Longterm Outcome of Therapeutic Vaccination with a Third Generation Pre-S/S HBV Vaccine (PreHevbrioR) of Chronically HBV Infected Patients.

Several antiviral treatment regimens for chronic hepatitis B (CHB) virus infection have been shown to be effective in suppressing viral load and reducing the risk of hepatocellular injury and its complications. It has been hypothesized that high levels of circulating HBV surface antigen(s) may lead to immune tolerance against HBV and contribute to chronic carriership. Conversely, low-level HBsAg may create a window for the reconstitution of an HBV-specific immune response through vaccination and control of infection. Previous studies in non-responders to yeast-derived HBV vaccines, using a third-generation pre-S/S vaccine, have led to up to 95% anti-HBs seroconversion. This report evaluates the long-term outcome after experimental vaccination with a pre-S/S HBV vaccine intended as a therapeutic intervention in chronic HBV carriers. Four low-level HBsAg carriers (<500 IU/mL) were vaccinated three to seven times with 20 µg PreHevbrioR. Three out of four carriers eliminated HBsAg completely and seroconverted to anti-HBs. One patient seroconverted to anti-HBs but remained with a borderline HBsAg titer (10 IU/mL). Serum anti-HBs levels following repeated vaccination varied between 27 and >1000 IU/L, respectively. Long-term observation (>6 years) showed that after discontinuing NUC treatment for at least two years, HBsAg and HBV DNA remained negative with anti-HBs positive titers ranging between 80 and >1000 IU/L. Based on our preliminary observations, there is a rationale to further evaluate the role of this vaccine as a therapeutic agent.

Factors Positively Correlated with Hepatitis B Surface Antigen Seroconversion in Chronic Hepatitis B.

BACKGROUND AND AIMS: Chronic hepatitis B virus (HBV) infection is a global public health challenge since more than 250 million individuals are affected worldwide. Since different treatment modalities are available and not all patients are candidates for antiviral treatment, biomarkers that potentially predict the possibility of HBsAg clearance and seroconversion may be useful in clinical practice. PATIENTS AND METHODS: In this retrospective study, we aimed to identify factors positively correlated with HBsAg seroconversion in a large cohort of 371 chronic hepatitis B patients treated at a German tertial center between 2005 and 2020. RESULTS: Seroconversion occurred in 25/371 (6.7%) and HBsAg loss in 29/371 patients (7.8%) with chronic HBV infection. Antiviral therapy was associated with a lower chance of seroconversion (seroconversion antiviral therapy 14/260 (5.4%) vs. therapy-naïve patients 11/111 (9.9%), p = 0.027). Seroconversion rates were higher in patients with (very) low titers of HBV DNA (best cut-off value 357 IU/mL) and quantitative HBsAg. The best cut-off value with regard to seroconversion was 357 IU/mL for HBV DNA (AUC 0.693 (95%-CI 0.063-0.422), sensitivity 0.714, specificity 0.729; p < 0.0005) and 33,55 IU/mL for HBsAg (AUC 0.794 (95%-CI 0.651-0.937), sensitivity 0.714, specificity 0.949; p < 0.0005). However, male gender was positively associated with seroconversion (seroconversion: males 7.6% vs. females 2.7%, p = 0.036). CONCLUSIONS: Treatment-naïve male chronic HBV patients with low viral load and inflammatory activity have the best chance to achieve seroconversion. In the absence of cirrhosis, antiviral therapy should therefore not be performed in this patient collective.

Prevention in Hepatology.

The prevention of liver disease has improved significantly in the last few decades, to the point that it can now be considered a true success story. The wide variety of interventions, including comprehensive vaccination strategies, novel medications, lifestyle changes, and even preventive surgeries, have reduced the morbidity and mortality of chronic liver diseases. However, the prevalence of chronic liver diseases is increasing worldwide. Currently, fatty liver disease alone is estimated to be present in as much as 30% of the adult population. Furthermore, there is a trend towards increasing incidences of chronic hepatitis B, and a global lack of success in efforts to eliminate chronic hepatitis C. Thus, improving and efficiently rolling out existing and successful prevention strategies for chronic liver diseases will play an essential role in healthcare throughout the upcoming decades. In this review, we summarize the current options and concepts for preventing chronic liver diseases, highlight their limitations, and provide an outlook on probable future developments to improve awareness, integrated care, and the analysis of big data.

