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Background Non-alcoholic fatty liver disease (NAFLD) affects more than 18 million individuals in Germany. Real-world data help to better characterize the natural history of disease and standard of care. Methods The German NAFLD-Registry is a prospective non-interventional study initiated by the German Liver Foundation and aims to describe clinical characteristics and observe outcomes in patients with NAFLD recruited in secondary and tertiary care. Results From this ongoing study, baseline data of the first 501 patients (mean age 54 years, 48% women) were analysed. 13 % of the study population had a high risk for advanced fibrosis (FIB-4 ≥2.67), approximately one-third had a liver stiffness value ≥9.6kPa measured by transient elastography, and the clinical diagnosis of liver cirrhosis was present in 10%. Typical comorbidities were more prevalent in high risk as compared to low risk patients (FIB-4 Conclusion First data of the German NAFLD registry show that approximately every 10th patient has advanced NAFLD, highlights T2DM patients as a high-risk group and gives insights in the use of comedication and life-style interventions in secondary and tertiary care.

The diagnostic value of liver biopsy in patients with acute liver injury or acute liver failure (ALI/ALF) was investigated.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.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.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.

The urgent need in HCV-infected patients with liver disease mandated the rapid implementation of IFN-free DAA combination therapies following their regulatory approval in 2014 and 2015 without full knowledge of the optimal combinations and regimens. Investigating the evolution of the DAA utilization patterns and treatment outcomes could provide learnings for future situations. This was an analysis of a prospective observational database from the German Hepatitis C Registry (DHC-R) covering a period from May 2014 to September 2015. Adult patients had evidence of chronic HCV GT1 or GT4 infection and were treated with an IFN-free combination regimen of simeprevir (SMV) + sofosbuvir (SOF) or other IFN-free regimens: daclatasvir + sofosbuvir (DCV + SOF), ledipasvir/sofosbuvir (SOF/LDV), paritaprevir/r + ombitasvir ± dasabuvir (PrOD), with or without ribavirine (R). A total of 5496 subjects were followed during the period. During this period, clinical recommendations and treatment patterns evolved rapidly in response to new evidence from clinical trials and clinical routine and regulatory approval of additional regimens. High SVR12 rates were seen in this cohort, even in hard-to-treat patient subgroups. In the multivariate analysis, gender, age, advanced cirrhosis, and intensified treatment for cirrhotics were associated with treatment outcome. Despite limited knowledge of the optimal utilization of the newly approved DAA combinations and treatment durations as well as their comparative efficacy and safety profiles, high SVR rates were achieved regardless of the DAA combination. These outcomes were facilitated by the rapid adaptation of clinical recommendations. Future situations with high unmet medical need may follow a similar approach. Die dringende Behandlungsbedürftigkeit HCV-infizierter Patienten mit Lebererkrankung verlangte die rasche Einführung IFN-freier DAA-Kombinationstherapien nach ihrer Zulassung in 2014 und 2015 trotz unvollständigem Wissen über deren optimalen Einsatz. Die Untersuchung der Evolution des Einsatzes und der Ergebnisse könnte wichtige Erkenntnisse für zukünftige Situationen bergen. Diese Analyse einer prospektiven Kohorte des Deutschen Hepatitis C-Registers (DHC-R) deckt den Zeitraum von Mai 2014 bis September 2015 ab. Erwachsene Patienten mit chronischer HCV-GT1 oder GT4-Infektion wurden mit einer IFN-freien Therapie aus Simeprevir (SMV) + Sofosbuvir (SOF), oder anderen IFN-freien Regimen: Daclatasvir + Sofosbuvir (DCV + SOF), Ledipasvir/Sofosbuvir (SOF/LDV), Paritaprevir/r + Ombitasvir ± Dasabuvir (PrOD), mit oder ohne Ribavirin (R) behandelt. 5496 Patienten wurden während des Zeitraums beobachtet. In dieser Periode wandelten sich die klinischen Leitlinien und Behandlungsmuster rasch in Folge neuer Evidenz aus klinischen Studien und klinischer Erfahrung und der Zulassung von neuen Regimen. Hohe SVR12-Raten wurden in dieser Kohorte, selbst in schwierig zu behandelnden Patienten-Subgruppen, beobachtet. Die multivariate Analyse zeigte, dass Geschlecht, Alter, fortgeschrittene Zirrhose und die intensivierte Therapie bei Patienten mit Zirrhose mit dem Behandlungserfolg assoziiert waren. Trotz begrenzten Wissens um den optimalen Einsatz von neu zugelassenen DAA-Kombinationen und deren Behandlungsdauer sowie dem Vergleich ihrer Wirksamkeits- und Sicherheits-Profile wurden hohe SVR12-Raten mit verschiedenen DAA-Kombinationen erzielt. Diese Ergebnisse wurden unterstützt von einer raschen Adaption klinischer Therapie-Empfehlungen. Zukünftige Szenarien mit einem erheblichen ungedeckten medizinischen Bedarf könnten einem ähnlichen Ansatz folgen.

