Background Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than 18 million individuals in Germany. Life-style choices including alcohol, coffee and smoking are frequent but prospective data are rare. Methods The German SLD-Registry aims to describe clinical characteristics and observe outcomes in secondary and tertiary care. Detailed data on life-style choices are prospectively collected. Results Baseline data of 903 patients were analysed. 40% (363/903) reported low grade alcohol consumption (mean 1.4 g/day). The alcohol subgroup had higher ferritin (152 vs. 205 ng/ml) but less frequently high-risk fibrosis scores (FIB-4 >2.67 8.5 vs. 15%; NFS >0.675 9.3 vs. 17%) or LS >= 9.6 kPa (25 vs. 73%; OR 0.546 [0.41-0.73], p<0.001). Smokers (current 83/544, former 136/544) had a trend towards higher CAP (326 and 314 vs. 305dB in never smokers (325/544)). No association of smoking to LS >= 9.6 kPa or cirrhosis stage could be observed (OR 0.94 [0.62-1.43], p=0.78). LS >= 9.6 kPa tended to be less frequent in coffee consumers (1-2 cups/day 229/464, 3-4 cups/day 117/464, >5 cups/day 36/464) than in non-consumers (36, 23 and 28% vs. 45%). CAP was not different between these groups. The OR for coffee consumers was reduced (0.58 [0.97-0.34]; p=0.04) with a significant dose dependency (p<0.003). Conclusion Alcohol and coffee consumption are frequent among MASLD patients. Low grade alcohol and any degree coffee consumption were associated with a decreased risk of advanced liver fibrosis. Our data may confirm the beneficial effects of coffee and indicate that very low alcohol consumption may at least not exert relevant unfavourable effects.

BACKGROUND:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of chronic liver disease. Metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of MASLD, can lead to fibrosis and cirrhosis. The incidence and burden of MASH in Germany are expected to double by 2030, while diagnostic and management challenges persist. Expert consensus on diagnostic strategies and treatment modalities in MASLD and MASH is required. OBJECTIVES:The panel aimed to gather insights and consensus on the diagnostic pathway and current treatment modalities for MASH in Germany. METHODS:A three-round web-based survey, integrating Delphi panel methodology with a standard survey, was conducted from February to May 2024 to reach consensus on predefined questions. The survey involved 12 gastroenterology, diabetology and/or hepatology specialists in Germany. RESULTS:The Delphi panel revealed that ~75% of MASH patients in Germany remain undiagnosed. Non-invasive measures, such as fibrosis scores (values from clinical and imaging tests to assess fibrosis), liver enzyme tests and liver stiffness measurement, were primary methods for diagnosing and monitoring MASH patients. Lifestyle modifications were the primary management strategy, given the absence of approved pharmacological treatments for MASH. The panel also highlighted significant challenges in managing MASH, including the lack of approved medications and the difficulty in sustaining lifestyle changes. CONCLUSIONS:The survey underscores the substantial underdiagnosis of MASH and the reliance on non-invasive diagnostic methods in Germany. The lack of approved treatments necessitates a focus on lifestyle modifications and comorbidity management. The Delphi panel's insights call for enhanced screening, early detection and standardised algorithms to improve patient outcomes.

Background: With the COVID-19 pandemic, a rapid adoption of telemedicine became necessary. Data regarding its implementation in specialized hepatology/IBD care remain limited. This study evaluated telemedicine's effectiveness and safety during the pandemic at a German tertiary center and explored its integration into future hybrid care models. Methods: In a retrospective study, we analyzed 3147 patient encounters at the outpatient clinic of the Department for Gastroenterology and Hepatology at the University Hospital Frankfurt between March and June 2020. We assessed patient characteristics, appointment adherence, and outcomes across the three specialized clinics: hepatology (n = 1963), liver transplant (n = 594), and IBD (n = 590). Multivariate regression analysis identified predictors of successful telemedicine utilization. Results: Out of all appointments, 1112 (35.3%) were conducted via telemedicine, with significantly different adoption rates across clinics (hepatology, 40.4%; liver transplant, 32.8%; IBD, 21.0%, p < 0.01). Adherence rates were comparable between telemedicine (91.3%) and in-person visits (90.5%). Multivariate analysis identified age (OR 1.009, 95%CI 1.004-1.014, p < 0.001), metabolic-associated steatotic liver disease (OR 1.737, 95%CI 1.400-2.155, p < 0.001), and post-liver transplant status (OR 1.281, 95%CI 1.001-1.641, p = 0.049) as independent predictors of successful telemedicine utilization. HBV/HDV coinfection (OR 0.370, 95%CI 0.192-0.711, p = 0.003) and required endoscopy (OR 0.464, 95%CI 0.342-0.630, p < 0.001) were associated with in-person care. Hospitalization rates were low and comparable across modalities, confirming telemedicine's safety. Conclusions: This study demonstrates that telemedicine can be successfully implemented in specialized gastroenterology and hepatology care, with high compliance rates comparable to in-person visits. Patient characteristics and disease-specific factors influence the suitability for telemedicine, supporting a stratified approach to hybrid care models, which can optimize resource utilization while maintaining quality of care. Particularly stable MASLD patients, well-controlled post-transplant recipients beyond one year, and IBD patients in sustained remission can be properly managed through telemedicine with annual in-person assessments.