Characteristics and Long-Term Outcome of 535 Patients with Autoimmune Hepatitis-The 20-Year Experience of a High-Volume Tertiary Center.

Background and aims: Autoimmune hepatitis (AIH) is a complex and progressive inflammatory liver disease characterized by immune-mediated destruction of the liver parenchyma, hypergammaglobulinemia, the presence of circulating autoantibodies, and good response to immunosuppressive therapy. Since the prevalence of AIH is relatively rare, data on the clinical course and the long-term outcome are scarce. Patients and methods: We retrospectively analyzed the data of 535 well-documented AIH patients treated at the University Hospital Essen between 2000 and 2020. Results: The majority of patients were middle-aged females (75% women, mean age 45 years) with AIH type 1 (97%). Approximately 32% of patients were diagnosed with cirrhosis due to AIH, 29% had concomitant autoimmune (predominantly autoimmune thyroiditis), and 10% had psychiatric diseases, respectively. Skin tumors were the most common malignant diseases (47% of all tumors), while hepatocellular carcinoma rarely occurred (only six cases). Overall long-term mortality and liver-associated mortality were 9.16% and 4.67%, respectively. However, long-term survival was strongly associated with disease remission. Conclusions: Although AIH is a silent disease and cirrhosis is present in many cases, a favorable long-term prognosis can be achieved by consequent immunosuppressive therapy. The incidence of (liver-associated) complications seems to be lower in comparison to other etiologies, such as viral hepatitis or NASH, and mainly depends on the long-term side effects of immunosuppressive therapy.

The tolerability of sofosbuvir/velpatasvir for 12 weeks in patients treated in the ASTRAL 1, 2 and 3 studies: A pooled safety analysis.

To evaluate the safety and tolerability of the fixed-dose, single-tablet regimen sofosbuvir/velpatasvir (SOF/VEL) for the treatment of hepatitis C virus (HCV) infection in three Phase 3 studies in patients with and without compensated cirrhosis. Data from three registrational trials (ASTRAL-1, NCT02201940; ASTRAL-2, NCT02220998; ASTRAL-3, NCT02201953) were pooled by treatment regimen. Researchers assessed treatment-emergent adverse events (TEAEs) and laboratory abnormalities in patients randomized to SOF/VEL or placebo for 12 weeks in ASTRAL-1 and SOF/VEL for 12 weeks in ASTRAL-2 and ASTRAL-3. Overall, 1035 patients were treated with SOF/VEL, and 116 patients received placebo. Rates of any TEAE were generally similar between patients receiving SOF/VEL (79.4%) and those receiving placebo (76.7%). The majority of TEAEs were mild to moderate, with 23 (2.2%) treatment-emergent serious AEs in patients treated with SOF/VEL. Of these treatment-emergent serious AEs, none led to premature study discontinuation, nor were they considered related to treatment. Presence of compensated cirrhosis, greater age and mild renal impairment did not impact incidence or severity of TEAEs with SOF/VEL treatment. The most common TEAEs (incidence ≥10%) were headache, fatigue, nausea and nasopharyngitis in patients receiving SOF/VEL; similar rates were observed in placebo-treated patients. Three deaths (<1%) were reported in patients treated with SOF/VEL, all posttreatment and none assessed as related to study treatment. Similar to that of placebo, SOF/VEL treatment of HCV infection had a safety/tolerability profile that was not affected by baseline factors, such as the presence of compensated cirrhosis, mild renal impairment or advanced age.

[Health economic evaluation of an internal medicine intermediate care unit (IMC) with gastroenterological focus at a maximum care university hospital - Evaluating the Profitability of Intermediate Care (IMC) in modern University Hospital Gastroenterology]. / Gesundheitsökonomische Bewertung einer internistischen Intermediate Care (IMC)-Station mit gastroenterologischem Schwerpunkt an einem universitären Klinikum der medizinischen Maximalversorgung ­ Wertung der Rentabilität einer Intermediate Care (IMC)-Station für die moderne universitäre Gastroenterologie.

