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BACKGROUND: Genesis and the prognostic value of olfactory dysfunction (OD) in COVID-19 remain partially described. The objective of our study was to characterize OD during SARS-CoV-2 infection and to examine whether testing of OD may be a useful tool in clinical practice in order to early identify patients with SARS-CoV-2 infection. METHODS: Olfactory function assessment was objectively carried out using the u-Smell-it® test. In a cross-sectional study part, we evaluated this test in a control cohort of SARS-CoV-2 negative tested patients, who attended the University Hospital Frankfurt between May 2021 and March 2022. In a second longitudinal study part, sensitivity and specificity of OD was evaluated as a diagnostic marker of a SARS-CoV-2 infection in Frankfurt am Main, Germany in SARS-CoV-2 infected patients and their close contacts. RESULTS: Among 494 SARS-CoV-2 negative tested patients, OD was detected in 45.7% and was found to be significantly associated with the male gender (p < 0.001), higher age (p < 0.001), cardiovascular and pulmonary comorbidities (p < 0.001; p = 0.03). Among 90 COVID-19 positive patients, OD was found in 65.6% and was significantly associated with male gender and positive smoking status (p = 0.04 each). Prevalence and severity of OD were significantly increased in infections with the Delta variant (B.1.617.2) compared to those with the Omicron variant (BA.1.1.529). Diagnostic sensitivity and specificity of OD for diagnosis of SARS-CoV-2 infection were 69% and 64%, respectively. CONCLUSION: OD is common in COVID-19 negative and positive tested patients with significantly different prevalence rates observed between different variants. Diagnostic accuracy of OD is not high enough to implement olfactory testing as a tool in diagnostic routine to early identify patients with a SARS-CoV-2 infection.

Background Before performing endoscopy to remove prophylactic pancreatic stents placed in patients with high risk of post‐endoscopic retrograde cholangiopancreatography pancreatitis (PEP), X‐ray imaging is recommended to confirm the stents position in the pancreatic duct. Objectives The aim of the present study was to investigate the feasibility of prophylactic pancreatic stent detection by transabdominal ultrasonography, to reduce the burden of X‐ray imaging, which is currently the golden standard. Methods All patients who received a pancreatic stent for PEP prophylaxis were included in the present prospective trial. First, stent position was determined by transabdominal ultrasonography. Afterwards, it was verified by X‐ray imaging. Retained stents were removed by esophagogastroduodenoscopy. Dislocated stents needed no further intervention. Results Fourty‐one patients were enrolled in this study. All prophylactic pancreatic stents were straight 6 cm long 5 Fr stents with external flap. All stents were removed between day 1 and 10 (median: 3 days) in all cases. In 34 of 41 cases (83.0%), the pancreatic stent was still in place on the day of examination. Twenty‐nine of 34 (85.3%) stents were detected correctly by transabdominal ultrasonography. Overlying gas prevented visualization of the pancreas in 3/41 (7.3%) cases. Sensitivity of sonographic detection of the stent was 93.5% (29/31). Six of seven stents were determined correctly as dislocated by ultrasonography. Here, specificity was 85.7%. A positive predictive value of 96.7% (29/30) was examined. The negative predictive value was 75.0% (6/8). Conclusion Transabdominal ultrasonography detects the majority of prophylactic pancreatic stents. Thereby, it helps to identify patients with an indication for endoscopy sufficiently. X‐ray imaging could subsequently be omitted in about 70% of examinations, reducing the radiation exposure for the patient and the endoscopy staff.

Data on the long-term persistence of HCV resistance-associated substitutions (RASs) after treatment with direct-acting antivirals (DAAs) are limited. This study evaluated the persistence of NS3, NS5A, and NS5B RASs for up to 5 years after the end of treatment (EOT).We included samples from 678 individuals with an HCV genotype (GT) 1 or 3 infection and virologic DAA treatment failure collected in the European Resistance Database. NS3, NS5A, and NS5B were sequenced, and clinical parameters were evaluated.A total of 242 individuals with HCV GT1a (36%), 237 with GT1b (35%), and 199 (29%) with GT3 and a DAA failure were included. After protease inhibitor failure, the frequencies of NS3 RASs were 40-90% after the EOT. NS3 RASs disappeared rapidly in GT1b and GT3 after follow-up month 3 but were stable (≥60%) in GT1a owing to Q80K. The SOF-resistant NS5B RAS S282T was only found in individuals with GT3a. Non-nucleoside NS5B RASs were frequent in GT1 (56-80%) and decreased to 30% in GT1a but persisted in GT1b. NS5A RASs were very common in all GTs after NS5A inhibitor failure (88-95%), and even after follow-up month 24, their frequency was 65% and higher. However, RASs in GT1b had a stable course, whereas RASs in GT1a and GT3 declined slightly after follow-up month 24 (GT1a, 68%; GT1b, 95%; and GT3, 65%), mainly because of the slow decline of high-level resistant Y93H.We found that low-to medium-level RASs persisted, whereas high-level resistant RASs disappeared over time. Different patterns of RAS persistence according to HCV subtype could have implications for retreatment with first-generation DAAs and for global HCV elimination goals.There are little data on the long-term persistence of HCV resistance-associated substitutions (RASs) after DAA treatment failure, and RASs could have an impact on the efficacy of a rescue treatment. Especially in countries with limited availability of VOX/VEL/SOF or G/P/SOF, different patterns of RAS persistence could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. The different patterns of RAS persistence identified in this study can be used to derive general rules regarding the persistence of RASs after DAA failure that could be applied by physicians in less developed countries to plan individualized HCV retreatment.