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.

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., Graphical abstract, Highlights • There has been little research on clinical characteristics and the clinical outcome of patients with hepatic sarcoidosis. • One-third of patients with hepatic sarcoidosis presented with clinically significant portal hypertension, and 14.5% suffered from cirrhosis. • Biochemically, a cholestatic pattern of liver enzyme elevations was the most common abnormality. • The correct and early identification of hepatic involvement in sarcoidosis is crucial because of the potentially progressive course of disease.

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. 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. 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 %). 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. Virologisches Versagen nach einer zugelassenen Kombinationstherapie aus direkt antiviral wirkenden Medikamenten (DAA) bei Patienten mit chronischer Hepatitis-C-Virus(HCV)-Infektion ist sehr selten. Zumeist handelt es sich, aufgrund von fortgeschrittener Lebererkrankung und vorangegangenen interferonbasierten Therapien, um schwierig zu behandelnde Patienten. Vor Zulassung von VOX/VEL/SOF erhielt eine geringe Zahl von Patienten eine Rescue-Therapie, und die Wahl der DAA-Kombination zur Re-Therapie unterlag individuellen Entscheidungskriterien. Die vorliegende Arbeit beschreibt Charakteristika und Rescue-Therapien, überwiegend basierend auf DAAs der ersten Generation, bei Patienten nach virologischem Versagen. Die Daten entstammen dem Deutschen Hepatitis C-Register (DHC-R). Dieses ist eine nationale, multizentrische, Real-World-Kohorte, die derzeit über 16 500 Patienten aus über 250 Zentren einschließt. Die aktuelle Analyse basiert auf 6683 Patienten mit initialer DAA-Therapie und kompletten Follow-up-Daten (Per-Protocol(PP)-Analyse). 188 Patienten (2,8 %) aus der PP-Population hatten einen virologischen Relapse. Die Relapse-Patienten waren verglichen zur SVR-Population signifikant häufiger männlich (77,7 % versus 56,9 %, p 0,001), hatten signifikant häufiger eine Zirrhose (48,4 % versus 28,1 %, p 0,001) und eine interferonbasierte Vortherapie (46,3 % versus 39,0 %, p = 0,049). Die meisten Patienten mit virologischem Versagen waren mit Genotyp 1 (57,4 %) gefolgt von Genotyp 3 (29,8 %) infiziert. 95 der Relapse-Patienten erhielten eine DAA-Re-Therapie. Die Charakteristika von Patienten mit Rescue-Therapie sind vergleichbar mit denen von Patienten mit Relapse nach initialer DAA-Therapie. 31 von 39 Patienten mit kompletten Follow-up-Daten erreichten SVR (79,5 %) und 8 Patienten erlitten einen erneuten Relapse (20,5 %). Patienten, die eine den Leitlinien entsprechende Rescue-Therapie mit einer neuen DAA-Klasse erhalten haben, ausgenommen VOX/VEL/SOF, zeigten höhere SVR-Raten als die Gesamtgruppe (21/25, 84 %). Alle Patienten, die VOX/VEL/SOF erhielten, erreichten einen SVR (n = 4, 100 %). Versager nach DAA-Kombinationstherapie entsprechen einer schwierig und zugleich dringlich zu behandelnden Patientengruppe mit häufigem Vorliegen einer Zirrhose und Versagen einer interferonbasierten Vortherapie. Rescue-Therapie mit einer neuen DAA-Klasse führt zu hohen SVR-Raten, eine Multi-Target-Therapie mit VOX/VEL/SOF scheint am effektivsten zu sein.