Intermediate care (IMC) units meet the complex treatment needs of patients with specific diseases and/or those requiring advanced nursing care and can help turning the occupancy management of intensive care unit (ICU) beds more efficient. Despite the exclusion of nursing staff costs from the Diagnosis-Related-Groups (DRG) reimbursement system, prolonged periods of below-average monthly revenues due to loss of complex DRGs and/or misallocation/blocking of IMC beds can lead to a fixed cost refinancing problem; this again brings to the fore the question of the profitability of an IMC unit. Thus, the aim of this work has been to evaluate the profitability of a gastroenterological IMC, as part of an interdisciplinary medical IMC (MIMC) at the University Hospital Essen, for the period 01.01.2014-31.12.2016. Retrospectively, 1015 cases of the MIMC ward of the Department of Gastroenterology and Hepatology (Med.G./MIMC; N=12 beds) were examined with regard to length of stay (LoS), admission/main diagnosis, procedures provided as well as secondary diagnoses, revenues, age, and sex (median patient age 57 years; ♂ 61%, ♀ 39%). Overall, 85% of DRG reimbursements comes from treatment cases within the top 20 base DRGs; these highlight the hepatology focus of Med.G./MIMC. The case-mix (CM) monthly average is 65; the CM index (CMI), which has significant seasonal variation (analogous to CM), monthly average is 10.891 (2014-2016). The average LoS on the Med.G./MIMC is 12.3 days, which is significantly higher than the average LoS in German hospitals (7.2 days). Concrete economic assessment of Med.G./MIMC reveals that the inpatient revenues increase from € 2.90 million to € 3.72 million (2014-2016). Thus, there is a positive development of primary revenues from € 2.98 million (2014) to € 3.56 million (2015) to € 3.81 million (2016), with largely constant expenses in the area of primary costs and of claimed secondary services. Empirically, taking into account the potential interdisciplinary synergy effects, this can be considered as an exceptionally good health economic development/outcome.

Performance of the Liver Maximum Function Capacity Test, Fibrinogen, and Transient Elastography in Patients with Acute Liver Injury.

BACKGROUND: Acute liver failure (ALF) occurs as a rare, sudden, extensive loss of liver function in a previously healthy liver. In advanced cases, ALF may require liver transplantation (LT). Available prognostic parameters have limited accuracy to decide, which patient to consider for LT. The liver maximum function capacity test (LiMAx) can accurately determine liver function and was assessed as predictor of survival, along with coagulation parameters and liver stiffness in nonacetaminophen-induced ALF. METHODS: Various liver function tests, including LiMAx measurements, coagulation factors, and transient elastography (TE), were analyzed retrospectively for associations with clinical outcome in 34 patients with ALF or acute hepatitis (AH). Data were compared between patients with spontaneous recovery (SR) and non-SR (3-month mortality/LT; NSR). RESULTS: The analysis included 34 patients (22 ALF, 12 AH; 19 males, 15 females; age 36.7 ± 14.6 years) with drug-induced liver injury (DILI) (n = 12), autoimmune hepatitis (AIH; n = 13), AIH-DILI overlap (n = 1), viral (n = 9), or cryptogenic liver failure (n = 1). Thirty-one patients recovered spontaneously, 2 patients died, and 1 patient underwent LT. The LiMAx was 197.6 (±68.4) for SR versus 92.33 (±65.0) for NSR (p = 0.0157). Fibrinogen was significantly lower in patients with NSR than in SR patients (209.0 vs. 106.3; p = 0.02). Mean liver stiffness measured by TE was 39.3 for NSR and 17.3 for SR (p = 0.26). KCC was fulfilled in only 4 patients (3 SR, 1 NSR). LiMAx results correlated positively with serum fibrinogen and antithrombin III concentrations and correlated negatively with liver stiffness. No other analyzed factor could differentiate between SR and NSR. CONCLUSION: Decision-making in ALF remains challenging. LiMAx and fibrinogen might predict the prognosis in patients with nonacetaminophen-induced ALF and in combination could be feasible tools to decide if LT is necessary.

Liver Function-How to Screen and to Diagnose: Insights from Personal Experiences, Controlled Clinical Studies and Future Perspectives.