Background:Hospitalized patients with end-stage liver disease are at risk of malnutrition, reduced body function, and cognitive impairment due to HE. This combination may have an impact on in-hospital falls and mortality. The purpose of this study was to identify factors associated with the risk of falls and to analyze the consequences regarding in-hospital mortality.Methods:We performed a retrospective analysis of patients hospitalized with liver cirrhosis between 2017 and 2019 at the Department of Gastroenterology at the University Hospital Frankfurt. Clinical data, laboratory work, and follow-up data were analyzed. Factors associated with the risk of falls and in-hospital mortality were calculated using a mixed effect poisson regression model and competing risk time-to-event analyses.Results:Falls occurred with an incidence of 4% (80/1985), including 44 injurious falls with an incidence rate of 0.00005/100 patient-days (95% CI: 0.00001-0.00022). In the multivariate analysis malnutrition (incidence risk ratio: 1.77, 95% CI: 1.04-3.04) and implanted TIPS (incidence risk ratio: 20.09, 95% CI: 10.1-40.1) were independently associated with the risk of falling. In a total of 21/80 (26.25%) hospitalizations, patients with a documented fall died during their hospital stay versus 160/1905 (8.4%) deaths in hospitalizations without in-hospital fall. Multivariable analysis revealed as significant clinical predictors for in-hospital mortality a Nutritional Risk Screening >= 2 (HR 1.79, 95% CI: 1.32-2.4), a falling incident during hospitalization (HR 3.50, 95% CI: 2.04-6.0), high MELD, and admission for infections.Conclusions:Malnutrition and TIPS are associated with falls in hospitalized patients with liver cirrhosis. The in-hospital mortality rate of patients with cirrhosis with falls is high. Specific attention and measures to ameliorate these risks are warranted.

INTRODUCTION: International guidelines suggest different possibilities for drying of endoscopes during reprocessing. Clinical results of these available drying methods are not satisfactory. The aim of this study was to compare the drying cycle of a standard endoscope washer-disinfector (EWD) (standard drying method [SD]) with a shortened mandatory drying by the EWD followed by a special drying device using laminar and turbulent air flow (novel drying method [ND]). METHODS: Sixty endoscopes (duodenoscopes, colonoscocopes, and gastroscopes) from 3 different manufacturers underwent high-level disinfection and drying depending on the randomization group. Operational time of drying was measured for both groups. Residual fluid in the channels was measured using a laboratory scale. After a 14-day storage period, a sample of the endoscope channels was obtained to determine bacterial contamination. RESULTS: ND had significantly fewer residual water in endoscope channels (SD: 90% vs ND: 0%; P < 0.001) after high-level disinfection and drying and less bacterial contamination after storage for 14 days (SD: 47% vs ND: 20%; P = 0.028). Time consumed for drying in ND was also significantly shorter (SD: 16 minutes 4 seconds vs ND: 5 minutes 59 seconds; P < 0.001). DISCUSSION: Drying with a special automatic drying device was superior compared with an EWD's drying program as evidenced by no measurable residual water, reduced microbiological contamination, and a more than 2-fold decrease in operational time. Thus, drying by laminar and turbulent airflow may represent an attractive alternative to the currently used standard approach in the reprocessing process of flexible endoscopes.