The Q80K polymorphism in the NS3-4A protease of the hepatitis C virus is associated with treatment failure of direct-acting antiviral agents. This polymorphism is highly prevalent in genotype 1a infections and stably transmitted between hosts. Here, we investigated the underlying molecular mechanisms of evolutionarily conserved coevolving amino acids in NS3-Q80K and revealed potential implications of epistatic interactions in immune escape and variants persistence. Using purified protein, we characterized the impact of epistatic amino acid substitutions on the physicochemical properties and peptide cleavage kinetics of the NS3-Q80K protease. We found that Q80K destabilized the protease protein fold (p < 0.0001). Although NS3-Q80K showed reduced peptide substrate turnover (p < 0.0002), replicative fitness in an H77S.3 cell culture model of infection was not significantly inferior to the WT virus. Epistatic substitutions at residues 91 and 174 in NS3-Q80K stabilized the protein fold (p < 0.0001) and leveraged the WT protease stability. However, changes in protease stability inversely correlated with enzymatic activity. In infectious cell culture, these secondary substitutions were not associated with a gain of replicative fitness in NS3-Q80K variants. Using molecular dynamics, we observed that the total number of residue contacts in NS3-Q80K mutants correlated with protein folding stability. Changes in the number of contacts reflected the compensatory effect on protein folding instability by epistatic substitutions. In summary, epistatic substitutions in NS3-Q80K contribute to viral fitness by mechanisms not directly related to RNA replication. By compensating for protein-folding instability, epistatic interactions likely protect NS3-Q80K variants from immune cell recognition.

BACKGROUND: The use of an indwelling peritoneal catheter system in hospitalized patients with ascites could facilitate patient management by the prevention of repetitive abdominal paracentesis. Despite these possible benefits, the use of indwelling catheters is not widely established. OBJECTIVE: This retrospective study aimed to evaluate the feasibility, effectiveness and safety of the use of an indwelling catheter for ascites drainage in the clinical routine. METHODS: This retrospective study included all indwelling peritoneal catheter placements in our department in hospitalized patients with cirrhosis between 2014 and 2017. RESULTS: A total of 324 indwelling catheter placements for ascites in 192 hospitalized patients with cirrhosis were included. The catheter (7F, 8 cm) was placed ultrasound-assisted bed-side on the hospital ward. The technical success rate of the catheter placement was 99.7% (323/324). In 17.5% (64/324) the catheter was placed to optimize ascitic drainage prior to an abdominal intervention (e.g. transjugular intrahepatic portosystemic shunt). The median time of catheter retention was 48 hours (8–168 hours) and the median cumulative amount of drained ascites 8000 ml (550–28,000). The most common adverse event was acute kidney injury (49/324, 15.1%); the risk was particularly higher in patients with a Model for End-Stage Liver Disease (MELD) score ≥ 16 (p = 0.028; odds ratio 2.039). Ascitic fistula after catheter removal was observed in 9.6% (31/324). Catheter-related infections occurred in 4.3% (14/324), and bleeding was documented in three cases (0.8%) with one major bleeding (0.3%). CONCLUSION: The placement of an indwelling catheter for repetitive ascitic drainage in hospitalized patients with cirrhosis can be established in the clinical routine, facilitating patient management. High-MELD patients especially have to be monitored for acute kidney injury.

Objectives The risk of post-ERCP pancreatitis (PEP) can be reduced effectively by the placement of a self dislodging pancreatic stent. The present study analyzed whether a prolonged interval until stent passage evaluation and removal of retained stents is associated with an increased risk for clinically relevant complications. Methods In the retrospective study 182 patients receiving a pancreatic stent for PEP prophylaxis were included and clinical data and complications until documented spontaneous stent dislodgement or removal were analyzed. Results The main indication for ERCP was choledocholithiasis (40.1%) followed by malignant stenosis (30.8%). Stent passage evaluation was performed in 34.1% at day 1–4, 23.6% at day 5–10, 17.6% at day 11–28 and 24.7% at day >28. PEP occurred in 13.1% of patients with no case of severe PEP. No association between PEP and day of stent passage evaluation (p = 0.719), retention of the pancreatic stent at time of evaluation (0.867) or prolonged stent retention >10 days (0.234) was observed. Only the duration of the procedure was associated with risk for PEP (p = 0.037). Besides PEP only one clinically relevant complication was observed in the cohort (0.5%) which was a late possibly stent related pancreatitis at day 9 after the procedure that resolved completely. Conclusions A prolonged interval for stent passage evaluation and stent retention is not associated with an increase of clinically relevant complications. A later evaluation and extraction of retained stents might be acceptable in selected cases where an additional endoscopic procedure can be saved due to a planned follow-up endoscopy.