Acute and chronic liver disease is a relevant problem worldwide. Liver function plays a crucial role in the course of liver diseases not only in estimating prognosis but also with regard to therapeutic interventions. Within this review, we discuss and evaluate different tools from screening to diagnosis and give insights from personal experiences, controlled clinical studies and future perspectives. Finally, we offer our novel diagnostic algorithm to screen patients with presumptive acute or chronic liver disease in the daily clinical routine.

LiMAx Prior to Radioembolization for Hepatocellular Carcinoma as an Additional Tool for Patient Selection in Patients with Liver Cirrhosis.

BACKGROUND AND AIMS: Radioembolization (RE) has recently demonstrated a non-inferior survival outcome compared to systemic therapy for advanced hepatocellular carcinoma (HCC). Therefore, current guidelines recommend RE for patients with advanced HCC and preserved liver function who are unsuitable for transarterial chemoembolization (TACE) or systemic therapy. However, despite the excellent safety profile of RE, post-therapeutic hepatic decompensation remains a serious complication that is difficult to predicted by standard laboratory liver function parameters or imaging modalities. LiMAx® is a non-invasive test for liver function assessment, measuring the maximum metabolic capacity for 13C-Methacetin by the liver-specific enzyme CYP 450 1A2. Our study investigates the potential of LiMAx® for predicting post-interventional decompensation of liver function. PATIENTS AND METHODS: In total, 50 patients with HCC with or without liver cirrhosis and not amenable to TACE or systemic treatments were included in the study. For patients prospectively enrolled in our study, LiMAx® was carried out one day before RE (baseline) and 28 and 90 days after RE. Established liver function parameters were assessed at baseline, day 28, and day 90 after RE. The relationship between baseline LiMAx® and pre-and post-interventional liver function parameters, as well as the ability of LiMAx® to predict hepatic decompensation, were analyzed. RESULTS: We observed a strong association between baseline LiMAx® and bilirubin, albumin, ALBI grade, and MELD score. Patients presenting with Child-Pugh score B 28 days after RE or with a deterioration in Child-Pugh score by at least one point had a significantly lower baseline LiMAx® compared to those with Child-Pugh score A or with stable Child-Pugh score. The ability of LiMAx® to predict hepatic decompensation after RE was determined using ROC curve analysis and was compared to MELD score and ALBI grade. LiMAx® achieved a substantial AUC of 0.8117, comparable to MELD score and ALBI grade. CONCLUSION: Patients with lower LiMAx® values at baseline have a significantly increased risk for hepatic decompensation after RE, despite being categorized as Child-Pugh A. Therefore, LiMAx® can be used as an additional tool to identify patients at high risk of post-interventional hepatic failure.

A Potential Role for Bile Acid Signaling in Celiac Disease-Associated Fatty Liver.

Celiac disease (CeD) is a chronic autoimmune disorder characterized by an intolerance to storage proteins of many grains. CeD is frequently associated with liver damage and steatosis. Bile acid (BA) signaling has been identified as an important mediator in gut-liver interaction and the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here, we aimed to analyze BA signaling and liver injury in CeD patients. Therefore, we analyzed data of 20 CeD patients on a gluten-free diet compared to 20 healthy controls (HC). We furthermore analyzed transaminase levels, markers of cell death, BA, and fatty acid metabolism. Hepatic steatosis was determined via transient elastography, by MRI and non-invasive scores. In CeD, we observed an increase of the apoptosis marker M30 and more hepatic steatosis as compared to HC. Fibroblast growth factor 19 (FGF19) was repressed in CeD, while low levels were associated with steatosis, especially in patients with high levels of anti-tissue transglutaminase antibodies (anti-tTG). When comparing anti-tTG-positive CeD patients to individuals without detectable anti-tTG levels, hepatic steatosis was accentuated. CeD patients with significant sonographic steatosis (defined by CAP ≥ 283 db/m) were exclusively anti-tTG-positive. In summary, our results suggest that even in CeD patients in clinical remission under gluten-free diet, alterations in gut-liver axis, especially BA signaling, might contribute to steatotic liver injury and should be further addressed in future studies and clinical practice.