Background Bulevirtide is a first-in-class peptidic entry inhibitor for hepatitis B virus (HBV) and hepatitis D virus infection. In July, 2020, bulevirtide 2 mg received conditional marketing authorisation by the European Medical Agency for treatment of chronic hepatitis D virus infection. We investigated the antiviral activity of bulevirtide in patients chronically infected with HBV and hepatitis D virus.Methods MYR202 (ClinicalTrials.gov, NCT03546621; EudraCT, 2016-000395-13) was a multicentre, parallel-group, randomised, open-label, phase 2 trial. Adults (aged 18-65 years) with chronic hepatitis D virus infection, including patients with cirrhosis and patients who had contraindications to PegIFN alpha treatment or for whom treatment did not work, were eligible and were enrolled from four hospitals in Germany and 12 hospitals in Russia. Patients were randomly assigned (1:1:1:1) to receive 2 mg (n=28), 5 mg (n=32), or 10 mg (n=30) subcutaneous bulevirtide once per day with tenofovir disoproxil fumarate (TDF; 245 mg once per day orally) or TDF alone (245 mg once per day orally; n=30) for 24 weeks. Randomisation was done using a digital block scheme with stratification, consisting of 480 randomisation numbers separated into 30 blocks. The primary endpoint was undetectable hepatitis D virus RNA or 2 log10 IU/mL or higher decline in hepatitis D virus RNA at week 24, which was analysed in the modified intention to-treat population, including patients who received study medication at least once after randomisation. Hepatitis D virus RNA concentrations were monitored until week 48. Safety was assessed for all patients who received at least one dose of bulevirtide or TDF.Findings Between Feb 16, 2016, and Dec 8, 2016, 171 patients with chronic hepatitis D virus infection were screened; 51 were ineligible based on the exclusion criteria and 120 patients (59 with cirrhosis) were enrolled. At week 24, 15 (54%, 95% CI 34-73) of 28 patients achieved undetectable hepatitis D virus RNA or a 2 log10 IU/mL or more decline in hepatitis D virus RNA (p<0.0001 vs TDF alone) with 2 mg bulevirtide, 16 (50%, 32-68) of 32 with 5 mg bulevirtide (p<0.0001), and 23 (77%, 58-90) of 30 with 10 mg bulevirtide (p<0.0001), versus one (4%, 0.1-18) of 28 with TDF alone. By week 48 (24 weeks after bulevirtide cessation), hepatitis D virus RNA concentrations had rebounded, with median changes from week 24 to week 48 of 1.923 log10 IU/mL (IQR 0.566-2.485) with 2 mg bulevirtide, 1.732 log10 (0.469-2.568) with 5 mg bulevirtide, and 2.030 log10 (1.262-2.903) with 10 mg bulevirtide. There were no deaths associated with treatment. Three (9%) patients in the bulevirtide 5 mg group, two (7%) patients in the bulevirtide 10 mg group, and one (4%) patient in the TDF group had serious adverse events. Common treatment-emergent adverse events included asymptomatic bile salt increases and increases in alanine aminotransferase and aspartate aminotransferase.Interpretation Bulevirtide induced a significant decline in hepatitis D virus RNA over 24 weeks. After cessation of bulevirtide, hepatitis D virus RNA concentrations rebounded. Longer treatment durations and combination therapies should be investigated.

Introduction: Standardization of diagnostic criteria of autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) variant syndrome (AIH-PBC VS) has not been achieved so far and evidence-based recommendations for monitoring and treatment of the disease are still lacking. Our study aimed to assess the prevalence, biochemical, and serological features, as well as the clinical course, of VS. Methods: We performed a retrospective study including all patients with VS between 1999 and 2020 in four German centers. Data on demographic parameters, biochemical and serological tests, treatment, and outcome were collected. Results: Of 90 patients (3.1%) meeting Paris criteria for VS diagnosis, 65.6% showed AIH and PBC histological features, while biochemical Paris criteria were observed comparatively rarely. Further antibodies, which were not part of the diagnostic criteria of VS, were found in a subgroup of patients with available data (ACA: 30.0%; anti-CENP-A: 25.0%; anti-CENP-B: 33.3%; anti-SP100: 21.4%). Biochemical response was more frequently observed in patients treated with a combined therapy of ursodeoxycholic acid (UDCA) and immunosuppression (IS). Liver cirrhosis was detected in 31 patients (34.4%) and 25 patients (27.8%) developed clinical manifestations of portal hypertension. Conclusions: Biochemical Paris criteria of VS were rarely detected, thus implying that these cut-off values should be redefined. Regarding pharmacological treatment, combined therapy of UDCA and IS appeared to be more effective than monotherapy with UDCA.