Liver cirrhosis is a systemic disease that substantially impacts the body's physiology, especially in advanced stages. Accordingly, the outcome of patients with cirrhosis requiring intensive care treatment is poor. We aimed to analyze the impact of cirrhosis on mortality of intensive care unit (ICU) patients compared to other frequent chronic diseases and conditions. In this retrospective study, patients admitted over three years to the ICU of the Department of Medicine of the University Hospital Frankfurt were included. Patients were matched for age, gender, pre-existing conditions, simplified acute physiology score (SAPS II), and therapeutic intervention scoring system (TISS). A total of 567 patients admitted to the ICU were included in the study; 99 (17.5 %) patients had liver cirrhosis. A total of 129 patients were included in the matched cohort for the sensitivity analysis. In-hospital mortality was higher in cirrhotic patients than non-cirrhotic patients (p 0.0001) in the entire and matched cohort. Liver cirrhosis remained one of the strongest independent predictors of in-hospital mortality (entire cohort p = 0.001; matched cohort p = 0.03) along with dialysis and need for transfusion in the multivariate logistic regression analysis. Furthermore, in the cirrhotic group, the need for kidney replacement therapy (p 0.001) and blood transfusion (p 0.001) was significantly higher than in the non-cirrhotic group. CONCLUSIONS: In the presented study, liver cirrhosis was one of the strongest predictors of in-hospital mortality in patients needing intensive care treatment along with dialysis and the need for ventilation. Therefore, concerted efforts are needed to improve cirrhotic patients' outcomes, prevent disease progression, and avoid complications with the need for ICU treatment in the early stages of the disease. Die Leberzirrhose ist eine systemische Erkrankung mit erheblichen Auswirkungen auf die Physiologie des Körpers, insbesondere in fortgeschrittenen Stadien. Dementsprechend schlecht ist das Outcome von Patienten mit Zirrhose in Abhängigkeit von der intensivmedizinischen Behandlung. Ziel unserer Studies war es, den Einfluss der Zirrhose auf die Mortalität von Patienten auf der Intensivstation (ICU) im Vergleich zu anderen häufigen chronischen Krankheiten und Zuständen zu analysieren. In diese retrospektive Studie wurden Patienten eingeschlossen, die in einem Zeitraum von drei Jahren auf der Intensivstation der Medizinischen Klinik des Universitätsklinikums Frankfurt aufgenommen wurden. Die Patienten wurden hinsichtlich Alter, Geschlecht, Vorerkrankungen, Simplified acute physiology score (SAPS II) und Therapeutic intervention scoring system (TISS) gematcht. Insgesamt wurden 567 Patienten, die auf der Intensivstation aufgenommen wurden, in die Studie aufgenommen; 99 (17,5 %) Patienten hatten eine Leberzirrhose. Für die Sensitivitätsanalyse wurden insgesamt 129 Patienten in die gematchte Kohorte aufgenommen. Die In-Hospital-Mortalität war bei zirrhotischen Patienten höher als bei nicht-zirrhotischen Patienten (p 0,0001) in der gesamten und gemachten Kohorte. Die Leberzirrhose blieb einer der stärksten unabhängigen Prädiktoren für die In-Hospital-Mortalität (gesamte Kohorte p = 0,001; gematchte Kohorte p = 0,03) zusammen mit Dialyse und Transfusionsbedarf in der multivariaten logistischen Regressionsanalyse. Darüber hinaus war in der zirrhotischen Gruppe der Bedarf an Nierenersatztherapie (p 0,001) und Bluttransfusion (p 0,001) signifikant höher als in der nicht zirrhotischen Gruppe. In der vorliegenden Studie war die Leberzirrhose einer der stärksten Prädiktoren für die In-Hospital-Mortalität bei Patienten, die eine intensivmedizinische Behandlung benötigten, zusammen mit Dialyse und Beatmungsbedarf. Daher sind konzertierte Anstrengungen erforderlich, um die Ergebnisse von zirrhotischen Patienten zu verbessern, ein Fortschreiten der Erkrankung zu verhindern und Komplikationen mit der Notwendigkeit einer intensivmedizinischen Behandlung bereits in den frühen Stadien der Erkrankung zu vermeiden.

Background: Chronic hepatitis C virus (HCV) infections are causally linked with metabolic comorbidities such as insulin resistance, hepatic steatosis, and dyslipidemia. However, the clinical impact of HCV eradication achieved by direct-acting antivirals (DAAs) on glucose and lipid homeostasis is still controversial. The study aimed to prospectively investigate whether antiviral therapy of HCV with DAAs alters glucose and lipid parameters. Methods: 50 patients with chronic HCV who were treated with DAAs were screened, and 49 were enrolled in the study. Biochemical and virological data, as well as noninvasive liver fibrosis parameters, were prospectively collected at baseline, at the end of treatment (EOT) and 12 and 24 weeks post-treatment. Results: 45 of 46 patients achieved sustained virologic response (SVR). The prevalence of insulin resistance (HOMA-IR) after HCV clearance was significantly lower, compared to baseline (5.3 &plusmn, 6.1 to 2.5 &plusmn, 1.9, p &lt, 0.001), which is primarily attributable to a significant decrease of fasting insulin levels (18.9 &plusmn, 17.3 to 11.7 &plusmn, 8.7, p = 0.002). In contrast to that, HCV eradication resulted in a significant increase in cholesterol levels (total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein (HDL-C) levels) and Controlled Attenuated Score (CAP), although BMI did not significantly change over time (p = 0.95). Moreover, HOMA-IR correlated significantly with noninvasive liver fibrosis measurements at baseline und during follow-up (TE: r = 0.45, p = 0.003, pSWE: r = 0.35, p = 0.02, APRI: r = 0.44, p = 0.003, FIB-4: r = 0.41, p &lt, 0.001). Conclusion: Viral eradication following DAA therapy may have beneficial effects on glucose homeostasis, whereas lipid profile seems to be worsened.