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.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).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), age70 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, age70 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.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.German Clinical Trials Register (DRKS; ID DRKS00009717).

Norursodeoxycholic acid is an orally administered side chain-shortened homologue of ursodeoxycholic acid that undergoes hepatic enrichment with hepatoprotective, anti-inflammatory, and antifibrotic activity. We assessed the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease.We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial in tertiary referral hospitals and medical centres in Austria (n=6) and Germany (n=23) for patients with non-alcoholic fatty liver disease with or without diabetes. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and serum alanine aminotransferase (ALT) concentrations of more than 0·8 times the upper limit of normal were randomly assigned (1:1:1) using a computer-generated central randomisation. Patients were randomly assigned to receive either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks with a subsequent 4-week follow-up period. All individuals involved in the trial were masked to treatment allocation. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment assessed in the intention-to-treat population. This trial is registered with EudraCT, number 2013-004605-38.Between March 30, 2015, and Sept 20, 2016, of 198 individuals included in the analysis, 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (mean change -27·8%, 95% repeated CI -34·7 to -14·4; p0·0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. 112 treatment-emergent adverse events occurred in the 1500 mg group, 99 in the 500 mg group, and 103 in the placebo group. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis).Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated encouraging further studies.Dr Falk Pharma GmbH.

Chronic hepatitis C virus infection is associated with a significant health burden. Long-term consequences are the development of liver cirrhosis and hepatocellular carcinoma. The introduction of direct-acting antivirals (DAA) has led to an increase in sustained virologic response rates (SVR), but is accompanied by higher treatment costs. The aim of this study was to assess the outcomes and costs of treating hepatitis C virus infected patients with DAAs in clinical practice in Germany.Data were derived from a noninterventional study including a pharmacoeconomic subset of 2673 patients with genotypes 1 and 3 who initiated and completed treatment between February 2014 and February 2017. Sociodemographic and clinical parameters as well as resource utilization were collected using a web-based data recording system. Costs were calculated using official remuneration schemes.The mean age of the patients was 54.6 years; 48% were men. 93.5% of all patients achieved an SVR. The average total treatment costs wereOV0556;67 979 (OV0556;67 131 medication costs,OV0556;824 ambulatory care,OV0556;24 hospital costs). The average costs per SVR ofOV0556;72 705 were calculated. Differences in SVR and costs according to genotype, treatment regimen, treatment experience, and cirrhosis were observed. Quality-of-life data showed no or a minimal decrease during treatment.This analysis confirms high SVR rates for newly introduced DAAs in a real-world setting. Costs per SVR estimated are comparable to first-generation DAA. Given the fact that the costs for the currently used treatment regimens have declined, it can be assumed that the costs per SVR have also decreased. Our insight into real-world outcomes and costs can serve as a basis for a comparison with the mentioned newly introduced treatment regimens.

ObjectiveHomozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants (‘Pi*Z’ and ‘Pi*S’), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse.DesignWe analysed multicentric case–control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed.ResultsThe Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (pConclusionThe Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%–4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.