ERCP in critically ill patients is safe and does not increase mortality.

ABSTRACT: Endoscopic retrograde cholangiopancreatography (ERCP) is the gold standard for minimally-invasive treatment of biliary or pancreatic tract disease. When treating patients on intensive care units (ICU) with ERCP, interventionalists are faced with considerably higher morbidity compared to patients in ambulatory settings. However, data on complications and outcome of critical ill patients undergoing emergency ERCP are limited.A retrospective analysis of 102 patients treated on ICUs undergoing 121 ERCP procedures at the University Hospital of Essen, Germany between 2002 and 2016 was performed. Indications, interventional success, outcome including survival and procedure-related complications were analyzed. Patients' condition pre-ERCP was categorized by using the "Simplified Acute Physiology Score" (SAPS 3).66/102 patients (64.7%) were referred to ERCP from surgical ICU, 36/102 (35.3%) from nonsurgical ICU. The majority of patients were male (63.7%), the mean age was 54.1 ±â€Š14.9 [21-88] years. Indications for ERCP were biliary complications after liver transplantation (n = 34, 33.3%), biliary leakage after hepatobiliary surgery (n = 32, 31.4%), and cholangitis/biliary sepsis (n = 36; 35.3%), respectively. 117/121 (96.7%) ERCPs were successful, 1 patient (1.0%) died during ERCP. Post-ERCP pancreatitis occurred in 11.8% of interventions. The median simplified acute physiology score 3 was 65 points, predicting a risk-adjusted estimated mortality of 48.8%, corresponding to an observed mortality of 52.2% (P = n.s.).ERCP is safe in critically ill patients on ICU, it does not increase overall mortality rate and has a relatively low rate of procedure-associated complications.

Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3.

The role of non-parenchymal liver cells as part of the hepatic, innate immune system in the defense against hepatotropic viruses is not well understood. Here, primary human Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells were isolated from liver tissue obtained after tumor resections or liver transplantations. Cells were stimulated with Toll-like receptor 1-9 ligands for 6-24 h. Non-parenchymal liver cells expressed and secreted inflammatory cytokines (IL6, TNF and IL10). Toll-like receptor- and cell type-specific downstream signals included the phosphorylation of NF-κB, AKT, JNK, p38 and ERK1/2. However, only supernatants of TLR3-activated Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells contained type I and type III interferons and mediated an antiviral activity in the interferon-sensitive subgenomic hepatitis C virus replicon system. The antiviral effect could not be neutralized by antibodies against IFNA, IFNB nor IFNL, but could be abrogated using an interferon alpha receptor 2-specific neutralization. Interestingly, TLR3 responsiveness was enhanced in liver sinusoidal endothelial cells isolated from hepatitis C virus-positive donors, compared to uninfected controls. In conclusion, non-parenchymal liver cells are potent activators of the hepatic immune system by mediating inflammatory responses. Furthermore, liver sinusoidal endothelial cells were identified to be hyperresponsive to viral stimuli in chronic hepatitis C virus infection.

Effects of Moderate Alcohol Consumption in Non-Alcoholic Fatty Liver Disease.

Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) have emerged as leading causes of chronic liver diseases worldwide. ALD and NAFLD share several pathophysiological patterns as well as histological features, while clinically, they are distinguished by the amount of alcohol consumed daily. However, NAFLD coexists with moderate alcohol consumption in a growing proportion of the population. Here, we investigated the effects of moderate alcohol consumption on liver injury, lipid metabolism, and gut microbiota in 30 NAFLD-patients. We anonymously assessed drinking habits, applying the AUDIT- and CAGE-questionnaires and compared subgroups of abstainers vs. low to harmful alcohol consumers (AUDIT) and Cage 0-1 vs. Cage 2-4. Patients who did not drink any alcohol had lower levels of γGT, ALT, triglycerides, and total cholesterol. While the abundance of Bacteroidaceae, Bifidobacteriaceae, Streptococcaceae, and Ruminococcaceae was higher in the low to harmful alcohol drinking cohort, the abundance of Rikenellaceae was higher in the abstainers. Our study suggests that even moderate alcohol consumption has an impact on the liver and lipid metabolism, as well as on the composition of gut microbiota.