Hepatic hydrothorax (HH) is defined as transudate in the pleural cavity in patients with decompensated liver cirrhosis (DC) without concomitant cardiopulmonary or pleural disease. It is associated with high short-term mortality. HH can evolve via translocation through diaphragmatic gaps. The aim of this study was to evaluate the feasibility and safety of injecting ultrasound contrast medium into the peritoneal cavity to detect HH. This study included patients with concomitant ascites and pleural effusion who were admitted to our hospital between March 2009 and February 2019. A peritoneal catheter was inserted and ultrasound contrast medium was injected into the peritoneal cavity. In parallel, the peritoneal and pleural cavities were monitored for up to 10 minutes. Overall, 43 patients were included. The median age was 60 years and the majority of patients were male (n = 32, 74 %). Most patients presented with right-sided pleural effusion (n = 32, 74 %), 3 (7 %) patients with left-sided and 8 (19 %) patients had bilateral pleural effusion. In 12 (28 %) patients ascites puncture was not safe due to low volume ascites. Thus, the procedure could be performed in 31 (72 %) patients. No adverse events occurred. In 16 of 31 (52 %) patients we could visualize a trans-diaphragmic flow of microbubbles. The median time until transition was 120 seconds. Our clinical real-world experience supports the safety and feasibility of intraperitoneal ultrasound contrast medium application to detect HH in patients with DC, as a non-radioactive real-time visualization of HH. Our study comprises the largest cohort and longest experience using this method to date.ZIEL: Der hepatische Hydrothorax (HH) ist definiert als pleurales Transsudat in Patienten mit dekompensierter Leberzirrhose (DC) ohne begleitende kardiopulmonale oder pleurale Erkrankungen. Er geht mit einer hohen Sterblichkeitsrate einher. Der HH kann durch Flüssigkeitstranslokation durch diaphragmale Lücken entstehen. Ziel dieser Studie war es, die Durchführbarkeit und Sicherheit der intraperitonealen Ultraschallkontrastmittelinjektion zur Detektion eines HH zu evaluieren. Die Studie umfasste Patienten mit simultanem Aszites und Pleuraergüssen, die zwischen März 2009 und Februar 2019 in unserer Klinik stationär waren. Nach Anlage eines Peritonealkatheters erfolgte die Injektion von Ultraschallkontrastmittel in die Peritonealhöhle. Parallel wurden Peritoneal- und Pleurahöhlen für bis zu 10 Minuten gemonitort. Insgesamt wurden 43 Patienten eingeschlossen. Das Durchschnittsalter betrug 60 Jahre, wobei die Mehrheit der Patienten männlich war (n = 32, 74 %). Die meisten Patienten wiesen rechtsseitige Pleuraergüsse auf (n = 32, 74 %), 3 Patienten (7 %) linksseitige und 8 Patienten (19 %) hatten beidseitige Pleuraergüsse. In 12 Patienten (28 %) war eine Aszitespunktion aufgrund zu geringer Aszitesmengen nicht sicher. Die Prozedur wurde so in 31 Patienten (72 %) durchgeführt. Es ereigneten sich keinerlei unerwünschte Ereignisse. In 16 der 31 Patienten (52 %) konnte ein transdiaphragmaler Fluss von Mikrobubbles beobachtet werden. Die mediane Zeit bis zum Übertritt betrug 120 Sekunden. Unsere Real-World-klinischen Erfahrungen unterstützen die Sicherheit und Durchführbarkeit der intraperitonealen Ultraschallkontrastmittelapplikation zur Detektion des HH in Patienten mit DC als nichtradioaktive Echtzeit-Untersuchung. Wir berichten über die bisher größte Kohorte und die längsten Erfahrungen in der Anwendung dieser Methodik.

Inhibitors against the NS3-4A protease of hepatitis C virus (HCV) have proven to be useful drugs in the treatment of HCV infection. Although variants have been identified with mutations that confer resistance to these inhibitors, the mutations do not restore replicative fitness and no secondary mutations that rescue fitness have been found. To gain insight into the molecular mechanisms underlying the lack of fitness compensation, we screened known resistance mutations in infectious HCV cell culture with different genomic backgrounds. We observed that the Q41R mutation of NS3-4A efficiently rescues the replicative fitness in cell culture for virus variants containing mutations at NS3-Asp168. To understand how the Q41R mutation rescues activity, we performed protease activity assays complemented by molecular dynamics simulations, which showed that protease-peptide interactions far outside the targeted peptide cleavage sites mediate substrate recognition by NS3-4A and support protease cleavage kinetics. These interactions shed new light on the mechanisms by which NS3-4A cleaves its substrates, viral poly-proteins and a prime cellular antiviral adaptor protein, the mitochondrial antiviral signaling protein MAVS. Peptide binding is mediated by an extended hydrogen-bond network in NS3-4A that was effectively optimized for protease-MAVS binding in Asp168 variants with rescued replicative fitness from NS3-Q41R. In the protease harboring NS3-Q41R, the N-terminal cleavage products of MAVS retained high affinity to the active site, rendering the protease susceptible for potential product inhibition. Our findings reveal delicately balanced protease-peptide interactions in viral replication and immune escape that likely restrict the protease adaptive capability and narrow the virus evolutionary space. Fil: Dultz, Georg. Goethe Universitat Frankfurt; Alemania Fil: Shimakami, Tetsuro. Kanazawa University Hospital; Japón Fil: Schneider, Markus. Universitat Technical Zu Munich; Alemania Fil: Murai, Kazuhisa. Universitat Technical Zu Munich; Alemania Fil: Yamane, Daisuke. Tokyo Metropolitan Institute of Medical Science; Japón Fil: Marion, Antoine. Universitat Technical Zu Munich; Alemania Fil: Zeitler, Tobias M.. Universitat Technical Zu Munich; Alemania Fil: Stross, Claudia. Goethe Universitat Frankfurt; Alemania Fil: Grimm, Christian. Goethe Universitat Frankfurt; Alemania Fil: Richter, Rebecca M.. Goethe Universitat Frankfurt; Alemania Fil: Bäumer, Katrin. Goethe Universitat Frankfurt; Alemania Fil: Yi, MinKyung. Goethe Universitat Frankfurt; Alemania Fil: Biondi, Ricardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina Fil: Zeuzem, Stefan. Goethe Universitat Frankfurt; Alemania Fil: Tampé, Robert. Goethe Universitat Frankfurt; Alemania Fil: Antes, Iris. Universitat Technical Zu Munich; Alemania Fil: Lange, Christian M.. Goethe Universitat Frankfurt; Alemania Fil: Welsch, Christoph. Goethe Universitat Frankfurt; Alemania