Einleitung: Die nicht alkoholische Fettlebererkrankung (non-alcoholic fatty liver disease, NAFLD) stellt heutzutage in der westlichen Welt die haufigste Ursache einer chronischen Lebererkrankung dar. In der europaischen und US-amerikanischen Bevolkerung liegt die Pravalenz bei bis zu 30 %. Unklar ist die Versorgungssituation deutscher Fettleberpatienten. Methoden: An samtliche universitaren Leberzentren in Deutschland (n = 34) wurden Fragebogen (11 Fragen) zur Versorgungssituation der NAFLD-Patienten verschickt. Gefragt wurde u. a. nach dem Anteil von Fettleberpatienten in den Hochschulambulanzen, metabolischen Begleiterkrankungen und der Art der Zuweisung. Auch wurden die klinikinternen Standards erfasst. Hierbei wurden die Situationen von 2008 und 2013 miteinander verglichen. Ergebnisse: Die Rucklaufquote betrug 65 % (n = 22). Es zeigte sich, dass der Anteil von Fettleberpatienten in den Leberambulanzen zwischen 2008 und 2013 gestiegen war, wobei der uberwiegende Anteil von Patienten in den meisten Zentren von extern und nicht aus der eigenen Klinik uberwiesen worden war. Nur wenige Patienten wurden einem Diabetologen oder Endokrinologen vorgestellt, andererseits wurden aber durch die meisten Leberambulanzen Stoffwechselstorungen abgeklart. Nur gering ausgepragt war die Zusammenarbeit zwischen den Leberambulanzen und anderen Fachdisziplinen, diese wurde nur als mittelmasig bewertet, gemeinsame Besprechungen wurden nur selten abgehalten. Verlaufskontrollen der Patienten finden in allen Zentren regelmasig statt, allerdings nach unterschiedlichen Kriterien. Ein einheitlicher Algorithmus zur Risikobeurteilung und invasiven Diagnostik existiert nicht. Schlussfolgerung: Das Problembewusstsein um NAFLD-Patienten scheint in den letzten Jahren gestiegen zu sein. Dennoch ist die Betreuung dieser Patienten heterogen, einheitliche Standards existieren nicht. Eine gemeinsame Leitlinie ist daher dringend erforderlich.

Non-alcoholic fatty liver disease (NAFLD) is frequent among obese individuals with metabolic syndrome. Variants PNPLA3 p.I148M, TM6SF2 p.E167K and MBOAT7 rs641738 are associated with higher liver fat contents. Here we analyzed 63 biopsied non-obese, non-diabetic patients with NAFLD (39 men, age: 20-72 years) recruited within the German NAFLD CSG program. The frequencies of the PNPLA3, TM6SF2 and MBOAT7 polymorphisms were compared with the remaining patients in the NAFLD CSG cohort and with a control population (n = 174). Serum CK18-M30 was measured by ELISA. In non-obese NAFLD patients, the frequency of the PNPLA3 p.I148M allele (74.6%), but not of the TM6SF2 or MBOAT7 polymorphisms, was significantly (P < 0.05) higher as compared to the other patients in the NAFLD CSG cohort (54.9%) or controls (40.2%). The presence of the minor PNPLA3 p.I148M risk allele increased the risk of developing NAFLD (OR = 3.29, P < 0.001) and was associated with higher steatosis, fibrosis, and serum CK18-M30 levels (all P < 0.05). According to the population attributable fraction (PAF), 49.8% of NAFLD cases could be eliminated if the PNPLA3 mutation was absent. The MBOAT7 polymorphism was more frequent (P = 0.019) in patients with severe hepatic steatosis. In conclusion, PNPLA3, and to a lesser extent, MBOAT7 variants are associated with NAFLD risk and modulate liver injury in non-obese patients without diabetes.

BackgroundIn pivotal studies with direct-acting antivirals (DAAs), rates of sustained virological response in hepatitis C genotype 1 infection are >90%.ObjectiveThe objective of this article is to assess real-world safety and effectiveness of DAA treatment in a prospective multicenter registry study.MethodsThe German Hepatitis C-Registry includes 6606 patients with genotype 1 from 246 centers, treated between February 2014 and June 2016 at the discretion of the physician.ResultsA total of 4846 patients completed treatment and follow-up; 51% of these patients were treatment experienced and 28% had liver cirrhosis. Comorbidities were reported in 76% of patients, including HIV co-infection in 8%. SVR12 was 92% with 91% in GT1a and 93% in GT1b. HIV co-infected patients (n = 247) had an SVR12 of 92%. Treatment was discontinued prematurely in 2.5%. In multivariate analysis, SVR12 was dependent on the choice of antiviral regimen (OR 1.33 (1.24–1.43); p

Poster-Abstract

Objectives The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively. Methods When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1); MELD range 7–21; HCC (n = 2); HCV genotype 1a (n = 8), 1b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)). Results Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy; subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in follow-up. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation; in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up. Conclusion DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted.