Risk factors for post-polypectomy bleeding; a retrospective case-control study of a high-volume colonoscopy center.

BACKGROUND AND AIM: Post-polypectomy bleeding (PPB) remains an uncommon although serious complication of colonoscopy. The aim of this study is to determine the PPB-prevalence in a secondary care hospital and its associated risk factors. PATIENTS AND METHODS: We collected data from 581 patients, with the removal of 1593 polyps between August 2017 and August 2019. A univariate binary logistic regression analysis was conducted retrospectively. RESULTS: PPB occurred in only 10 cases, representing 1.7% of patients: immediate in 1.2% and delayed in 0.5%. The number of removed polyps per patient [4.5 (SD 2.59) for hemorrhagic vs. 2.74 (SD 1.98) for non-hemorrhagic group] and the propofol dose [232 mg (SD 93.07) for hemorrhagic vs. 133 mg (SD 57.28) for non-hemorrhagic group] were relevant patient-related risk factors. The polyp-based analysis showed the polyp size [18.4 mm (SD 10.44) for hemorrhagic vs. 4.42 mm (SD 4.29) for non-hemorrhagic group], the morphology [wide-based: OR 24.83 (95 % CI 2.76 - 223.44), pedunculated: OR 56.67 (95 % CI 5.03 - 638.29)], the location at ileocecal valve [OR 20.48, 95 % CI 1.81 - 231.97)], and the polypectomy method [hot snare piecemeal with epinephrine injection: OR 75.38 (95 % CI 7.67 - 741.21)] as significant risk factors for PPB, too. CONCLUSIONS: The low rate of PPB confirms the safety of the procedure in non-tertiary, high-volume colonoscopy centers. The number of polyps removed per patient, the polyp size, morphology and location, as well as the sedation dose and the method of polypectomy were shown as relevant risk factors.

Anti-TNFα treatment in Crohn's disease: Impact on hepatic steatosis, gut-derived hormones and metabolic status.

BACKGROUND AND AIMS: An association between Crohn's disease (CD) and hepatic steatosis has been reported. However, the underlying mechanisms of steatosis progression in CD are not clear. Among the most effective CD treatments are agents that inhibit Tumor-Necrosis-Factor (TNF) activity, yet it is unclear why anti-TNFα agents would affect steatosis in CD. Recent studies suggest that microbiome can affect both, CD and steatosis pathogenesis. Therefore, we here analysed a potential relationship between anti-TNF treatment and hepatic steatosis in CD, focusing on the gut-liver axis. METHODS: This cross-sectional study evaluated patients with established CD, with and without anti-TNFα treatment, analysing serum markers of liver injury, measurement of transient elastography, controlled attenuation parameter (CAP) and MRI for fat detection. Changes in lipid and metabolic profiles were assessed by serum and stool lipidomics and metabolimics. Additionally, we analysed gut microbiota composition and mediators of bile acid (BA) signalling via stool and serum analysis. RESULTS: Patients on anti-TNFα treatment had less hepatic steatosis as assessed by CAP and MRI. Serum FGF19 levels were significantly higher in patients on anti-TNFα therapy and associate with reduced steatosis and increased bowel motility. Neutral lipids including triglycerides were reduced in the serum of patients on anti-TNF treatment. Bacteria involved in BA metabolism and FGF19 regulation, including Firmicutes, showed group-specific alterations with low levels in patients without anti-TNFα treatment. Low abundance of Firmicutes was associated with higher triglyceride levels. CONCLUSIONS: Anti-TNFα treatment is associated with reduced steatosis, lower triglyceride levels, alterations in FXR-signalling (eg FGF19) and microbiota composition in CD.

Enzymatic liver function measured by LiMAx is superior to current standard methods in predicting transplant-free survival after TIPS implantation.