Background and Aims: The aim of the study was to evaluate the risk of hepatocellular carcinoma (HCC) development after treatment with direct-acting antivirals (DAAs) and to compare HCC occurrence in these patients with that among patients treated with interferon (IFN)-based therapies. Methods: We analyzed a large cohort with chronic hepatitis C virus patients for the onset of new HCC after DAA treatment. A historical IFN-treated cohort was investigated for comparison. Results: A total of 819 patients were included in the DAA group. The median follow-up period was 263 days (0–1,001). Twenty-five patients (3.6 HCCs/100 person-years; 3.1%) were diagnosed with de novo HCC within the time of observation. No patient without cirrhosis had developed HCC. Patients with newly diagnosed HCC were mostly male, older, and treatment-experienced and had a lower 12-week sustained virologic response (SVR12) rate and higher levels of liver inflammation markers. The median time to HCC was 312 days (0–880). Investigation of the subcohort of 269 cirrhotic patients yielded an HCC rate of 8.9 HCCs/100 person-years. In this cohort, non-SVR12 was an independent risk factor for de novo HCC (HR 4.48; 95% CI 1.51–13.12; p = 0.007). Twenty-four patients (96%) with new HCC were Child-Pugh class A and 17 (68%) were diagnosed in early BCLC stage A. For the IFN-treated patients, we calculated an overall risk of HCC occurrence of 1.3/100 person-years (19 patients out of 351; 5.4%). The median time to diagnosis was 38.8 months (0–113). Conclusion: The de novo HCC rates did not differ between the DAA-treated patients and those who received IFN. Achievement of SVR is of utmost importance for HCC prevention.

Background Patients with chronic HCV infection are at increased risk of developing B-cell non-Hodgkin lymphoma (B-NHL). Regression of HCV-associated B-NHL (HCV-NHL) can be achieved through HCV eradication using interferon (IFN). However, only about two-thirds of patients with sustained virological response (SVR) also had a consecutive lymphoma response. miRNA-26b is associated with HCV-NHL response to antiviral therapy. Recent data suggest that IFN-free direct-acting antiviral (DAA) regimens also have anti-lymphoma activity in this patient population. Methods We report four patients with HCV-NHL who were treated with different IFN-free DAA regimens as oncological monotherapy in our centre between 2015 and 2016. We analysed the virological and lymphoproliferative disease response. Moreover, we analysed miRNA-26b expression in peripheral blood mononuclear cells at different time points during antiviral therapy for all included patients as well as for a total of 10 controls with ( n=5) and without ( n=5) chronic HCV infection. Results All patients had marginal zone lymphoma subtype and received different DAA regimens for 12–24 weeks. All four patients achieved SVR, but only three patients also had lymphoma response (one complete response, two partial responses). One patient showed progression to a high-grade lymphoma subtype after SVR. miRNA-26b expression was generally decreased in patients with HCV-NHL. Moreover, miRNA-26b expression was restored in those HCV-NHL patients with lymphoma response after 6 months ( P=0.009). Conclusions We have demonstrated that IFN-free DAA treatment of HCV can improve or even cure NHL. miRNA-26b-levels could be a potentially useful biomarker to predict lymphoma response in HCV-NHL patients.

Chronic hepatitis C virus (HCV) infection is a major public health burden in Europe, being one of the leading causes of chronic liver disease, liver cirrhosis, and hepatocellular carcinoma. Properties of the HCV disease burden are heterogeneous across the European continent, with differences in incidence, prevalence, diagnosis and treatment rates, transmission routes, and genotype distribution. Recent estimates expect an increase in HCV-related morbidity and mortality in most European countries until 2030 even when current treatment options are taken into account. The European perspective on hepatitis C virus infection is summarized herein.

Recent data highlighted the association of the macrophage activation marker CD163 with histological inflammation and fibrosis in chronic hepatitis C virus (HCV) infection. The aim of this study was to investigate the influence of successful antiviral treatment and IL28B genotypes on macrophage activation reflected by CD163 levels in HCV infected patients. In a retrospective cohort study, serum sCD163 levels were correlated with results of liver histopathology, IL28B genotyping and clinical parameters in 329 patients with HCV infection, 15 healthy controls and in 161 patients who achieved a sustained virologic response after antiviral treatment. sCD163 levels were significantly higher in patients with chronic HCV infection in comparison to healthy controls (5202 vs 896 ng/mL, P < 0.001). In the multivariate logistic regression analyses, sCD163 was independently associated with histologically determined inflammation (P = 0.043) but not with fibrosis (P = 0.091). sCD163 dropped significantly after successful antiviral treatment in comparison to baseline values (5202 vs 3093 ng/mL, P < 0.001). In the univariate analyses, sCD163 was significantly associated with IL28B genotype (C/C vs C/T+T/T) with higher values in the C/C group (6098 vs 4812 ng/mL, P = 0.003). In the multivariate logistic regression model, sCD163 levels were significantly associated with IL28B genotype (P = 0.003) and sustained virologic response (SVR) (P < 0.001). Our data support the association of activated liver macrophages with hepatic necroinflammation in chronic HCV infection as sCD163 levels drop rapidly after SVR. The irresponsiveness of IL28B minor genotypes to interferon might be related to a lower level of macrophage activation in these patients.

SummaryThe establishment of robust HCV cell culture systems and characterization of the viral life cycle provided the molecular basis for highly innovative, successful years in HCV drug development. With the identification of direct-acting antiviral agents (DAAs), such as NS3/4A protease inhibitors, NS5A replication complex inhibitors, nucleotide and non-nucleoside polymerase inhibitors, as well as host cell targeting agents, novel therapeutic strategies were established and competitively entered clinical testing. The first-in-class NS3/4A protease inhibitors telaprevir and boceprevir, approved in 2011, were recently outpaced by the pan-genotypic nucleotide polymerase inhibitor sofosbuvir that in combination with pegylated interferon and ribavirin, further shortens therapy durations and also offers the first interferon-free HCV treatment option. In the challenging race towards the goal of interferon-free HCV therapies, however, several oral DAA regimens without nucleotide polymerase inhibitors that combine a NS3/4A protease inhibitor, a NS5A inhibitor and/or a non-nucleoside polymerase inhibitor yielded competitive results. Second generation NS3/4A protease and NS5A inhibitors promise an improved genotypic coverage and a high resistance barrier. Results of novel DAA combination therapies without the backbone of a nucleotide polymerase inhibitor, as well as treatment strategies involving host targeting agents are reviewed herein.