Background: The combination of sofosbuvir (SOF), ribavirin (RBV) and peg-interferon-alfa-2a (peg-IFN-alfa-2a) as well as the combination of SOF and RBV for the treatment of patients infected with hepatitis c virus (HCV) has improved rates of sustained virological response (SVR) considerably in recent trials. However, there is only limited data concerning the efficacy and safety in a “real-life” cohort. Methods: We analyzed a cohort of 119 patients with chronic HCV infection treated at four investigational sites in Germany. All patients received either a combination treatment of SOF, RBV and peg-IFN-alfa-2a or SOF and RBV. Results: The rates of SVR at 12 weeks after end of treatment (SVR 12) were as follows: Among 76 patients with genotype 1 infection the SVR 12 rate was 74 % (n = 56), among 14 patients with genotype 2 infection the SVR 12 rate was 79 % (n = 11), among 24 patients with genotype 3 infection the SVR 12 rate was 92 % (n = 22) and among 5 patients with genotype 4 infection the SVR 12 rate was 80 % (n = 4). Of all 26 patients with a relapse in our cohort, 69 % (n = 18) of these patients presented with liver cirrhosis and 58 % (n = 15) were treatment experienced. Notably, the level of HCV-RNA after 4 weeks of treatment was a significant predictor of treatment response in genotype 1 patients. Patients with HCV-RNA levels ≥ 12 IU ml-1 after 4 weeks of treatment achieved SVR 12 only in 30 % (n = 17/56, p

We had synthesized the bile acid-phospholipid conjugate UDCA-LPE which was demonstrated to be cytoprotective against TNF-α-induced apoptosis with a mechanism involving cFLIP/caspase 8 signalling. We found that UDCA-LPE activated ERK1/2 phosphorylation. It is known that ERK1/2/MAPK pathway regulates cellular survival and apoptosis, we now ask a question whether ERK1/2 could regulate cFLIP during intrinsic apoptosis. HepG2 cells were subjected to knockdown experiments using cFLIP, ERK1/2 or control siRNAs, and subsequently treated with UDCA-LPE or vehicle. cFLIP mRNA and protein was analyzed by RT-PCR and Western Blot. Caspase 3 and 8 activities were measured by luminescence. By using cFLIP- or ERK1/2-knockdown, we now showed that UDCA-LPE was protective against TNF-α-induced apoptosis in HepG2 cells via cFLIP/caspase 8 but not ERK1/2 pathway. UDCA-LPE also strongly rescued the expression of cFLIP proteins (55 and 43 KDa) and mRNA when their expression levels were decreased upon cFLIP knockdown. cFLIP knockdown did not inhibit ERK1/2 protein expression. On the contrary, ERK1/2 knockdown inhibited cFLIP protein expression and suppressed the ability of UDCA-LPE to upregulate cFLIP. ERK1/2 knockdown induced intrinsic mitochondrial cell death by markedly increasing caspase 3 and, to a lesser extent, caspase 8 activities, both of which were inhibitable by UDCA-LPE. The ability of UDCA-LPE to inhibit caspase 8 activity despite of no increase in cFLIP indicated the lack of role of cFLIP in UDCA-LPE protection during intrinsic apoptosis. Thus, UDCA-LPE inhibited extrinsic TNF-α-induced apoptosis by interfering with cFLIP/caspase 8, but not by ERK1/2/MAPK pathway. UDCA-LPE suppressed intrinsic apoptosis by activating ERK1/2 and inhibiting caspase 3 activation, which was likely as a result of UDCA-LPE’s ability to stabilize mitochondrial membrane. Anti-apoptotic effects of UDCA-LPE in both forms of cell death render it as a therapeutic agent to treat liver disease.