Transjugular intrahepatic portosystemic shunt (TIPS) is one of the main treatment options in patients with decompensated liver cirrhosis but is still associated with partly severe complications. For adequate patient selection, prognostic parameters are of crucial importance. The liver maximum capacity (LiMAx) breath test measures enzymatic liver function and could potentially represent an efficient prognostic marker. We therefore aimed to assess the role of LiMAx in predicting survival of TIPS patients in a prospective analysis. LiMAx was performed for patients who underwent TIPS implantation between October 2016 and February 2018. Associations with transplant-free survival after 24 weeks were assessed by logistic regression. A total number of 30 patients were included, of whom seven received liver transplantation (N = 2) or died (N = 5) during follow-up. LiMAx values after (P = 0.01, OR = 1.24, 95% CI = 1.04-1.47) and before (P = 0.03, OR 1.21, 95% CI = 1.02-1.43) TIPS implantation and MELD score (P = 0.03, OR = 0.79, 95% CI = 0.63-0.98) were significantly associated with transplant-free survival according to univariate logistic regression. In AUROC analysis, LiMAx at day one after TIPS (sensitivity 85.7%, specificity 78.3%, AUROC 0.85, cut-off ≤ 165 µg/kg/h), LiMAx value at the day before TIPS (sensitivity 100%, specificity 73.9%, AUROC 0.82, cut-off ≤ 205 µg/kg/h) and MELD score (sensitivity 71.4%, specificity 73.9%, AUROC 0.82, cut-off ≥ 15) had the highest prognostic accuracy. LiMAx values prior and after TIPS procedure seem to be good prognostic parameters regarding prediction of transplant-free survival of patients undergoing TIPS implantation.

Hippo Pathway Counter-Regulates Innate Immunity in Hepatitis B Virus Infection.

Whether hepatitis B virus (HBV) activates or represses innate immunity continues to be debated. Toll-like receptor (TLR) 2 has been identified to recognize HBV particles in human hepatocytes. The Hippo pathway, known for growth control, is suggested to play a vital role in immune regulation. Here, molecular interactions between HBV-triggered TLR signaling and the Hippo pathway were comprehensively investigated. Reanalysis of GSE69590 data, in which human hepatocytes have been treated with cell culture-derived HBV particles, identified changes in Hippo and NF-κB signaling. Immunocytochemical staining and western blotting revealed time-dependent nuclear translocation of YAP and NF-κB in HBV-exposed primary human and murine hepatocytes (PMH). Analysis of PMH isolated from MyD88- or IRAK4-deficient mice and the inhibition of TLR2 and MST1/2 in vitro confirmed the relation between TLR2 and Hippo signaling in HBV-induced immunity. Loss and gain of function experiments implied that Hippo-downstream effector YAP directly regulated IκBα expression. Functional investigations confirmed the regulation of Nfkbia promoter activity by the YAP/TEAD4 transcription factor complex. Administration of TLR ligands to mice highlighted the relevance of the TLR2-MyD88-IRAK4-Hippo axis in hepatic immunity. Interestingly, reanalysis of gene expression pattern in liver biopsies of patients chronically infected with HBV (GSE83148, GSE65359) indicated an activation of TLR2 and however, an MST1-dominated Hippo control in the immune clearance phase of patients with chronic HBV infection. We demonstrated that MyD88-dependent TLR signaling activates NF-κB and Hippo signaling, with YAP prompting the IκBα-mediated negative feedback, alongside NF-κB. Imbalance between immune induction and Hippo activation may have implications for the safety of novel HBV cure strategies interfering with pathogen recognition receptors.

Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab.

BACKGROUND: Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2). METHODS: Serum AFP was measured at baseline and every three cycles. The prognostic and predictive value of baseline AFP was assessed by Cox regression models and Subpopulation Treatment Effect Pattern Plot method. Associations between AFP (≥ 20% increase) and radiographic progression and efficacy were assessed. RESULTS: Baseline AFP was confirmed as a continuous (REACH, REACH-2; p < 0.0001) and dichotomous (≥400 vs. <400 ng/ml; REACH, p < 0.01) prognostic factor, and was predictive for ramucirumab survival benefit in REACH (p = 0.0042 continuous; p < 0.0001 dichotomous). Time to AFP (hazard ratio [HR] 0.513; p < 0.0001) and radiographic (HR 0.549; p < 0.0001) progression favoured ramucirumab. Association between AFP and radiographic progression was shown for up to 6 (odds ratio [OR] 5.1; p < 0.0001) and 6-12 weeks (OR 1.8; p = 0.0065). AFP response was higher with ramucirumab vs. placebo (p < 0.0001). Survival was longer in patients with an AFP response than patients without (13.6 vs. 5.6 months, HR 0.451; 95% confidence interval, 0.354-0.574; p < 0.0001). CONCLUSIONS: AFP is an important prognostic factor and a predictive biomarker for ramucirumab survival benefit. AFP ≥ 400 ng/ml is an appropriate selection criterion for ramucirumab. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, REACH (NCT01140347) and REACH-2 (NCT02435433).