Soluble CD163 (sCD163), a marker for macrophage activation, was found to be associated with the severity of liver cirrhosis. The aim of the current study was to investigate whether serum sCD163 levels correlate with liver inflammation and fibrosis in patients with chronic hepatitis B virus (HBV) infection. In a retrospective cohort study, serum sCD163 levels were assessed by ELISA together with clinical and laboratory data in 186 patients with chronic HBV infection and 15 healthy controls. The relation between parameters for liver fibrosis and necroinflammation and sCD163 levels was analysed. Additionally, sCD163 was quantified in a subset of follow-up serum samples after initiation of antiviral treatment. sCD163 levels differed among phases of chronic HBV infection (P < 0.0001), and sCD163 concentrations were associated with inflammatory activity and fibrosis in the liver. sCD163 levels ≥ 1961 ng/l had a high specificity in the identification of subjects with substantial fibrosis (F ≥ 2). sCD163 concentrations decreased significantly after initiation of antiviral treatment. The correlation of sCD163 levels with necroinflammation and fibrosis and the sCD163 decline under treatment indicates that macrophage activation plays a role in HBV-related liver pathogenesis.

Hepatitis C virus (HCV) substantially affects lipid metabolism, and remodeling of sphingolipids appears to be essential for HCV persistence in vitro. The aim of the current study is the evaluation of serum sphingolipid variations during acute HCV infection. We enrolled prospectively 60 consecutive patients with acute HCV infection, most of them already infected with human immunodeficiency virus (HIV), and serum was collected at the time of diagnosis and longitudinally over a six-month period until initiation of antiviral therapy or confirmed spontaneous clearance. Quantification of serum sphingolipids was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Spontaneous clearance was observed in 11 out of 60 patients (18.3%), a sustained viral response (SVR) in 43 out of 45 patients (95.5%) receiving an antiviral treatment after follow-up, whereas persistence of HCV occurred in six out of 60 patients (10%). C24-ceramide (C24-Cer)-levels increased at follow-up in patients with spontaneous HCV eradication (p < 0.01), as compared to baseline. Sphingosine and sphinganine values were significantly upregulated in patients unable to clear HCV over time compared to patients with spontaneous clearance of HCV infection on follow-up (p = 0.013 and 0.006, respectively). In summary, the persistence of HCV after acute infection induces a downregulation of C24Cer and a simultaneous elevation of serum sphingosine and sphinganine concentrations.

Chronic hepatitis C virus (HCV) infection is a major public health burden in Europe, being one of the leading causes of chronic liver disease, liver cirrhosis, and hepatocellular carcinoma. Properties of the HCV disease burden are heterogeneous across the European continent, with differences in incidence, prevalence, diagnosis and treatment rates, transmission routes, and genotype distribution. Recent estimates expect an increase in HCV-related morbidity and mortality in most European countries until 2030 even when current treatment options are taken into account. The European perspective on hepatitis C virus infection is summarized herein.

Background & Aims: Thrombopoietin receptor agonists are a new class of compounds licenced for the treatment of immune thrombocytopenic purpura. They are currently being studied for patients with thrombopenia in advanced liver disease or under therapy for hepatitis C. There are indications that the risk for development of portal vein thrombosis in patients with advanced liver cirrhosis might be increased under therapy with thrombopoietin receptor agonists. We report a case of a patient with Child class B liver cirrhosis with concurrent immune thrombocytopenic purpura that developed portal vein thrombosis under therapy with the thrombopoietin receptor agonist romiplostim. Methods: A 50-year-old woman with hepatitis C virus associated immune thrombocytopenic purpura and Child class B liver cirrhosis presented in our emergency with rapidly evolving hydropic decompensation and general malaise. For immune thrombocytopenic purpura, the patient was started on the thrombopoietin receptor agonist romiplostim nine months ago. Results: During hospitalization, the platelet count was measured above 330,000/ll and partial portal vein thrombosis was diagnosed by imaging studies. The thrombotic event was assumed to be associated with the romiplostim treatment for immune thrombocytopenic purpura via excessive elevation of platelet count. After anticoagulation with heparin and cessation of romiplostim treatment, complete recanalisation of the portal vein was achieved. Conclusions: We conclude that romiplostim should be used with precaution in patients with hepatitis C-associated immune thrombocytopenic purpura and advanced liver cirrhosis as the risk for thrombotic complications may increase significantly. 2011 European Association for the Study of the Liver. Published

356 Background: The aim of the study was to evaluate the risk of HCC development after treatment with direct-acting antivirals (DAA) and to compare hepatocellular carcinoma (HCC) occurrence to patients treated with interferon (IFN)-based therapies. Methods: We analyzed a large cohort with chronic HCV patients for the onset of new hepatocellular carcinoma after DAA treatment. A historic interferon treated cohort was investigated for comparison. Results: 819 patients were included in the DAA group, 269 (32.8%) had established cirrhosis. Median follow up was 263 days (0-1001). 25 patients (3.1%) were diagnosed with de novo HCC within the observation time. All of these patients had established cirrhosis. Patients with new HCC were mostly male, older, treatment experienced, had a lower SVR12 rate and higher levels of liver inflammation markers. Investigation of the subcohort of 269 cirrhotic patients yielded a HCC rate of 9.3% during the follow-up of approximately one year. Non-SVR12 was an independent risk factor for de novo HCC (OR 4.983, 1.39-17.88, 0.014). Most HCCs were diagnosed in early stage BCLC A. In the historical cohort of 351 IFN treated patients the rate of de novo HCC was 5.4% overall and 11.8% in patients with already established cirrhosis (n = 68). In the multivariate analysis failed SVR (OR 5.386, 1.155-25.108, p = 0.032) remained an independent risk factor for de novo HCC. In a combined analysis of all patients (DAA and IFN treated) in a multivariate approach male gender, failed SVR and cirrhosis were independent factors for HCC development. Conclusions: DAA treatment in cirrhotic patients does not seem to reduce the risk of HCC development in the short term. HCC rates were not different between DAA-treated patients and those who received interferon. Achievement of SVR seems to be the most important aim to prevent HCC development.