We had synthesized the bile acid-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) which was designed to target hepatocytes via bile-acid transport systems. By using a fluorescent labelled analog UDCA-NBDPE, we showed that the conjugate was taken up by HepG2 cells and also targeted the liver in vivo. We also showed that UDCA-LPE was cytoprotective in HepG2 cells during starvation and TNF-α-induced apoptosis. Here we demonstrated that PI3K inhibitor LY294002 reversed cytoprotective effects of UDCA-LPE in both experimental models indicating that PI3K/Akt pathway may be involved in cytoprotection. Western analyses revealed that UDCA-LPE activated phosphorylation of ERK1/2(Thr202/Tyr204) as well as Akt(Ser473). The activation of both pathways was inhibited by an inhibitor of EGFR activation PD168383; thus, UDCA-LPE may interact with and activated EGFR kinase in plasma membrane to trigger survival signals. Downstream of ERK1/2 activation, we found that UDCA-LPE consistently induced phosphorylation of p90RSK, and pBad(Ser112) in a dose- and time-dependent manner. Downstream of PI3K/Akt activation, UDCA-LPE (but not its metabolite LPE or UDCA) evoked phosphorylation of GSK-3α/β. UDCA-LPE also upregulated cFLIP expression and this was concomitant with an inhibition of cleaved caspase 8 during TNF-α-induced apoptosis. Collectively, UDCA-LPE is a potent hepatoprotectant by activating the two major survival ERK1/2 MAP kinase and PI3K/Akt pathways. UDCA-LPE may be of potential therapeutic importance for treatment of liver diseases.

Einleitung: D-Galaktosamin/Lipopolysaccharid (Gal/LPS) verursacht in der Maus eine akute, Endotoxin-vermittelte Hepatitis; einer der zentralen Mediatoren dieser inflammatorischen Leberschadigung ist TNFα. In Vorarbeiten wurde gezeigt, dass das Gallensaure-Phospholipid-Konjugat UDCA-LPE Leberzellen vor TNFα-induzierter Apoptose und Inflammation schutzen kann und in vivo selektiv in die Leber aufgenommen wird. Die Wirkung des Konjugats wurde in dieser Studie im Maumodell fur einen Gal/LPS-induzierten Leberschaden untersucht. Ergebnisse: In C57BL/6 Mausen wurde durch i.p. Injektion von Gal/LPS eine akute Hepatotoxizitat induziert. Eine Vorbehandlung der Mause mit 30mg/kg UDCA-LPE 1h vor Gal/LPS-Gabe konnte die akute Hepatitis stark abschwachen, einhergehend mit einer 80–90%-igen Abnahme der Serum-Aktivitaten von GOT, GPT und LDH. Die HE-Farbung der Leberschnitte zeigte einen deutlichen Ruckgang der histologischen Zeichen einer akuten Hepatitis durch UDCA-LPE. Die Aktivitaten von Caspase 3/7- und 8 im Serum der vorbehandelten Tiere waren um 90% reduziert, analog war eine Abnahme der apoptotischen Hepatozyten im TUNEL Assay nachweisbar. Der Schutz gegenuber Gal/LPS durch UDCA-LPE ging mit einer Hemmung der PhospholipaseA2-Aktivitat einher, sowie konsekutiv mit einer signifikanten Abnahme der Konzentration von Lysophosphatidylcholin (LPC) bzw. des LPC/PC Verhaltnisses in Leberlysaten, sowie mitochondrialen Lipiden. Microarray Analyse und quantitative RT-PCR aus Lebergewebe ergaben eine reduzierte Expression von proinflammatorischen Cyto- und Chemokinen, wie z.B. MCP1, RANTES und VCAM1, sowie eine signifikante Konzentrationsabnahme der Chemokine im Serum durch UDCA-LPE. Schlussfolgerung: Zusammenfassend konnte eine deutliche Reduktion des Gal/LPS-induzierten Leberschadens durch UDCA-LPE im Mausmodell nachgewiesen werden. UDCA-LPE zeigt damit ein vielversprechendes Wirkungsprofil, das in Hinblick auf mogliche therapeutische Anwendungen weiter evaluiert werden sollte.