Objectives The diagnostic value of liver biopsy in patients with acute liver injury or acute liver failure (ALI/ALF) was investigated. Methods Data from the initial event and follow-up visits were retrospectively analyzed in all patients with a liver biopsy during ALI/ALF from January 2010 to May 2020 at the University Hospital Frankfurt, Germany. Results The cohort comprised 66 patients. Post-biopsy hemorrhage occurred in 2 of 66 but was self-limited. In five patients suspected liver involvement by a systemic extrahepatic disease was confirmed and excluded in eight patients. In 4 of 66 patients, the etiology of ALI/ALF remained unknown. Liver biopsy hinted at the etiology of ALI/ALF in 2 of 6 patients with rare diagnoses (hemophagocytic lymphohistiocytosis: 2 of 66; ischemic liver injury: 1 of 66, ALI/ALF due to a systemic infection: 3 of 66). In 31 of 34 patients with drug-induced liver injury (DILI), histopathology suggested DILI; in further 2 patients, DILI was among the differential diagnoses. However, DILI was also the histopathologically preferred diagnosis in 12 of 15 patients with autoimmune hepatitis (AIH). Only in 3 of 15 patients, histopathology was considered compatible with AIH. Serum immunoglobulin G (IgG) and autoantibodies during ALI/ALF were higher in patients with AIH than with DILI. Patients with AIH did not show a more pronounced biochemical response to corticosteroids in the first 10 days of treatment than patients with DILI. Conclusions Liver biopsy is indispensable when liver involvement by an extrahepatic disease is suspected. To distinguish AIH from DILI in ALI/ALF, serum IgG, and autoantibodies seem more helpful than liver biopsy; long-term follow-up is needed in these patients.

Background & Aims: Clinical manifestation of hepatic involvement in sarcoidosis can vary from asymptomatic disease to severe complications such as cirrhosis and portal hypertension. However, data on hepatic sarcoidosis are limited, and evidence-based recommendations are lacking. Our study aimed to assess the features and clinical course of hepatic sarcoidosis in a predominantly Caucasian cohort. Methods: We performed a retrospective study including all patients with hepatic sarcoidosis between 2004 and 2020 in 5 German centres. The median follow-up time was 36 months (range 0.0-195). Data on demographic parameters, clinical manifestations, diagnostic test results, treatment, and outcome were collected. Results: A total of 1,476 patients with sarcoidosis and 62 patients with hepatic involvement (4.2%) were identified. Of the patients, 51.6% were female, and 80.6% were Caucasian. Most patients were asymptomatic and were observed to have a cholestatic pattern of liver enzyme elevations. Cirrhosis was detected in 9 patients (14.5%), of whom 6 developed clinical manifestations of portal hypertension. Fifty-four patients were medically treated, most commonly with glucocorticoids (69.4%) or ursodeoxycholic acid (UDCA) (40.3%). Levels of alkaline phosphatase (ALP) decreased by 60.8% on average from baseline in patients treated with glucocorticoids and by 59.9% in patients treated with UDCA. Seventeen patients received treatment augmentation with a second line agent, of whom 8 patients normalised ALP levels during follow-up. None of the patients underwent liver transplantation or developed hepatocellular carcinoma (HCC). Three of the patients died during follow-up owing to liver-related complications. Conclusions: Hepatic involvement in sarcoidosis was found in 4.2% of patients with sarcoidosis and was clinically significant in 14.5% of those. These findings highlight the importance of early identifying, monitoring, and treating hepatic sarcoidosis, given its increased mortality when associated with end-stage liver disease. Lay summary: Clinical diagnostic and surveillance of hepatic involvement in sarcoidosis has not been standardised, and management of hepatic involvement is a clinical challenge, since it remains poorly characterised in many ways. Our results show that one-third of patients with hepatic sarcoidosis presented with clinically significant portal hypertension, 14.5% suffered from cirrhosis, and 3 patients died owing to liver-related complications. Regarding pharmacological treatment options, corticosteroids and UDCA were the medical agents most frequently used, and both of them have been shown to induce biochemical response in the majority of patients. These findings highlight the importance of correctly and early identifying hepatic involvement in sarcoidosis, because of the potentially progressive course of disease. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).