Die autoimmunen Schilddrusenerkrankungen mit den Hauptvertretern Morbus Basedow und Hashimoto-Thyreoiditis gehoren zu den haufigsten Autoimmunerkrankungen uberhaupt. Genetische Faktoren spielen eine entscheidende Rolle in der Atiologie dieser Erkrankungen, und in den letzten Jahren konnten mehrere Risikogene identifiziert werden. Dabei handelt es sich einerseits um immunregulatorische Gene wie Gene der HLA-Klasse II, das CTLA-4-Gen und das PTPN22-Gen und andererseits um schilddrusenspezifische Gene fur den TSH-Rezeptor und das Thyreoglobulin. Obwohl dies zu einem besseren Verstandnis der Pathogenese der autoimmunen Schilddrusenerkrankungen gefuhrt hat, wurde die klinische Relevanz der neuen Erkenntnisse bislang nur unzureichend diskutiert. Deshalb gibt diese Ubersicht ein Update der relevanten Risikogene fur die Autoimmunitat der Schilddruse und diskutiert ihre Bedeutung fur die klinische Arbeit.

SummaryBackground Proton pump inhibitors (PPI) are widely used in patients with liver diseases. Within the last years, there have been concerns about the PPI use as they may promote infections in patients with cirrhosis. Aim As there are sparse data of the prognostic relevance of PPI treatment, to perform a prospective study investigating the relation of PPI treatment and overall survival (OS) in cirrhotic individuals. Methods Patients with cirrhosis were enrolled and followed prospectively. The primary end point was OS. PPI treatment and additional clinical and laboratory data were assessed at the day of the study inclusion. The time until the end point death was assessed and the individual risks were calculated with Cox regression analyses. Results A total of 272 patients were included and 213 individuals (78.3%) were on PPI treatment. In multivariate logistic regression analysis, PPI treatment was associated with higher MELD scores (P = 0.027) and ascites (P = 0.039). In a multivariate Cox regression model, PPI use was an independent predictor of mortality (hazard ratio 2.330, 95% confidence interval 1.264–4.296, P = 0.007) in addition to the model of end-stage liver disease (MELD) score, hepatocellular carcinoma and hepatic decompensation. Conclusions PPI use is an independent risk factor for mortality in patients with cirrhosis. Although a causative role for increased mortality in patients taking PPI is still missing, the prescription of PPI in cirrhotics should be considered carefully taking into account its potential adverse effects.

Antiviral therapy can stop progression of liver fibrosis and partially reverse it. Non-invasive methods have shown good diagnostic accuracies for the assessment of liver fibrosis. First studies have shown that transient elastography (TE) can be used to monitor fibrosis after antiviral therapy. Acoustic-Radiation-Force-Impulse (ARFI)-Imaging is an elastography method integrated in a conventional ultrasound machine. The aim of the present study was to demonstrate a significant difference of ARFI-values in patients with sustained-virological-response (SVR) as compared to patients without.Ninety-eight patients infected with chronic hepatitis C virus (HCV) who had completed antiviral treatment were prospectively included in the study and received ARFI-imaging, TE and laboratory evaluation.Significantly lower ARFI and TE values were observed for 47 patients with SVR as compared to 51 patients without SVR (1.37 m/s vs. 2.00,p=0.0021; 4.9 kPa vs. 11.1 kPa,p0.001), respectively.Liver stiffness values and shear wave velocity using ultrasound-based elastography methods are different in patients with SVR as compared to patients without SVR after antiviral therapy for chronic hepatitis C. However, the causes of this difference (fibrosis regression, cytolysis, baseline fibrosis) remain unclear and require further evaluation in future studies.

The autoimmune thyroid diseases with the main phenotypes Graves' disease and Hashimoto's thyroiditis belong to the most frequently occurring autoimmune diseases. Genetic factors play a major role in their etiology, and in the past a couple of susceptibility genes have been identified. These are immunoregulatory genes like the HLA class II genes, the CTLA-4 gene and the PTPN22 gene and thyroid-specific genes for the TSH receptor and thyroglobulin. Even though this knowledge contributed to a better understanding of the pathogenesis of the autoimmune thyroid diseases, up to now the clinical relevance has been discussed insufficiently. Hence, this review provides an update of all relevant susceptibility genes for thyroid autoimmunity and discusses their significance for the clinical work.

The lymphoid tyrosine phosphatase (LYP) encoded by the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene is a strong inhibitor of T cells. The single nucleotide polymorphism (SNP) C1858T within the PTPN22 gene was recently associated with autoimmune thyroid disease (AITD) and type I diabetes (T1D). The purpose of this study was to examine the joint association of this polymorphism with the co-occurrence of AITD and T1D.In this association study, 310 white subjects were genotyped for the C1858T polymorphism. The study population included 70 patients with both AITD and T1D (AITD+T1D), 70 patients with AITD only, 70 patients with T1D only, and 100 healthy controls. Patients with both AITD and T1D, and controls were also typed for HLA-DRB1. PTPN22 C1858T genotyping was performed by minisequencing. For HLA-DRB1 typing, polymerase chain reaction (PCR) sequence-specific oligonucleotide probes were used.The PTPN22 1858 minor T-allele frequency was strongly increased in patients with AITD+T1D (23.6%) compared with controls (8.0%, pc0.001), with patients with AITD only (8.6%, pc=0.006), or with T1D only (10.7%, pc=0.028). T-allele carriers were also more frequently present in the group with AITD+T1D versus controls (41.4% vs. 14.0%, OR=4.35, 95% CI=2.08-9.09), AITD (17.1%, OR=3.42, 95% CI=1.56-7.48), and T1D (21.4%, OR=2.59, 95% CI=1.23-5.45). Especially in subjects with Hashimoto's thyroiditis (HT)+T1D, T-allele carriers were mostly frequent (50% vs. 14%, OR=6.14, 95% CI=2.62-14.38, pc0.001). Considering all included patients with AITD, T-allele carriers were 29.3% vs. 14.0% in controls (p=0.008, OR=2.54, 95% CI=1.30-4.98). Patients carrying the PTPN22 1858 T allele had a twofold increased frequency of the HLA-DRB1*03 allele (64.7% vs. 37.3%, pc=0.034).The PTPN22 gene is a joint susceptibility locus for AITD (especially HT) and T1D.

