy with noncommercial serum markers using TE as reference. Further prospective long-term follow-up is necessary to compare biomarkers with TE concerning liver-related outcome and overall mortality.

The use of interferon-free direct-acting antiviral agents (DAAs) is associated with a rapid short-term decrease in liver stiffness in chronic hepatitis C-infected patients with sustained virologic response (SVR).The objective of this article is to evaluate long-term changes in liver elasticity in hepatitis C patients with SVR using transient elastography (TE), FIB-4 and APRI.A total of 143 patients were treated with DAAs and reached SVR. Patients received TE measurement (median (range)) at treatment start (baseline), follow-up week 24 (FU24) and follow-up week 96 (FU96). Laboratory data were examined at each date and FIB-4 and APRI were calculated.Liver elasticity showed a significant decrease from baseline to FU24 (13.1 (3.1-75) kPa to 9.3 (2.9-69.1) kPa;During long-term follow-up, the majority of patients with SVR had further improved liver stiffness values. Still, a significant proportion of patients may show long-term liver stiffness progression and thus continued TE follow-up is recommended.

BackgroundThe main strategy to contain the current SARS-CoV-2 pandemic remains to implement a comprehensive testing, tracing and quarantining strategy until vaccination of the population is adequate.MethodsTen dogs were trained to detect SARS-CoV-2 infections in beta-propiolactone inactivated saliva samples. The subsequent cognitive transfer performance for the recognition of non-inactivated samples were tested on saliva, urine, and sweat in a randomised, double-blind controlled study.ResultsDogs were tested on a total of 5242 randomised sample presentations. Dogs detected non-inactivated saliva samples with a diagnostic sensitivity of 84% and specificity of 95%. In a subsequent experiment to compare the scent recognition between the three non-inactivated body fluids, diagnostic sensitivity and specificity were 95% and 98% for urine, 91% and 94% for sweat, 82%, and 96% for saliva respectively.ConclusionsThe scent cognitive transfer performance between inactivated and non-inactivated samples as well as between different sample materials indicates that global, specific SARS-CoV-2-associated volatile compounds are released across different body secretions, independently from the patient’s symptoms.FundingThe project was funded as a special research project of the German Armed Forces. The funding source DZIF-Fasttrack 1.921 provided us with means for biosampling.

Dysregulation of glucose homeostasis plays a major role in the pathogenesis of non-alcoholic steatohepatitis (NASH) as it activates proinflammatory and profibrotic processes. Beneficial effects of antiglycemic treatments such as GLP-1 agonist or SGLT-2 inhibitor on NASH in patients with diabetes have already been investigated. However, their effect on NASH in a non-diabetic setting remains unclear. With this aim, we investigated the effect of long-acting GLP1-agonist dulaglutide and SGLT-2 inhibitor empagliflozin and their combination in a non-diabetic mouse model of NASH. C57BL/6 mice received a high-fat-high-fructose (HFHC) diet with a surplus of cholesterol for 16 weeks. After 12 weeks of diet, mice were treated with either dulaglutide, empagliflozin or their combination. Dulaglutide alone and in combination with empagliflozin led to significant weight loss, improved glucose homeostasis and diminished anti-inflammatory and anti-fibrotic pathways. Combination of dulaglutide and empagliflozin further decreased MoMFLy6CHigh and CD4+Foxp3+ T cells. No beneficial effects for treatment with empagliflozin alone could be shown. While no effect of dulaglutide or its combination with empaglifozin on hepatic steatosis was evident, these data demonstrate distinct anti-inflammatory effects of dulaglutide and their combination with empagliflozin in a non-diabetic background, which could have important implications for further treatment of NASH.