Background and Aims Liver function tests (alanine aminotransferase, ALT; gamma-glutamyltransferase, GGT) not always normalize after elimination of hepatitis C virus (HCV) by direct acting antivirals (DAAs), possibly indicating concomitant non-viral liver diseases. We analysed factors determining the biochemical response (normalized ALT/GGT) of DAA therapy in a large real-world cohort. Method The German Hepatitis C-Registry is a national multicenter registry study. Normal ALT was defined <= 35 U/L (female) and <= 50 U/L (male) or, according to AASLD, <= 19 U/L (female) and <= 30 U/L (male), normal GGT <= 40 U/L (female) and <= 60 U/L (male). Results At baseline, ALT was elevated in 3705/4946 (74.9%), ALT (AASLD) in 4669/4946 (94.4%) and GGT in 3018/4906 (61.5%). In this study, 97% of patients achieved SVR12. At week 12 after end of therapy, ALT was elevated in 451/4946 (9.1%), ALT according to AASLD in 1906/4946 (38.5%) and GGT in 863/4879 (17.7%). Persistently elevated ALT after DAA therapy was independently associated with high body mass index (BMI), age <70 years, liver cirrhosis, diabetes, alcohol consumption and not achieving SVR12. Using the stricter AASLD criteria, opioid substitution and male sex were additional predictors. Higher GGT at week 12 was associated with high BMI, age >70 years, liver cirrhosis, diabetes, alcohol consumption, opioid substitution and non-SVR. Importantly, persistently elevated liver tests after treatment, particularly GGT, were associated with hepatic decompensation and mortality during 4-years follow-up. Conclusion Risk factors at baseline (obesity, diabetes, liver cirrhosis, alcohol consumption) are independently associated with persistently elevated liver function tests after SVR, indicating that these patients warrant further hepatological follow-up. Clinical trial registration: German Clinical Trials Register (DRKS; ID DRKS00009717).

Prescription and efficacy of daclatasvir and sofosbuvir ± ribavirin, including patient-reported outcomes, in routine practice in three European countries: the CMPASS-EU cohort study. Objectives: To identify patient characteristics associated with routine prescription of daclatasvir (DCV) in chronic hepatitis C virus (HCV) infection and evaluate effectiveness, safety and quality-of-life (QoL) changes for DCV-based regimens. Methods: A prospective, observational cohort study in Germany, Belgium and the Netherlands collected baseline data from all patients initiating a new HCV regimen, with 12-month follow-up of DCV-based treatments. Baseline predictors of prescription, longitudinal efficacy, and patient-reported QoL outcomes (EQ-5D, EQ-VAS and SF-36 global physical/mental health) on DCV were assessed. Results: Of 914 patients analyzed, 470 were prescribed DCV (469 with sofosbuvir [SOF] ± ribavirin [RBV]) and 444 non-DCV regimens. A high proportion prescribed DCV were cirrhotic (36%) and/or illicit drug users (IDU; 24%). Multivariate predictors of DCV treatment included genotype 3 infection (odds ratio 85.9 [95% confidence interval 43.5–170]), age ≥65 years (2.0 [1.2–3.3]), and cirrhosis (3.3 [2.0–5.3]). Sustained virologic response on DCV+SOF±RBV (observed) was 96–100% across subgroups of IDU, HIV co-infection, HCV genotype and cirrhosis status. Statistically significant improvements in all QoL outcomes were observed over 12 months of DCV+SOF±RBV irrespective of RBV use or cirrhosis status, but IDU had no change in SF-36 global mental health although other outcomes improved. Conclusions: In this cohort, DCV+SOF±RBV was efficacious for HCV treatment across a range of subgroups and associated with QoL improvements.