P0188 HEPATOPULMONARY SYNDROME. PREVALENCE, ASSOCIATED FACTORS AND IMPACT IN SURVIVAL AFTER LIVER TRANSPLANTATION E. Duenas, R. Rota, J. Ribas, A. Ruiz-Mayoral, M.E. Gonzalez, A. Amador, C. Baliellas, J. Fabregat, X. Xiol, J. Castellote. Hepatology and Liver Transplant Unit. Gastroenterology Department, Pneumology Department, Cardiology Department, Hepatology and Liver Transplant Unit. Digestive Surgery Department, Hospital Universitari de Bellvitge – IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain E-mail: eduenas@bellvitgehospital.cat

As mentioned by Lin and Dong patients taking PPIwere sicker, indicated by higher MELD and Child Pughscores, and are therefore considered to have a worseprognosis. However, there is little evidence whether PPIuse might be an additional risk factor for overall mortal-ity in cirrhotics in addition to well established prognosticparameters such as the MELD score or occurrence ofcomplication of cirrhosis. To consider the disease stage,MELD score and Child Pugh score were included in themultivariate analysis and PPI-usage turned out to be anindependent predictive factor for mortality.The lack of data concerning the relation of PPI use tooverall survival was the rationale for conducting thisstudy. We acknowledge the suggestions of Lin and Dong,and included additional parameters in the multivariateanalysis. We added hepatorenal syndrome (HRS), spon-taneous bacterial peritonitis (SBP) and the indication forPPI use (acute bleeding episode, reflux disease or currentvariceal band ligation) in the multivariate analysis.However, we did not have data concerning the durationof PPI treatment or about antibiotic regimens used inthe patients.In the extended analysis SBP [hazard ratio (HR)2.105, 95% confidence interval (CI), 1.107–4.002,P = 0.023], PPI use (HR 1.926, 95% CI 1.010–3.675,P = 0.047), hepatocellular carcinoma (HCC; HR 5.117,95% CI 2.948–8.884, P < 0.001), MELD score (HR 1.111,95% CI 1.069–1.154, P < 0.001), hepatic decompensation(HR 1.865, 95% CI 1.009–3.448, P = 0.047) and indica-tion for PPI use (HR 1.867, 95% CI 1.166–2.990,P = 0.009) were independent prognostic parameters. Linand Dong proposed to exclude patients with short obser-vation times. We consider it inappropriate to excludepatients who fulfil inclusion criteria which may bias theresults of studies. Furthermore, the relation of risk andobservation time is valued in Cox survival models. Over-all survival was the primary objective of the study. Wedo not have complete follow-up data concerning bleed-ing events in patients according to their PPI use at theday of study inclusion.There are two central results of our study which areevident and should be emphasised once more. First, PPIuse was common among our cirrhotic patients, withmany patients taking PPI without an evidence-basedindication. Second, PPI use was associated with a higherrisk of death, independent from severity of liver diseaseand hepatic complications, which is evident and con-firmed by multivariate Cox regression analysis. However,although PPI use was a risk factor for death, HCC andMELD were stronger predictors of prognosis.Although Lin and Dong might have the impressionthat we claimed PPI use was the main risk factor formortality, we can only state that use of PPI was some-how associated with a higher risk of death. We cannotdraw further causative conclusions from a monocentricobservational study. PPI use comes along with anincreased risk of death. Whether the higher risk of deathcan be attributed to PPI therapy, or whether it is an epi-phenomenon, needs to be clarified by further studies.Nonetheless, PPIs should be prescribed cautiously inpatients with cirrhosis, and the indication for a PPIshould be verified repeatedly in those on long-term treat-ment.ACKNOWLEDGEMENTThe authors’ declarations of personal and financial inter-ests are unchanged from those in the original article.

Background and Aims: In patients with advanced liver cirrhosis due to chronic hepatitis C virus (HCV) infection antiviral therapy with peginterferon and ribavirin is feasible in selected cases only due to potentially life-threatening side effects. However, predictive factors associated with hepatic decompensation during antiviral therapy are poorly defined. Methods: In a retrospective cohort study, 68 patients with HCV-associated liver cirrhosis (mean MELD score 9.18±2.72) were treated with peginterferon and ribavirin. Clinical events indicating hepatic decompensation (onset of ascites, hepatic encephalopathy, upper gastrointestinal bleeding, hospitalization) as well as laboratory data were recorded at baseline and during a follow up period of 72 weeks after initiation of antiviral therapy. To monitor long term sequelae of end stage liver disease an extended follow up for HCC development, transplantation and death was applied (240weeks, ±SD 136weeks). Results: Eighteen patients (26.5%) achieved a sustained virologic response. During the observational period a hepatic decompensation was observed in 36.8%. Patients with hepatic decompensation had higher MELD scores (10.84 vs. 8.23, p14, respectively. Baseline MELD score was significantly associated with the risk for transplantation/death (p