Zusammenfassung Einleitung Der Hepatitis C Genotyp 1 ist der häufigste Genotyp in West- und Zentraleuropa. In dieser Arbeit werden die Veränderungen der Baselinecharakteristika von 17 093 HCV-Patienten mit Genotyp 1a/1b, die im Zeitraum 2004–2018 in Deutschland antiviral therapiert wurden, analysiert. Es wurden insgesamt 5 Zeiträume betrachtet: (i) 2004–2007, (ii) 2008–2010, (iii) 2010–2013, (iv) 2014–2016, (v) 2017–2018. Methoden Die vorliegende Analyse basiert auf 5 deutschlandweit durchgeführten nicht-interventionellen Registern und umfasst Daten von Patienten, die mit dem HCV-GT1a und HCV-GT1b infiziert waren und zwischen 2004 und 2018 dokumentiert wurden [ML17071, ML19464, ML21645, ML25724 (Peginterferon alfa-2a® non-interventional study (PAN)) und dem Deutschen Hepatitis-C-Register (DHC-R)]. Ergebnisse Im Untersuchungszeitraum (2004–2018) hatten 7662 Patienten eine HCV-GT1a- und 9431 Patienten eine HCV-GT-1b-Infektion. GT1a-Patienten waren im Vergleich zu GT1b-Patienten jünger (46,5 Jahre vs. 51,2 Jahre) und häufiger männlich (70 % vs. 52 %). Drogenkonsum in der Vorgeschichte oder derzeit war im Untersuchungszeitraum häufiger bei GT1a-Patienten mit höchster Frequenz im aktuellsten Zeitraum (2017–2018; 44 % GT1a, 10 % GT1b). Metabolische Komorbiditäten wie Übergewicht und Diabetes mellitus waren häufiger bei mit GT1b infizierten Frauen. Der Anteil des Genotyps 1a nahm von 34 % (Zeitraum 2004–2007) auf ca. 50 % (Zeitraum 2017–2018) relevant zu. 2004–2018 zeigte sich ein relevanter Wechsel des GT1a/1b-Quotienten bei Männern (2004–2007: 38 %/63 %; 2017–2018: 59 %/41 %) bei weitgehend konstantem GT1a-Anteil der Frauen von ca. 30 % deutschlandweit über alle 5 untersuchten Zeiträume.Der Anteil der weiblichen Patienten mit GT1a in der Region Ost war im Vergleich zu den anderen 3 Regionen über nahezu alle Zeiträume niedriger, am deutlichsten ausgeprägt 2004–2007: 14 % GT1a vs. 86 % GT1b. Zusammenfassung Im untersuchten Zeitraum (2004–2018) zeigte sich ein relevanter Anstieg der Genotyp-1a-Infektion bei Männern, nicht bei Frauen, assoziiert mit Drogenkonsum. Die Daten zeigen eine grundlegende Änderung in der HCV-Epidemiologie in Deutschland an, die Konsequenzen für das Therapiemanagement und die allgemeine Versorgung der Hepatitis-C-Patienten haben.

Abdominal pain is a frequent cause of consultation to doctors' offices and emergency rooms. The most common differential diagnoses can be confirmed with readily available, cost-effective, and low-risk diagnostic tools such as laboratory tests, ultrasound, or gastroscopy. Additional diagnostic tests are required to exclude rare causes such as small, solid, or hematological malignancies, metabolic disorders, or polyneuropathies of varying origin. In the following, we present the case of a patient with severe epigastric pain due to neuroborreliosis, and recapitulate the diagnostic steps for clarifying abdominal pain using this example.Abdominelle Schmerzen sind oft Konsultationsanlass in Arztpraxen und Notaufnahmen. Die häufigsten Differenzialdiagnosen lassen sich mit gut verfügbarer, kosteneffektiver und risikoarmer Diagnostik (Laboruntersuchungen, Sonographie, Gastroskopie) bestätigen. Zum Ausschluss seltener Ursachen, wie kleiner solider oder hämatologischer Malignome, Stoffwechselstörungen oder Polyneuropathien unterschiedlichster Genese, kann eine erweiterte Diagnostik erforderlich sein. Im Folgenden stellen wir den Fall eines Patienten mit massivsten epigastrischen Beschwerden infolge einer Neuroborreliose vor und rekapitulieren die diagnostischen Schritte zur Abklärung des abdominellen Schmerzes.