CTLA-4 Expression Plays a Role in PSC and PBC Progression.

BACKGROUND & AIMS: The pathogenesis of primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) remains unclear. The aim of this study was to reveal certain single nucleotide polymorphisms (SNP) in genes for regulatory proteins in the immunologic pathway possibly going along with susceptibility of attaining PBC or PSC. METHODS: 126 patients with either PBC or PSC with clinical and laboratory data were enrolled in the study. SNPs in three genes (CTLA-4, ICOS, and FOX-P3) which are suspected to play a key role in the autoimmune pathway were analyzed to determine allele variants. Gene expression was measured by RealTime PCR using mRNA. RESULTS: Patients with cirrhosis had a lower number of CTLA-4 copies than patients without cirrhosis (p = 0.04). Accordingly, patients with lower CTLA-4 copies had a poorer recovery of gamma-glutamyltransferase (GGT) in course of their disease (-69.8 U/l vs. -176.1 U/l p = 0.04). Two SNP allele variants (CTLA4 rs733618 and FOXP3 rs2280883) associated with low CTLA-4 expression could be determined. Patients having both variants showed worsening of GGT (-61.7 U/l vs. -132.6 U/l, p = 0.04) and a trend towards a more progressive disease in terms of cirrhosis. (24% vs. 13% p = ns). CONCLUSIONS: Low expression of CTLA-4 is associated with a more advanced disease in patients with PBC and PSC. Furthermore, we identified two SNP allele variants (CTLA4-SNP rs733618 and FOXP3-SNP rs2280883) associated with a lower CTLA-4 expression and possibly a more severe course of the diseases. Taken together, these results provide further evidence for the involvement of the immune system in the pathogenesis of these two cholestatic liver diseases. Lay summary: Primary biliary cholangitis and primary sclerosing cholangitis are chronic diseases of the bile ducts. Their cause remains widely unclear, but evidence suggests the immune system plays a central role. This study shows that gene alterations connected to the immune system might play a role in the course of the disease.

Hepatocyte KLF6 expression affects FXR signalling and the clinical course of primary sclerosing cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is characterized by chronic cholestasis and inflammation, which promotes cirrhosis and an increased risk of cholangiocellular carcinoma (CCA). The transcription factor Krueppel-like-factor-6 (KLF6) is a mediator of liver regeneration, steatosis, and hepatocellular carcinoma (HCC), but no data are yet available on its potential role in cholestasis. Here, we aimed to identify the impact of hepatic KLF6 expression on cholestatic liver injury and PSC and identify potential effects on farnesoid-X-receptor (FXR) signalling. METHODS: Hepatocellular KLF6 expression was quantified by immunohistochemistry (IHC) in liver biopsies of PSC patients and correlated with serum parameters and clinical outcome. Liver injury was analysed in hepatocyte-specific Klf6-knockout mice following bile duct ligation (BDL). Chromatin-immunoprecipitation-assays (ChIP) and KLF6-overexpressing HepG2 cells were used to analyse the interaction of KLF6 and FXR target genes such as NR0B2. RESULTS: Based on IHC, PSC patients could be subdivided into two groups showing either low (<80%) or high (>80%) hepatocellular KLF6 expression. In patients with high KLF6 expression, we observed a superior survival in Kaplan-Meier analysis. Klf6-knockout mice showed reduced hepatic necrosis following BDL when compared to controls. KLF6 suppressed NR0B2 expression in HepG2 cells mediated through binding of KLF6 to the NR0B2 promoter region. CONCLUSION: Here, we show an association between KLF6 expression and the clinical course and overall survival in PSC patients. Mechanistically, we identified a direct interaction of KLF6 with the FXR target gene NR0B2.