Background Virologic failure to approved combinations of direct antiviral agents (DAA) in patients with chronic hepatitis C virus (HCV) infection is rare. Mostly it involves difficult to treat patients with advanced liver disease and prior interferon-experience. Before approval of VOX/VEL/SOF, a restricted number of patients received rescue treatment, and the choice of DAA combinations for re-treatment were selected on an individual basis. In the present analysis, patient characteristics and rescue-regimens after virologic failure mainly based on first generation DAAs are described. Patients and methods Data were obtained from the German Hepatitis C-Registry (DHC-R), which is a national multicenter real-world cohort currently including about 16 500 patients recruited by more than 250 centers. The present analysis is based on 6683 patients who initiated a DAA therapy and for whom follow-up data (per-protocol analysis) were available. Results Among the patients, 188 (2.8 %) experienced a virologic relapse. Compared to SVR-patients, relapse patients were significantly more often male (77.7 % versus 56.9 %, respectively, p < 0.001), showed cirrhosis significantly more (48.4 % versus 28.1 %, respectively, p < 0.001) and a prior interferon-containing therapy (46.3 % versus 39.0 %, respectively, p = 0.049). The majority of patients who relapsed were infected with genotype 1 (47.4 %) followed by genotype 3 (29.8 %), and 95 relapse patients started DAA re-treatment. Characteristics of patients with rescue-treatment are similar to these of patients with relapse after initial DAA treatment. Thirty-one of 39 patients with complete follow-up data achieved SVR (79.5 %), and 8 patients had a relapse again (20.5 %). Patients who received rescue treatment including a new DAA class according to guidelines, except patients who received VOX/VEL/SOF, showed higher SVR rates than the entire group (21/25, 84 %). All patients who received VOX/VEL/SOF achieved SVR (n = 4, 100 %). Conclusions Patients with failure with DAA combination therapies are a difficult but urgent to treat population with the frequent presence of cirrhosis and prior treatment failure with interferon-based therapies. Rescue therapy with inclusion of a new DAA class leads to high SVR rates, but multiple targeted therapy with VOX/VEL/SOF seems to be most effective.

BACKGROUND:Limited data exist regarding tenofovir disoproxil fumarate (TDF) safety and effectiveness in chronic hepatitis B virus-infected (CHB) patients with renal impairment (RI).AIMS:To compare real-world data on renal safety and effectiveness of TDF vs entecavir (ETV) in CHB patients with moderate-to-severe RI.METHODS:Retrospective, non-interventional, cohort study analysing medical records for TDF/ETV-treated CHB patients (54 European centres). Included patients experienced moderate-to-severe RI (creatinine clearance 20-60 mL/min [Cockcroft-Gault]) either before TDF/ETV initiation ('before' subgroup [baseline = treatment initiation]) or after TDF/ETV initiation ('after' subgroup [baseline = first RI occurrence]). The primary objective was TDF safety, particularly renal-related adverse events of special interest (AESI). TDF and ETV safety and effectiveness were compared and multivariate analyses were performed using inverse probability treatment weighting.RESULTS:'Before' subgroup included 107 TDF- and 91 ETV-treated patients; 'after' subgroup included 212 TDF- and 77 ETV-treated patients. Mean baseline creatinine clearance was higher for TDF- vs ETV-treated patients (both subgroups). Median follow-up was 3.1 years (both treatments). AESI were more frequent with TDF vs ETV ('before': 18.7% vs 8.8%; 'after': 9.9% vs 3.9%); however, differences were not significant by multivariate analysis. Only TDF-treated patients experienced renal tubular dysfunction (6.5% 'before'; 1.9% 'after') as well as renal adverse events leading to treatment discontinuation (8.4% 'before'; 7.1% 'after'). Effectiveness was similar between treatments.CONCLUSIONS:Overall safety was similar for TDF vs ETV (both subgroups). Given that renal tubular dysfunction occurred with TDF and not with ETV, renal safety concerns may be greater with TDF in CHB patients with RI.

Elevated liver function tests (ALT, GGT) in chronic hepatitis C not always normalize after successful elimination of HCV by DAAs, indicating concomitant additional liver diseases. We analysed the factors determining biochemical response (normal ALT or GGT) of DAA therapy in a large real-world cohort, the German Hepatitis C-Registry.

Polymorphisms of GVIA calcium-independent PLA2 (iPLA2β) implicate its role in plasma lipids, type-2 diabetes, and nonalcoholic fatty liver disease (NAFLD). iPLA2β is thought as a target for NAFLD therapy. We investigated the role of hepatic phospholipids in three NAFLD models: genetic Ob/Ob mice, long-term high-fat diet (HFD)-fed mice (representing obese NAFLD), and mice fed with methionine-choline-deficient (MCD) diet (representing nonobese NAFLD). A defect in hepatic fatty-acyl remodeling of phosphatidylcholine (PC) was observed in these three NAFLD models. By using iPLA2β-null mice, our profiling results revealed that the defect in PC remodeling was rescued in obese NAFLD associated with fatty liver and obesity protection. The rescue of PC remodeling and steatosis protection was not observed in MCD-fed mice. Our results indicate a critical role of hepatic PC for protection by iPLA2β inactivation, suggesting that iPLA2β inhibitors may be used as a therapy for obese but not nonobese NAFLD.

Cholangiocarcinoma (CCA) may arise in the intra- or extrahepatic biliary tract and is associated with a poor prognosis. Despite recent advances, to date there is still no established targeted therapeutic approach available. Non-surgical therapeutic agents are urgently needed, as most patients are non-eligible to surgical resection. Anti-PD-L1 therapy prevents cancer cells from evading the immune system and has emerged as a new treatment option in several cancer entities. Recently, PD-L1 expression has been analyzed in comparably small CCA patient cohorts. However, a systematic validation of different PD-L1 antibodies has not been performed in CCA so far. We stained a tissue microarray consisting of 170 patients, including 72 intrahepatic cholangiocarcinomas (iCCAs), 57 perihilar cholangiocarcinomas (pCCAs) and 41 distal cholangiocarcinomas (dCCAs) by immunohistochemistry and evaluated PD-L1 positivity in tumor and stromal cells. We analyzed three different PD-L1 antibodies (clones 28–8, SP142, and SP263) that are frequently used and recommended for predictive diagnostic testing in other cancer types. For PD-L1 antibody clone SP263, 5% of iCCAs, 4% of pCCAs and 3% of dCCAs exhibited PD-L1 expression on tumor cells, thereby showing the highest frequencies of PD-L1 positivity. Accordingly, highest PD-L1 positivity rates of stromal cells with 31% in iCCA, 40% in pCCA and 61% in dCCA were detected for clone SP263. Agreement of PD-L1 positivity in tumor cells was moderate for clone 28–8 and SP263 (κ = 0.44) and poor between 28-8 and SP142 (κ = 0.13), as well as  SP142 and SP263 (κ = 0.11), respectively. Statistical analyses of PD-L1 expression (clone SP263) on tumor cells with clinicopathological data revealed a positive correlation with shortened overall survival in CCA patients. Selection of appropriate PD-L1 antibodies and careful evaluation of immunohistochemical staining patterns have a significant impact on PD-L1 testing in CCA. Clinical trials are necessary to investigate the putative beneficial effects of PD-L1 targeted immunotherapy in CCA patients.

Carboxylesterase 2 (CES2) is instrumental for conversion of ester-containing prodrugs in cancer treatment. Novel treatment strategies are exceedingly needed for cholangiocarcinoma (CCA) patients. Here, we assessed CES2 expression by immunohistochemistry in a CCA cohort comprising 171 non-liver fluke associated, intrahepatic (n = 72) and extrahepatic (perihilar: n = 56; distal: n = 43) CCAs. Additionally, 80 samples of high-grade biliary intraepithelial neoplastic tissues and 158 corresponding samples of histological normal, non-neoplastic biliary tract tissues were included. CES2 expression was highest in non-neoplastic biliary tissue and significantly decreased in CCA. Patients showing any CES2 expression in tumor cells had a significantly better overall survival compared to negative cases ( p = 0.008 ). This survival benefit was also maintained after stratification of CES2-positive cases, by comparing low, medium and high CES2 expression levels ( p-trend = 0.0006 ). Evaluation of CCA subtypes showed the survival difference to be restricted to extrahepatic tumors. Correlation of CES2 expression with data of tumor-infiltrating immune cells showed that particularly CD8+ T cells were more frequently detected in CES2-positive CCAs. Furthermore, treatment of CCA cell lines with the prodrug Irinotecan reduced cell viability, increased cytotoxicity and modulated inflammatory gene expression. In conclusion, reduced CES2 expression is associated with poor outcome and low CD8+ T cell infiltration in CCA patients. Further clinical studies could show, whether CES2 expression may serve as a predictive marker in patients treated with prodrugs converted by CES2.